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Fragmin

® 20th Jubilee

Dr. Zvi G. WirschubskyMD, PhDMedicine and science communication

Zvi G Wirschubsky earned his PhD in 1986 at the Department of Tumor Biology, Karolinska Institutet, under Professor George Klein. The title of his thesis was “Trisomy 15 and Oncogene Activation in murine T-cell Leukemias, a cytogenetic and molecular study.” In 1990, Dr Wirschubsky finished his MD at Karolin-ska Institutet. After some years of postdoctoral work in the USA, Dr Wirschubsky completed a journalistic course at New York University, 1994-95.

Dr Wirschubsky began his work with medical and science writing and communication while completing his medical studies. During his research in the US, this led him to work full-time in this area, covering and documenting medical and scientific conferences and symposiums, sending reports and writing numer-ous articles in both the Swedish and international medical media. Dr Wirschubsky has successfully built up a unique medical news website in Sweden, www.nymedicin.com, that started 2001.

Dr Wirschubsky is a member of the Swedish Society for Medical Journalists, the Swedish As-sociation for Science Journalists and the National Association of Science Writers (USA). Dr Wirschubsky is accredited by the world’s foremost medical and science magazines such as The Lancet, British Medical Journal, Journal of the American Medical Associa-tion, New England Journal of Medicine, Nature and Science, among many others.

For this project, Dr Wirschubsky has interviewed all lecturers and written the articles as well as contrib-uted with ideas for design and content of the book.

318-Pfizer-02-2008-7646

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Copyright by Pfizer AB. All rights reserved. This publication may not reproduced or distributed in any form or by any means without the prior written permission by Pfizer AB. Upplaga 2

Fragmin® 20th Jubilee

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ContentsPrologues

Landmark studies

CVs

Thesises

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by David Bergqvist and Erik Holmer 2 – 3

History of Fragmin (dalteparin) 4 – 11

Fragmin in Abdominal/General surgery 12 – 17

Fragmin in Orthpaedic surgery 18 – 21

Fragmin in Cardiology 22 – 27

Fragmin in Medically ill patients 28 – 31

Fragmin in Oncology 32 – 39

Fragmin – Future possibilities 40 – 43

Fragmin in Abdominal/General surgery 46 – 48

Fragmin in Orthopaedic surgery 49 – 52

Fragmin in Cardiology 53 – 55

Fragmin in Medically ill patients 56

Fragmin in Cancer 57

Fragmin – Future possibilities 58 – 60

Pfizer operations in Strängnäs 62 – 67

David Bergqvist 70

Ola Dahl 71

Gun Jörneskog 72

Ajay Kakkar 73

Agnes Y.Y. Lee 74

Carl-Gustav Olsson 75

Lars Christer Wallentin 76

Selection of Nordic thesises 80 – 86

The 27th of November dalteparin had over

810 hits on www.pubmed.com

For further information contact your local Pfizer office

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There have been many discoveries of importance to our understanding of venous thromboembolic disease over the centuries. These have included the function of the vein valve (Fabrizio, 1603), the circulatory system with the heart as a pump (Harvey, 1628), pulmonary embolism as a conse-quence of deep vein thrombosis during pregnancy (Wiseman, 1676), treatment of phlegmasia alba dolens with leeches, Hirudo medicinalis (Davis, 1822), the un-derstanding of the pathophysiology of the thrombotic process (Virchow’s triad, 1856) and thrombosis as a paramalignant phe-nomenon (Trousseau’s syndrome, 1865).

The modern treatment of venous throm-boembolism in the form of anticoagula-tion can be said to have started during the 1940s with heparin in combination with vitamin K antagonism. This Swed-ish author mentions four names, not only because they were Swedes but because they made fundamental contributions. Eric Jorpes purified and determined the struc-ture of heparin; Clarence Craaford started with heparin prophylaxis and treatment of patients – being a thoracic surgeon, his focus was mainly on pulmonary embolism; Gunnar Bauer made systematic studies of the use of phlebography and of heparin for treatment; and Jörgen Lehman described the antithrombotic effect of coumarin.

Although the heparin effect was de-scribed in 1916 by Jay McLean, a medi-cal student in William Howell’s labora-tory, and heparin was named in 1918 by Howell, it was not until 1976 that three groups of researchers fractionated the large and heterogeneous heparin molecule and studied the effect of those fractions on the haemostatic system. Those experiments raised the hope that it would be possible to dissociate the antithrombotic and the anticoagulant effects which, theoretically at least, would induce less bleeding than unfractionated heparin.

This paved the way for what was soon developed into the low-molecular-weight heparins, pharmacological substances which could be fragmented from the hepa-rin molecule through various chemical and

enzymatic procedures and which came to be of the utmost clinical importance.

Again, with some patriotic pride, we may mention that two of the three groups of researchers were Swedish: Ulf Lindahl and his colleagues at the medical faculty of Uppsala University; and Lars-Olov Anders-son and Eric Holmer with colleagues at the pharmaceutical company Kabi in Stock-holm. The third was Rosenberg’s group in Boston.

Kabi 2165, which later became dalteparin or Fragmin, was first of the low-molecular-weight heparins. Whether it is 30, 25 or 20 years old could be a matter for discussion. Formal approval, however, came 20 years ago, and that is certainly a milestone worth marking. Dalteparin – and for that matter the low-molecular-weight heparins as a group – have had enormous importance for millions of patients suffer-ing from venous thromboembolism and ischemic heart disease. The success of Frag-min in haemodialysis and its use, including perioperatively, to prevent fatal pulmonary embolism in risk groups is also worth celebrating, perhaps even more so than the origin of the substance itself.

David Bergqvist, MD, PhD, FRCSEmeritus Professor of Vascular SurgeryAcademic Hospital and University of Upp-sala, Sweden

Dalteparin – celebrating 20 years

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Heparin was discovered in 1916 but it was not until the early 1940s that preparations suitable for clinical use became available. Clinical investigations in Canada and Swe-den demonstrated its antithrombotic effect, and schemes for the administration for prophylaxis and treatment of thromboem-bolic disorders were established. Due to its lack of demonstrable toxicity (bleeding was the only significant problem) and also the (incorrect) assumption that heparin was a physiological anticoagulant, the substance rapidly gained wide clinical acceptance.

Since then, our knowledge about hepa-rin – its biosynthesis, structure, mechanism of action, anticoagulant activities and other areas – has greatly increased.

An important breakthrough came in 1976 when Kabi researchers (Professor Lars Olov Andersson and the author) – in collaboration with a group at NIBSC, Lon-don – demonstrated that certain heparin molecules of low molecular weight, around 5 000, actually possessed significant anticoagulant activity, in contrast to what was generally believed. Such small heparin molecules had until then been considered inactive because they essentially lack the ability to potentiate inhibition of thrombin and to prolong clotting time as measured by, for example, the APTT test, methods normally used to monitor anticoagulant activity. We used newly developed tech-niques that also allowed us to investigate the effect of heparin on other coagulation factors specifically and found that Factor Xa was highly susceptible to inhibition in the presence of certain low-molecular-weight heparin fractions that only slightly prolonged clotting time.

Kabi initiated a formal product project, aimed at developing a new heparin-derived antithrombotic drug, in 1978; this selected a drug candidate, Heparin Fragment Kabi 2 165 (later given the name Fragmin by the author). This led to development of a production process and a full preclinical documentation package including phar-maceutical formulations, pharmacology, toxicology and more. In 1982, the first-in-man injection was given (subcutaneously,

to the author) under the supervision of Professor David Bergqvist. The results were really encouraging; the bioavailability after subcutaneous injection was nearly 100% (compared with about 5-10% for heparin) and the half-life was doubled. This indi-cated that one single daily injection could be enough for prophylaxis of deep vein thrombosis.

An extensive clinical program, led by Professor Thomas Wahlberg, was initiated in Sweden and several other European countries. Pivotal proof-of-concept studies were conducted successfully in patients undergoing haemodialysis, leading to marketing approval for this indication in West Germany in October 1985. Fragmin was the first low-molecular-weight heparin on the market. The first order, placed in October 1985, was for two ampoules of Fragmin and three packages of Selucos, a dandruff shampoo. The order was labeled “Urgent.” It is still not known whether the urgency was regarding a thrombotic complication or a hair problem.

Kabi extended the clinical program and Fragmin received marketing approval in Sweden for the important indication “pro-phylaxis of post-operative thrombosis in general surgery” in 1988, a milestone that we are celebrating today.

Fragmin is used around the world today, and has probably been approved for more indications than any other low-molecular-weight heparin. Extensive clinical programs are still running and its use is likely to be expanded. Investigations exploring the potential use of Fragmin beyond the tra-ditional thrombosis indications – in areas such as the healing of wounds and the inhi-bition of metastasis – are of special interest, and we will learn more about these in the near future.

Today we are celebrating Fragmin, a modern, 20-year-old drug with a bright future.

Erik Holmer, PhDFragmin project manager, 1978-1990

Bright future ahead for 20-year-old Fragmin

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2008

1988

– Milestones

– History of Fragmin as told by leading researchers

• Professor David Bergqvist • Professor VV Kakkar • Professor Ajay Kakkar

2008

1988

History of Fragmin (dalteparin)

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Milestones (compiled from reference 2)

1877 Erlich discovers mast cells.

1916 MacLean discovers heparin.

1917 Howell coins the term “antitrombin,” which later become “heparin.”

1930s Charles and Scott find heparin in many organs throughout the body.

1933 Charles and Scott invent a purification method for the large-scale production of heparin.

1937 Jorpes and Bergström clarify the chemical structure of heparin.

1937 Jorpes, Holmgren and Wilander discover that heparin is formed and stored in the granules of mast cells.

1937-42 Murray et al, Craaford, Craaford and Jorpes and Bauer started clini-cal investigations and established the antithrombotic effect of the drug. Schemes were made for the administration both for prophylaxis of postoperative thrombosis and for the treatment of thromboembo-lic disorders.

1962 Sharnoff uses small doses of heparin in the prevention of postopera-tive thrombosis.

1971 VV Kakkar et al. use the 125I-fibrinogen uptake test for the diagnosis of thrombosis in large studies. The efficacy of low-dose heparin was convincingly demonstrated.

1975 VV Kakkar et al. carry out the first international multicentre trial of low-dose unfractionated heparin (UFH) for prophylaxis in surgical patients (1975). Frequency of isotopic DVT (deep vein thrombosis) was reduced from 24.6% in patients not receiving prophylaxis to 7.7% in patients who received low-dose UFH.

References 1. Kakkar VV, Corrigan TP, Fossard DP. Prevention of fatal postoperative pulmonary embolism by low doses of heparin: An international

multicentre trial. Lancet 1975; 2 :45-51.

2. Erik Holmer, Heparin and its low molecular weight derivatives basic and applied studies in the development of a new antithrombotic drug, Uppsala: Sveriges lantbruksuniv., 1987, ISBN/ISSN: 9157630496.

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Professor David BergqvistInstitution of Vascular SurgeryUppsala University Hospital, Sweden

Dalteparin was one of the first LMWHs available for clinical use. We started to study the clinical effects of dalteparin in the late 1970s after gaining greater insight into the action mechanism of unfractionated heparin (UFH). The identification of UFH as a heterogeneous mixture of polysac-charide chains led to the development of low-molecular-weight heparin (LMWH) fractions (dalteparin) with several practical advantages over UFH, including reduced non-specific binding to plasma proteins and more targeted inhibitory effects on factor Xa; longer plasma half-life leading to once-daily dosing without the need for laboratory monitoring; and more effective anticoagulant properties, with less bleeding than with UFH.

Dalteparin was first made available for the prevention of venous thromboembolic disease, and its first clinical indication and registration was for patients undergoing haemodialysis.

Several well-designed, randomized trials have shown that dalteparin is effective and well tolerated in a wide range of clinical indications. To date, dalteparin is the only LMWH with sufficient data on efficacy, safety and dosage to support its use as a long-term antithrombotic therapy in cancer patients.

ReferenceBerggqvist David. Dalteparin: over 20 years of clinical experience. EJHPP Practice, 2008/2, Volume 14.

Professor VV Kakkar Thrombosis Research Institute, Chelsea, London, UKV

Development of 125I-fibrinogen uptake testIn the past, one major difficulty in the management of DVT had been the lack of means for recognizing the condition accurately at an early stage. One possible method to detect venous thrombosis was to use fibrinogen labeled with a radioactive isotope, the 125I-fibrinogen uptake test (FUT). Studies published by other investiga-tors confirmed our initial observation that FUT was an accurate method for detecting thrombi in the deep veins. However, several clinicians questioned the clinical signifi-cance of such thrombi and whether their treatment also reduced mortality caused by pulmonary embolism. This issue was resolved by analysis of the incidence of fatal pulmonary embolism, proved by autopsy, in groups of surgical patients undergo-ing major elective operations, where early detection and treatment of isotopic thrombi significantly reduced its frequency. Us-ing FUT as a routine screening procedure, several of our prospective studies showed that the disease occurs quite frequently in patients undergoing major abdominal, thoracic, orthopedic and other surgical procedures as well as in chronically ill medi-cally ill patients.

The natural history of DVT was im-portant, because the treatment of venous thromboembolism available in the late 1960s was neither simple nor safe, and therefore could not be justified in every patient.

Low-dose heparin prophylaxis era beginsThe information generated by FUT regard-ing the high incidence of postoperative DVT, its natural history and the definition

History of Fragmin as told by leading researchers

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of the “high-risk” group laid the founda-tions for developing an effective method of prevention. It was apparent that any sig-nificant reduction in postoperative venous thromboembolism would require a method that could be applicable to all patients, easily adopted on a large scale and free of any complications. The search for such an effective method of prophylaxis against venous thromboembolism had been going on for nearly 90 years, a method which was effective in the total elimination of this condition had yet to be developed.

There were two main reasons for this state of affairs: there was a lack of essential knowledge about the trigger mechanism for intravascular coagulation; and the ab-sence of a sensitive and accurate technique for assessing the effects of prophylaxis had certainly been a major hurdle. To a large extent, the latter difficulty had been overcome, as mentioned above, thanks to the use of FUT. FUT made it possible to determine, with greater accuracy than ever before, the true incidence of DVT, and the efficacy of a specific regimen for the preven-tion of such thrombi. In the mid-1960s the main attempts to prevent postoperative thrombosis.

Several studies had shown that oral anti-coagulant therapy, when properly employed (started well before surgery), was the most effective and proven method of preventing major venous thromboembolism. However, a major drawback was the risk of serious bleeding both during and after surgery, despite strict laboratory control of the dos-age. The incidence of severe hemorrhage in the reported studies varied between 2.00% and 6.97%, and mortality within the range of 0.8-1.0%. This undoubtedly contributed to the relatively low level of acceptance of this form of prophylaxis among surgeons in general, at least in the United States and the United Kingdom. A form of therapy that was both effective and without the draw-backs of oral anticoagulant therapy would

therefore fulfill a real clinical need. The use of low-dose heparin given subcutaneously appeared to be a promising approach – if it could be shown to prevent thrombosis without increasing the risk of bleeding.

Rationale for low-dose heparin prophylaxisThe rationale for the use of low-dose heparin suggested that low-dose heparin prophylaxis administered before, during and after surgery may be effective in pre-venting postoperative thromboembolism. The effectiveness of fixed low-dose heparin prophylaxis was investigated in 53 consecu-tive patients over the age of 50 undergoing repair of inguinal hernia. Heparin (5 000 IU) was given two hours before and every 12 hours after surgery for the next five postoperative days. DVT was detected by means of FUT in seven of the control pa-tients (26%), while this was reduced signifi-cantly to 4% in the 26 similar patients who received heparin before and after surgery.

Low-dose heparin and major surgeryWe then assessed the efficacy of low-dose heparin prophylaxis in high-risk patients undergoing major operations. The pub-lished evidence from our pivotal trials and those reported subsequently by others sug-gested that low-dose heparin prophylaxis might reduce the frequency of life-threat-ening, postoperative venous thromboem-bolism.

Some clinicians argued that unequivocal evidence must be presented that fixed low-dose heparin prophylaxis prevented postoperative deaths and was free of bleeding complications before this form of prophylaxis could be adopted on a large scale. We therefore organized an interna-tional multicentre trial. There were four main difficulties in the design of this trial: selection of the participating centers, the nature of the trial to be performed, the number of patients required and the criteria for defining endpoints.

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25

20

15

10

5

0

Without prophylaxis

UFH, unfractionated heparin

Low-dose UFH prophylaxisStudy group

Inci

denc

e (%

)

N=625

P < 0.005

24.6 %

7.7 %

The frequency of isotopic DVT was reduced from 24.6 % in the control group to 7.7 % in the heparin group (P < 0.005).

An interesting finding of this landmark trial related to a significant reduction in the frequency of fatal pulmonary embolism in 953 patients who underwent surgery for malignant disease; a careful objective analysis of operative and postoperative bleeding in 1 475 patients showed no statistically significant difference in blood-transfusion requirements or in the fall in the postoperative hemoglobin level either in the individual operative groups or in the group as a whole.

LMWH have served us well in clinical practice. They are easy to administer, in most cases do not need laboratory monitor-ing and have proved to be highly effective and safe for the prophylaxis and treatment of venous thromboembolism; their use is likely to increase over the coming years. The post-marketing survey has indicated that, in 2001, approximately 52.6 million high-risk surgical patients received LMWH prophylaxis; 43 million of these were undergoing general surgery and 8.9 million were having various orthopedic procedures; 234 000 had operations for trauma and 527 000 were suffering from cancer. It can be argued that – as the mortality due to postoperative fatal pulmonary embolism in such cases is approximately 1% and LMWH is effective in protecting 50% of such at-risk patients – at least 250 000 lives are being saved each year. Furthermore, the use of LMWH to treat selected patients

with venous thromboembolism at home has also dramatically reduced the cost of healthcare. These major clinical benefits and improved cost-effectiveness have stim-ulated the development of new rationally designed LMWH of reduced chain length and less polydispersity, with more predict-able pharmacokinetics after subcutaneous administration leading to improved in-vivo activity and greater safety. With these new molecules, it is likely that our ability to prevent and treat both arterial and venous thrombosis will continue to improve sub-stantially.

Reference Kakkar VV, Low-dose heparin to low molecular weight heparin prophylaxis: in pursuit of excellence – a personal perspective .J Thromb Haemost 2005; 3: 195–209.

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Professor Ajay Kakkar London School of Medicine and Dentistry, Queen Mary, University of London

The pivotal work in the area of low molecular weight heparin (LMWH) and prophylaxis of deep vein thrombosis (DVT)and pulmonary embolism (PE) i.e. e venous thromboembolism (VTE) started in the late 60s. The first trial used fibrinogen scanning to establish the true burden of DVT after abdominal surgery intervention.

These studies demonstrated that without treatment large number of patients got as-ymptomatic calf vein thrombi that in some patients would progress to thrombus in the proximal vein. Forty percent of these pa-tients progressed to pulmonary embolism that was clinically silent in some patients and clinically apparent in others.

Having established the technique of fibrinogen scanning, V.V. Kakkar and his group1 were able to first demonstrate that low-dose heparin reduces the frequency of asymptomatic DVT. Later a multi centre randomized clinical study showed the same effects in the prophylaxis of PE.

Although there were no differences between the active group that received low-dose heparin and the control group with regards to major bleeding, the unfraction-ated heparin (UFH) increased the incidence of wound hematoma.

LMWH is bornThe quest started in V.V Kakkars labora-tory and in the Swedish company Kabi to develop fractions of heparin that poten-tially would be more effective, safer and convenient than UFH.

The developed product, dubbed dalteparin, had a higher proportion of the pentasackaride sequence which potentiate the activity of anti-thrombin to neutral-ize activated factor X more than activated factor II. UFH would potentiate anti-thrombin in such a way that one molecule

of thrombin and one molecule of activated factor X. The ratio is 1:1. LMWH gives a greater ratio in favor of inhibiting factor Xa more than factor II, 4:1, 6:1, 10:1 etc.

-So the LMHW were born, said Ajay Kakkar.

LMWH species from the laboratory work was also found to less frequently bind to plasma protein and endothelium so injection of LMWH was associated with a more predictable bioavailability after a single s c administration in Fragmin than in UFH.

Dosing became more predictable both for the individual patient as well as for the population which meant that for treat-ment of DVT there was no longer a need for monitoring. -What you gave, was what ended up in circulation and what was available to treat the patient, said Kakkar.

The longer plasma half-life of LMWH meant that one could give it once a day for prevention and treatment rather than giv-ing UFH three times a day for prophylaxis or for treatment.

Also the frequency of reported heparin-induced thrombocytopenia and osteoporo-sis was much less seen with LMWH than with UFH.

Because of these reasons LMWH were born and they went into clinical evaluation which was shown to be highly effective both for the prevention and treatment of acute coronary syndrome arterial throm-bosis.

Comparison of LMWH with WarfarinLMWH is also associated with the release of tissue factor pathway inhibition and potential inhibition of the TF pathway. Warfarin has its effects through another mechanism, reduction of the synthesis of key clotting proteins, factors 2, 7, 9, and 10, so called zymogens (inactive enzyme precursor factors). By reducing the produc-tion of these factors from the liver they are less available for the clotting system.

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LMWH offer a real advantage because warfarin also is unpredictable, has multiple food interactions, drug interactions and no predictable dose-response which means they require regular and monitoring of anti-coagulation chronically. LMWH were, in contrast, designed for acute treatment, management and prevention of thrombosis but their uses have been extended even in the long-term because response to anti-coagulation is so predictable and no thus need for monitoring.

Attitudes from colleaguesHistorically there was considerable inhibi-tion to LMWH. One big reason was that because one was unable to measure any effect of LMWH on the activated partial thromboplastin time, APTT or on the prothrombin time. These were traditional ways of monitoring UFH or warfarin.

When a dose of LMWH was given, there was no effect in the measurable laboratory haemostatic parameters. The clinician thus said that if he could not measure the effect, there can’t be any ef-fect. Colleagues were very skeptical until laboratory homeostasis improved tests, such as the activated clotting time, ACT, and more important, the anti Xa levels and the anti Xa activity of LMWH became available.

But it was the clinical evidence in terms of the efficacy of prophylaxis and treat-ment that really drove the application of LMWH.

CollaborationThe development of LMWH was a true collaboration between a number of aca-demic institutions and some of the major pharmaceutical companies in terms of first taking forward the fractionation of hepa-rin, then evaluating it preclinically, and then support of large clinical trials that allowed its comparison against UFH in a variety of venous and arterial indications.

Different LMWH speciesIn general, 20 years after their introduc-tion, LMWH have been exhaustible evalu-ated in certain indication. The two LMWH that withstood the greatest scrutiny and have been subjected to the greatest inter-vention is enoxaparin and dalteparin.

Kakkar states that in terms of VTE prevention where both products have been equally evaluated, there are more studies with dalteparin in the cancer area while there are more trials with enoxaparin in cardiology.

Of course one has to look at individual trials to get an understanding of the differ-ent LMWH.

Awareness of VTE protectionIt is in this time and age, after many clini-cal trials, not justifiable not to give some surgical cancer patients undergoing an operation, adequate protection against thrombosis, stated Kakkar. Whereas one provides LMWH or one is fearful of bleed-ing, mechanical methods should be given to patients that should be protected.

There are still some gaps in our data concerning medical oncology patients. There are many populations of cancer pa-tients where there is no evaluation outside the surgical setting. However, Kakkars perspective is that if we fear risk of throm-bosis, we can extrapolate from the data we have, to provide LMWH for prophylaxis.

Recurrence of DVTAccording to trials there is currently about eight to nine percent of recurrence of DVT in cancer patients who have been treated with LMWH once. This is due to the ongo-ing malignant disease which has a powerful drive for activating coagulation.

Whether new oral agents will do better than LMWH, time will tell when there will be results from clinical trials. According to Kakkar, LMWH is at this stage “the gold standard” for preventing recurrent throm-

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bosis in cancer patients. -The available data speaks to dalteparin as the agent of choice.

Future directionsOne area of LMWH that has not been fully established and were there today is intrigu-ing evidence is that LMWH can prolong survival in cancer. There are currently three clinical studies with dalteparin indicating that if you give a cancer patient dalteparin chronically, it prolongs their survival. These trials have shown benefits up to two years.

There are ongoing trials with a number of LMWH. One of the largest clinical stud-ies will be initiated soon and it concerns a very difficult cancer, pancreatic cancer with a very poor survival. There is hope, judging from the early trials that a real benefit will be established to these poor patients and desperate situation, not only to prevent their thrombosis but more importantly, to prolong their survival.

New oral agents will be used in cancer patients and trials will commence in spe-cific cancer populations, says Kakkar. –But as we can see with the LMWH it takes time for the new agents to be introduced and for the benefit between risk and poor clinical outcome takes time to be established. For some time to come, the most powerful data sets are with LMWH.

Reference1. Kakkar VV et a. Prevention of fatal post-operative pulmonary embolism

by low doses of heparin: an International Multicentre Trial. Lancet, 1975; 1: 45.

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Fragmin in Abdominal/General surgery

Interview: Professor David Bergqvist

1988

2008

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Interview with Professor David Bergqvist

Early studiesIn 1976, three independent research groups fractioned heparin and found that one of the small molecules had very good anti-Xa inhibitory activity. At the time, it was supposed that by using this fragment one could prevent thrombosis without induc-ing bleeding. This was later shown to be perfectly true, says Bergqvist, who started experimenting with a substance called Kabi 2165.

In an experimental model (rabbits), Bergqvist demonstrated that the new sub-stance had a very good prophylactic effect on thrombosis. Experiments in a homeo-stasis model showed that the substance did not cause bleeding.

Based on the rabbit results, the first clinical trial randomized patients to con-ventional UFH or to dalteparin, which later became known as Fragmin. Fragmin had the same prophylactic effect as UFH, but when started just before surgery it caused some bleedings. The next step was to give the Fragmin dose the evening before sur-gery. Fragmin proved very effective, with fewer complications than UFH.

The evening dose was chosen because an earlier study had shown that, although the intention was to give Fragmin two hours before surgery (as in conventional UFH), in reality the nurses gave the dose 20 minutes to 12 hours beforehand. It was difficult to predict a time two hours before surgery since many factors could lead to the opera-tion being postponed.

The next step was to study different doses of Fragmin. While at the time 2 500 units were enough for prophylaxis in patients undergoing surgery for benign dis-ease, patients undergoing major orthopedic surgery or operations for malignancy were shown to need a higher dose, 5 000 units, for good prophylactic effect without an increased risk of bleeding.

These results led to a discussion about doses, because most companies with LMWH had one low dose and one high dose, to differentiate between high-risk and lower-risk patients. Most cancer surgery and major orthopedic surgery patients needed the higher dose for prophylaxis.

Prophylaxis against thrombiProphylaxis is always following statistics, says Bergqvist who does not think we will ever reach the goal of totally eradicating thromboembolic complications.

Thrombosis is a multifactorial, complex disease with changes in the hemostatic sys-tem because of trauma, such as surgery. To reduce the risk of thrombosis properly, one therefore probably needs a combination treatment involving, for example, antico-agulants and compression stockings.

An analysis of a three-year study of routine prophylaxis at the Department of Orthopedic Surgery at the Academic University Hospital in Uppsala, studying elective arthroplasty for knees and hips, showed that no patient died from pul-monary embolism (PE) during the study period. “This shows that PE can be almost entirely avoided”, said Bergqvist. There are still hip-fracture surgery patients dying from PE, but these patients are often old and fragile, and may also have cancer.

However, we know that patients with-out any clinical symptoms in the legs can still die from PE, something that Bergqvist says could be due to adrenal turn-on; this prevents symptoms during surgery but thrombi continue to develop and suddenly travel to the lung.

Extended long-term prophylaxis Autopsy studies from Bergqvist’s time in Malmö at the beginning of the 1980s indicated that some patients died from PE a month after discharge from hospital. The thought at the time was that the thrombi probably started to form during the opera-

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tion. At the same time, John Scurr’s group in London used venography on the day of discharge to examine patients who had un-dergone surgery for abdominal malignant disease. After one month, 25% of patients who tested negatively during venography developed late thrombosis.

These results showed that some patients were not healthy when they left the hospital after surgery. Bergqvist therefore suggested that some high-risk patients should receive prolonged prophylaxis. Several companies were asked and Rhone-Poulenc Rorer agreed to sponsor a study on prophylaxis in elective hip surgery. The results showed that venographically confirmed and also clinical thromboembolism could be reduced by prolonging treatment from one week to one month.

Several studies repeated these results with the LMWH dalteparin. Trials and meta-analysis conducted together with Rus-sell Hull in Canada showed that prophy-laxis with dalteparin was also beneficial in hip surgery.

A further suggestion from Bergqvist dealt with prophylaxis for cancer patients as a high-risk group for VTE. An addi-tional trial with enoxaparin confirmed that prolonging prophylactic treatment with LMWH from one week to one month re-duced the incidence of venous thromboem-bolism in these patients too.

Four years later a similar trial, also with good results, was carried out with dalteparin (Rasmussen). LMWH pro-phylaxis in high-risk patients who have undergone abdominal-cancer or hip surgery is today included in clinical guidelines and recommendations worldwide.

RRR=77 %

P = 0.009

9%

1.8 %

Prolonged Fragminprophylaxis (28 days)

Short–term Fragminprophylaxis (7 days)

RRR, relative risk reduction; DVT, deep vein thrombosis

Inci

denc

e of

pro

xim

al D

VT

(%) 12

10

8

6

4

2

0

Study group

Incidence of proximal DVT 28 days after major abdominal surgery for malig-nant disease from the FAME study

Diagnostic pendulumAt the start of the era of prophylaxis, thrombosis was only a clinical diagnosis that was rather unreliable. Venography was developed during the 1940-50s, but was a fairly cumbersome test for patients; the fibrinogen uptake test, which replaced venography, was developed in the 1960s. Many studies were performed with the up-take test but opponents asked what clinical significance it had. Some of the thrombi de-tected were very small. In addition, there is often a hematoma after orthopedic surgery which can mask a thrombus.

Some clinicians therefore did not rely on the uptake test and went back to venog-raphy. Most modern orthopedic trials use venography. Today more and more trials are done with clinical end-points, especially PE. “But if you are doing trials with PE as the end-point, you need thousands of patients,” Bergqvist says.

The uptake test is currently not allowed because it is hard to separate fibrinogen from HIV. There are some trials using ultrasonography but Bergqvist says this is a tricky test.

LMWH and cancer survivalSeveral meta-analyses show undoubtedly that the LMWH dalteparin prevents VTE. But LMWH may also perhaps prolong life by mechanisms other than thromboprophy-laxis, for example by influencing angio-

14 1514

genesis or tumors factors. Most studies have been based on gastrointestinal and colorectal cancer, but the results are not conclusive.

Guidelines/clinical recommendationsThree surveillance studies, carried out in Sweden 10 years ago, lead to increased awareness of VTE prophylaxis in high-risk patients. Awareness is probably 100% in terms of orthopedic surgery in Scandinavia. There will be a Swedish registry of all diag-noses of and complications stemming from VTE, not only those arising after surgery.In the USA there is an ongoing discussion about the issue because surgeons are con-cerned about patients bleeding, possibly to death, under the watchful eyes of lawyers. This led US surgeons to start LMWH after surgery. “This can perhaps lead to slightly less bleeding,” says Bergqvist, who adds that studies have shown no difference in bleeding if LMWH is started the evening before or six hours after the operation.The new oral Xa and thrombin inhibitors, which are also started postoperatively, are being compared to LMWH, which often is given preoperatively. This is not really a fair comparison Bergqvist says, because you change two parameters instead of one. Most current guidelines recommend start-ing VTE prophylaxis postoperatively.

BleedingsThrombosis and PE are very clear-cut: their diagnosis is either “yes” or “no.” But bleeding can be from 1ml to several liters. It can be diffuse or distinct. One liter of bleeding in the retroperitoneal area is not good; one liter in the brain is fatal. It is difficult to classify bleedings and there are numerous definitions in the literature. This makes it difficult to compare trials that could well have different results simply because of different definitions.

One problem is a lack of consensus on the definition of bleeding, Bergqvist says.

Another problem is the use of substances to prevent thrombosis without influencing hemostasis. It is naïve to think that bleed-ing should never happen; it is a question of doses and intervals when one changes hemostasis.

WarfarinSome patients are already treated with war-farin because of atrial fibrillation or prob-lems with heart valve dysfunction when they come to surgery. One can continue with warfarin during surgery – it is very effective – but there is a real risk of bleed-ing as well as interactions with many other drugs. It also requires careful monitoring. Most surgeons change to LMWH during surgery and then change back to warfarin one week later.

LMWH and the futureLMWH is today standard in VTE prophy-laxis shown both by individual trials and meta-analysis. The bleeding risk is as low as that for placebo. The different LMWHs are, from a clinical point of view, equally effective, cheap and safe. New substances have to show that they are better, safer, cheaper and more cost-effective, which is very difficult. But it would be convenient if there were a substance that could be given both subcutaneously as well as orally in the long term. Patients could learn to inject themselves for a month, if necessary; many diabetic patients do so routinely. The patients would probably prefer tablets for four to six weeks postoperatively.

References1. Bergqvist D. Long-term prophylaxis following orthopedic surgery. Hae-

mostasis 1993; 23 Suppl 1: 27-31.

2. Bergqvist D, Agnelli G, Cohen AT, Eldor A, Nilsson PE, Le Moigne-Amrani A, Dietrich-Neto F. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346 (13): 975-80.

3. Bergqvist D, Benoni G, Bjorgell O, Fredin H, Hedlundh U, Nicolas S, Nilsson P, Nylander G. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335 (10): 696-700.

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4. Bergqvist D, Burmark US, Flordal PA, Frisell J, Hallbook T, Hedberg M, Horn A, Kelty E, Kvitting P, Lindhagen A, et al. Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 XaI units in 2070 patients. Br J Surg 1995; 82 (4): 496-501.

5. Bergqvist D, Burmark US, Frisell J, Hallbook T, Lindblad B, Risberg B, Torngren S, Wallin G. Low molecular weight heparin once daily compared with conventional low-dose heparin twice daily. A prospective double-blind multicentre trial on prevention of postoperative thrombosis. Br J 1986; Surg 73 (3): 204-8.

6. Bergqvist D, Hedner U, Sjorin E, Holmer E. Anticoagulant effects of two types of low molecular weight heparin administered subcutaneously. 1983; Thromb Res 32 (4): 381-91.

7. Bergqvist D, Lindblad B. A 30-year survey of pulmonary embolism verified at autopsy: an analysis of 1274 surgical patients. Br J Surg 1985; 72 (2): 105-8.

8. Bergqvist D, Matzsch T, Burmark US, Frisell J, Guilbaud O, Hallbook T, Horn A, Lindhagen A, Ljungner H, Ljungstrom KG, et al. Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombosis. Br J Surg 1988; 75 (9): 888-91.

9. Bjorck CG, Bergqvist D, Esquivel C, Nilsson B, Rudsvik Y. Effect of heparin, low molecular weight (LMW) heparin, and a heparin analogue on experimental venous thrombosis in the rabbit. Acta Chir Scand 1984; 150 (8): 629-33.

10. Esquivel CO, Bergqvist D, Bjorck CG, Nilsson B, Bergentz SE. Effect of volume expanders on the lysability of ex vivo thrombi in the rabbit. Acta Chir Scand 1982; 148 (4): 359-62.

11. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edi-tion). Chest 2008; 133 (6 Suppl): 381S-453S.

12. Holmer E, Soderberg K, Bergqvist D, Lindahl U. Heparin and its low molecular weight derivatives: anticoagulant and antithrombotic proper-ties. Haemostasis 1986; 16, Suppl 2:1-7.

13. Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, Holmqvist A, Mant M, Dear R, Baylis B, Mah A, Brant R. Low-molec-ular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty pa-tients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000; 160 (14): 2208-15.

14. Hull RD, Pineo GF, Stein PD, Mah AF, MacIsaac SM, Dahl OE, Butcher M, Brant RF, Ghali WA, Bergqvist D, Raskob GE. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001; 135 (10): 858-69.

15. Rasmussen MS, Jorgensen LN, Wille-Jorgensen P, Nielsen JD, Horn A, Mohn AC, Somod L, Olsen B. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicentre randomized open-label study. J Thromb Haemost 2006; 4 (11): 2384-90.

16. Scurr JH, Coleridge-Smith PD, Hasty JH. Deep venous thrombosis: a continuing problem. Bmj 1988; 297 (6640): 28.

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18 1918

Interview: Professor Ola Dahl

Fragmin in Orthopaedic surgery1988

2008

18 1918

Interview with Professor Ola Dahl

In the early 1960s, the largest single cause of mortality after total hip replacement was pulmonary embolism (PE).1

The famous British orthopedic specialist John Charnley, designer of the prosthetic hip, therefore started to treat patients with anticoagulation compounds. After many trials and errors with major bleeding in some patients, the researchers applied an acceptable prophylaxis regimen that re-duced both fatal and non-fatal PE by about 50%.1

At the same time, other researchers started to do systematic randomized blind trials on prophylaxis for venous throm-boembolism (VTE). One of the scientists who carried out many of the studies, VV Kakkar, published his classical trial in 1975 2, in which he showed that low-dose unfractionated heparin (UFH) significantly reduced the incidence of PE in abdominal-surgery patients. Low-dose UFH saved seven lives for every 1 000 operated patients.

Another double-blind study3 at the time showed that almost identical, highly statistically significant prophylactic effects on PE could be achieved with the Swedish compound Dextran-70.

Dextran-70 substitute provides anti-thrombotic benefits in lung microcircula-tion, smoothes the endothelium in the vasculature, reduces tissue factor (TF) expression on monocytes, and makes the fibrin structure and the thrombus more fragile.

Mandatory venography regularly showed a higher frequency of DVT with dextran than with heparin derivatives. This gave Dextran-70 a bad reputation but, Dr Dahl says, colleagues forgot that most of the DVT found were not dangerous be-cause the structure of fibrin was so fragile that they were dissolving in the body. A clot formed in spite of heparin prophylaxis

is a really tough clot that is much more resistant to fibrinolysis. The venographic outcome studies therefore provide a false view of this situation.

Unique clinical trial on extended prophylaxis of VTE in orthopedic patients.

Overall accumulated rate of DVT during 3 weeks prosdischarge1

(schematic by OE Dahl)

1 Scurr JH, et al. BMJ. 1988;297:282 Dahl OE, et al. Thromb Res. 1995;80:299-306.3 Dahl OE, et al. Thromb Haemost. 1997;77:26-31

Presented at ISTH in Tel Aviv 1995

Discharge 1 weekOp

Repeated radiological screening and analyses of markers of blood coagulation and fibrinolysis2,3

Background for prolonging prophylaxis beyond hospital discharge

Day 7

OP

Day 35

6 weeks Plac

ebo

Frag

min

Chest X-rayV/Q scanVenography

Chest X-rayV/Q scanVenography

The patients in the study were randomized to receive active treatment of dextran-70, dalteparin (Fragmin) and T.E.D. (Thrombo Embolic Deterrent stockings) orthopedic stockings or placebo for 35 days. Measurements, repeated diagnostic procedures on the lungs and legs were performed after seven and after 35 days

In the late 1980s and early 1990s, the research group of which Dr Dahl was a member (Research Forum Ullevål Hospital, Oslo) started to collaborate with a col-league at Pharmacia, Per Blom, the medical director of Pharmacia in Norway.

At the time, orthopedic patients re-ceived VTE prophylaxis during surgery and a week after while they stayed in the hospital. The group focused on the time after discharge from the hospital when the patients were not protected. This was shown in, for example, a study by John Scurr, who used the fibrinogen scan test to establish the overall accumulated rate of DVT (25%) occurring within one to six weeks of abdominal surgery.4

It was known that orthopedic patients had a much higher rate of both DVT and PE, and this led to collaboration with Pharmacia.

The trial looked at extended five-week VTE prophylaxis for patients who under-went elective hip replacement surgery.5,6

For practical reasons, it was decided upon an arbitrary five weeks vs. one week

20 2120

of Fragmin prophylaxis after the operation. The patients in the study were randomly

assigned active treatment of Dextran-70, dalteparin (Fragmin) and TED (throm-boembolic deterrent) orthopedic stockings or placebo for 35 days. Measurements and repeated diagnostic procedures on the lungs and legs were carried out after seven and after 35 days.

This study design has been misinter-preted by many in, for example, meta-analysis. The study got approval from the ethics committee to ignore patients who did not have clinical symptoms of VTE. The participants in this study got the same treatment as patients overall i.e. not in the study. This design was unique.

In their clinical trial Dahl et al obtained a very high rate of DVT because of the inclusion of real-life patients instead of spe-cifically selected patients. During the first week, the rate of DVT incidence was 16% (including 5% for proximal DVT). Patients receiving placebo got double the rate of DVT, 32% (14% proximal). Dalteparin for 35 days reduced the DVT rate to approxi-mately the same level as after one week, 19% DVT (9% proximal DVT).

The unique design of repeated venog-raphies and V/Q scans made it possible to study thrombus development with a specially designed scoring system. The incidence of new DVT at day 35 was 26% with placebo compared with 12% after treatment with Fragmin, a relative risk reduction of 46%.

“Clinical DVT” rates were in the post-randomized period equal for placebo and for dalteparin, at 3%. The low rate of “clinical DVT” in this study is explained by the fact that Dahl et al did not look actively for DVT in the patients, which would drive up the rate, but obtained the information passively (if doctors in the wards them-selves suspected DVT in the patients). This trial was also unique because of results of clinical PE from days 7 and 35.

The rate of PE was about 7% while the rate after treatment with dalteparin was about 4%, nearly a 50% reduction. In view of this, Dahl et al. were criticized for giving patients placebo out-of-hospital despite the fact that patients could get serious PE. Dr Dahl responds that this was not known at the time of the study and this was the first clinical trial to evaluate lung changes after VTE prophylaxis.

High risk for at least five weeks, but prob-ably for three monthsAs a result of these studies (Bergqvist, Planes, Lassen, Hull and Comp), prolonged thromboprophylaxis is recommended for four to five weeks. Several supportive mechanistic studies that were spin-offs of the PTP study showed that the D-dimer levels correlate closely to the levels of thrombin generation and activation which again correlated to the prevalence of DVT. These data show that the risk for thrombo-sis continues for up to three months.

The challenge for the future is to identify patients who are high-thrombin-generating responders.

Dr Dahl and his associates are now working closely with a Danish group head-ed by Michael Lassen and Lars Borris, who are developing a way of using urine sticks rather than blood samples to predict the risk of venous and/or arterial thrombosis by measuring excreted thrombin products F1 and 2.

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Clinical study about the best timing for starting prophylaxis.

*Relative risk reduction versus warfarin initiated postoperatively on the evening of hip replacement surgery; DVT, deep vein thropmbosis; RRR, relative risk reduction

20

18

16

14

12

10

8

6

4

2

0

All DVT Major bleeding, Days 2–8

*RRR=55 %P < 0.001

*RRR=45 %P < 0.001

N=336N=337 N=487N=496

Fragmin prophylaxis initiated

Freq

uenc

y (%

)

4 h postoperative2 h postoperative

Efficacy and safety of Fragmin given in close proximity to surgery in the NAFT study

The dose given of dalteparin was halved in order to minimize bleeding. The results were compared to warfarin and showed that dalteparin given in close proximity to surgery was superior to warfarin.

An important clinical trial published in 20007 asked whether it was better to start prophylaxis before or after surgery. In Eu-rope, Professor Bergqvist and others have shown that it is more convenient to start the evening before surgery with a given dose of LMWH because it is harder to find the exact smaller dose to balance efficacy and safety when treatment starts closer to surgery.

The NAFT study The dose of dalteparin was halved in order to minimize bleeding. The results were compared to warfarin and showed that dalteparin given in close proximity to surgery was superior to warfarin.

Treatment two hours before surgery meant more bleeding than postoperative treatment, but Dr Dahl says these results are based more on definitions of bleeding than on actual bleedings. Slightly increased bleeding during surgery is an indicator of an effective antithrombotic regimen and may prevent severe intraoperative initiation of thrombotic and microembolic events. Data show that patients do not die from bleedings but from thromboembolic events related to the operation.

Future of dalteparinIt will be a real challenge to replace inject-able LMWHs, says Dr Dahl, who thinks that dalteparin will be used in acute and intensive care patients in need of parenteral administration. These include patients who cannot take any oral prophylaxis, such as patients vomiting after abdominal surgery, patients with a paralyzed intestinal tract, trauma patients, intensive-care patients, those on artificial respiration, after painful myocardial infarction, stroke, severe septi-cemia and so on. These patients need injec-tions, sometimes in extended prophylaxis. However, most out-of-hospital extended prophylaxis will gradually be taken over by the new oral agents.

References 1. Johnson R, Green JR and Charnley J. Pulmonary embolism and its

prophylaxis following the Charnley total hip replacement. Clin. Orthop. Rel. Res 1977; 127: 123-32.

2. Kakkar VV et al. Prevention of fatal post-operative pulmonary embolism by low doses of heparin: an International Multicentre Trial. Lancet, 1975; 1: 45.

3. Kline, A, Hughes, LE, Campbell, H, et al (1975) Dextran 70 in pro-phylaxis of thromboembolic disease after surgery: a clinically oriented randomized double-blind trial. BMJ 2,109-112.

4. Scurr JH, et al. Deep venous thrombosis: a continuing problem. BMJ. 1988 Jul 2; 297(6640): 28.

5. Dahl OE, et al. Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophy-laxis after hip replacement surgery. Thromb Res 1995; 80:299-306.

6. Dahl OE, et al. Prolonged thromboprophylaxis following hip replace-ment surgery -- results of a double-blind, prospective, randomized, placebo-controlled study with dalteparin (Fragmin).Thromb Haemost. 1997; 77: 26-31.

7. Hull R, et al. Low-Molecular-Weight Heparin Prophylaxis Using Dalteparin Extended Out-of-Hospital vs In-Hospital Warfarin/Out-of-Hospital Placebo in Hip Arthroplasty Patients Arch Intern Med 2000; 160: 2199-2297.

22 2322

Fragmin in Cardiology

Interview: Professor Lars Wallentin

1988

2008

22 2322

Interview with Professor Lars Wallentin

The trial “Low-molecular-weight hepa-rin during instability in coronary artery disease”1 was really the very first trial that showed the effects of LMWH in acute coronary artery disease (ACS). This study in the 1980s was able to compare LMWH with placebo in coronary artery disease. At that stage, not even regular heparin was an established treatment for this condition, so this was a pivotal trial establishing the role of heparin and especially LMWH as a recommended treatment for ACS. There has never been another placebo-controlled trial of anticoagulation for this condition since then.

Wallentin’s research group was one of the few groups in the 1980s studying the effects of unfractionated heparin (UFH) on unstable coronary disease. Pharma-cia, which owned dalteparin, was asked to sponsor a trial for this indication but declined. It took more than 10 years until a researcher at Pharmacia, Thomas Pollare, agreed to sponsor and design two trials of Fragmin in unstable coronary artery disease: the FRISC trial in Sweden with Lars Wallentin as leader and the FRIC trial internationally with Werner Klein as head investigator.

The FRISC trial tested whether dalteparin was effective in the acute phase of ACS as well as during six weeks of pro-longed treatment. It showed a pronounced effect in the acute phase of the disease and even a maintained benefit as long as the treatment was continued for up to six weeks (see figure).

%

days

p=0.001Placebo (n=759)

Dalteparin v. Placeboin addition to aspirin in unstable CAD

5

4

3

2

1

00 1 2 3 4 5 6 7

Dalteparin (n=743)

FRISC. Lancet, 1995

Pro

babi

lity

of d

eath

, MI

Efficacy of Fragmin + aspririn versus aspirin alone in the FRISC trial

The trial undoubtedly showed that LMWH, when added on top of aspirin, was as effective and could therefore re-place UFH in the acute phase. But would dalteparin also be effective after prolonged treatment? The European FRIC study did not show a significant benefit in long-term treatment when the patients were random-ized after acute-phase treatment with either heparin or dalteparin. The interpretation of these studies was that LMWH was very effective and should be used as a standard treatment in the acute phase of ACS. There was also the hypothesis that LMWH might also reduce the incidence of new cardiac events during long-term treatment.

These results were received very posi-tively by the cardiology community. The competing pharmaceutical companies were surprised that LMWH, which was per-ceived as effective only in venous disease, could have a pronounced effect in arterial disease as well. The main competitor at this time was Rhone-Poulenc Rorer with its enoxaparin product. This company there-fore started a full-scale registration pro-gram to establish its product by performing a series of well-designed prospective clinical trials on ACS.

Professor Wallentin, together with Klein, argued strongly that there needed to be at least one large-scale confirmatory trial to verify the FRISC results. However Pharma-cia was unfortunately reluctant to invest in further trials. Dalteparin was therefore

24 2524

approved only for acute-phase treatment of ACS in a large number of countries outside the USA. Surprisingly, dalteparin was never submitted to the FDA for approval for this indication. However, when Rhone-Poulenc Rorer submitted its first application for approval of enoxaparin, the FRISC trial was used as one of the two pivotal trials to support it for this indication. Accord-ingly, enoxaparin got approval for the ACS indication partly based on as the pioneering FRISC results with dalteparin.

“Pharmacia was far too cautious and did not realize the potential of the whole area of ACS, with millions of cardiac patients entering hospitals,” says Professor Wallentin. He adds that ACS was and still is the most common reason for admission to a coronary unit. Today every such pa-tient gets aspirin, clopidogrel and LMWH.

In Sweden, about 15 000-20 000 patients receive this treatment every year. Around the world, millions are treated according to this scheme, which is recom-mended in European and US treatment guidelines.

The FRISC trial results are the standard for the effect of LMWH in ACS. If a new trial is planned, the new anticoagulant product has to show noninferiority to LMWH, which means it maintains at least half the benefits of LMWH.

The FRISC study was a completely Swedish trial.

Biomarkers for ACSIn the middle of the 1990s, troponin was only a recently developed circulat-ing marker of myocardial infarction; as a result, it was almost unknown and was not used routinely in coronary units. Today, the measurement of troponin in ACS is standard.

In the 15 years since then, Professor Wallentin and his research group have been pivotal players in showing the prognos-tic importance of measuring troponin

in patients with ACS, based largely on substudies from the FRISC program.2,3 Wallentin et al was the first group to show that troponin is not only a marker for myocardial necrosis but also an indicator of an underlying thrombotic process in the coronary artery. Minor troponin elevations early in patients with acute coronary syn-drome are therefore in many cases caused by microembolization and small areas of myocardial necrosis. Furthermore, Profes-sor Wallentin’s group also showed that only these patients (60-80% of all ACS patients) respond to anticoagulant treatment. The benefit of LMWH was clearly shown in the troponin-positive population and not in the troponin-negative.

Troponin is used routinely today as a key risk stratifier in all guidelines in Europe and the USA.

It can be measured immediately after ACS and, as needed, repetitively after four to six hours. Professor Wallentin’s research group has stayed with troponin for the past 15 years and there is now a super-sensitive troponin that can be measured in everybody, not only after MI. A very low level of troponin can be seen circulating in the blood; when some cardiac cells die, the level of troponin increases slightly. The levels are probably higher in people with a high turnover of cardiac cells, and this might be indicative of microembolization, small microinfarctions occurring in patients with atherosclerotic coronary disease. Therefore, slight elevations of troponin, even in the healthy elderly population, are related to survival.

FRISC IIProfessor Wallentin did not convince Phar-macia to support large trials for registra-tion of the treatment in the acute phase. He succeeded in persuading the company that long-term treatment with dalteparin as prophylaxis in ACS might be a completely new area for anticoagulation treatment.

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The FRISC II 4,5 trial had at the time a popular factorial design. On one hand, the patients were randomized to dalteparin for five days or three months. On the other, the same patients were simultaneously random-ized either to early invasive procedures such as bypass surgery or PCR or to a conservative pharmacological approach with invasive procedures based on signs or symptoms of ischemia.

While Pharmacia was naturally interest-ed in the effects of the long-term prophy-laxis, the cardiologists participating in the trial were interested mainly by the second question, of the eventual effects of an early invasive treatment strategy. At the time there was a heated debate about the pros and cons of early invasive procedures. “To-day, when patients are immediately taken to the cath lab, the situation at the time can almost not be imagined,” says Profes-sor Wallentin, who adds that nobody had shown the convincing effects of an early invasive treatment approach before the FRISC II trial. The half-year results showed that patients treated with early invasive procedures had a slightly increased risk of potential complications during the first weeks but thereafter the risk for a new MI was much lower. The published long-term follow-up after one, two and five years also showed improved survival, less readmission to hospital and improved quality of life.

In contrast to later trials on the same question, patients in the FRISC II trial remained in their allotted treatment groups and had few early crossovers between the treatment arms. Adherence to protocol has been a much greater problem in later studies, something that led to problems interpreting the results because of the high proportion of crossover patients. Yet sev-eral of the later trials still corroborated and supported the advantages of an invasive treatment approach. The early invasive treatment strategy from the FRISC II trial has therefore become standard and changed

the treatment of this patient population across the whole world.

The launching of a trial with long-term subcutaneous injection of an anticoagulant in the FRISC II trial was of course chal-lenging. In order to persuade authorities and patients to inject dalteparin subcutane-ously for three months, the term “insulin for myocardial infarction” was used. The results showed that long-term prophylaxis with dalteparin was beneficial for two months but unfortunately the statistical sig-nificance was lost during the last month of follow-up. A key reason for that was that the endpoint used was a composite of death and MI. In the trials with enoxaparin, the triple composite endpoint of death, MI or revascularization was the primary objec-tive. The outcome of the FRISC II trial also showed a very convincing long-term benefit with the triple composite. If this endpoint had been chosen, long-term prophylaxis with dalteparin might today have been an approved treatment worldwide – at least while waiting for revascularization proce-dures.

Although the primary endpoint was not reached, the concept of long-term prophy-laxis with dalteparin in ACS remained. Pro-fessor Wallentin and other research groups have continued to pursue this concept using the new oral anticoagulants. In view of the positive effects of long-term prophylaxis on ACS, the question is why treatment with dalteparin at the time of the FRISC II trial failed to show significant results even though the concept of long-term prophy-laxis for ACS was proved.

Wallentin’s group investigated compli-ance but dismissed this as a reason.

Another hypothesis for which there is some evidence is that the subcutaneous injection in itself induces an inflammatory reaction and endothelial dysfunction.

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ST elevation MIThe FRISC II trial was performed on un-stable coronary artery disease, which today is called non-ST elevation ACS. Profes-sor Wallentin says the positive results of prophylaxis with partial occlusion of the artery led to the concept that this treatment also should be effective as an adjunct when also opening the totally occluded coronary artery in ST elevation MI.

The positive effects of dalteparin in combination with fibrinolytic treatment could be documented in a series of small trials with very sophisticated measurements of myocardial damage, measurements with PET etc.6,7

Finally a larger pilot trial (ASSENT plus) confirmed that dalteparin (four-seven days) was at least as effective as 48-hour UFH infusion as a supportive treatment to alteplase, recombinant tissue-plasminogen activator in acute ST elevation MI. 8

Although the dalteparin results were pioneering in this area too, Pharmacia unfortunately decided not to pursue the development of LMWH. As a result, the enoxaparin alternative took precedence thanks to several large-scale trials; the results led to agents being recommended as routine treatment in ST elevation MI as well.

ConclusionOverall, the dalteparin program for ACS has been extremely successful, says Profes-sor Wallentin. “We have been able to establish LMWH in general, and especially dalteparin, as a very important treatment for lowering the risk of recurrent events in the acute phase of both non-ST elevation ACS and ST elevation MI”. The pioneering trials with long-term anticoagulation after the acute phase of

ACS have paved the way for the current era of trials with the new oral thrombin and factor Xa inhibitors. Within these pharmaceutical trials, the Wallentin

research group has also elucidated the im-portance of biomarkers such as troponin, nt-pro-bnp, Cystatin-C and CRP for risk stratification and tailoring of treatment for ACS. Finally, in the FRISC trial, the group pioneered the use of the early invasive treatment strategy worldwide in non-ST elevation MI.

The impact of the FRISC trials in practi-cal cardiology can easily be seen today in Sweden’s unique National Registry of ACS (RIKS-HIA) started by Professor Wallentin 13 years ago. Practice began to change soon after the studies were published, and these treatments are now used in the overwhelming majority of cardiology units in Sweden.

Despite the scientific success, Professor Wallentin is disappointed that Pharmacia did not have a stronger belief in the poten-tial of dalteparin in cardiology and that it never embarked on the large registration trials needed for worldwide approval.

Professor Wallentin thinks that LMWH will remain as the prophylaxis standard in all high-risk ACS for several years to come because it is a rather inexpensive treatment. However, a new synthetic anticoagulant (fondaparinux) has recently been shown to have the same efficacy as LMWH but with less bleeding. In the near future, there will be several oral alternatives that might make the subcutaneous treatment with LMWH obsolete for arterial and for venous disease.

References1. Wallentin L and the FRISC study group. Low-molecular-weight heparin

during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet. 1996 Mar 2; 347(9001): 561-8.

2. Lindahl B, Venge P, Wallentin L. Troponin T identifies patients with un-stable coronary artery disease who benefit from long-term antithrombotic protection. Fragmin in Unstable Coronary Artery Disease (FRISC) Study Group. J Am Coll Cardiol. 1997 Jan; 29(1): 43-8.

3. Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. 2000; 343(16): 1139-47.

4. Wallentin L, Husted S, Kontny F, Swahn E.and the FRISC II study group. Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomized multicentre study. Fragmin and Fast Revascularisation during InStability in Coronary artery disease. Investigators. Lancet. 1999 Aug 28; 354(9180): 701-7.

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5. Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E and the FRISC II study group. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomized multicentre study. Fragmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999; 354(9180): 708-15.

6. Husted S, Wallentin L, Lagerqvist B, Kontny F, Ståhle E, Swahn E.

Benefits of extended treatment with dalteparin until revascularization in unstable coronary artery disease. Eur Heart J 2002; 23(15): 1213-8.

7. Frostfeldt G, Ahlberg G, Gustafsson G, Helmius G, Lindahl B, Nygren A, Siegbahn A, Swahn E, Venge P, Wallentin L. Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysisin acute myo-cardial infarction--a pilot study: biochemical markers in acute coronary syndromes (BIOMACS II). J Am Coll Cardiol. 1999 Mar; 33(3): 627-33.

8. Wallentin L, Bergstrand L, Dellborg M, Fellenius C, Granger C, Lindahl B MD, Lins L-E, Nilsson T, Pehrsson K, Siegbahn A, Swahn E, for the ASSENT PLUS Investigators. Low molecular weight heparin (dalteparin) compared to unfractionated heparin as an adjunct to rt-PA (alteplase) for improvement of coronary artery patency in acute myocardial infarction - the ASSENT Plus study. Eur Heart J. 2003; 24(10): 897-908.

28 2928

Interview: MD, PhD Carl–Gustav Olsson

Fragmin in Medically ill patients1988

2008

28 2928

Interview with Dr Carl–Gustav Olsson

The early yearsCarl-Gustav Olsson’s interest in venous thromboembolism (VTE) started in the 1970s. At that time, the hospital in Lund routinely used plethysmography to exclude DVT. Dr Olsson found out that this test was unreliable and missed many patients. He therefore started to use 125-I-labeled fibrinogen, which was quite a slow test. He later labeled plasmin, which discovered DVT as quickly as phlebography did.

In his thesis, Dr Olsson showed that the X-ray contrast media used in phlebography could cause deep vein thrombosis. One-third of the investigated patients showed accumulation of 125-I-labeled fibrinogen in the leg together with clinical symptoms of pain, edema and discoloration of the leg.

“It took some time for my colleagues and me to accept that the X-ray contrast media could cause DVT because at the time, in 1975, phlebography had been in use for decades,” Dr Olsson says.

He submitted his results to The Lancet. After only a week, the editor sent an accep-tance letter stating that the results were so important that he wanted to publish them immediately.

When visiting a congress in Edinburgh that year, Dr Olsson heard that Torsten Al-mén, a colleague in Malmö, had construct-ed a low-osmolar X-ray contrast media. Using the isotope test, Dr Olsson followed his patients for seven days after phlebog-raphy with the new contrast medium and found neither objective nor subjective signs of complications.

After these tests, radiologists all over the world soon started to use the new type of X-ray contrast media in phlebography. If the old X-ray contrast media had been used for a further 30 years, a substantial number of patients would have had DVT. One-third of these patients would have had pulmonary embolism (PE) and many left

untreated would have died. “Torsten Al-mén’s discovery probably saved the lives of about a million patients,” Dr Olsson says.

The MEDENOX trialIn June 1975, Dr Olsson visited VV Kakkar in London just a week before his historic Lancet paper appeared on the prophylaxis of venous thromboembolism (VTE) in sur-gical patients. During that visit, he decided to push for a future trial of VTE prophy-laxis in medically ill patients. Throughout the 1980s, Dr Olsson repeatedly asked unwilling pharmaceutical companies to sponsor a trial. Prophylaxis of VTE with low-molecular-weight heparin (LMWH) in medically ill patients had been used in France for many years. But it was not until the medical authorities demanded that the company Rhone-Poulenc Rorer show scien-tific proof of its effects that a clinical trial was designed. In 1993, Michel M Samama asked Dr Olsson to join the steering com-mittee of the MEDENOX trial.

The positive results of the MEDENOX trial 1 were presented at the ISTH Wash-ington Congress in 1999. The presentation was received with interest but there was still skepticism and not everyone believed that medically ill patients would benefit from VTE prophylaxis.

Another interesting finding in this trial was that while a dose of 20 mg/day of enoxaparin was sufficient for prophylaxis in surgical patients, medically ill patients needed a higher dose, 40 mg/day.

30 3130

The PREVENT trial 2

PREVENTPrimary Efficacy Endpoint: VTE

(Day 21 + 3)

DalteparinN=1518

PlaceboN=1473

Difference in Incidence (%)

RiskRatio

2.77 % 4.96 % -2.19 0.55

95 % Cl -3.57 to -0.81 0.38 to 0.80

P* = 0.0015

*Cochran-Mantel-Haenszel Test

Results of the PREVENT trial

Dr Olsson discussed with Alain Leizorovicz and Amiram Eldor the need for a second study on risk reduction for VTE in medical-ly ill patients. Drs Olsson and Leizorovicz discussed the trial outline with Pharmacia in 2000. A decision was made to take the suggestion to the company board. At the same time, Dr Olsson realized that Ameri-can colleagues were to start the same trial. After contact with Samuel Goldhaber, Drs Leizorovicz and Olsson joined the steering committee.

The PREVENT trial 2 (see figure) showed good results with 5 000 IU of dalteparin/day over 14 days as VTE prophylaxis in medically ill patients.

Yet after two large trials showing the benefits of VTE prophylaxis in medically ill patients, many colleagues in Europe and Sweden still did not want to accept these results. The US colleagues were more posi-tive and more accepting of the concept of VTE prophylaxis in medically ill patients.

The ARTEMIS trialAlexander Cohen participated in both the MEDENOX and the PREVENT trial. He then embarked on a third, smaller trial with fondaparinux, a synthetic, selective inhibitor of factor Xa, as VTE prophylaxis in medically ill patients.

The relative risk reduction with fonda-parinux in this trial3 was consistent with re-

sults obtained by the low-molecular-weight heparin group in the placebo-controlled studies that used venography.

Acceptance of VTE prophylaxis VTE prophylaxis should be given to a very high–risk group of 5% of all medically ill patients in hospital and mostly to cancer patients, as shown by Kucher and col-leagues.5

Current data indicate that cancer pa-tients survive longer with LMWH prophy-laxis.

The futureToday we have three positive, large, con-trolled clinical trials showing that cancer patients need VTE prophylaxis. Since treat-ment in this patient group most probably will be life-long, the new oral drugs for anticoagulation are very exciting.

References1. A comparison of enoxaparin with placebo for the prevention of venous

thromboembolism in acutely ill medical patients. Prophylaxis in Medi-cal Patients with Enoxaparin Study Group. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N. N Engl J Med. 1999 Sep 9; 341(11): 793-800.

2. Randomized, Placebo-Controlled Trial of Dalteparin for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study Group. Circulation. 2004 Aug 17; 110(7): 874-9. Epub 2004 Aug 2.

3. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. Alexander T Cohen, Bruce L Davidson, Alexander S Gallus, Michael R Lassen, Martin H Prins, Witold Tomkowski, Alexander G G Turpie, Jan F M Egberts, Anthonie W A Lensing and ARTEMIS Investigators BMJ, doi:10.1136/bmj.38733.466748.7C (published 26 January 2006).

4. Evidens för trombosprofylax till medicinpatienter med hög risk, Själander A, Jansson, J-H, Bergqvist D, Erisson, H, Svensson, P. Läkartidningen 2007; volym 104: nr 20–21

5. Kucher N, Koo S, Quiroz R, Cooper JM, Paterno MD, Soukonnikov M,et al. Electronic alerts to prevent venous thromboembolism among hospital-ized patients. N Engl J Med. 2005; 352: 969-77.

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32 3332

1988

2008

Article by: Professor Agnes Y.Y. LeeInterview: Professor Ajay Kakkar

Fragmin in Oncology

32 3332

Dalteparin sodium in the treatment of venous thromboembolism in patients with cancer

Article by: Professor Agnes Y.Y. Lee

The Past, Present and Future

SummaryLow-molecular-weight heparins (LMWH) have largely replaced unfractionated hepa-rin (UFH) for the prevention and treatment of venous and arterial thromboembolic disease because they are efficacious, safe and more convenient.

One of the best-studied LMWH is dalteparin sodium. Produced by controlled nitrous acid depolymerization of UFH, it has a broad scope of applications and clinical uses, with regulatory approval for use in preventing venous thromboembo-lism (VTE) following major abdominal and orthopedic surgery, preventing VTE in acutely medically ill patients, treating acute deep vein thrombosis, and preventing recurrent VTE in cancer patients. This last indication is unique to dalteparin and has established it as the only and most effective anticoagulant approved for the treatment of cancer-associated thrombosis. More recent research efforts have examined the poten-tial role of dalteparin as an antineoplastic agent.

Initial treatment of venous thromboembolismSeveral randomized controlled trials have compared the relative efficacy and safety of subcutaneous dalteparin with intrave-nous UFH for treatment of acute deep vein thrombosis (DVT). Most of the studies were small and used improvement in the venographic Marder score as the primary outcome measure. However, these studies consistently showed that dalteparin, given as 10-120 IU/kg twice daily or 200 IU/kg once daily, was comparable to APTT-ad-justed UFH infusion in preventing recurrent

thrombosis. Based on these studies, the recommended treatment dose of dalteparin for initial treatment of VTE is 200 IU/kg subcutaneously once daily. Cancer patients were included in some of these studies, but the total numbers were small and the published experience is limited. Nonethe-less, dalteparin is widely used for initial treatment of VTE in all patients, usually on an outpatient basis. Because of the reduc-tion in hospitalization and the elimination of APTT monitoring, dalteparin is more cost effective than traditional intravenous UFH therapy.

Long-term treatment of venous thromboem-bolism One pivotal study has examined the use of dalteparin in comparison with warfarin for long-term treatment to prevent recurrent VTE in cancer patients. The CLOT study (Randomized comparison of low molecular weight heparin versus oral anticoagulant therapy for the prevention of recurrent venous thromboembolism in patients with cancer) was a multicentre, randomized, open-label study in which 676 cancer patients with proximal DVT, PE or both were randomized to usual treatment with dalteparin initially followed by coumarin therapy or dalteparin therapy alone for six months. In the dalteparin group, patients received therapeutic doses at 200 IU/kg once daily for the first month and then 75-80% of the full dose for the next five months. Prefilled syringes containing fixed doses of dalteparin were used during the five-month period. Over the total six-month treatment period, dalteparin significantly re-duced the incidence of recurrent VTE from 17% to 9% (risk reduction 52%; p=0.002). There were no differences in bleeding or overall mortality between the groups. This landmark study changed clinical practice worldwide and is the basis for treatment guideline recommendations from the American College of Chest Physicians, the

34 3534

American Society of Clinical Oncology, the Italian Medical Oncology Association and other authoritative bodies. Other LMWH have been investigated for this use but none have shown the superior results reported for dalteparin. Meta-analyses of these studies have confirmed the efficacy of LMWH over warfarin therapy and have found a consis-tent survival benefit in patient groups who were randomized to receive LMWH.

Antineoplastic effects of dalteparinDalteparin has been investigated in a few small clinical trials for potential antican-cer effects and in experimental settings to examine the possible mechanisms, which may include angiogenesis, interference with tumor cell adhesion, and inhibition of tumor invasion and metastasis. Although the role of dalteparin and other LMWH as anticancer drugs remains controversial and the exact mechanisms remain elusive, it is now well established that activation of coagulation is critically involved in tumor growth and progression.

The famous study is the first randomized, placebo-controlled trial to investigate the effect of dalteparin 5 000 IU once daily on overall survival in patients with advanced solid tumors. Therapy was continued for one year or until death, if it occurred within the year. A trend for survival benefit was observed but was not statistically signifi-cant. In contrast, a small study from Turkey of patients with newly diagnosed small-cell lung cancer showed a survival benefit with low-dose dalteparin. In this study, patients were randomized to standard chemotherapy with or without dalteparin, 5 000 IU once daily. Significant differences were seen in overall, median and progression-free surviv-al, favoring the dalteparin group. A large, multicentre trial (fragmatic study) enrolling newly diagnosed patients with lung cancer is now under way in the United Kingdom to confirm the findings observed in the Turk-ish study. Results from this ambitious trial

will no doubt advance our knowledge of dalteparin in this setting.

Conclusion and future perspectiveDespite the advances that dalteparin has provided, many areas of cancer-associated thrombosis management require further study. These include optimal duration of treatment of VTE, optimal dosing and treat-ment of refractory or breakthrough throm-bosis (recurrent thrombosis during standard anticoagulation). In the CLOT trial, 9% of patients with cancer and VTE experi-enced recurrent VTE while on dalteparin. Whether such patients would benefit from higher doses of dalteparin needs to be ad-dressed. Understanding the mechanisms be-hind refractory thrombosis and identifying these patients early on would help towards streamlining and individualizing anticoagu-lant therapy.

Whether the novel oral agents that do not require laboratory monitoring will replace traditional anticoagulants, including LMWH, remains unknown. The conve-nience of these new drugs is definitely an advantage that is highly welcomed by physi-cians and patients. However, their use in oncology patients has not yet been studied. Given the aggressive nature of cancer-asso-ciated thrombosis and the frequent failure of warfarin therapy in these patients, it is critical that careful research and endpoint-driven clinical trials are carried out to show efficacy and safety in the high-risk oncology population before they are accepted for use in these patients.

Dalteparin is a LMWH with a 20-year history in the management of thrombotic disorders. Its indication for prevention of recurrent VTE in cancer patients makes it unique among LMWH and it may have a future role as an antineoplastic agent. Its contribution to improving and simplifying patient care is remarkable and it will remain an anticoagulant of choice in the oncology population.

34 3534

Prevention of Venous Thromboembolism in the cancer surgical patient

Professor Ajay Kakkar

Increased risk for venous thromboembolism in cancer surgical patients

The association between cancer surgery and thrombosis has long been known. The most common thrombotic events in patients with cancer are venous throm-boembolism (VTE) presenting as deep vein thrombosis (DVT) and pulmonary embo-lism (PE).

The issue of preventing thromboembo-lic disease in patients undergoing surgical intervention for their cancer is an area that has benefited from most research because the problem of thromboembolic disease in patients undergoing laparotomy for abdominal or pelvic malignancy has been a subject of intensive research investigation for the past three decades.

Data from a large discharge database for patients leaving hospitals in the California health care system shows that operating in the presence of cancer substantially in-crease the reported rate of thromboembolic complications1. These are both symp-tomatic deep vein thrombosis (DVT) and pulmonary embolism (PE) occurring as a consequence of surgical intervention.

Data from asymptomatic screening of DVT using fibrogen scanning or venogra-phy shows that the frequency of throm-boembolic disease is between 40-80 % in patients without thromboprophylaxis having undergone laparotomy for cancer.

Historic autopsy series when no prophy-laxis has been provided in the periopera-tive period indicates that between 1-5% of patients will die of PE after surgical intervention.

The frequency of reported PE is 2,3% in patients undergoing laparotomy for cancer compared with 0.36% for patients under-going surgical intervention at the same ana-

tomical site but with no malignant disease, an odds ratio of 6.7.2

There is no doubt that the presence of malignant disease and operation for cancer increase the development of serious throm-boembolic complications, said Kakkar who pointed to data that shows additional features in the surgical cancer population that gives added burden of potential fatal thromboembolism.

In an Italian registry of 3 000 patients3 having undergone laparotomy for can-cer followed for up to 30 days after the operation, certain features in addition to the presence of malignant disease further heighten the potential risk for the devel-opment of postoperative venous throm-boembolism (VTE). These include age over 60, a previous history of VTE, operation lasting longer than two hours, operation for advances versus early stage disease and prolonged bed rest in excess of four days in the postoperative period. All of these features are associated with odds ratios between two and six, indicating a substan-tial additional risk for patients with these features compared to patients with cancer but without undergoing operative interven-tion.

In terms of surgical practice, we are very able to identify patients with a particularly high risk for the development of potentially fatal VTE in the postoperative period, states Kakkar who thinks that the current available method for preventing throm-boembolic disease in the large number of patients undergoing operation without can-cer also are effective and safe in high-risk surgical cancer population.

Thromboprophylaxis in surgical patients with cancerThe first major study4 that analysed the impact of thromboprophylaxis in surgi-cal patients with cancer was published 30 years ago by the international multicentre trial. The original study evaluated the po-

36 3736

tential benefits of low dose unfractionated heparin (UFH) for the prevention of fatal PE in the postoperative period. In this trial, 4 000 patients who were undergoing major surgical intervention were randomized to receive low dose UFH commenced two hours prior to operation and three times a day in the postoperative period or random-ized to a control group with no thrombo-prophylaxis.

The endpoint in this study was autopsy-proven fatal PE in the period up to dis-charge from hospital. 16 patients out of 2 000 patients in the control group devel-oped autopsy-proven fatal PE compared to only two out of 2 000 patients who under-went operation but received perioperative low dose heparin. This was a substantial reduction in the frequency of fatal PE.

23% or 953 patients in this trial un-derwent operation for malignant disease. 1.6% of patients died of fatal PE in the control group. This was reduced to only 0, 4% where patients had received active perioperative thromboprophylaxis. The re-sults show clear evidence that prophylaxis is indeed effective in this high risk surgical population where the operation has been for malignant disease, said Kakkar.

A pivotal meta-analysis published in NEJM 19885 compared thromboprophy-laxis with low dose UFH with no pro-phylaxis in 12 000 randomized patients. Heparin prophylaxis reduced total surgical mortality by 21%, reduced the frequency of fatal PE confirmed by autopsy by nearly 70%, as well as the frequency of DVT.

Heparin prophylaxis in the perioperative period including patients who have under-gone or is undergoing operative interven-tion for cancer has a substantial impact on clinical outcome.

A very important clinical question that often worries surgeons with regard to pharmacological thromboprophylaxis is the potential adverse impact of bleeding complications.

But there were no difference between heparin and control group in these trials with regard to the frequency of bleeding adversely impacting on the outcome of the intervention.

–We know in the perioperative period that high risk populations such as those undergoing surgical intervention for cancer are more likely to die of a blood clot than of fatal bleeding, said Kakkar, who added that certainly pharmacological prophylaxis have no impact on increasing frequency of fatal bleeding events associated with the surgical intervention.

The LMWH era in thromboprophylaxisIn the last 20 years clinical practice of thromboprophylaxis moved on in terms of surgical prophylaxis away from UFH to low molecular weight heparin (LMWH).

One of the interesting studies was a Canadian trial6 on patients undergoing intervention for colorectal cancer where the patients were randomized to UFH or LMWH during the period of hospital stay. Perioperatively, the LMWH appeared to provide more efficient thromboprophylaxis than low dose UFH without any significant increase in bleeding complications.

A pivotal study with regards to deter-mining the dose of LMWH for patients undergoing surgical intervention for their cancer but also a study that helped to iden-tify the appropriate dose for prophylaxis across broader cancer populations was the trial published by Bergqvist and colleagues in the British Journal of Surgery in 1995.7

In this trial, 2 000 patients undergo-ing laparotomy for intraabdominal pelvic malignancy were randomized to one or two doses of LMWH dalteparin , 2 500 anti Xa units, the dose given for general surgical procedures i e cholecystectomy, or 5 000 units, the dose normally given to high risk surgical intervention such as knee or heal replacement. Using screening with venogra-phy 10 days after operation, Bergqvist et al

36 3736

were able to demonstrate a substantial re-duction in the frequency of DVT associated with giving the double dose of LMWH to patients undergoing laparotomy for cancer.

There was no sign of increased bleeding complications associated with doubling the dose of dalteparin for the cancer popula-tion in this study indicating that patients with malignant disease need a higher dose of LMWH for prophylaxis and that this strategy is safe.

Meta-analysis8 for general surgery in terms of prophylaxis include about 48 000 patients who have been random-ized to prospective clinical trials compar-ing low dose IFH given three times a day with LMWH given once a day. Whatever endpoint that has been used in these trials; screening detected asymptomatic DVT, PE, symptomatic thromboembolic disease, or perioperative mortality, providing LMWH once a day compared to UHF three times per day is as effective and certainly safe in terms of bleeding, haemorrhagic complica-tions and transfusion requirement. This benefit seems to attend both cancer and non-cancer populations equally in these clinical trials.

Mechanical method for thromboprophylaxisIn certain circumstances it is not possible to provide pharmacological thrombopro-phylaxis to a surgical patient undergoing intervention for cancer because the patients are actively bleeding or there is a great fear of the risk of potential bleeding complica-tions beyond those normally seen on the course of clinical practice.

In these circumstances there is an oppor-tunity to use a variety of different mechani-cal method such as graduated compres-sion stockings, or intermittent pneumatic compression which is normally applied when the patient is on the operating table to improve venous return.

Mechanical methods show across medi-cally ill and surgical patient populations, a

reduction of 67% in the reported frequency of DVT compared to no intervention.9

The reduction in PE is not significant suggesting either that a to small number of patients have been evaluated for the potential benefits of mechanical methods as monotherapy for preventing PE or that the mechanical method alone has no impact on the activation of coagulation and is sub-standard in terms of preventing potential fatal PE.

According to Kakkar, there is however no doubt, where pharmacological meth-ods cannot be adopted, that the use of a mechanical method will provide some protection.

A further opportunity is to combine mechanical with pharmacological methods, low dose UFH, in the perioperative period for patients undergoing laparotomy for cancer.

The published studies10 have small number of patients but one sees an efficacy of low dose UFH combined with graduated compression stockings compared to UFH alone. A strategy followed by many sur-geons is to combine pharmacological meth-ods, such as UFH or today more frequently LMWH with compression stockings.

Extended prophylaxis with LMWH beneficial More recently, a very large study11 have been published with 23 000 patients who underwent surgical intervention and were randomized to receive either low dose UFH three times a day or LMWH once a day. The endpoint is this trial was autopsy-proven fatal PE within 14 days of discon-tinuation of prophylaxis. The primary endpoint was to compare the two heparin strategies. The results are that there was no difference between the two groups indicat-ing that once daily LMWH was effective in preventing fatal PE in the postoperative period.

Subsequently, Kakkars and colleagues performed a secondary analysis12 of this

38 3938

data-set with 23 000 patients treated with heparin. The question posed was whether there was a different outcome for patients who underwent a laparotomy for cancer. 6 000 patients in the study were com-pared to 17 000 patients who underwent operation without cancer. The results show that the perioperative mortality within 14 days of discontinuation of prophylaxis was substantially higher in cancer patients compared to non–cancer patients as was the frequency of fatal PE autopsy-proven. There was 15 cases out of 17 000 operated for non-cancer compared to 20 cases out of 6 000 operated for cancer despite the use of heparin based prophylaxis.

These findings indicate that we need to do more than just to provide prophylaxis in hospital to a cancer surgical patient to ensure that they are adequately protected, said Kakkar.

Twenty percent of the total throm-boembolic burden presents itself after discharge from hospital in patients who have undergone major surgical intervention for cancer.13

Two trials in the published litera-ture have tried to prospectively evaluate whether extended thromboprophylaxis into the post discharge period can have a sub-stantial impact on reducing the frequency of DVT.

In the first trial14, all patients received the LMWH enoxaparin in hospital after laparotomy for cancer. At a time of dis-charge they were randomized to continue receive heparin or a placebo injection. Screening with venography for DVT was performed 21 days after discharge and there was a 60% reduction in all throm-boembolic events in favor of extending thromboprophylaxis to 30 days after operation. Following those patients for two months after they discontinued prophylaxis showed that the benefit of adding LMWH to the discharge period is maintained.

A similar designed trial was performed

with the LMWH dalteparin.15 All patients in hospital were receiving dalteparin and were then randomized to continue with dalteparin or no further prophylaxis for additional 21 days. Assessment with venog-raphy demonstrates similar results, 55% reduction in the frequency of all thrombi screened 30 days after operation in favor of patients receiving extended thrombopro-phylaxis with dalteparin.

Analysis of the most serious thrombi, in the proximal segment of the venous system, also shows a substantial reduction in favor of extending thromboprophylaxis into the post discharge period.

Pooled analysis showed that there is for all DVT benefits of extending prophylaxis. 15% of patients having DVT if they only received prophylaxis in hospital practice were reduced to 6,5% if they had extended prophylaxis.16

Proximal venous thrombi are also less frequently seen in patients receiving ex-tended prophylaxis, but symptomatic DVT, the DVT that surgeons will see without screening with venography are reduced only from 1 to 0,3%, a not significant dif-ference. However, there were only a small number of patients in these trials.

There are today a number of trials evaluating thousands of patients to de-termine the potential benefits of extended prophylaxis.

ConclusionsVTE is common after cancer surgery, prophylaxis with LMWH effective and safe and extended prophylaxis should be considered for highest risk populations.

References1. White RH, et al. Incidence of symptomatic venous thromboembolism

after different elective or urgent surgical procedures. Thromb Haemost. 2003; 90: 446-55.

2. Huber O, et al. Postoperative pulmonary embolism after hospital dis-charge. An underestimated risk... Arch Surg. 1992; 127: 310-3.

3. Agnelli G, et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: The @RISTOS project. Ann Surg. 2006; 243: 89-95.

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4. Kakkar VV et al. Prevention of fatal postoperative pulmonary embolism by low doses of heparin: An international multicentre trial.Lancet.1975; 2: 45-51.

5. Collins R et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: Overview of results of randomized trials in general, orthopedic, and urologic surgery. New Engl J Med. 1988; 318: 1162-73.

6. McLeod R, et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery. Ann Surg 2001; 233: 438-444.

7. Bergqvist D et al. Risk of venous thromboembolism in patients undergo-ing cancer surgery and options for thromboprophylaxis.Br J Surg. 1995; 82: 496-501.

8. Mismetti P, et al. Meta-analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery Br J Surg 2001; 88: 913–30.

9. Roderick P, et al. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophy-laxis. Health Technology Assessment 2005; Vol. 9: No. 49.

10. IUA Consensus statement. New International Guidelines Highlight Evidence-Based Recommendations to Prevent Venous Thromboembolism (VTE) - a Major Global Health Problem Int. Angiol. 2006

11. Haas S, et al. Prevention of fatal pulmonary embolism and mortality in surgical patients: a randomized double-blind comparison of LMWH with unfractionated heparin. Thromb Haemost. 2005; 94: 814-9.

12. Kakkar AK et al. Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients: The MC-4 cancer substudy. Thromb Haemost. 2005; 94: 867-871.

13. Huber O, et al. Postoperative pulmonary embolism after hospital discharge. An underestimated risk. Arch Surg. 1992; 127: 310-3.

14. Bergqvist D, et al, Duration of prophylaxis against venous thromboem-bolism with enoxaparin after surgery for cancer. New Engl Med. 2002; 346: 975−980.

15. Rasmussen MS, et al. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: A multicentre randomized open-label study. Journal of Thrombosis and Haemostasis, 2006; 4: 2384–2390

16. Rasmussen MS et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against venous thromboembolism In patients after cancer operations: A meta-analysis. J Thromb Haemost. 2005; 3 Suppl 1: P2213.

40 4140

Interview: Gun Jörneskog

Fragmin – Future possibilities1988

2008

40 4140

Interview with Gun Jörneskog

Fragmin in the treatment of chronic neurois-chemic foot ulcers in diabetic patientsDiabetes mellitus affects more than 100 million people worldwide. Hyperglyce-mia induces vascular changes involving both micro- and macrocirculation. The manifestations of vascular diseases are the main causes of death and disability among patients with diabetes. Macrovascular dis-eases include peripheral arterial occlusive disease, cardiovascular and cerebrovascular disease. The retina, kidneys and neural system are affected by microangiopathy.

Diabetes can also be seen as a pro-thrombotic syndrome with elevated levels of coagulation factors such as thrombin, fibrinogen, and von Willebrand factor. Fibrinolysis is reduced and Plasminogen activator inhibitor-1 (PAI-1) is increased. Several proteins – Antithrombin III, Fi-brinogen/fibrin and Plasminogen/plasmin – are functionally changed.

The number of patients with diabetes is increasing, as is the number of patients with diabetes-related complications such as chronic foot ulcers. Diabetic foot ulceration causes much suffering for patients and is an expensive complication both for patients and society. Chronic diabetic foot ulcers affect about 5-15% of diabetic patients during their lifetimes. Foot ulcers lead in 10-25% of these patients to amputations which are, in 80% of cases, preceded by a chronic foot ulcer. 50-60% of all non-traumatic amputations are carried out on diabetic patients, and a majority of them will be followed by a contralateral amputa-tion within three to five years.

Diabetic foot ulcers, treatment (see figures)

% o

f gr

oup

40

30

20

10

0Healed Improved Unchanged Impaired Amputation

DalteparinPlacebo

Combined endpoints, p=0.042

Diabetes and chronic neuro-ischemic foot ulcersImproved ulcer outcome during treatment with dalteparin (n=43)

as compared to placebo (n=42)

Kalani M, Jörneskog G et al. Diabetes Care 2003; 26: 2575-2580

N=14

N=15

N=11

N=7 N=9

5 5

5

2

N=9

Patients treated with dalteparin had improved combined ulcer outcome i.e. increased healing with intact skin, decreased ulcer size, and decreased amputation rate in the dalteparin group. Pathophysiogically, haemeostasis was changed with decreased thrombin generation (F1+2), improved fibrinolytic function (tPA ag) and less thrombogenic fibrin network.

Per

mea

bilit

y co

effic

ient

Ks

(cm

2x1

0-9

) 22

20

18

16

14

12

10

8

6

4

2Baseline

n=42Baseline

n=43Endpoint

n=42Endpoint

n=43

Dalteparinp<0.01

Placebo

As less thrombogenic fibrin network was seen during treatment with dalteparin

Kalani M, Jörneskog G et al. Thromb Res, 2007

Further analysis in the patients showed that dalteparin treatment leads to a less thrombogenic fibrin gel structure and improved local skin microcircula-tion with increased skin oxygenation

Both micro- and macroangiopathies are important contributing factors to the non-healing of diabetic foot ulcers, as are the neuropathy, trauma and infection. There is today no effective treatment for neu-roischemic foot ulcers in diabetic patients if vascular reconstruction or angioplasty is not possible. General treatments are of-floading of the ulcer, antibiotics, improved metabolic control and recommendations to stop smoking.

Heparin has several beneficial clinical effects, such as antithrombotic, anti-inflam-matory properties; fibrinolysis is improved and angiogenesis may be stimulated in hypoxic tissues.

The research group of Jörneskog and Kalani et al. therefore carried out a pro-

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spective, randomized, double-blind, place-bo-controlled study to analyze in a clinical trial 1 whether the low-molecular-weight heparin (LMWH) dalteparin had any ef-fects on outcome of chronic neuroischemic foot ulcers in patients with diabetes.

Eighty seven diabetic patients with neuroischemic foot ulcers were random-ized either to receive daily subcutaneous injections of 5 000 IU dalteparin (n=43) or matching placebo (0.2 ml saline; n=42) until ulcers healed or for a maximum of six months.

Patients treated with dalteparin had improved combined ulcer outcome – i.e. in-creased healing with intact skin, decreased ulcer size and decreased amputation rate in the dalteparin group. Pathophysiologically, hemeostasis was changed with decreased thrombin generation (F1+2), improved fibrinolytic function (tPA ag) and a less thrombogenic fibrin network.

Further analysis2 of the patients showed that dalteparin treatment leads to a less thrombogenic fibrin gel structure and improved local skin microcirculation, with increased skin oxygenation.

Conclusion Foot skin microcirculation in diabetic patients with neuroischemic foot ulcers is related to a tight and rigid fibrin network. Dalteparin increases fibrin gel porosity in favor of fibrinolysis and production of a less thrombogenic fibrin network.

The beneficial effect of dalteparin on ulcer outcome seems mediated by improved hemostatic function and local skin oxygen-ation. Dalteparin improves ulcer outcome in diabetic patients with neuroischemic foot ulcers.

Using dalteparin to treat 100 diabetic patients with chronic neuroischemic foot ulcers will heal roughly 12 additional pa-tients and prevent 14 amputations.

Further studies are needed to verify the above results, as well as to assess whether

the presence of a small foot ulcer improve the quality of life compared to a bigger ulcer and how often is a patient better off with an amputation and a good prosthesis compared with a persistent (or even healed) ulcer on a neuroischemic, poorly function-ing marginal limb.

References1. Kalani M, Apelqvist J, Blombäck M, Brismar K, Eliasson B, Eriksson JW,

Fagrell B, Hamsten A, Torffvit O, Jörneskog G. Effect of dalteparin on outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind and placebo-controlled study. Diabetes Care 2003; 26(9): 2575-2580.

2. Kalani M, Silveira A, Blombäck M, Apelqvist J, Eliasson B, Eriksson JW, Hamsten A, Jörneskog G. Beneficial effects of dalteparin on haemostatic function and local tissue oxygenation in patients with diabetes, severe vascular disease and foot ulcers. Thromb Res. 2007; 120(5): 653-61.

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44 4544

Landmark studies

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Fragmin in Abdominal/General surgery 46 – 48

Fragmin in Orthopaedic surgery 49 – 52

Fragmin in Cardiology 53 – 55

Fragmin in Medically ill patients 56

Fragmin in Cancer 57

Fragmin – Future possibilities 58 – 60

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Fragmin in Abdominal/General surgery

Bergqvist D, Burmark US, Frisell J, Hallbook T, Lindblad B, Risberg B, Torngren S, Wallin G. Low molecular weight heparin once daily compared with conventional low-dose heparin twice daily. A prospective double–blind multicentre trial on prevention of postoperative thrombosis Br J Surg. 1986 Mar; 73(3): 204-8.

In a randomized, prospective, double–blind multicentre trial, the effect of conventional low-dose heparin 5 000 units twice daily, was com-pared with that of a low molecular weight heparin fragment (4 000–5 000) 5 000 anti–factor Xa units once daily. 432 patients ful-filled the inclusion criteria and were analyzed for development of deep vein thrombosis (125I-labelled fibrinogen test) and haemorrhagic com-plications. Thrombosis occurred in a 4.3 % of patients in the low–dose heparin group and in 6.4 % of patients in the heparin fragment group, a difference which is not significant. There was a significant delay in the onset of thrombosis in the heparin fragment group. Mortality did not differ between the groups, nor did peroperative blood loss or transfu-sion requirements or infectious complications. Haemorrhagic complica-tions occurred significantly more often in the fragment group (11.6 %) than in the conventional heparin group (4.6 %). Patients in the heparin fragment group experienced local pain following the subcutaneous injection significantly less often.

Bergqvist D, Burmark US, Frisell J, Guilbaud O, Hallböök T, Horn A, Lindha-gen A, Ljungner H, Ljungström KG, Mätzsch T, et al. Thromboprophylactic effect of low molecular weight heparin started in the evening before elective general abdominal surgery: a comparison with low–dose heparin. Semin. Thromb. Hemost. 1990 Oct; 16 Suppl: 19-24.

A prospective randomized double-blind trial was performed comparing conventional low-dose heparin with a LMWH fragment (Kabi 2165, Fragmin) for thromboprophylaxis in elective general abdominal surgical patients. The first dose of the fragment was given in the evening before surgery, and thereafter every evening. There were 1 002 analyzable patients, 826 having received correct prophylaxis. 63 % of the patients were operated on for malignant diseases. The frequency of DVT was significantly reduced among patients with correct prophylaxis with the heparin fragment (9.2 to 5.0 %, P = 0.02). In patients with malignan-cies the reduction was from 11.2 to 6.4 % (P = 0.06). The frequency of bleeding was 6.7 % among the heparin fragment patients and 2.7 % among the patients given conventional heparin (p = 0.01). The cor-responding frequencies for patients with malignancies were 3.2 and 2.8 %, respectively (P = 0.28). All bleedings were minor and of no clini-cal significance. Local pain at the injection site was reported significant-

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ly less often among patients with the fragment. Twenty patients died, 13 with malignant disease, mortality being the same in the two groups. It is concluded that heparin fragment administered in the evening before surgery and then every evening is a practically acceptable alternative to prevent postoperative DVT in patients undergoing elective abdominal surgery, also when the histology shows malignancy. Thus, the advantag-es of using LMWH compared with conventional low–dose heparin are simplified administration routines, better thromboprophylactic effect, and less local pain at injection sites. A disadvantage is the slight increase in hemorrhagic side effects, all of minor clinical importance and not seen in patients undergoing surgery for malignancy.

Bergqvist D, Burmark US,Flordal PA et al. Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 Xa units in 2070 patients. Br J Surg 1995; 82: 496-501.

The optimal administration regimens of low molecular weight heparins (LMWHs) have not yet been established. The aim of this study was to compare the efficacy and safety of 2 500 and 5 000 Xa units of the LMWH dalteparin in patients undergoing elective general surgery for malignant and benign abdominal disease. Prophylaxis was started in the evening before surgery and given once–daily every evening there-after. The study was designed as a prospective, randomized, double-blind, multicentre trial. Some 66.4 % of patients were operated on for a malignant disorder. The primary endpoint was deep vein thrombosis (DVT) detected with the fibrinogen uptake test. Bleeding complications were recorded and classified. Analysis was made both on an intention to treat basis and in patients given correct prophylaxis (86.3 %). A total of 2 097 patients were randomized and 27 excluded after randomiza-tion. A technically correct fibrinogen uptake test was obtained in 1 957 patients. The incidence of DVT was significantly lower in patients given 5 000 XaI units, this being true for both correct prophylaxis (6.8 versus 13.1 %, P < 0.001), on an intention to treat basis (6.6 versus 12.7 %, P < 0.001), and in patients with malignant disease (8.5 versus 14.9 %, P < 0.001). 67 patients (3.2 %) died within 30 days with no difference between the groups. There were two cases of fatal pulmonary embo-lism. The frequency of bleeding complications in the whole series was higher in patients randomized to 5 000 Xa units (4.7 versus 2.7 %, P = 0.02), although this was not the case in those operated on for malig-nant disease (4.6 versus 3.6 %, P not significant). Dalteparin in the dose of 5 000 XaI units started in the evening before surgery has a good thromboprophylactic effect in high-risk general surgery at the cost of a small bleeding risk. In patients with malignant disease there was no increased risk of bleeding. The overall frequency of fatal pulmonary embolism with dalteparin is extremely low, even in this high–risk group of patients.

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Rasmussen MS, Jorgensen LN, Wille-Jørgensen P, Nielsen JD, Horn A, Mohn AC, Sømod L, Olsen B. Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicentre randomized open–label study. FAME Investigators. J Thromb. Haemost. 2006 Nov; 4(11): 2384-90. Epub 2006 Aug 1.

BACKGROUND: Patients undergoing major abdominal surgery carry a high risk of venous thromboembolism (VTE), but the optimal duration of postoperative thromboprophylaxis is unknown.

OBJECTIVES: To evaluate the efficacy and safety of thromboprophylaxis with the low-molecular–weight heparin (dalteparin), administered for 28 days after major abdominal surgery compared to 7 days’ treatment.

PATIENTS/METHODS: A multicentre, prospective, assessor–blinded, open label, randomized trial was performed in order to evaluate prolonged thromboprophylaxis after major abdominal surgery. A total of 590 patients were recruited, of whom 427 were randomized and received at least one day of study medication, and 343 reached an evaluable end–point. The primary efficacy endpoint was objectively verified VTE occurring between 7 and 28 days after surgery. All patients underwent bilateral venography at day 28.

RESULTS: The cumulative incidence of VTE was reduced from 16.3 % with short–term thromboprophylaxis (29/178 patients) to 7.3 % after prolonged thromboprophylaxis (12/165) (relative risk reduction 55 %; 95 % confidence interval, CI, 15–76; P = 0.012). The number needed–to–treat to prevent one case of VTE was 12 (95% CI, 7–44). Bleeding events were not increased with prolonged compared with short–term thromboprophylaxis.

CONCLUSIONS: Four–week administration of dalteparin, 5 000 IU once daily, after major abdominal surgery significantly reduces the rate of VTE, without increasing the risk of bleeding, compared with one week of thromboprophylaxis.

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Fragmin in Orthopaedic surgery

Eriksson BI, Kalebo P, Anthymyr BA, Wadenvik H, Tengborn L, Risberg B. Prevention of deep–vein thrombosis and pulmonary embolism after total hip replacement. Comparison of low–molecular–weight heparin and unfractionated heparin. J Bone Joint Surg Am. 1991 Apr; 73(4): 484-93.

In a prospective, randomized, double–blind study, the efficacy and safety of a low–molecular–weight heparin were compared with those of unfractionated sodium heparin (standard heparin) in 136 patients who had elective total hip replacement. The patients received subcutaneous injection of either 5 000 international units of low–molecular–weight heparin once daily or 5 000 international units of standard heparin three times a day. Treatment with low–molecular–weight heparin began 12 h before the operation, and treatment with standard heparin began 2 h preoperatively; both regimens were continued for ten days. 12 days postoperatively, bilateral ascending phlebography was performed in 122 patients, 63 in the treatment group that received low–molecular–weight heparin and 59 in the treatment group that received standard heparin. Pulmonary scintigraphy was performed in 127 patients. Deep–vein thrombosis was diagnosed in 44 patients: 19 (30 %) of the 63 who received low–molecular–weight heparin and 25 (42 %) of the 59 who received standard heparin. All but four patients, two from each treatment group, were asymptomatic. The difference in the total rate of thrombosis in the two groups was not significant (P = 0.189). However, thrombosis occurred in the thigh in only six (10 %) of the patients who received low–molecular–weight heparin but in eighteen (31 %) of those who received standard heparin, a significant difference (P = 0.011). Pul-monary embolism was detected in 27 patients: eight (12.3 %) of those who received low–molecular–weight heparin and 19 (30.6 %) of those who received standard heparin. Only three patients had clinical signs of embolism. Pulmonary embolism was significantly more frequent in the group that received standard heparin (P = 0.016). Total loss of blood and the total amount of blood that was transfused were significantly reduced in the patients who received low–molecular–weight heparin compared with those who received standard heparin. Prophylaxis was not discontinued because of hemorrhage in any patient. The efficacy of low–molecular–weight heparin was superior to that of standard heparin in the prevention of femoral thrombosis and pulmonary embo-lism, although the over–all incidence of deep–vein thrombosis was not statistically different.

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Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery – results of a double–blind, prospec-tive, randomized, placebo–controlled study with dalteparin (Fragmin). Thromb Haemost. 1997; 77(1): 26-31.

Discontinuation of thromboprophylaxis a few days after surgery may unmask delayed hypercoagulability and contribute to late formation of deep venous thrombosis (DVT). To investigate whether thrombopro-phylaxis should be prolonged beyond the hospital stay, a prospective, double–blind randomized study was conducted in 308 patients. All pa-tients received initial thromboprophylaxis with dalteparin, dextran and graded elastic stockings. On day 7, patients were randomized to receive dalteparin (Fragmin) 5 000 IU once daily, or placebo, for 4 weeks. All patients were subjected to bilateral venography, perfusion ventilation scintigraphy and chest X–ray on days 7 and 35. Patients with veno-graphically verified proximal DVT on day 7 were withdrawn from the randomized study to receive anticoagulant treatment. The overall prevalence of DVT on day 7 was 15.9 %. On day 35, the prevalence of DVT was 31.7 % in placebo–treated patients compared with 19.3 % in dalteparin–treated patients (P = 0.034). The incidence of DVT from day 7 to day 35 was 25.8 % in the placebo–treated group vs 11.8 % in the dalteparin–treated group (P = 0.017). The incidence of symptom-atic pulmonary embolism (PE) from day 7 to day 35 was 2.8 % in the placebo–treated group compared with zero in the dalteparin–treated group. This included one patient who died from PE. No patients expe-rienced serious complications related to the injections of dalteparin or placebo. This study shows that prolonged thromboprophylaxis with dalteparin. 5 000 IU, once daily for 35 days significantly reduces the frequency of DVT and should be recommended for 5 weeks after hip replacement surgery.

Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, Holmqvist A, Mant M, Dear R, Baylis B, Mah A, Brant R. Low–molecular–weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double–blind, randomized com-parison. The North American Fragmin Trial Investigators, (NAFT). Arch Intern Med. 2000 Jul 24; 160(14): 2199-207.

BACKGROUND: Based on the current understanding that venous throm-bosis starts perioperatively, administration of just–in–time low–molec-ular–weight heparin immediately before or in close proximity after hip arthroplasty may be more effective than usual clinical practice.

METHODS: We performed a randomized, double–blind trial comparing subcutaneous dalteparin sodium given once daily immediately before or early after surgery with the use of postoperative warfarin sodium in 1 472 patients undergoing elective hip arthroplasties. The primary end

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point was deep vein thrombosis detected using contrast venography performed after surgery (mean, 5. 7 days) in each group.

RESULTS: The frequencies of deep vein thrombosis for patients with interpretable venograms receiving preoperative and postoperative dalteparin for all deep vein thrombosis were 36 (10.7 %) of 337 (P< .001) and 44 (13.1 %) of 336 (P < .001), respectively, vs. 81 (24.0 %) of 338 for warfarin; for proximal deep vein thrombosis, 3 (0.8 %) of 354 (P =.04) and 3 (0.8 %) of 358 (P =.03), respectively, vs. 11 (3.0 %) of 363. Relative risk reductions for the dalteparin groups ranged from 45 % to 72 %. Symptomatic thrombi were less frequent in the preop-erative dalteparin group (5/337 patients [1.5 %]) vs the warfarin group (15/338 patients [4.4 %]) (P =.02). Serious bleeding was similar among groups. Increased major bleeding at the surgical site was observed for patients receiving preoperative dalteparin vs. warfarin (P =.01).

CONCLUSIONS: A modified dalteparin regimen in close proximity to surgery resulted in substantive risk reductions for all and proximal deep vein thrombosis, compared with warfarin therapy. Such findings have not been observed with low–molecular–weight heparin therapy commenced 12 h preoperatively or 12 to 24 h postoperatively vs. oral anticoagulants. Increased major but not serious bleeding occurred in patients receiving preoperative dalteparin. Dalteparin therapy initiated postoperatively provided superior efficacy vs. warfarin without signifi-cantly increased overt bleeding.

Hull RD, Pineo GF, Francis C, Bergqvist D, Fellenius C, Soderberg K, Holmqvist A, Mant M, Dear R, Baylis B, Mah A, Brant R. Low–molecular–weight heparin prophylaxis using dalteparin extended out–of–hospital vs. in–hospital warfarin/out–of–hospital placebo in hip arthroplasty patients: a double–blind, randomized comparison. North American Frag-min Trial Investigators (NAFT). Arch Intern Med. 2000 Jul 24; 160(14): 2208-15.

BACKGROUND: No randomized trials have directly evaluated the need for extended out–of–hospital thromboprophylaxis for patients who have hip arthroplasty in the US or Canada. The uncertainty as to the need for extended prophylaxis in North American patients is compli-cated by early hospital discharge, resulting in a short thromboprophy-laxis interval.

METHODS: To resolve this uncertainty, we performed a randomized double–blind trial in 569 patients who underwent hip arthroplasty comparing the use of dalteparin sodium started immediately before surgery or early after surgery and extended out–of–hospital to an over-all interval of 35 days with the use of warfarin sodium in–hospital and placebo out–of–hospital.

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RESULTS: For patients with interpretable venograms in the preopera-tive, postoperative, and combined dalteparin groups, new proximal vein thrombosis out–of–hospital was observed in 1.3 %, 0.7 % (P = .04), and 1.0 % (p = .02) of patients, respectively, compared with 4.8 % in the in–hospital warfarin/out–of–hospital placebo group. The respec-tive overall cumulative frequencies of all deep vein thrombosis were 30 (17.2 %) of 174 patients (P < .001), 38 (22.2 %) of 171 (P = .003), and 68 (19.7 %) of 345 (P < .001) in the dalteparin groups compared with 69 (36.7 %) of 188 for the in–hospital warfarin/out–of–hospital pla-cebo group. For proximal deep vein thrombosis, the respective frequen-cies were 5 (3.1 %) of 162 (P = .02), 3 (2.0 %) of 151 (P = .007), and 8 (2.6 %) of 313 (P = .002) compared with 14 (9.2 %) of 153. No major bleeding occurred during the extended prophylaxis interval.

CONCLUSIONS: Extended dalteparin prophylaxis resulted in significantly lower frequencies of deep vein thrombosis compared with in–hospital warfarin therapy. Despite in-hospital thromboprophylaxis, patients having hip arthroplasty in the US and Canada remain at moderate risk out–of–hospital. The number needed to treat provides a public health focus; only 24 to 28 patients require extended prophylaxis to prevent 1 new out–of–hospital proximal vein thrombosis. Recent studies dem-onstrate that asymptomatic deep vein thrombi cause the postphlebitic syndrome; thus, extended out–of–hospital prophylaxis will lessen the burden to both the patient and society.

52 5352

Fragmin in Cardiology

Wallentin L and the FRISC study group. Low–molecular–weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet. 1996 Mar 2; 347(9001): 561-8.

BACKGROUND: Intravenous heparin is at least as effective as aspirin in preventing new cardiac events after an episode of unstable coronary artery disease (CAD), though the benefits are short–lived. Low–molec-ular–weight heparin has similar antithrombotic properties but can be given subcutaneously and is therefore suitable for long–term treatment. We have investigated whether subcutaneous low–molecular–weight heparin, in addition to aspirin and antianginal drugs, is protective against new cardiac events in unstable cad.

METHODS: 1 506 patients with unstable CAD (unstable angina or non–Q–wave myocardial infarction) took part in a double–blind trial and were randomly assigned subcutaneous dalteparin (Fragmin; 120 IU per kg bodyweight [maximum 10 000 IU] twice daily for 6 days then 7 500 IU once daily for the next 35–45 days) or placebo injections. The primary endpoint was the rate of death and new myocardial infarction during the first 6 days. Secondary endpoints were the rates of death and new myocardial infarction after 40 and 150 days, the fre-quency of revascularisation procedures and need for heparin infusion, and a composite endpoint.

FINDINGS: During the first 6 days the rate of death and new myocardial infarction was lower in the dalteparin group than in the placebo group (13 [1.8 %] vs. 36 [4.8 %]; risk ratio 0.37 [95 % CI 0.20-0.68]), as were the frequencies of need for intravenous heparin (28 [3.8 %] vs. 58 [7.7 %]; 0.49 [0.32- 0.75]) and need for revascularisation (3 [0.4 %] vs. 9 [1.2 %]; 0.33 [0.10-1.10]). The composite endpoint (death, myocar-dial infarction, revascularisation, intravenous heparin) also showed a significant difference in favor of dalteparin (40 [5.4 %] vs. 78 [10.3 %]; 0.52 [0.37-0.75]). At 40 days the differences in rates of death and myocardial infarction and the composite endpoint persisted, although subgroup analysis showed that the effect was confined to non–smokers (80 % of sample). Survival analysis showed a risk of reactivation and reinfarction when the dose was decreased, more pronounced in smok-ers. 4–5 months after the end of treatment, there were no significant differences in the rates of death, new myocardial infarction, or revascu-larisation. The regimen was safe and compliance was adequate.

INTERPRETATION: We recommend that treatment with a combination of dalteparin and aspirin for at least 6 days should be considered in pa-

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tients with unstable CAD to reduce the risk of new cardiac events and to allow time for risk stratification and selection of a long–term treat-ment strategy. Long–term dalteparin treatment instead of or in addition to early invasive procedures warrants further assessment.

Swahn E, Wallentin L. Low-molecular-weight heparin (Fragmin) during instability in coronary artery disease (FRISC). FRISC Study Group. Am J Cardiol. 1997 Sep 4; 80(5A): 25E-29E.

This study evaluated whether the low–molecular–weight (LMW) heparin dalteparin sodium (Fragmin) had protective effects against cardiac events in aspirin–treated patients with unstable coronary artery syndromes. Patients (n = 1,506) with unstable angina or non–Q–wave myocardial infarction were randomized to double–blind, placebo–-controlled treatment with LMW heparin. The treatment was given as subcutaneous injections: 120 IU/kg body weight/12 h during the first 5–7 days and 7 500 IU once daily during the following 35–45 days. The primary endpoint, death or myocardial infarction after 6 days, showed a 3 % (4.7 %–1.7 %) absolute and a 65 % relative reduction in the LMW heparin group. There was a 6.8 % (15.5 %–8.7 %) absolute and a 47 % relative reduction of urgent revascularization or need for heparin or nitroglycerin infusions in combination with the primary endpoint. After 40 days there was an absolute reduction of death or myocardial infarction of 2.8 % (10.7 %–7.9 %) and its combination with incapacitating angina was reduced by 5.9 % (30.7 %–24.8 %). The survival analysis indicated a reactivation of the instability soon after lowering the dose at 5–7 days. With long–term follow–up, 3–4 months after termination of LMW heparin, the differences between groups were no longer statistically significant. However, the cumulative reduc-tion in death, myocardial infarction, and revascularization because of incapacitating angina of 5.1 % (25.3 %–20.4 %) was maintained. No cerebral and few major bleeds occurred. Compliance was adequate. Thus, subcutaneous LMW heparin protects against cardiac events in the acute phase of unstable coronary artery disease. The subcutaneous regimen also allows prolongation of treatment in the outpatient setting, which might maintain the initial benefits over a longer

Wallentin L, Husted S, Kontny F, Swahn E.and the FRISC II study group. Long-term low–molecular–mass heparin in unstable coronary-artery disease: FRISC II prospective randomized multicentre study. Fragmin and Fast Revascularisation during InStability in Coronary artery disease, Investigators. Lancet. 1999 Aug 28; 354(9180):701-7

BACKGROUND: In unstable coronary–artery disease early invasive procedures are common, despite lack of evidence for the superiority of this approach. We compared an early invasive with a non–invasive treatment strategy in unstable coronary–artery disease.

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METHODS: In a prospective randomized multicentre study, we randomly assigned 2 457 patients in 58 Scandinavian hospitals (median age 66 years, 70 % men) an early invasive or non–invasive treatment strat-egy with placebo–controlled long–term low–molecular–mass heparin (dalteparin) for 3 months. Coronary angiography was done within the first 7 days in 96 % and 10 %, and revascularisation within the first 10 days in 71 % and 9 % of patients in the invasive and non–invasive groups, respectively. We followed up patients for 6 months. Analysis was by intention to treat.

FINDINGS: After 6 months there was a decrease in the composite end-point of death or myocardial infarction of 9.4 % in the invasive group, compared with 12.1 % in the non–invasive group (risk ratio 0.78 [95 % CI 0.62–0.98], P=0.031). There was a significant decrease in myocar-dial infarction alone (7.8 vs. 10.1 %, 0.77 [0.60–0.99]; P=0.045) and non–significantly lower mortality (1.9 vs. 2.9 %, 0.65 [0.39-1.09]; P=0.10). Symptoms of angina and re–admission were halved by the in-vasive strategy. Results were independent of the randomized dalteparin treatment. The greatest advantages were seen in high–risk patients.

INTERPRETATION: The early invasive approach should be the preferred strategy in most patients with unstable coronary–artery disease who have signs of ischaemia on electrocardiography or raised biochemical markers of myocardial damage.

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Fragmin in Medically ill patients

Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ; PREVENT Medical Thromboprophylaxis Study Group. Randomized, place-bo-controlled trial of dalteparin for the prevention of venous thromboem-bolism in acutely medically ill patients. Circulation 2004;110:874-879.

BACKGROUND: Considerable variability exists in the use of pharmaco-logical thromboprophylaxis among acutely medically ill patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicentre, random-ized, double–blind, placebo–controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the preven-tion of venous thromboembolism in such patients.

METHODS AND RESULTS: Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5 000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymp-tomatic proximal deep vein thrombosis detected by compression ultra-sound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96 % (73 of 1 473 patients) in the placebo group to 2.77 % (42 of 1 518 patients) in the dalteparin group, an absolute risk reduction of 2.19 % or a relative risk reduction of 45 % (relative risk, 0.55; 95 % CI, 0.38 to 0.80; P = 0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49 %) compared with the placebo group (3 patients; 0.16 %).

CONCLUSIONS: Dalteparin 5 000 IU once daily halved the rate of ve-nous thromboembolism with a low risk of bleeding.

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Fragmin in Cancer

Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Comparison of Low–Molecular–Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low–molecular–weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with can-cer. N Engl J Med. 2003 Jul 10; 349(2): 146-53.

BACKGROUND: Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low–molecular–weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer.

METHODS: Patients with cancer who had acute, symptomatic proximal deep–vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low–molecular–weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months).

RESULTS: During the six–month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as com-pared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P = 0.002). The probability of recurrent thromboembolism at six months was 17 % in the oral-anticoagulant group and 9 % in the dalteparin group. No significant difference between the dalteparin group and the oral–anticoagulant group was detected in the rate of major bleeding (6 % and 4 %, respectively) or any bleeding (14 % and 19 %, respectively). The mortality rate at six months was 39 % in the dalteparin group and 41 % in the oral–anticoagulant group.

CONCLUSIONS: In patients with cancer and acute venous thromboem-bolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding.

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Fragmin – Future possibilities

Jörneskog G, Brismar K, Fagrell B. Low molecular weight heparin seems to improve local capillary circulation and healing of chronic foot ulcers in diabetic patients. Vasa. 1993; 22(2): 137-42.

Ten diabetic patients with peripheral arterial occlusive disease, pe-ripheral polyneuropathy and chronic foot ulcers were given 2 500 IU low molecular weight heparin (Fragmin, Kabi-Pharmacia AB, Sweden) subcutaneously once a day during 8 weeks. The mean age was 63 (47-80) years and the mean duration of foot ulcers 8 (4-12) months. All patients had previously received conventional treatment during 12 weeks, without any noticeable improvement on ulcer healing. The ulcer area was measured, and the skin microcirculation of the forefoot and around the ulcers was investigated before, during and after treatment with Fragmin. The total skin microcirculation was measured by laser Doppler fluxmetry, the nutritional skin microcirculation by vital capil-laroscopy and the macrocirculation by determination of the ankle/arm pressure ratio. The ulcer area decreased significantly in eight patients of which four healed the ulcers completely. Of the remaining two patients one deteriorated, whereas one showed a decrease of the ulcer area during treatment, but an increase when treatment was stopped. The macro- and total microcirculation were unchanged in all patients, whereas the nutritional capillary circulation improved in seven out of nine patients, concomitantly with clinical improvement. The biologi-cal zero value (a flow–independent part of the LD signal) was high in 4 patients before treatment, but decreased during treatment and remained low even after treatment with Fragmin. –The results indicate that Fragmin positively influences the healing process of chronic foot ulcers in diabetic patients, possibly by improving the capillary circula-tion in the ulcer margin, in spite of an unchanged arterial and total skin microcirculation of the region.

Kalani M, Apelqvist J, Blombäck M, Brismar K, Eliasson B, Eriksson JW, Fagrell B, Hamsten A, Torffvit O, Jörneskog G. Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double–blind, placebo–controlled study. Diabetes Care 2003 Sep; 26(9): 2575-80.

OBJECTIVE: Chronic foot ulcers are a common, severe, and expensive complication threatening life and limb in patients with diabetes. The aim of the present study was to investigate the effect of dalteparin on ulcer outcome in patients with diabetes, peripheral arterial occlusive disease, and chronic foot ulcers.

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RESEARCH DESIGN AND METHODS: A total of 87 patients were investi-gated in a prospective, randomized, double–blind, placebo–controlled trial. Participants were randomized to treatment with subcutaneous in-jection of 5 000 units dalteparin (Fragmin, Pharmacia Corporation; n = 44) or an equivalent volume of physiological saline (n = 43) once daily until ulcer healing or for a maximum of 6 months. Ulcer outcome was investigated by evaluating the number of patients 1). who healed with intact skin; 2). in whom the study ulcer was improved, unchanged, or impaired; or 3). who were amputated above or below the ankle level, as compared with control subjects.

RESULTS: Two patients, one on dalteparin and one on placebo, dropped out of the study. Ulcer outcome was significantly better (P = 0.042, two-sided chi(2) test for trend) in the dalteparin group (n = 43) compared with the placebo group (n = 42). A total of 29 patients healed with intact skin (n = 14) or decreased the ulcer area > or = 50 % (n = 15) in the dalteparin group compared with 20 (n = 9 and 11, respectively) in the placebo group. Five patients in each group showed impaired ulcer healing, i.e., the ulcer area increased > or = 50 %. Two patients in the dalteparin group were amputated compared with eight in the placebo group. Time to healing with intact skin was 17 +/- 8 weeks in the dalteparin group compared with 16 +/- 7 weeks in placebo group (NS).

CONCLUSIONS: The results of the present study indicate that dalteparin improves the outcome of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease.

Kalani M, Silveira A, Blombäck M, Apelqvist J, Eliasson B, Eriksson JW, Fagrell B, Torffvit O, Hamsten A, Jörneskog G. Beneficial effects of dalteparin on haemostatic function and local tissue oxygenation in patients with diabetes, severe vascular disease and foot ulcers. Thromb Res. 2007; 120(5): 653-61. Epub 2007 Feb 2.

INTRODUCTION: A state of hypercoagulation and fibrinolytic dysfunc-tion is present in individuals with diabetes, which may contribute to disturbed skin microcirculation and impaired ulcer healing. We have previously reported an improved outcome of chronic diabetic foot ulcers during treatment with dalteparin. In the present study we inves-tigated the effects of dalteparin on skin microcirculation and haemo-static function.

MATERIALS AND METHODS: 87 patients with diabetes, peripheral arte-rial obliterative disease and chronic foot ulcers were investigated in a prospective, randomized, double–blind and placebo–controlled study. They were randomized to treatment with subcutaneous injections of 5 000 IU dalteparin (n=44) or placebo (n=43), once daily until ulcer healing or for a maximum of six months. Plasma fibrinogen, fibrin

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gel structure [permeability coefficient (Ks) and fiber mass/length ratio (mu)], prothrombin fragment 1+2 (F1+2) antigen, plasminogen activa-tor inhibitor–1 (PAI-1) activity and tissue plasminogen activator (TPA) antigen were analysed before randomization (baseline value), and at the end of the treatment period. The skin microcirculation of the foot was investigated by transcutaneous oxygen tension (TcPO(2)) and laser Doppler fluxmetry (LDF).

RESULTS: The changes (Delta-values) of Ks, mu, tPA and TcPO(2) were higher (P < 0.05) during treatment with dalteparin, as compared to the changes during treatment with placebo. At baseline, plasma fibrinogen and Ks were significantly correlated to TcPO(2).

CONCLUSIONS: Local skin oxygenation improved and a less throm-bogenic fibrin gel structure was formed in patients treated with dalteparin. Beneficial effects on haemostatic function are likely to con-tribute to the improved skin oxygenation observed during treatment with dalteparin.

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Pfizer operations in Strängnäs, Sweden – manufacturing of Fragmin and Genotropin – an environmental success story

Discussions about the environment is higher up on politicians’, corporations’ and the public’s agenda than ever before. Environmental issues affect everyone, both privately and professionally, and that includes all the people working at Pfizer. At Pfizer, the world’s leading pharmaceuti-cal company, we help people live longer, healthier and better lives by developing, manufacturing and distributing innovative medicines. We want to do everything for the patient, so we invest more into research and development than any other company.

Pfizer is represented in Sweden by a marketing & sales office with about 300 employee in Sollentuna, north of Stock-holm, and by a manufacturing facility with about 250 employees in Strängnäs, southwest of Stockholm. Operations in Strängnäs started back in the early 1950s. They grew significantly during the 1980s, focusing on biotechnology processes and the production of active pharmaceutical substances. We are now investing an ad-ditional SEK 1.5 billion in a new manufac-turing facility on the Strängnäs site.

Pfizer in Strängnäs manufactures a growth hormone, Genotropin, and Frag-min, which is celebrating its 20th anni-versary this year. Fragmin is used in areas including treatment of acute deep venous thrombosis and pulmonary embolism, thromboprophylaxis in connection with surgery, prophylaxis for patients with sub-stantially increased risk for venous throm-boembolism due to temporary immobiliza-tion caused by acute illness and extended thromboprophylaxis in cancer patients.

Biotechnology processes are in principal less environmentally harmful than chemical processes, which are widely used within the industry. Biotech operations help reduce the usage of solvents and other chemicals

because they avoid the need for chemical synthesis. Genotropin is produced using modified microorganisms. The manufac-ture of Fragmin could be described as the refining of raw heparin harvested from pig intestines – an interesting, and environmen-tally friendly, biotech reactor. The reduced environmental impact of biotech processes is one of the reasons Strängnäs was chosen as an early environmental pilot plant within the corporation back in the early 1990s. The plant was granted approval under the EU’s Eco-Management and Audit Scheme (EMAS) back in 1996, making it the 11th approved body of any kind across the whole of Sweden.

Our Corporate Environmental, Health and Safety Policy clearly states our strong commitment to environmental awareness.

Pfizer Inc Environmental, Health & Safety PolicyConsistent with our mission of improv-ing the health and wellbeing of people worldwide, Pfizer has long considered effective management of the natural and workplace environments to be one of our highest corporate priorities. We reaffirm that commitment and pledge our continued efforts to protect our communities and the environment.

We shall:Seek continuous improvements in our environmental, health and safety perfor-mance by

– monitoring scientific and technical developments and remaining sensi-tive to environmental, health and safety expectations and community needs;

– establishing corporate guidelines and model programs for conducting operations in a safe and environ-mentally sound manner, with legal requirements as the starting point;

– ensuring the development and imple-

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mentation of environmental, health and safety policies and procedures at the group/divisional level that reflect corporate guidelines; and

– measuring environmental, health and safety performance through regular assessments of compliance with internal guidelines/procedures and external regulations.

Maintain safe and environmentally sound manufacturing operations by

– designing and developing facilities that are efficient in the use of energy, minimizing the generation of waste, and disposing of any residual materi-als safely and responsibly;

– assessing and controlling environ-mental, health and safety impacts of existing operations, before starting up a new project or facility, or before decommissioning an existing one;

– understanding the implications of waste materials generated by facil-ity operations and modifying and/or controlling such operations to prevent adverse health effects or environmental degradation; and

– developing and maintaining, where significant hazards exist, emergency preparedness plans in conjunc-tion with local emergency services, relevant authorities, and local com-munities.

Integrate environmental, health and safety considerations into our research and prod-uct development activities by

– continuing to investigate potential impacts on the natural and work-place environments of processes and products and the means of avoiding adverse impacts;

– developing product packaging that can be recycled, reused or disposed of safely;

– contributing to the dissemination of

safe and environmentally sound tech-nologies and management methods, consistent with intellectual property rights; and

– seeking environmental, health and safety improvements through techno-logical development.

Contribute to the common effort to protect the natural and workplace environments by

– educating, training, and motivating colleagues to conduct their activi-ties in a safe and environmentally responsible manner;

– advising purchasers and users, as appropriate, about the safe handling and disposal of our products; and

– supporting the formulation of responsible and scientifically valid business, government, and intergov-ernmental programs and policies that enhance environmental protection and sustainable development.

Foster openness and dialogue with col-leagues and the public by

– anticipating and responding to concerns about the potential impacts of products, operations or wastes on the natural and workplace environ-ments.

Climate change is our top environmental concern today. Our Energy and Climate Change program addresses sustainability through our conservation guidelines, en-ergy-efficient projects, emission-reduction goals and green buildings. Energy teams and colleagues at Pfizer facilities around the world completed more than 430 conservation-related projects during 2007, an increase of 40 projects over the previ-ous year, and a commendable achievement demonstrating our commitment.

Pfizer has had a company standard requiring the conservation of energy and reduction of greenhouse gases since 1996.

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In 2002, Pfizer became a charter member of the Climate Leaders Program, a part-nership between the US Environmental Protection Agency (EPA) and industry that aims to develop long-term, comprehensive climate-change strategies and sets goals for reducing greenhouse-gas emissions. As a climate leader, Pfizer established a compa-ny-wide goal of reducing CO2 emissions by 35% per million dollars of revenue and, most recently, a second-generation CO2 goal of a 20% reduction in absolute terms by 2012. The company is also evaluating and implementing several projects to gener-ate electricity from clean energy sources.

The Strängnäs facility supports the CO2 goal with projects aiming to decrease carbon-dioxide emissions. The marketing & sales office for Pfizer Sweden also plays an important role by ensuring high levels of energy efficiency. In 2007, it became a European GreenBuilding Partner: its office building uses roughly half the energy per square meter that a standard office build-ing would use. This excellent track record earned Pfizer the EU GreenBuilding Award for 2008. Its offices in Sollentuna are regarded as one of the most energy-efficient buildings in Europe.

The EU GreenBuilding Program is de-signed to encourage the construction of en-ergy-efficient buildings throughout Europe which, in turn, helps reduce greenhouse-gas emissions and the use of fossil fuels. Given this objective, the office building was con-structed to use energy-efficient lighting and state-of-the art ventilation systems, and to get maximal benefit from cutting-edge tech-nologies such as climate shells to optimize solar heat capture.

Aside from its EU GreenBuilding Award, Pfizer Sweden has made major efforts at the Strängnäs facility to minimize its Swed-ish environmental footprint. In addition to energy conservation, efforts here include water conservation, waste recycling and minimization, and reducing discharges of

waste water and gaseous emissions. Over the years, the plant has managed to reduce its environmental footprint and remain well below the limits set in its environmen-tal impact permit.

Conditions in the permit include:– a maximum production volume– limits on releases of organic com-

pounds, phosphorus and nitrogen to Lake Mälaren

– limits on particle releases from boil-ers, and

– a maximum noise level.

To strengthen its environmental perfor-mance even further, the facility has, in addition to its EMAS recognition, chosen to certify its operations according to ISO 14001. It received this certification in 2004, at the same time as it received ISO 9001:2000 quality certification. In mid-2005, the site was also awarded OHSAS 18001:1999 certification. This makes the factory unique within Pfizer: it has all three internationally relevant quality, environ-mental, and health & safety certifications.

An essential requirement for the continuing success of our environmental, health and safety programs in Strängnäs is that everyone there feels a personal com-mitment and a shared responsibility for the results. Everyone contributes with their own unique competence, and the common knowledge that has been shared among all colleagues through training programs. Our strong commitment to the continuing success of not only the Strängnäs plant, but of all Pfizer operations worldwide, is shown by our membership, dating back to October 2002, of the UN Global Compact (http://www.unglobalcompact.org ). The Global Compact is a voluntary scheme setting guiding principles, a code of conduct, for corporations on human rights, labor, environmental and anti-corruption activities. Our programs related to the

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Global Compact and all our other efforts in the area of Corporate Responsibility are presented in detail on the internet (in Swedish: www.pfizer.se under “Pfizer i samhället” and “Vårt ansvarstagande” or on the corporate homepage www.pfizer.com/responsibility). You are also invited to participate in an open dialogue, in Swedish, with Bengt Mattson, head of Corporate Social Responsibility and Environmental Affairs for Pfizer Sweden, on http://ansvars-blogg.pfizer.se.

Fragmin and Genotropin are two grow-ing 20-year-olds (Genotropin turned 20 in 2007) with a bright future. Biotechnology products and processes are the right choice, both for now and for the future.

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CVs

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David Bergqvist 70

Ola Dahl 71

Gun Jörneskog 72

Ajay Kakkar 73

Agnes Y.Y. Lee 74

Carl–Gustav Olsson 75

Lars Christer Wallentin 76

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DAVID BERGQVIST was born in 1941. He studied medicine in Uppsala, Sweden, and his PhD thesis examined hemostatic plug formation and stability in rabbit mesenteric microcirculation. Professor Bergqvist com-pleted his surgical training at the county hospital in Skövde, Sweden, and became associate professor of surgery at the Univer-sity of Lund, Sweden, in 1979. Since 1993, he has been Professor of Vascular Surgery at the University of Uppsala and Head of Vascular Surgery at the University Hospital, Uppsala.

Professor Bergqvist has authored around more than 700 original articles, several

Professor David Bergqvist, MD, PhD, FRCSProfessor of Vascular SurgeryInstitution of Surgical SciencesUppsala University Hospital, Uppsala, Sweden

reviews and book chapters, and three textbooks. His main areas of research deal with prophylaxis of post-operative venous thromboembolism, epidemiological and pathogenetic aspects of aortic aneurismal disease, and formation of pseudointimal le-sions during arterial reconstructive surgery and balloon trauma. He is an honorary member of the Royal Australasian College of Surgeons’ Division of Vascular Surgery, the Hellenic Angiological Society, the Amer-ican Venous Forum, the Vascular Surgical Society of Great Britain and Ireland, the European Society for Vascular Surgery and the Swedish Society for Vascular Surgery

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OLA E. DAHL received his medical education and academic degrees at the University of Oslo in Norway, specializing initially in general surgery and later in orthopedic surgery. He has been involved in labora-tory and clinical research for many years. His discovery of the lung vasculature as a thrombin-generating organ during bone surgery was a breakthrough in the under-standing of the occurrence of posttraumat-ic, systemic, thromboembolic complications and vascular mortality as the leading cause of death after major orthopedic surgery. He pioneered studies on out-of-hospital hyper-coagulation and thromboembolism, which were later confirmed in North America and Europe.

Professor Dahl has been a frequently invited speaker, has chaired and been on the boards of expert conferences at inter-national conventions, and has cooperated with colleagues around the world. He is an international opinion leader in the field

of thrombosis and hemostasis related to trauma and surgery.

He has published numerous papers and abstracts on a variety of surgical and toxicological issues. These have had a particular emphasis on posttraumatic pathophysiology, bone cement cytotoxicity, bleeding, initiation and duration of hyper-coagulability, its clinical consequences, and several long-term epidemiological studies on vascular outcomes following major surgical procedures. Professor Dahl has extensive experience from clinical develop-ment programs of new anticoagulant com-pounds. He is a referee for several journals and a member of various societies. He is an executive director of the International Sur-gical Thrombosis Forum (ISTF), a global society combining cutting-edge knowledge within thrombosis and hemostasis with skilled surgical experience. In addition, he is Honorary Professor at the Thrombosis Research Institute in London.

Professor Ola E. Dahl, Executive Director, MD, PhD, Prof.International Surgical Thrombosis Forum,Thrombosis Research Institute, London, UK

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GUN JÖRNESKOG studied medicine at the Karolinska Institutet, Stockholm, Sweden, and her PhD thesis examined functional microvascular disturbances in patients with diabetes. Dr Jörneskog became Associate Professor of Medicine at the Karolinska In-stitutet in 2005. She completed her medical training at Karolinska University Hospital in Stockholm and became a specialist in internal medicine and endocrinology. In 2002, she moved to Danderyd University

Hospital, where she is Head of the Micro-circulatory Laboratory, and the Endocrinol-ogy & Diabetology department.

Dr Jörneskog’s research concentrates on diabetes-related vascular complications, with a focus on microvascular function. She was principal investigator for a study into the effects of low-molecular-weight heparin on the healing of foot ulcers in diabetic patients with peripheral arterial occlusive disease.

Gun JörneskogAssociate Professor, Division of Medicine,Danderyd University Hospital, Stockholm

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AJAY KAKKAR is Professor and Head of the Center for Surgical Science and Dean for External Relations at Barts and the London School of Medicine and Dentistry, Queen Mary, University of London. He is also a Consultant Surgeon at St Bartholomew’s Hospital London and Director-designate of the Thrombosis Research Institute, Lon-don, UK. He received his medical education at King’s College Hospital Medical School, University of London, and was awarded an MBBS in 1988, and a PhD in 1998. He was made a fellow of the Royal College of

Surgeons of England in 1992. His awards include Hunterian Profes-

sor, Royal College of Surgeons of England 1996, the David Patey Prize, Surgical Research Society of Great Britain and Ireland 1996, the Knoll William Harvey Prize, International Society on Thrombosis and Haemostasis 1997 and the James IV Association of Surgeons Fellow 2006.

Professor Kakkar’s research interests are the prevention and treatment of venous thromboembolic disease and cancer-associ-ated thrombosis.

Professor Ajay Kakkar MBBS (Hons), BSc, PhD, FRCSHead of the Center for Surgical Science andDean for External Relations at Barts and the London School of Medicine and Dentistry, Queen Mary, University of London

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AGNES Y. Y. LEE is a member of the Division of Hematology and a consultant on the Hematology service at Vancouver Gen-eral Hospital. She also holds an Associate Clinical Professor position at McMaster University in Hamilton, Ontario.

Dr Lee’s clinical research interests include thrombotic disease in high-risk populations, with a focus on venous thromboembolism in patients with malig-nancy. She was co-principal investigator for the CLOT study (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Preven-tion of Recurrent Venous Thromboem-bolism in Patients with Cancer, CLOT), a landmark study that established low-molecular-weight heparin as the treatment of choice for preventing recurrent venous thromboembolism in cancer patients. Her additional research activities include studies in catheter-related thrombosis, diagnosis of deep-vein thrombosis and pulmonary em-bolism in pregnant women, and thrombo-

prophylaxis in patients undergoing major orthopedic surgery. Dr Lee is also involved in translational research exploring the role of coagulation in cancer biology and phase II/III development of novel anticoagulants.

Dr Lee is the recipient of several prestigious research awards, including the New Investigator Award from the Cana-dian Institutes of Health Research/Rx&D Research Program, and research fellow-ships from the Heart & Stroke Scientific Research Corporation of Canada and the Heart & Stroke Foundation of Canada.Dr Lee earned her doctorate of medicine at the University of British Columbia, completing her residency in Internal Medicine at UBC and in Hematology at McMaster Univer-sity. She is a certified Fellow of the Royal College of Physicians of Canada in these specialties. She also completed a research fellowship in Thromboembolism and obtained her Master of Science in Health Research Methodology from McMaster University.

Dr. Agnes Y. Y. LeeMD, MSc, FRCP(C)Medical Director, Thrombosis ProgramVancouver General Hospital and Univer-sity of British Columbia, Vancouver, BC, Canada

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CARL - GUSTAV OLSSON was born in 1940. In 1959-60 he completed courses in psycholo-gy, sociology and theoretical philosophy at the University of Lund, Sweden. He entered the Medical Faculty in 1961, earned an MB in 1962 and the title of “medicine licenti-ate” in 1970.

In 1974, he was a specialist in Internal Medicine, and also started his research at the Department of Clinical Physiology in Lund.

In 1979 he defended his thesis “On the Diagnosis of Deep Vein Thrombosis (DVT).”

In 1980-85 he was responsible physician for emergency medicine at the University Hospital in Lund. Further research focused on venous thromboembolism (VTE) and on acute myocardial infarction (AMI). He was Swedish coordinator for 15 hospitals in the ASSET trial.

In 1983-84 he was temporarily the first non-surgeon chief physician at the hospi-tal’s emergency unit, getting the resources to rebuilt the unit after 24 years of continu-ous use.

Member of steering committees for ex-tensive international trials on (a) enox-aparin for the prophylaxis of immobilized medical patients (b) enoxaparin for therapy for DVT, with or without P.E. and (c) dalteparin for prophylaxis of immobilized medically ill patients.

Member of the working group on VTE at SBU (the Swedish Council on Technology Assessment in Health Care) for the evalu-ation of evidence-based medicine (1500-page book printed October 2002);

Member (1985-2001) of the LMK (Läns-styrelsens medicinska katastrofgrupp, County Medical Disaster Team) for the Skåne region, with responsibility for medi-cal treatment of radiation injuries from nuclear power-plant emergencies.

Dr. Carl-Gustav Olsson MD, PhDFormer senior consultant in Emergency Medicine, University Hospital, Lund, Sweden. Chief of the Specialist Outpatient Clinic, Hörby, Sweden

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LARS CHRISTER WALLENTIN became the institution’s first Professor of Cardiology in 1991 and was head of the Department of Cardiology from 1991 to 1999. In addi-tion, he founded the Cardiothoracic Center at Uppsala, becoming its first Chairman in 1994, and going on to serve as Vice Chairman from 1995 to 1999. In 2001, Professor Wallentin founded the Uppsala Clinical Research Center, where he contin-ues to serve as director. Since 2002, he has also held the title of director of the First Swedish Competence Center for National Quality Registers in Health Care.

Professor Wallentin has received several prestigious research awards. He is a mem-ber of several medical societies, taskforces, working groups and editorial boards, and is an expert for the Swedish Board of Health and Welfare, as well as the Swed-

ish Medical Products Agency. From 1998 to 1999, he was President of the Swedish Cardiac Society, and from 2000 to 2002, he served as President of the Swedish Heart Association. Professor Wallentin is currently chairman of the Committee for National Guidelines for Treatment of Heart Diseases in Sweden and a member of the Royal Swedish Academy of Sciences.

The professor has published more than 300 papers in peer-reviewed international journals, in addition to a large numbers of other publications and book chapters.

His main scientific contributions have concerned unstable coronary syndrome, an area in which he has developed many new concepts concerning pathogenesis, diagno-sis, risk stratification, and antithrombotic and interventional treatments.

Professor Lars Christer Wallentin, MD, PhDProfessor of Cardiology at the Department of Medical Sciences, and Director of the Uppsala Clinical Research Center at the University Hospital Uppsala, Sweden

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Selection of Nordic thesisesThe 27th of November Dalteparin had over

810 hits on www.pubmed.com

For further information contact your local Pfizer office

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Frostfeldt Gunnar 80

Holmström Margaretha 80

James Stefan 81

Lapidus Lasse 82

Matthiasson Stefan E. 83

Mälarstig Anders 83

Näsström Birgit 84

Toss Henrik 85

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Frostfeldt Gunnar Coagulation Inhibition and Development of Myocardial Damage in ST–Elevation Myocar-dial Infarction.

Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, 2 000.

In 101 patients with ST–elevation myocar-dial infarction treated with streptokinase the additional effects of LMW–heparin (dalteparin) were investigated. The prog-nostic value of troponin–T (TNT) was elucidated and the development of myocar-dial damage was investigated with Positron Emission Tomography (PET). Dalteparin tended to provide a higher rate of TIMI grade 3 flow in the infarct-related artery at 24 h compared to placebo. In patients with signs of early reperfusion there was a higher rate of TIMI grade 3 flow in the dalteparin group compared to placebo. There were significantly fewer patients with ischemic episodes at 6–24 h in the dalteparin compared to placebo group. The increase in coagulation activity was attenuated in the dalteparin group. There was a tendency to more ischemic episodes and lower frequency of TIMI grade 3 flow in patients with persistent elevation of coagulation activity at 18 h. Among de-ceased patients the coagulation activity was significantly higher than in survivors. The association between elevated TNT on ad-mission and long–term mortality might be explained by longer delay, episodes of chest pain during the last 24 h, less non–invasive signs of reperfusion at 90 minutes, and lower patency in the infarct-related artery at 24 h. Eight patients were investigated with pet at 3 h, 24 h and after 3 weeks. PET outlines the infarct region with reduced perfusion and metabolism. The oxidative metabolism in the infarct region at 3 h cor-related with the water–Perfusable Tissue Fraction (PTF) and its improvement over

time. Dalteparin seems to improve main-tenance of coronary patency, which can be explained by attenuation of the increased coagulation activity. Elevated TNT level on admission is associated with a worse outcome, which can partly be explained by less successful fibrinolytic treatment. PET investigations might to be a useful method in future trials evaluating new agents in the treatment of acute myocardial infarction.

Holmström Margaretha Clinical aspects on treatment of deep venous thrombosis with a low molecular weight heparin.

Stockholm: Karolinska institutet, 1998.

Dalteparin is a low molecular weight heparin (LMWH) with a mean MW of 4–6000 D. Compared to unfractionated heparin (UFH), a higher bioavailability, a longer half-life and a more predictable dose-response is achieved after subcutane-ous injections. In three clinical studiees including 424 patients with deep venous thrombosis (DVT) in the lower extremity, we have shown that one daily subcutane-ous injection of dalteparin in a fixed dose according to body weight is as effective as a continuous intravenous i.v. infusion of unfractionated heparin (UFH) in patients with DVT in the lower extremity. Monitor-ing of patients treated with dalteparin mea-suring anti FXa-activity is not necessary. During the first week of treatment with either dalteparin or UFH, a reduction of thrombus size was observed in about 60 % of the patients and < 10 % showed progress of thrombus after 1 week. Repeated venog-raphy after 6 months showed improvement in > 90 % of the patients, and complete lysis was achieved in nearly 40 % of the patients. No difference comparing treatment with UFH or dalteparin was observed. The re-sult on venography after 6 months, evalu-

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ated by Marder score, did not correlate to the risk for recurrent VTE, but the post-thrombotic score at 4–7 years of follow-up was strongly correlated to the venographic result after 6 months (paper 5). Analysis of risk-factors for recurrent VTE during a 4–14 years of follow–up showed that a temporary risk–factor for DVT (previous surgery, temporary immobilization, oral contraceptives or estrogen substitution), a longer duration of treatment with oral an-ticoagulants and an initial treatment with dalteparin were significantly associated with a lower risk for recurrent VTE. Malig-nant disease diagnosed during the follow-up period was associated with an increased risk for recurrent VTE. apc-resistance, the associated fv-gene mutation (fv : r506q) and fibrinolytic parameters (plasminogen activator inhibitor –1 and tissue plasmino-gen activator antigen) did not increase the risk for recurrent VTE. During a follow-up period of 5–14 years, 40,7 % of the patients had died (paper 5). Most of the deaths were related to malignant disease and to cardio-cerebrovascular events. 5 % of the deaths were caused by VTE. No differ-ence in mortality was observed comparing patients treated with dalteparin or UFH.

James Stefan Coagulation, Inflammation and Myocardial Dysfunction in Unstable Coronary Artery Disease and the Influence of Glycoprotein IIb/IIIa Inhibition and Low Molecular Weight Heparin.

Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, 2003.

Patients with unstable coronary artery disease (CAD) have an increased risk of subsequent myocardial infarction and death. This study evaluated the safety and efficacy of treatment with glycoprotein IIb/

IIIa inhibition in addition to aspirin, low molecular-weight heparin and its influence on coagulation and inflammation. Also, early and differentiated risk assessment utilising markers of inflammation, myocar-dial damage and dysfunction were evalu-ated. The Global Utilisation of Strategies To open Occluded arteries- IV (GUSTO–IV) trial randomized 7 800 patients with unstable CAD to 24 h or 48 h infusion of abciximab or placebo in addition to rou-tine treatment with aspirin and unfaction-ated heparin or dalteparin. Baseline levels of creatinine, C-reactive protein (CRP), Troponin-T (TNT) and N-terminal pro-brain natriuretic peptide (NT-PROBNP) were analysed. At selected sites, all patients received subcutaneous dalteparin (n=974), in stead of unfractionated heparin infu-sion (n=6826). In a sub-population of dalteparin treated patients (n=404), serial measurements of markers of inflamma-tion, coagulation and fibrinolysis were also performed. Addition of abciximab to dalteparin as the primary treatment of unstable CAD was not associated with any significant reduction in cardiac events but a doubled risk of bleedings. The combination of abciximab and dalteparin seemed to be as safe as when used with unfractionated heparin. Despite full dose dalteparin and aspirin there was a simultaneous activa-tion of the inflammation, coagulation and fibrinolysis systems without any influence of the abciximab treatment. Elevated levels of CRP, TNT, and NT-PROBNP and reduced creatinine clearance were inde-pendently related to short and long-term mortality. The best prediction of high and low risk was provided by a combination of NT-PROBNP and creatinine clearance. Any detectable elevation of tnt and reduced creatinine clearance, but neither eleva-tion of CRP nor NT-PROBNP, were also independently associated to a raised risk of subsequent myocardial infarction.

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Lapidus LasseThromboembolism following orthopaedic sur-gery: Outcome and diagnostic procedures after prophylaxis in lower limb injuries.

Department of Clinical Science and Educa-tion, Södersjukhuset. Stockholm: Karolin-ska Institutet, 2007.

Deep vein thrombosis (DVT) and pulmo-nary embolism (PE) frequently occur after major orthopaedic surgery. The clinical as-sessment of DVT and PE is unreliable and most cases are asymptomatic. However, even in asymptomatic DVTs, the risk for a PE is considerable. Low-molecular-weight heparins (LMWHs) have been shown to be safe and effective for this purpose and are used especially in patients undergoing ma-jor orthopaedic surgery. Whether prophy-laxis is necessary after minor surgery and plaster cast immobilization of the lower limb still remains an issue of debate. Avail-able techniques for the objective diagnosis of DVT include both invasive and non-invasive methods. Technical advances and increased experience have improved the accuracy of non-invasive methods such as colour duplex sonography (CDS).

In an observational study of 30 816 consecutive patients (Paper I) undergo-ing orthopaedic surgery the mortality and incidence of DVT and PE was recorded prospectively during a 6–week follow-up. After major joint surgery of the lower ex-tremity, after spinal surgery and after lower limb fracture surgery, thromboprophylaxis (LMWHs) was administered during 7 to 10 days. The overall DVT and PE incidence was 1.0 % and 0.3 %, respectively, and the 6–week mortality was 2.3 %. The high-est incidence of venous thromboembolism (VTE) with the LMWH prophylaxis was seen after pelvic fracture surgery (13.0 %) and knee replacement (3.5 %). The highest incidence without prophylaxis was found after Achilles tendon repair (7.0 %).

The sensitivity and specificity of CDS were compared with that of phlebography in a prospective trial (Paper II) with 180 consecutive patients surgically treated for ankle fracture. With a sensitivity of 96 % and a negative predictive value of 99 %, the results showed that CDS is highly reliable for ruling out DVT for screening purposes.

In a randomized placebo-controlled double-blind study (Paper III) on patients surgically treated for an ankle fracture, one week of open-labeled treatment with dalteparin was followed by 5 weeks of dalteparin prophylaxis or placebo. The phlebography verified a DVT incidence of 21 % in the dalteparin group and 28 % in the placebo group. This difference was not statistically significant and the results do not support the use of prolonged thrombo-prophylaxis after ankle fracture surgery.

In another randomized placebo-con-trolled study (Paper IV), thromboprophy-laxis with dalteparin during 6 weeks was compared with placebo during immobili-zation after Achilles tendon repair. DVT screening was performed with CDS and all DVTs were confirmed with phlebography. The phlebography verified that the DVT incidence was 34 % in the treatment group and 36 % in the placebo group. This dif-ference was not statistically significant and thromboprophylaxis after Achilles tendon repair cannot be recommended on the basis of these results.

In summary, despite prophylaxis VTE remains an important cause of morbidity and mortality after orthopaedic surgery. Adequate thromboprophylaxis is essential after major procedures although prolonged prophylaxis after ankle fracture surgery and Achilles tendon repair did not reduce the risk of DVT.

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Matthiasson Stefan E. Low molecular weight heparin and dextran in thromboprophylaxis: human and experi-mental studies.

Lunds universitet, 1994.

AbstractThe antithrombotic properties and the haemostatic effect was investigated for: low molecular heparins (LMWHs; nadroparin(N; Fraxiparin®), enoxaparin (E; Klexane®), dalteparin (D; Fragmin®) and tinzaparin (T; Logiparin®)), dextran 70 (Dx; Macrodex), dermatan sulphate (DS; MF 701) and rec-hirudin (H;CGP 39393). Special attention was paid to the effects of the combination of LMWH and Dx. The substances were administered by i.v. route. The LMWHs in doses recommended by the manufacturer in thromboprophylaxis, ad-justed to body weight, DS (3.0 mg/kg) and H (2.0 mg/kg) in possible antithrombotic doses. In a jugular vein thrombosis model in rabbits: a) the antithrombotic effect of D (70 anti-Xa IU/kg), DX (1.0 g/kg) and their combination was investigated, as well as b) the antithrombotic effect of D (50 anto-Xa IU/kg) combined with Dx (1.0 g/kg) in relation to induction of surgical trauma, c) the antithrombotic effect of the different LMWHs (N, E, D, and T) as well as DS and H. In a haemostasis model in rats: d) the haemostatic effect of the different sub-stances in c) was studied. In a experimental carotid model in sheep: e) the effect of E (73 anti-Xa IU/kg), Dx (1.0 g/kg) and their combination on early ePTFE graft throm-bogenicity was investigated. In human volunteers: f) the effect of E and Dx (0.5 g/kg) and their combination on haemostatic parameters in plasma was investigated.

Certain augmentative thromboprophy-lactic effects of D in combination with Dx were observed in a) and b). The admin-istration of D alone or in combination with Dx, after surgical trauma and during

endothelial damage, was as effective as when administered before trauma in b). The tested substances in c) were all effec-tive antithrombotics when compared with controls but with numerical differences. The same substances provoked different bleeding volume and the bleeding of the LMWHs did not correlate with either anti-IIa or –Xa plasma levels in d). E, Dx and their combination were likewise effective in reducing early eptfe graft thrombigenic-ity in e). The results in f) do not indicate impaired haemostasis in humans when E and Dx are combined.

In conclusionThe tested substances are effective anti-thrombotics with individual properties and effect on haemostasis. The combination of LMWH and Dx may increase the thrombo-prophylactic efficacy without increased risk for bleeding complications.

Mälarstig Anders Tissue Factor and CD40 Ligand: Markers for the Interplay of Coagulation and Inflamma-tion in the Acute Coronary Syndrome.

Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, 2006.

BACKGROUND: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein known as the main initiator of blood coagula-tion. CD40 ligand is another membrane molecule, which ligates to cell types associ-ated with atherosclerotic plaques thereby mediating intraplaque inflammation and weakening of the fibrous cap. Acute coro-nary syndrome (ACS) is a multi-factorial disease in which TF and CD40 ligand have prominent roles. Single nucleotide poly-morphisms (SNPs) in the TF and CD40 li-gand genes may influence the development, pro-gression and outcome in ACS.

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AIM: The aim of this thesis was to investi-gate the genetic and molecular control of TF expression in healthy individuals and in patients with ACS. More-over, the aim was to investigate whether SNPs in the TF and CD40L genes respectively were associated with risk and outcome in ACS and/or with plasma concentrations of these pro-teins.

RESULTS: A real-time PCR method that allowed sensitive and dynamic quantifica-tion of TF mRNA was established and used for the identification of a high and low response phe-nomenon of TF mRNA. The TF high and low response correlated with the expression of toll-like receptor 4 (TLR-4) thus linking TF to innate immu-nity in a novel fashion. Investigation of several SNPs in the TF and CD40L genes led to the identification of the 5466 A>G in the TF gene and the -3459 A>G SNP in the CD40L gene. The 5466 G allele was associated with cardiovascular death in patients with ACS and increased TF procoagulant activity in human monocytes, which explained the clinical association. The -3459 G allele regulated the produc-tion of soluble CD40L but was not related with patient outcome. Soluble CD40L levels above median were associated with the risk of MI in patients with ACS. A pro-longed treatment with dalteparin was more efficient in patients presenting with high levels of sCD40L, which further supports sCD40L as a marker of a prothrombotic state.

CONCLUSIONS: The results of this thesis adds to our current knowledge of factors influencing TF expression and activity by demonstrating the effects of TF gene vari-ants, cell signalling molecules, CD40 ligand protein and gene variation. All of these effects have the potential to modify the risk of development, progression and outcome in the acute coronary syndrome and exem-plify the interplay between coagulation and

inflammation, in which both TF and CD40 ligand are active.

Näsström Birgit Lipoprotein lipase in hemodialysis patients and healthy controls: effects of heparin.

Faculty of Medicine, Public Health and Clinical Medicine. Umeå university, 2004.

Mortality from cardiovascular disease in patients on chronic hemodialysis (HD) is 10 to 20 times greater than in the general population. One major risk factor is renal dyslipidemia, characterised by an impaired catabolism of triglyceride (TG)-rich lipo-proteins with accumulation of atherogenic remnant particles. A contributing factor may be derangement of the lipoprotein lipase (LPL) system, the major lipase in the catabolism of TG-rich lipoproteins. The functional pool of LPL is located at vascu-lar surfaces, and is released by heparin into the circulating blood and extracted and de-graded by the liver. Unfractionated heparin (UFH) is commonly used during dialysis to avoid clotting in the extracorporeal devices, but is increasingly replaced by various low molecular weight heparin (LMWH) preparations. Plasma LPL activity is usually lower after injection of LMWH which is therefore said to release less LPL and cause less disturbance of lipoprotein metabolism than UFH. However, animal studies have revealed that LMWH is as efficient as UFH in releasing LPL but is less efficient in retarding hepatic uptake. The aim of this study was to explore the effects of UFH and a LMWH (dalteparin) on LPL activity and TG concentrations in HD-patients compared with healthy controls, matched for age and gender. A disturbed LPL system might contribute to an impaired lipopro-tein metabolism, and hence, an aggravated cardiovascular condition.

An 8-hour primed infusion of UFH to

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controls gave rise to an initial peak of LPL activity within 30 minutes. The activity then dropped by almost 80% over the next two hours and levelled off to a plateau that corresponded to 15% of the peak level. When UFH was infused to HD-patients the curve for LPL activity resembled that for controls, but was reduced by 50% during the peak, while the plateau activities were comparable. The interpretation was that the functional pool, represented by the initial peak, was impaired in HD-patients, while the production of lipase molecules, reflected by the plateau, was only mar-ginally reduced. During the peak of LPL activity TG decreased in both groups, but less in HD-patients, as was expected from the lower circulating lipase activity. During the plateau phase with low lipase activity, TG increased towards and beyond baseline values.

When dalteparin was infused, the same pattern of plasma LPL activity was observed, although remarkably reduced. In controls the peak was only 30% and the subsequent plateau 40% compared with the activities during the UFH infusion. A bolus of UFH given when the LPL activity had levelled off to a plateau brought out about the same amount of activity, regard-less of whether dalteparin or UFH had been infused. The conclusion was that both hep-arin preparations had reduced endothelial LPL to a similar extent, but that dalteparin less efficiently retarded the hepatic uptake of the enzyme. As a consequence to this, TG tended to reach higher levels after the dalteparin infusion. The LPL activities were further reduced in HD-patients dur-ing infusion with dalteparin, the peak was only 27% and the plateau 35% compared with the activities when UFH was infused. There was no decrease in TG, but rather a continuous increase, suggesting a profound depletion of functional LPL.

In another study in HD-patients, two anticoagulation regimes based on pres-

ent clinical practice were compared, and the doses were adjusted to the respective manufacturers recommendation. UFH was administered as a primed infusion, whereas dalteparin was given only as a single bolus pre-dialysis, not followed by an infusion. The results were in line with those in the experimental studies and indicate that also in the clinical setting LMWH interferes with the LPL system as least as much as an infusion of UFH does, and temporarily impairs lipolysis of TG. This interference might, in consequence, contribute to an aggravated cardiovascular condition in HD-patients.

Toss Henrik Unstable coronary artery disease : studies on inflammation, infection, hemostasis, and the effects of low-molecular-mass heparin treatment.

Uppsala: Karolinska institutet, 1998.

The occurrence and prognostic importance, of inflammatory activity, signs of Chlamyd-ia pneumoniae infection. APC resistance, hemostasis, and the effects of low-molecu-lar-mass heparin (LMMH) was evaluated in patients with unstable coronary artery disease (UCAD). Increased inflammatory activity at admission (n=961), evaluated by fibrinogen and C-reactive proteincon-centrations, was associated with a worse outcome during a 150-day follow-up period, independently from the influence of myocardial damage. The prevalence of persistent Chlamydia pneumoniae infec-tion was 36% in individuals with UCAD (n=256) compared to 19% in a reference population (n=190); p<0.001. Increased C. pneumoniae IgA antibody titers were as-sociated with elevated fibrinogen concen-trations. Resistance to activated protein C (APC resistance) was identified in 7.2% of 318 patients with UCAD,compared to

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5.8% in a reference population (n=69); p=0.16. Despite increased thrombin gen-eration in APCresistance. as indicated by elevated prothrombin fragment 1+2 con-centrations, no relationship to the short-term outcome was found. The protective effect of LMMH was more pronounced in women than in men. In the 737 patients treatedwith LMMH there was an increased relative risk (CI) of minor bleeding among females compared to malesduring the acute phase treatment. 2.88 (1.78-4.67), as well as during the following 5 weeks reduced LMMH dose treatment. 2.36 (2.37-2.63). The anticoagulant effect, evaluated by the anti-Xa activity, was higher among females (n= 44) compared to males (n= 131). Markers of coagulation and fibrinolytic activity was determined in a subgroup during the placebo controlled LMMH treatment. In the LMMH treated group (n=42) a more pronounced increase in t-PA levelswas not linked to elevated plasmin antiplasmin (PAP) complex concentra-tions. as compared to the placebogroup (n=45). In conclusion the results indicate that increased inflammatory activity, to some extent associated withchronic C. pneumonias infection, is linked to a worse outcome in UCAD. Resistance to APC was not moreprevalent in UCAD. LMMH treatment seemed to induce a more promi-nent anticoagulant effect amongfemales as compared to males. The main mechanism of the antithrombotic effect of LMMH is its anticoagulant property, while the influ-ence on the fibrinolytic system seems to be without clinical importance.

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