4

CONGRESS DAILYThrombosis 2010

Milan, July 8th

realized with the contribution of

The great therapeutic opportunitieslaunched by the new molecules are thethe topical theme of this Congress. Thedebate of experiences, monitoring andexperimentations starts from the con-solidated applicative field in orthopedicsto turn into a wide range of pathologies(such as infarction, coronary diseases,stroke and rare kinds of thrombosis)which are not treated with oral drugsnow. This was the theme of the ses-sion “New anticoagulant: highlights onmethodolical issues”, chaired by M.G.Franzosi and J. Harenberg. Fourworks have been presented during thescientific symposium.Ola E. Dahl has spoken of “Lack ofstandardization between antithrombot-ic trials in orthopedics: the scenario”.Clinical developments of newantithrombotics are basically conduct-ed in patients undergoing elective majorjoint surgery. In 7 recent trial pro-grams, 10 divergent bleeding termswere identified. Major bleeding (MB)was the most frequent phrase for pri-mary bleeding. Basic bleeding parame-ters like the volume of blood loss, thehaemoglobin fall and the number oftransfused units blood, were reportedinfrequently. In only 2/8 trial programsbleeding volume during surgery waspresented and in 3/8 trial series data onpostoperative blood loss was given.None reported concomitantly thesethree essential parameters from preop-erative baseline and during the subse-

quent postoperative days until stabi-lized. Similar scenario was found forthe efficacy outcomes. Charles Marc Samama dealt with“Methodological issues in trials assess-ing primary prophylaxis of venousthromboembolism”. Recent clinicalstudies of pharmacological agents -Samama explains - have used asympto-matic DVTs assessed by bilateralascending venography as a surrogateend-point. The high rate of eventsobserved with this method means thatthe numbers of patients included intoPhase II and Phase III studies havebeen relatively small. However,although there may be a relationshipbetween venographic and symptomaticthrombosis, it ranges from a factor of 5for total hip replacement to a factor of21 for total knee arthroplasty.The overall safety of the drugs used in

prophylaxis is good but most newantithrombotic agents are eliminatedvia the kidney. Since efficacy is guaran-teed with a rate of thromboembolicevents of 1.5% at 3 months, the currentemphasis is naturally on safety.Job Harenberg has illustrated “Makeclinical studies in medical patients clos-er to usual hospital care”. Clinical stud-ies for treatment of thromboembolicdiseases in hospital or outpatients set-tings with new anticoagulants includemanifold exclusion criteria. Afterapproval of the anticoagulant, patientsmay be treated with these compoundsalso if they would have met an exclu-sion criterion during the study. Newanticoagulants are developed withoutlaboratory monitoring of the anticoagu-lant effect. Ajaj K. Kakkar has discussed“Guidelines on clinical testing of newantithrombotic drugs in surgicalpatients”. Recent years - Kakkar says -have seen evaluation of novelantithrombotic drugs in surgical popu-lations to establish efficacy and safetyfor the prophylaxis of venous throm-boembolism. Evaluation in surgicalpopulations is appropriate since venousthromboembolism represents a majorclinical challenge for patients undergo-ing high risk surgical procedures suchas elective joint arthroplasty or majorabdominal surgery for cancer.However, it is important that commonendpoints both for evaluation of effica-cy and safety are used. These vary bystage of clinical development - eitherphase II or phase III clinical trials butshould be consistent.

In the photos: Job Harenberg (left)and Ajaj K. Kakkar

The new drugs which will enableto overcome present limits in mat-ter of treatment of thromboembolicdiseases, arise great expectationsfor diseases such as infarction andstroke. This important and delicatetopic is the focus of the third day ofthe 21st International Congress onThrombosis reported by this news-daily while the session is still incourse.Danilo Toni, Emergency Depar-tment Stroke Unit, SapienzaUniversity of Rome, Italy, statesthat the RCTs with alteplase per-formed in the late 90s demonstrat-ed the safety and efficacy of i. v.thrombolysis given within 3 hoursof acute ischemic stroke onset.The use of modern imaging tech-niques as diffusion and perfusionMR or perfusion CT, made it clearthat the therapeutic window ismore “brain tissue” based than“clock” based. This means thatindividual patients may have sal-vageable brain tissue even morethan 6 hours after onset of symp-toms. Future lines of researchinclude looking for a possible moreeffective dose of alteplase, reducingthe tendency of thrombolytic drugsto cause intracerebral hemorrhage,testing new thrombolytic agents,exploiting new and faster imagingmethods to guide treatment,increasing the extent of lysis withultrasound, antithrombotic agentsor intra-arterial clot manipulation.Ale Algra, Department of Neuro-logy and Julis Center, University

Medical Center Utrecht, theNetherlands states that aspirinreduces the risk of new vascularevents after cerebral ischaemia ofarterial origin by only 13%, thussomething stronger is needed.Three trials assessed the efficacy oforal anticoagulants, but nonefound them to be more effectivethan aspirin CAPRIE comparedclopidogrel with aspirin and founda relative risk reduction (RRR) of7% (95%-CI -6; 19%).MATCH compared aspirin plusclopidogrel (A+C) with clopidogrelmonotherapy and found that A+Chad an RRR of 6% (95%-CI -7;17%).CHARISMA included patientswith clinically manifest vasculardisease or a high risk thereof andcompared A+C with aspirinmonotherapy: overall RRR 7%(95%- CI -5; 17%). Both MATCHand CHARISMA found more

haemorrhages with A+C, thuscancelling positive trends for vas-cular events.In his “Secondary prevention ofcardioembolic stroke: old and newdrugs” José Ferro, Department ofNeurosciences, Hospital SantaMaria, Lisbon, Portugal, says thatcardioembolic stroke accounts for1/5 of all strokes. Cardioembolicstrokes are more severe and moreoften fatal than other types ofischaemic strokes.The diagnosis of cardioembolicstroke can be highly suspected onclinical grounds or on neuroimag-ing findings, but the demonstrationof a cardioembolic disease relies onECG, trans-thoracic and trans-esophageal echocardiography andcardiac monitoring.

The therapeutic opportunitiesby new molecules are

the topical theme of this Congress

New anticoagulant: highlightson methodological issues

Quick check-up, drugs & speedWinning combination to defeat strokes

CONGRESS DAILY is a special edition of NTR - Notiziario in Tempo Reale by e.press® srl - registration Trib. NA no. 4560Editor and Director Enrico Sbandi Professional journalist Claudio Ravel - Translation Giovanna Basilio - direct printing at Marriot Hotel, Milan

Exclusive distributor for medical and health sector: VALUE RELATIONS INTERNATIONAL srl, via G. B. Morgagni, 30 - 20129 Milan, Italy

Ways of intervention todayand chances after introduction

of the new molecules

6.00 p.m. - real time edition

continues in page 4In the photo: h 5.10 p. m. - The beginning

of the scientific symposiumwith D. Toni, A. Algra and J. Ferro

Current guidelines such as those of the ESO recommendprolonged oral anticoagulation with warfarin (INR 2.0-3.0) for all patients with stroke or TIA and a high-risk ofcardioembolic stroke including AF, irrespective of the ageof the patient. A new anti-arrhythmic drug, dronedarone,demonstrates a preventive effect on recurrent stroke andembolism. For patients with real contraindications to oralanticoagulation, the combination of aspirin with clopidogreloffers a better protection than aspirin alone, but producesmore hemorrhagic side effects. The combination of war-farin with triflusal appears to be efficacious and safe. Thedirect thrombin inhibitor dabigatran at a moderate dosageis as efficacious as warfarin in preventing embolism, butproduces less hemorrhagic complications, while a higherdosage is more efficacious but causes as many haemor-rhages as warfarin.

Quick check-up, drugs & speedWinning combination to defeat strokes

from page 1

1 hour left to catch the opportunity of a 1st class stalls at Teatroalla Scala, for “Romeo and Juliet”, ballet produced by KennethMacMillan, with the dancers Antonella Albano e AlexanderVolchkov. “La Scala” is a world renowned opera house inMilan. The tickets (250,00 euros, including the bus transfer anda light dinner at the renown Savini Restaurant) are available atSocial Event Gate, ground floor.

Tonight at Scala

Sergio Coccheri (in thephoto above), Professor atthe University of Bologna,has discussed “Is aspirin lesseffective in patients with dia-betes?” during this morningsession, chaired by D.Prisco. Although aspirin remainsthe “reference” and “firstline” antiplatelet agent, sev-eral limitations emerged inrecent years. Concepts asrelative vs absolute riskreduction,residual vascularrisk and resistance to aspirinor clopidogrel are presentlyitems of wide debate.Patients with Type 2 dia-betes carry a high risk ofcardiovascular events andwould therefore appear idealcandidates to aspirin thera-py. However, results of rele-vant clinical trials aredeceiving.Distinction between 'pri-mary' and 'secondary' pre-vention is less clear inpatients with diabetes, a con-dition that is a potent riskfactor per se, often associat-ed with additional factors ashypertension, dyslipidemia,

obesity and others.Diabetics are largely unevenin relation to this cluster andtheir global risk level is high-ly variable. Already in theantiplatelet meta-analysis of2002, the risk reduction indiabetics was low and non-significant, especially underaspirin. In the primary pre-vention study, aspirin wastotally ineffective in the dia-betic group. In the JPAD pri-mary prevention study, theresults were inconclusive.More recently, in diabeticswith only asymptomaticPAD (POPADAD Study)aspirin again failed to preventcardiovascular events. In afinal meta-analysis (2009)aspirin once more resulted lit-tle effective except for areduction of non-fatal AMI,similarly to primary preven-tion in non-diabetics. Thus,aspirin appears scarcelyeffective in patients withoutprevious cardiovascularevents in diabetics as in non-diabetics, and may also beless effective in those withevents in presence of dia-betes.

Rosanna Abbate (Dipar-timento di Area Criticamedico Chirurgica, Uni-versity of Florence, Ita-ly) has spoken of“Moderate hyperhomo-cysteinemia: marker orcause of a disease”?During the morning ses-sion chaired by G. DiMinno.She supports the concept that pathophysiological and clinicaldata suggest a casual role of moderate hyperhomocysteinemiafor vascular disease, but data on a reduction of cardiovascularevents associated with the correction of hyperhomocysteine-mia are inconclusive.It is well known that homocysteine circulating levels aredependent on B12, B6 and folic acid levels or genetic alterationof enzymes such as MTHFR (methylenetetrahydrofolatereductase) or CBS (cystathionine beta-synthase).VISP, NORVIT and HOPE 2 trials were designed on thebasis that vitamin supplementation with B-vitamins and folicacid could reduce vascular risk by about 30%. On the otherhand, a large meta-analysis of previous observational studiesfound that a 25% reduction in Hcy levels might determine areduction by 11% in cardiovascular risk and 19% in cere-brovascular risk.Furthermore, these large prospective trials have enrolledpatients with a previous vascular event. It is conceivable thatreduction of Hcy in these patients could have an effect whichis diluted by the concomitant antihypertensive, anticoagulantand hypolipidic therapies. An extended follow-up of these tri-als could have enhanced their statistical power by increasingthe number of vascular events.

2 3

Is it marker or cause of a disease? Clinical datasuggest a casual role. The studies go on

“Considering that warfarinwas introduced 65 years a-go, the dabigatran exetilatemolecule represents one ofthe most relevant noveltiesof the medical-scientific re-search of the recentyears”. This is the idea ofProf. Raffaele De Cateri-na, Professor of Cardiolo-gy at the University ofChieti, presenting today atthe symposium on “Trans-forming the managementof venous and arterialthrombosis”, sponsored byBoehringer Ingelheim. DeCaterina has focused hisspeech on “Stroke preven-tion in atrial fibrillation:changing the paradigm?”.W. Ageno, B. I. Eriksson eP. Mismetti have also par-ticipated to the meetingchaired by A. K. Kakkar.“The main problem of atri-al fibrillation - De Caterinagoes on - is the high throm-boembolic risk for the leftatrium which is the main

cause of stroke. Oral anti-coagulants are used to re-duce such an incidence.The anti-vitamin K havebeen the only availabledrugs by now, with the ad-vantage of blocking somecoagulation factors, name-ly: II, VII, IX and X. Inpast years we have evalu-ated alternatives to the an-ti-vitamin K, such as as-pirin, yet it came out asless effective. Aspirin andclopidogrel have been test-ed together but the anti-vi-tamin K has given the bestresult. Difficulty in the useand bleeding, interactionwith other drugs and foodhave represented the maincontraindications of of thetherapy with anti-vitaminK by now, which hascaused a scarce approvalreaching even a 45% rateamong patients. In the last years a develop-ment of new oral anticoag-ulant drugs has taken

place, they do not needmonitoring and do notcause interaction problemswith food and other drugs.This is the case of dabiga-tran exetilate, a reversibiledirect thrombin inhibitor. A pro-drug which turns in-to an active drug.Results from the largesttrial ever conducted on theeffects of atrial fibrillation(18,113 patients), thephase III RE-LY trial,showed that, compared towarfarin, dabigatran 150mg BID (optimal dose) sig-nificantly reduced the riskof stroke and systemic em-bolism in 34% of patientswith atrial fibrillation with-out increasing the risk ofmajor bleeding. Dabiga-tran 110 mg BID showedsimilar reductions instroke and systemic em-bolism with a 20% declinein the risk of major bleed-ing as compared to war-farin”.

The study of Prof. Raffaele De Caterina emphasisesthe role of new oral anticoagulant drugs

“No monitoring needed, no interactions with foods”

In his lecture, James C. Grotta, Univer-sity of Texas-Houston Medical School,Houston, TX, USA has dealth with an-tithrombotic agents to amplify thrombol-ysis in ischemic stroke”.Tissue plasminogen activator (TPA) hassubstantial clinical benefit in only ~33%of stroke patients, and only ~25% of Mid-dle Cerebral Artery (MCA) occlusionscompletely recanalize. Furthermore, ~5% of patients will have symptomatic in-tracerebral hemorrhage (sICH). The di-rect thrombin inhibitor argatroban pro-duces immediate dose-dependent antico-agulation, is rapidly eliminated, can beeasily monitored by the aPTT, and in an-

imal models when combined with TPAincreases reperfusion and improves func-tional outcome compared to TPA alonewithout producing increased bleeding.We are conducting a Phase 2 safety s-

tudy of this combination in acute strokepatients. Acute ischemic stroke patientspresenting to one of 5 U.S. stroke centerswho meet criteria for IV TPA treatmentwithin 3 hours of symptom onset are in-

cluded. Other criteria are that they musthave MCA occlusion documented byTranscranial Doppler (TCD) or Com-puted Tomography Angiogram (CTA),and very severe strokes in the very oldare excluded. After obtaining consent,argatroban (bolus 100 ug/kg then 1ug/kg/min titrated to aPTT 1.75 X base-line value) is started anytime during the 1hour TPA infusion and continued for 48hrs. Results: In the first 40 patients treat-ed to date, 2 hour recanalization is 65%(complete in 39 %), and 24 hr completerecanalization in 72%, all substantiallyhigher than historical controls (TPAalone). sICH in 2 patients (5%). In con-clusion, the addition of the direct throm-bin inhibitor to IV TPA appears to besafe and may increase the number of pa-tients achieving timely arterial recanal-ization.

Antithrombotic agents can amplify thrombolysis

Aspirin isless effectivein patients with diabetes

Addition of argatroban to IV TPAappears to be safe and favors timely

arterial recanalization

In the course of the session“Platelets and inflamma-tion” chaired by R. Lan-dolfi and R. Lorenzet, LinaBadimon, Barcelona Car-diovascular Research Cen-ter (CSIC-ICCC), IIB-Sant Pau, Hospital de SantPau, UAB and CIBERobnInstituto Salud Carlos III,Barcelona, Spain, has dis-cussed on “Platelets, in-flammation and acute coro-nary syndrome”. Modern pathology aims atdiscovering the molecularcauses of disease. Indeed,this is the accurate andgenuine pathway to findfirstly new mechanismsand secondly new therapiesaddressed to improve thesuccess of cardiovascularmedicine. Inflammationhas been shown to be a ma-jor factor in cardiovascularpathology and inflammato-ry pathways have beenshown to participate inplatelet activation andatherothrombosis. Longconsidered merely a by-stander in vascular disease,new evidence indicates thatCRP may be not only amarker, but also an activeplayer in the developmentof cardiovascular patholo-gy. Our findings show thatthe presence of CRP inplasma is not associated toplatelet aggregation; it isthe tissue-associated CRPthe isoform that induces athrombotic triggering effect.The role of the differentTF-pools in the thromboticprocess is also a matter ofinvestigation. No doubtthat thrombosis and inflam-mation are intertwinedprocesses that by activatingone another in the athero-sclerotic vascular wall mi-croenvironment determinethe thrombotic risk of aplaque and hence the pres-entation of a clinical car-diovascular event.

Platelet, inflammationand acute

coronary syndrome

Badimon: discoveringthe molecular causes

in cardiovascular pathology

Preventing atrial fibrillation A paradigm to be changed

HyperhomocysteinemiaA role to be defined

“Variable antiplatelet response to thyenopiridines: shouldwe use lab tests? Yes/No”. This was the topic of the debateheld this morning in Washington Hall A. The meeting,chaired by Professor Gensini, was attended by Jean-Philippe Collet, Institute of Cardiology Inserm U 937,Groupe Hospitalier Pitié Salpetriere of Paris and BiancaRocca, Institute of Pharmacology, Medicine Department ofthe University Cattolica of Rome.

Duel: Lab test for thyenopiridines

Sergio Coccheri (in thephoto above), Professor atthe University of Bologna,has discussed “Is aspirin lesseffective in patients with dia-betes?” during this morningsession, chaired by D.Prisco. Although aspirin remainsthe “reference” and “firstline” antiplatelet agent, sev-eral limitations emerged inrecent years. Concepts asrelative vs absolute riskreduction,residual vascularrisk and resistance to aspirinor clopidogrel are presentlyitems of wide debate.Patients with Type 2 dia-betes carry a high risk ofcardiovascular events andwould therefore appear idealcandidates to aspirin thera-py. However, results of rele-vant clinical trials aredeceiving.Distinction between 'pri-mary' and 'secondary' pre-vention is less clear inpatients with diabetes, a con-dition that is a potent riskfactor per se, often associat-ed with additional factors ashypertension, dyslipidemia,

obesity and others.Diabetics are largely unevenin relation to this cluster andtheir global risk level is high-ly variable. Already in theantiplatelet meta-analysis of2002, the risk reduction indiabetics was low and non-significant, especially underaspirin. In the primary pre-vention study, aspirin wastotally ineffective in the dia-betic group. In the JPAD pri-mary prevention study, theresults were inconclusive.More recently, in diabeticswith only asymptomaticPAD (POPADAD Study)aspirin again failed to preventcardiovascular events. In afinal meta-analysis (2009)aspirin once more resulted lit-tle effective except for areduction of non-fatal AMI,similarly to primary preven-tion in non-diabetics. Thus,aspirin appears scarcelyeffective in patients withoutprevious cardiovascularevents in diabetics as in non-diabetics, and may also beless effective in those withevents in presence of dia-betes.

Rosanna Abbate (Dipar-timento di Area Criticamedico Chirurgica, Uni-versity of Florence, Ita-ly) has spoken of“Moderate hyperhomo-cysteinemia: marker orcause of a disease”?During the morning ses-sion chaired by G. DiMinno.She supports the concept that pathophysiological and clinicaldata suggest a casual role of moderate hyperhomocysteinemiafor vascular disease, but data on a reduction of cardiovascularevents associated with the correction of hyperhomocysteine-mia are inconclusive.It is well known that homocysteine circulating levels aredependent on B12, B6 and folic acid levels or genetic alterationof enzymes such as MTHFR (methylenetetrahydrofolatereductase) or CBS (cystathionine beta-synthase).VISP, NORVIT and HOPE 2 trials were designed on thebasis that vitamin supplementation with B-vitamins and folicacid could reduce vascular risk by about 30%. On the otherhand, a large meta-analysis of previous observational studiesfound that a 25% reduction in Hcy levels might determine areduction by 11% in cardiovascular risk and 19% in cere-brovascular risk.Furthermore, these large prospective trials have enrolledpatients with a previous vascular event. It is conceivable thatreduction of Hcy in these patients could have an effect whichis diluted by the concomitant antihypertensive, anticoagulantand hypolipidic therapies. An extended follow-up of these tri-als could have enhanced their statistical power by increasingthe number of vascular events.

2 3

Is it marker or cause of a disease? Clinical datasuggest a casual role. The studies go on

“Considering that warfarinwas introduced 65 years a-go, the dabigatran exetilatemolecule represents one ofthe most relevant noveltiesof the medical-scientific re-search of the recentyears”. This is the idea ofProf. Raffaele De Cateri-na, Professor of Cardiolo-gy at the University ofChieti, presenting today atthe symposium on “Trans-forming the managementof venous and arterialthrombosis”, sponsored byBoehringer Ingelheim. DeCaterina has focused hisspeech on “Stroke preven-tion in atrial fibrillation:changing the paradigm?”.W. Ageno, B. I. Eriksson eP. Mismetti have also par-ticipated to the meetingchaired by A. K. Kakkar.“The main problem of atri-al fibrillation - De Caterinagoes on - is the high throm-boembolic risk for the leftatrium which is the main

cause of stroke. Oral anti-coagulants are used to re-duce such an incidence.The anti-vitamin K havebeen the only availabledrugs by now, with the ad-vantage of blocking somecoagulation factors, name-ly: II, VII, IX and X. Inpast years we have evalu-ated alternatives to the an-ti-vitamin K, such as as-pirin, yet it came out asless effective. Aspirin andclopidogrel have been test-ed together but the anti-vi-tamin K has given the bestresult. Difficulty in the useand bleeding, interactionwith other drugs and foodhave represented the maincontraindications of of thetherapy with anti-vitaminK by now, which hascaused a scarce approvalreaching even a 45% rateamong patients. In the last years a develop-ment of new oral anticoag-ulant drugs has taken

place, they do not needmonitoring and do notcause interaction problemswith food and other drugs.This is the case of dabiga-tran exetilate, a reversibiledirect thrombin inhibitor. A pro-drug which turns in-to an active drug.Results from the largesttrial ever conducted on theeffects of atrial fibrillation(18,113 patients), thephase III RE-LY trial,showed that, compared towarfarin, dabigatran 150mg BID (optimal dose) sig-nificantly reduced the riskof stroke and systemic em-bolism in 34% of patientswith atrial fibrillation with-out increasing the risk ofmajor bleeding. Dabiga-tran 110 mg BID showedsimilar reductions instroke and systemic em-bolism with a 20% declinein the risk of major bleed-ing as compared to war-farin”.

The study of Prof. Raffaele De Caterina emphasisesthe role of new oral anticoagulant drugs

“No monitoring needed, no interactions with foods”

In his lecture, James C. Grotta, Univer-sity of Texas-Houston Medical School,Houston, TX, USA has dealth with an-tithrombotic agents to amplify thrombol-ysis in ischemic stroke”.Tissue plasminogen activator (TPA) hassubstantial clinical benefit in only ~33%of stroke patients, and only ~25% of Mid-dle Cerebral Artery (MCA) occlusionscompletely recanalize. Furthermore, ~5% of patients will have symptomatic in-tracerebral hemorrhage (sICH). The di-rect thrombin inhibitor argatroban pro-duces immediate dose-dependent antico-agulation, is rapidly eliminated, can beeasily monitored by the aPTT, and in an-

imal models when combined with TPAincreases reperfusion and improves func-tional outcome compared to TPA alonewithout producing increased bleeding.We are conducting a Phase 2 safety s-

tudy of this combination in acute strokepatients. Acute ischemic stroke patientspresenting to one of 5 U.S. stroke centerswho meet criteria for IV TPA treatmentwithin 3 hours of symptom onset are in-

cluded. Other criteria are that they musthave MCA occlusion documented byTranscranial Doppler (TCD) or Com-puted Tomography Angiogram (CTA),and very severe strokes in the very oldare excluded. After obtaining consent,argatroban (bolus 100 ug/kg then 1ug/kg/min titrated to aPTT 1.75 X base-line value) is started anytime during the 1hour TPA infusion and continued for 48hrs. Results: In the first 40 patients treat-ed to date, 2 hour recanalization is 65%(complete in 39 %), and 24 hr completerecanalization in 72%, all substantiallyhigher than historical controls (TPAalone). sICH in 2 patients (5%). In con-clusion, the addition of the direct throm-bin inhibitor to IV TPA appears to besafe and may increase the number of pa-tients achieving timely arterial recanal-ization.

Antithrombotic agents can amplify thrombolysis

Aspirin isless effectivein patients with diabetes

Addition of argatroban to IV TPAappears to be safe and favors timely

arterial recanalization

In the course of the session“Platelets and inflamma-tion” chaired by R. Lan-dolfi and R. Lorenzet, LinaBadimon, Barcelona Car-diovascular Research Cen-ter (CSIC-ICCC), IIB-Sant Pau, Hospital de SantPau, UAB and CIBERobnInstituto Salud Carlos III,Barcelona, Spain, has dis-cussed on “Platelets, in-flammation and acute coro-nary syndrome”. Modern pathology aims atdiscovering the molecularcauses of disease. Indeed,this is the accurate andgenuine pathway to findfirstly new mechanismsand secondly new therapiesaddressed to improve thesuccess of cardiovascularmedicine. Inflammationhas been shown to be a ma-jor factor in cardiovascularpathology and inflammato-ry pathways have beenshown to participate inplatelet activation andatherothrombosis. Longconsidered merely a by-stander in vascular disease,new evidence indicates thatCRP may be not only amarker, but also an activeplayer in the developmentof cardiovascular patholo-gy. Our findings show thatthe presence of CRP inplasma is not associated toplatelet aggregation; it isthe tissue-associated CRPthe isoform that induces athrombotic triggering effect.The role of the differentTF-pools in the thromboticprocess is also a matter ofinvestigation. No doubtthat thrombosis and inflam-mation are intertwinedprocesses that by activatingone another in the athero-sclerotic vascular wall mi-croenvironment determinethe thrombotic risk of aplaque and hence the pres-entation of a clinical car-diovascular event.

Platelet, inflammationand acute

coronary syndrome

Badimon: discoveringthe molecular causes

in cardiovascular pathology

Preventing atrial fibrillation A paradigm to be changed

HyperhomocysteinemiaA role to be defined

“Variable antiplatelet response to thyenopiridines: shouldwe use lab tests? Yes/No”. This was the topic of the debateheld this morning in Washington Hall A. The meeting,chaired by Professor Gensini, was attended by Jean-Philippe Collet, Institute of Cardiology Inserm U 937,Groupe Hospitalier Pitié Salpetriere of Paris and BiancaRocca, Institute of Pharmacology, Medicine Department ofthe University Cattolica of Rome.

Duel: Lab test for thyenopiridines

4

CONGRESS DAILYThrombosis 2010

Milan, July 8th

realized with the contribution of

The great therapeutic opportunitieslaunched by the new molecules are thethe topical theme of this Congress. Thedebate of experiences, monitoring andexperimentations starts from the con-solidated applicative field in orthopedicsto turn into a wide range of pathologies(such as infarction, coronary diseases,stroke and rare kinds of thrombosis)which are not treated with oral drugsnow. This was the theme of the ses-sion “New anticoagulant: highlights onmethodolical issues”, chaired by M.G.Franzosi and J. Harenberg. Fourworks have been presented during thescientific symposium.Ola E. Dahl has spoken of “Lack ofstandardization between antithrombot-ic trials in orthopedics: the scenario”.Clinical developments of newantithrombotics are basically conduct-ed in patients undergoing elective majorjoint surgery. In 7 recent trial pro-grams, 10 divergent bleeding termswere identified. Major bleeding (MB)was the most frequent phrase for pri-mary bleeding. Basic bleeding parame-ters like the volume of blood loss, thehaemoglobin fall and the number oftransfused units blood, were reportedinfrequently. In only 2/8 trial programsbleeding volume during surgery waspresented and in 3/8 trial series data onpostoperative blood loss was given.None reported concomitantly thesethree essential parameters from preop-erative baseline and during the subse-

quent postoperative days until stabi-lized. Similar scenario was found forthe efficacy outcomes. Charles Marc Samama dealt with“Methodological issues in trials assess-ing primary prophylaxis of venousthromboembolism”. Recent clinicalstudies of pharmacological agents -Samama explains - have used asympto-matic DVTs assessed by bilateralascending venography as a surrogateend-point. The high rate of eventsobserved with this method means thatthe numbers of patients included intoPhase II and Phase III studies havebeen relatively small. However,although there may be a relationshipbetween venographic and symptomaticthrombosis, it ranges from a factor of 5for total hip replacement to a factor of21 for total knee arthroplasty.The overall safety of the drugs used in

prophylaxis is good but most newantithrombotic agents are eliminatedvia the kidney. Since efficacy is guaran-teed with a rate of thromboembolicevents of 1.5% at 3 months, the currentemphasis is naturally on safety.Job Harenberg has illustrated “Makeclinical studies in medical patients clos-er to usual hospital care”. Clinical stud-ies for treatment of thromboembolicdiseases in hospital or outpatients set-tings with new anticoagulants includemanifold exclusion criteria. Afterapproval of the anticoagulant, patientsmay be treated with these compoundsalso if they would have met an exclu-sion criterion during the study. Newanticoagulants are developed withoutlaboratory monitoring of the anticoagu-lant effect. Ajaj K. Kakkar has discussed“Guidelines on clinical testing of newantithrombotic drugs in surgicalpatients”. Recent years - Kakkar says -have seen evaluation of novelantithrombotic drugs in surgical popu-lations to establish efficacy and safetyfor the prophylaxis of venous throm-boembolism. Evaluation in surgicalpopulations is appropriate since venousthromboembolism represents a majorclinical challenge for patients undergo-ing high risk surgical procedures suchas elective joint arthroplasty or majorabdominal surgery for cancer.However, it is important that commonendpoints both for evaluation of effica-cy and safety are used. These vary bystage of clinical development - eitherphase II or phase III clinical trials butshould be consistent.

In the photos: Job Harenberg (left)and Ajaj K. Kakkar

The new drugs which will enableto overcome present limits in mat-ter of treatment of thromboembolicdiseases, arise great expectationsfor diseases such as infarction andstroke. This important and delicatetopic is the focus of the third day ofthe 21st International Congress onThrombosis reported by this news-daily while the session is still incourse.Danilo Toni, Emergency Depar-tment Stroke Unit, SapienzaUniversity of Rome, Italy, statesthat the RCTs with alteplase per-formed in the late 90s demonstrat-ed the safety and efficacy of i. v.thrombolysis given within 3 hoursof acute ischemic stroke onset.The use of modern imaging tech-niques as diffusion and perfusionMR or perfusion CT, made it clearthat the therapeutic window ismore “brain tissue” based than“clock” based. This means thatindividual patients may have sal-vageable brain tissue even morethan 6 hours after onset of symp-toms. Future lines of researchinclude looking for a possible moreeffective dose of alteplase, reducingthe tendency of thrombolytic drugsto cause intracerebral hemorrhage,testing new thrombolytic agents,exploiting new and faster imagingmethods to guide treatment,increasing the extent of lysis withultrasound, antithrombotic agentsor intra-arterial clot manipulation.Ale Algra, Department of Neuro-logy and Julis Center, University

Medical Center Utrecht, theNetherlands states that aspirinreduces the risk of new vascularevents after cerebral ischaemia ofarterial origin by only 13%, thussomething stronger is needed.Three trials assessed the efficacy oforal anticoagulants, but nonefound them to be more effectivethan aspirin CAPRIE comparedclopidogrel with aspirin and founda relative risk reduction (RRR) of7% (95%-CI -6; 19%).MATCH compared aspirin plusclopidogrel (A+C) with clopidogrelmonotherapy and found that A+Chad an RRR of 6% (95%-CI -7;17%).CHARISMA included patientswith clinically manifest vasculardisease or a high risk thereof andcompared A+C with aspirinmonotherapy: overall RRR 7%(95%- CI -5; 17%). Both MATCHand CHARISMA found more

haemorrhages with A+C, thuscancelling positive trends for vas-cular events.In his “Secondary prevention ofcardioembolic stroke: old and newdrugs” José Ferro, Department ofNeurosciences, Hospital SantaMaria, Lisbon, Portugal, says thatcardioembolic stroke accounts for1/5 of all strokes. Cardioembolicstrokes are more severe and moreoften fatal than other types ofischaemic strokes.The diagnosis of cardioembolicstroke can be highly suspected onclinical grounds or on neuroimag-ing findings, but the demonstrationof a cardioembolic disease relies onECG, trans-thoracic and trans-esophageal echocardiography andcardiac monitoring.

The therapeutic opportunitiesby new molecules are

the topical theme of this Congress

New anticoagulant: highlightson methodological issues

Quick check-up, drugs & speedWinning combination to defeat strokes

CONGRESS DAILY is a special edition of NTR - Notiziario in Tempo Reale by e.press® srl - registration Trib. NA no. 4560Editor and Director Enrico Sbandi Professional journalist Claudio Ravel - Translation Giovanna Basilio - direct printing at Marriot Hotel, Milan

Exclusive distributor for medical and health sector: VALUE RELATIONS INTERNATIONAL srl, via G. B. Morgagni, 30 - 20129 Milan, Italy

Ways of intervention todayand chances after introduction

of the new molecules

6.00 p.m. - real time edition

continues in page 4In the photo: h 5.10 p. m. - The beginning

of the scientific symposiumwith D. Toni, A. Algra and J. Ferro

Current guidelines such as those of the ESO recommendprolonged oral anticoagulation with warfarin (INR 2.0-3.0) for all patients with stroke or TIA and a high-risk ofcardioembolic stroke including AF, irrespective of the ageof the patient. A new anti-arrhythmic drug, dronedarone,demonstrates a preventive effect on recurrent stroke andembolism. For patients with real contraindications to oralanticoagulation, the combination of aspirin with clopidogreloffers a better protection than aspirin alone, but producesmore hemorrhagic side effects. The combination of war-farin with triflusal appears to be efficacious and safe. Thedirect thrombin inhibitor dabigatran at a moderate dosageis as efficacious as warfarin in preventing embolism, butproduces less hemorrhagic complications, while a higherdosage is more efficacious but causes as many haemor-rhages as warfarin.

Quick check-up, drugs & speedWinning combination to defeat strokes

from page 1

1 hour left to catch the opportunity of a 1st class stalls at Teatroalla Scala, for “Romeo and Juliet”, ballet produced by KennethMacMillan, with the dancers Antonella Albano e AlexanderVolchkov. “La Scala” is a world renowned opera house inMilan. The tickets (250,00 euros, including the bus transfer anda light dinner at the renown Savini Restaurant) are available atSocial Event Gate, ground floor.

Tonight at Scala