Hospital acquired venous thromboembolism constitutes a major health burden Venous thromboembolism (VTE) constitutes a major health problem and is associated with significant mortality and morbidity. Population studies suggest that the annual incidence of VTE (deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) is in the order of one in 1000 (0.1%) of the adult population [1]. It is well recognised that VTE is associated with significant mortality. Indeed previous studies have estimated that at least 25,000 deaths per annum are attributable to PE in the UK alone [2]. Consequently, overall deaths due to VTE are approximately five times greater than the combined total of deaths from breast cancer, acquired immunodeficiency syndrome and road traffic accidents. Approximately half

of all fatal PE cases occur in hospital [3]. Moreover, post-mortem analyses have shown that in-patient PE is directly responsible for 10% of all hospital deaths [4]. Furthermore, PE also represents the commonest cause of maternal death during pregnancy in the developed world. In addition to this significant mortality, VTE is also associated with significant long-term morbidity in the form of post-thrombotic or post-phlebitic syndrome.

Despite the significant mortality and morbidity associated with hospital-acquired VTE, audits have consistently found that the use of thromboprophylaxis in hospital in-patients remains sub-optimal [5]. This important issue was highlighted in a

systematic review by the US Agency for Healthcare Quality and Research that ranked PE as the most common preventable cause of hospital death [6]. For many years, anticoagulation with heparin and/or warfarin have been established as the treatment of choice for the prevention of VTE. Unfractionated heparin (UFH) and low molecular weight heparins (LMWH) require parenteral administration and exert their anticoagulant effect indirectly by enhancing plasma antithrombin. In contrast, warfarin and other coumarin anticoagulants function as vitamin K antagonists. Although warfarin therapy is administered orally, it has a number of clinically important limitations. In particular, a clinically significant anticoagulant effect

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice.

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.

3. PLAN - If I have identified a knowledge gap - will this article

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5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 4 previous steps, log and record your findings.

CPD 2: Venous Thromboembolism

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Biography - Prof James O’Donnell PhD, MD, FRCPI, PRCPath, Professor of Haematology and Director Haemostasis Research Group, National Centre for Coagulation Disorders, Trinity College Dublin, IrelandJames O’Donnell obtained his MB from Trinity College Dublin, and completed his clinical haematology training in the Hammersmith and Royal Free Hospitals in London. He obtained a prestigious Medical Research Council Training Fellowship in 1998, and was awarded his PhD by Imperial College London

in 2001. Prior to returning to Dublin, James spent three years as a Senior Lecturer and Principal Investigator in Imperial College, during which time he was funded through a Clinician Scientist award

from the British Heart Foundation. His principal research interests include the role of carbohydrate structures in determining the biological activity of coagulation proteins; the molecular mechanisms through which coagulation is regulated at the feto-maternal interface; and the molecular basis of constitutional thrombophilia. Following his return to Ireland in 2005, he has since became the first clinician scientist to receive the prestigious Science Foundation Ireland President of Ireland Young

Investigator award. In addition, he is Director of the large Haemostasis Research group in the Institute of Molecular Medicine in Trinity College. This group has already been successful in obtaining in excess of €5M in peer-reviewed grant awards over the past five years. Prof O’Donnell has more than 70 peer-reviewed publications in high impact journals, (including 5 papers in Blood and 3 papers in the Journal of Biological Chemistry) and has given a series of invited presentations at leading international meetings

including the American Society for Hematology and the ISTH congresses.

60 Second SummaryPopulation studies suggest that the annual incidence of VTE (deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) is in the order of one in 1000 (0.1%) of the adult population [1]. It is well recognised that VTE is associated with significant mortality. Indeed previous studies have estimated that at least 25,000 deaths per annum are attributable to PE in the UK alone [2].

The therapeutic options available for the prevention of hospital-acquired VTE have developed rapidly in recent years. In particular, a number of novel oral anticoagulants (NOACs) have been developed.

A number of inherited and acquired risk factors for the development of hospital-acquired VTE have been defined. These include constitutional thrombophilias, pregnancy, malignancy and surgery. In particular, it is well recognised that major orthopaedic surgery is associated with a marked increased risk of VTE. With the emergence of the NOACs, major changes in clinical practise are likely to emerge in the coming years. Both direct thrombin and factor Xa inhibitors show great promise. However it is critical to appreciate that the different commercial products have significant differences with respect to their individual pharmacokinetic and pharmacodynamics properties.

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Prof James O’Donnell

is not observed until several days following the initiation of warfarin therapy. Consequently, combined administration of both LMWH and warfarin is necessary until the INR has reached the target therapeutic range (INR≥2 for two consecutive days).

Novel oral anticoagulant therapies and VTE prophylaxis

The therapeutic options available for the prevention of hospital-acquired VTE have developed rapidly in recent years. In particular, a number of novel oral anticoagulants (NOACs) have been developed. These include the direct factor Xa inhibitors (e.g. Rivaroxiban and Apixiban) and direct thrombin inhibitors (e.g. Dabigatran) (Figure 1). Unlike warfarin, these NOACs have predictable pharmacokinetics so that routine monitoring is not required. In addition, these agents are fast-acting so that overlapping cover with LMWH at initiation is not necessary. Nevertheless, it is important to emphasise that there a number of important differences between the NOACs that have direct importance in relation to their use in clinical practise. Although a comprehensive review of the pharmacokinetic and

pharmacodynamics properties of each of the different commercial available NOACs is beyond the scope of this brief review, some of the important properties are outlined below.

Apixaban (Eliquis )

Apixaban is a new oral anticoagulant that specifically inhibits procoagulant factor Xa. Clinical studies have shown that apixaban is rapidly absorbed with an absolute bioavailability of approximately 50%. Absorption is not influenced by food intake, and peak plasma anticoagulant effects are reached 3-4 hours after oral administration. Unlike warfarin, clinical studies have demonstrated that apixaban has predictable pharmacokinetic and pharmacodynamic profiles. Consequently, apixaban can be given at fixed doses without the need for regular coagulation monitoring in most patients. In terms of clearance, apixaban has multiple routes of elimination plasma and has a plasma half-life of approximately 12-14 hours. It is metabolised in the liver in a cytochrome P450-dependent manner. In addition, 27% of the drug is eliminated unchanged by the kidneys. Consequently, apixiban therapy is not recommended

in patients with severe hepatic impairment, or in patients with creatinine clearance < 15ml/min. Moreover, apixiban is not recommended in patients receiving concomitant treatment with inhibitors of cytochrome P450 and P-glycoprotein (e.g. keatconazole, itraconazole, voriconazole, ritonavir).

Rivaroxaban (Xarelto®)

Rivaroxaban is another oral anticoagulant that is a highly selective direct factor Xa inhibitor. Like apixaban, rivaroxaban is well absorbed, with bioavailability of 60-80% and reaches peak plasma concentrations within 2-4 hours following oral administration. Rivaroxaban also demonstrates predictable pharmacokinetic and pharmacodynamic properties, and therefore can be administered at fixed doses without the need for regular coagulation monitoring in most patients. With respect to clearance, one third of rivaroxaban is eliminated unchanged by the kidneys. The remaining two thirds is metabolised mainly by cytochrome P450-mediated metabolism within the liver. The terminal half-life of rivaroxaban

is approximately 5-9 hours in young individuals with normal renal and hepatic function. However some anticoagulant effect remains detectable for up to 24 hours, so that once-daily dosing is feasible. Similar to apixaban, rivaroxaban is not recommended in patients with creatinine clearance < 15ml/min, and should be used with caution in patients with creatinine clearance 15 – 29ml/min. Furthermore, again in keeping with apixaban, concomitant use of potent inhibitors of cytochrome P450 and P-glycoprotein (e.g. keatconazole, itraconazole, voriconazole, ritonavir) should be avoided as these agents significantly increase plasma rivaroxaban levels and consequent bleeding risk.

Dabigatran etexilate (Pradaxa®)

Dabigatran etexilate is an orally available synthetic small molecule direct thrombin inhibitor. It is a prodrug that is rapidly converted into the active metabolite dabigatran which has a high affinity for thrombin. The bioavailability of dabigatran is low (approximately 6.5%). Moreover, dabigatran absorption is markedly influenced by pH. Consequently, the low bioavailability is further reduced in the presence of proton pump inhibitors. Peak plasma dabigatran concentrations are achieved within 2-3 hours after oral administration, and the plasma half-life has been estimated as ranging between 12-14 hours, which enables once-daily dosing. Dabigatran clearance is primarily mediated via the kidneys, with 85% being excreted unchanged in the urine. Consequently, dabigatran treatment is contraindicated in patients with creatinine clearance < 30ml/min. Moreover, phase I studies suggested that the exposure (area under

CPD 2: Venous Thromboembolism

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X Factor Xa

Fibrinogen Fibrin

Prothrombin

IXaIX

VIIIaPlCa 2+

XIaXI

New oral anticoagulants

Factor Xa inhibitors- Rivaroxaban

- Apixaban

Thrombin Direct thrombin inhibitors

- Dabigatran

Figure 1

curve or AUC) following the oral administration of dabigatran was approximately 2.7-fold higher in individuals with even moderate renal insufficiency (creatinine clearance 30-50ml/min).

NOACs and orthopaedic surgery

A number of inherited and acquired risk factors for the development of hospital-acquired VTE have been defined. These include constitutional thrombophilias, pregnancy, malignancy and surgery. In particular, it is well recognised that major orthopaedic surgery is associated with a marked increased risk of VTE. For example, post-operative VTE has been reported in 50-70% of patients undergoing elective hip- replacement (THR) or total knee replacement (TKR) who do not receive appropriate thromboprophylaxis. As a result, international consensus guidelines recommend that thromboprophylaxis be used routinely in this cohort of patients. Until recently, subcutaneous LMWH (e.g. enoxaparin or tinzaparin) has been used widely regarded as constituting optimal thrombopropyhylaxis following elective major orthopaedic surgery. Importantly however, emerging data from a number of large prospective randomised studies has suggested that the oral administration of the NOACs may also have a role to play in this context. In particular, use of oral direct anti-Xa inhibitors has been reported to offer a number of therapeutic benefits. Given the fact that extended duration thromboprophylaxis treatment is recommended after both TKR and THR (typically 2 weeks and 5 weeks respectively), the potential benefits to the patient from using an oral rather than subcutaneous treatment regimen are readily apparent.

[1] Apixaban in major elective orthopaedic surgery

The efficacy and safety of apixaban thromboprophylaxis following major elective orthopaedic surgery has been investigated in a number of large randomised prospective trials. In the ADVANCE-1 and ADVANCE-2 trials, apixaban treatment was compared to standard enoxaparin thromboprophylaxis regimens. In ADVANCE-2, 3057 patients undergoing elective TKR were randomised to receive oral apixaban 2.5mg twice daily or subcutaneous enoxaparin 40mg once daily [7]. Apixaban therapy was initiated 12-24 hours after wound closure, whilst the enoxaparin was started 12 hours before surgery. Both treatment regimens were continued for 10-14 days post-operatively. The primary outcome measure was the composite of asymptomatic and symptomatic DVT, non-fatal PE, and all-cause death during treatment. This primary outcome was recorded in 15% of patients on apixiban compared to 24% of those on enoxaparin, suggesting that the apixaban regimen

was more efficacious (relative risk 0.62; 95% CI 0.51-0.74; p<0.0001). Moreover, the risk of bleeding was similar in both patient cohorts, with major bleeding observed in 4% of patients on apixaban compared to 5% of those on enoxaparin.

Similarly, in the ADVANCE-3 trial, 5407 patients undergoing elective THR were randomised to receive either apixaban (2.5mg orally twice daily commenced 12 to 24 hours after closure of the surgical wound) or enoxaparin (40mg subcutaneously once daily initiated 12 hours before surgery) [8]. Both prophylaxis regimens were continued for 35 days after surgery. A total of 1949 patients in the apixaban group and 1917 patients in the enoxaparin group were evaluated for the same primary outcome measure as in ADVANCE-2. The primary efficacy outcome occurred in 1.4% of patients in the apixaban group compared to 3.9% of patients in the enoxaparin cohort (relative risk 0.36; 95% CI 0.22-0.54; p<0.001). These data suggest that apixaban thromboprophylaxis

is associated with a statistically significant lower rate of VTE compared to standard enoxaparin therapy. In addition, similar rates of major and clinically significant bleeding complications were observed in both the apixaban and enoxaparin cohorts (4.8% versus 5.0% respectively).

Cumulatively, a total of four randomised controlled trials involving more than 14,000 patients have addressed the question regarding the clinical efficacy of oral apixaban thromboprophylaxis for elective major orthopaedic surgery. On the basis of these data, a recent meta-analysis concluded that apixaban was both more effective, and had a similar safety profile, compared to the standard enoxaparin regimen for thrombopropylaxis following THR and TKR [9].

[2] Rivaroxaban in major elective orthopaedic surgery

The efficacy and safety of rivaroxaban treatment compared to LMWH thromboprophylaxis

CPD 2: Venous Thromboembolism

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has also been assessed in patients undergoing major orthopaedic surgery. Once again, the cumulative data suggest that rivaroxaban is either superior, or at least certainly non-inferior, to LMWH thromboprophylaxis in this setting. For example, in the RECORD1 trial, 3153 patients undergoing total hip arthroplasty were randomised to receive either oral rivaroxaban (10mg once daily beginning 6-8 hours after wound closure) or subcutaneous enoxaparin (40mg once daily initiated 12 hours before surgery and restarted 6-8 hours after wound closure) [10]. Thromboprophylaxis was continued for 35 days post-operatively in all patients. The primary outcome measure was again the composite of DVT (either symptomatic or asymptomatic detected by bilateral venography), non-fatal PE, or death from any cause at 36 days. This primary efficacy outcome occurred in 1.1% in the rivaroxaban group compared to 3.7% in the enoxaparin group (absolute risk reduction 2.6%; 95% CI 1.5 to 3.7; p<0.001), suggesting that the rivaroxaban regimen was more effective for extended thromboprophylaxis than a once-daily 40mg subcutaneous dose of enoxaparin in patients undergoing elective THR. Moreover, major VTE was significantly reduced in the rivaroxaban group compared to the enoxaparin group (0.2%

versus 2%; p<0.001). Despite the improved efficacy of once-daily oral rivaroxaban compared to subcutaneous enoxparin, the risk of major bleeding was not significantly different between the two patient groups, with major bleeding observed in 0.3% of patients on rivaroxaban compared to 0.1% of those on enoxaparin (p=0.18).

Similarly, the RECORD3 trial compared rivaroxaban to enoxparin thromboprophylaxis in 2531 patients undergoing elective knee arthroplasty [11]. Once again, the risk of major VTE was significantly reduced in the patients randomised to receive rivaroxaban rather than enoxaparin (1% versus 2.6%; p=0.01). Based upon the three RECORD studies, together with six other randomised controlled trials (including a total of more than 15,000 patients), a recent systematic review concluded that oral rivaroxaban 10mg once-daily is superior to subcutaneous enoxaparin in VTE prophylaxis for patients undergoing either THR or TKR [12].

Conclusion

Alternative anticoagulant therapies to warfarin have been long awaited. With the emergence of the NOACs, major changes in clinical practise are likely to emerge in the coming

years. Both direct thrombin and factor Xa inhibitors show great promise. However it is critical to appreciate that the different commercial products have significant differences with respect to their individual pharmacokinetic and pharmacodynamics properties. Furthermore, it remains unclear whether the effectiveness of these novel agents demonstrated in the published clinical trials will also apply in real-world clinical practise. Clearly trial participants are often younger, more motivated, and less likely to have multiple significant co-morbidities such as renal impairment. In addition, patients in the setting of a trial are more likely to be compliant with their daily dosing regimens. Consequently, the importance of close post-marketing surveillance will be of particular significance with respect to optimising the use of the NOACs in general clinical practise. Nevertheless, the novel anticoagulants certainly constitute a major therapeutic advance and provide a unique opportunity to significantly enhance patient care.

CPD 2: Venous Thromboembolism

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REFERENCES

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[2] Hunt BJ. The prevention of hospital-acquired venous thromboembolism in the United Kingdom. Br J Haematol. 2009 Mar;144(5):642-52.

[3] Spencer FA, Lessard D, Emery C, Reed G, Goldberg RJ. Venous thromboembolism in the outpatient setting. Arch Intern Med. 2007 Jul 23;167(14):1471-5.

[4] Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest. 1995 Oct;108(4):978-81.

[5] Hunt BJ. Awareness and politics of venous thromboembolism in the United kingdom. Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):398-9.

[6] Shojania KG, Duncan BW, McDonald KM, Wachter RM, Markowitz AJ. Making health care safer: a critical analysis of patient safety practices. Evid Rep Technol Assess (Summ). 2001;(43):i-x, 1-668.

[7] Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010 Mar 6;375(9717):807-15.

[8] Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010 Dec 23;363(26):2487-98.

[9] Li XM, Sun SG, Zhang WD. Apixaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials. Chin Med J (Engl). 2012 Jul;125(13):2339-45.

[10] Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75.

[11] Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86.

[12] Turun S, Banghua L, Yuan Y, Zhenhui L, Ying N, Jin C. A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thromb Res. 2011;127(6)525-34.