APC/DTC Briefing Document

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1 Page 1 London New Drugs Group APC/DTC Briefing Document DABIGATRAN (PRADAXA) FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM Contents Summary 1 Points for consideration 2 Background 3 Hip and knee replacement surgery 3 Coagulation cascade 4 Current therapy 4 Dabigatran 4 Clinical efficacy 6 RE-NOVATE study 8 RE-MODEL study 10 Risk management plan 10 Cost 11 References 12 Appendix 1 14 Appendix 2 15 Appendix 3 16 Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager (Projects & New Products) Contact: Alexandra Denby Regional MI Manager (Projects & New Products) London New Drugs Group Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: alexandra.denby@nwlh.nhs.uk Further copies of this document are available from URL: Summary Dabigatran (Pradaxa) is the first oral, fixed-dose, direct thrombin inhibitor licensed in the UK. It is licensed for the prevention of venous thromboembolic events in adult patients following elective total hip or total knee replacement surgery. No monitoring of its coagulation effects is necessary. By specifically and selectively inhibiting thrombin, dabigatran prevents the conversion of fibrinogen to fibrin and the development of clots. The first oral direct thrombin inhibitor, ximelagatran was withdrawn from the EU market due to the potential to cause severe hepatic injury when used for more than 11 days. Abnormal liver function tests had also been reported with shorter durations of use. Three main phase III studies were conducted: RE-MODEL (total knee replacement), RE-NOVATE (total hip replacement) and RE-MOBILIZE (total knee replacement). RE-MODEL and RE-NOVATE were the two pivotal studies and were conducted in Europe. Dabigatran (150mg and 220mg, both started 1-4 hours after surgery) was compared with enoxaparin 40mg, started the evening before surgery. RE-MOBLIZE was a supportive study conducted in North America and differed from the pivotal studies with respect to: patient randomisation (after surgery), the dose of enoxaparin used (30mg twice daily instead of 40mg, started hours after surgery) and when dabigatran was given (after a delay of hours; reflective of the US perception of the bleeding risk and inconsistent with the recommendations in the UK Summary of Product Characteristics). A limited number of patients in the RE-MODEL and RE-NOVATE trials had concomitant diseases, such as coronary artery disease, heart failure or history of prior VTE. A large proportion of patients (63%-70%) had never smoked, and over 90% were abstinent at trial entry. Only 3.3% to 4.1% of patients were also taking aspirin, which may reflect clinical practice when patient discontinue prior to surgery. As with other trials in this disease area, a quarter of patients randomised into the RE-NOVATE and RE-MODEL trials were not eligible for the primary efficacy analysis, mainly due to missing or inadequate venography data. The primary efficacy analysis for both trials was the total number of venous thromboembolic events (VTE) both asymptomatic (as shown on venograms) and symptomatic (deep vein thrombosis (DVT) or pulmonary embolism (PE)) and all-cause mortality during treatment. The secondary endpoints included major VTEs (composite of proximal DVT and PE) and VTE-related mortality. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 In both pivotal studies a clear dose-response for dabigatran was seen with no significant difference in the rates of major VTE and thrombosis related death with either dose of dabigatran versus enoxaparin. (a trend towards higher efficacy with the 220mg dose, but with an associated small increase in bleeding risk). The absolute difference in the rate of major VTE and VTE related mortality with either dose of dabigatran versus enoxaparin during the treatment period was not significant. For all bleeding outcomes, there was no significant difference between either dose of dabigatran and enoxaparin in either trial. RE-MODEL and RE-NOVATE were non-inferiority trials. This means that the aim of the trials was to demonstrate that dabigatran was not worse than enoxaparin by more than a pre-specified, small amount (the non-inferiority margin). Non-inferiority of dabigatran to enoxaparin for both doses of dabigatran was shown (for both the primary and secondary endpoints). Dabigatran should not be used in patients with raised liver transaminases (more than 2x upper limit of normal). The NHS list prices of dabigatran etexilate are: 10x75mg capsules 21.00; 60 x 110mg capsules These prices do not take into account any local purchasing agreements. The Scottish Medicines Consortium has recently accepted dabigatran for use within NHS Scotland for the primary prevention of VTE events in adult patients who have undergone elective total hip or total knee replacement surgery. Points for consideration The efficacy of dabigatran in the prevention of VTE has only been compared with enoxaparin, the current standard treatment for this indication. The primary endpoint was that for an exploratory, rather than confirmatory trial, i.e. the incidence of patients with total DVT. The number of distal DVTs (symptomatic and asymptomatic), proximal DVT, PE and death from all causes were recommended secondary endpoints. Treatment was longer in the RE-NOVATE study (mean 33 days compared with 8 in the RE-MODEL study) and dabigatran was associated with a lower incidence of asymptomatic, but not symptomatic, VTE. Results do match previous findings which showed a lower incidence of symptomatic VTEs following knee replacement surgery compared with hip replacement. In order to see a significant difference in the rate of symptomatic VTEs between treatments, many thousands of patients would be required. Fewer asymptomatic VTEs occurred in the dabigatran 220mg group than the enoxaparin group in the RE-NOVATE study, and a similar number in the RE-MODEL study. Patients are not routinely given venograms post orthopaedic surgery to determine if there are asymptomatic VTEs occurring as these can cause a small number of DVTs themselves. Asymptomatic VTEs are usually small and resolve spontaneously. Doppler ultrasound is used when clinically indicated. No monitoring is required with dabigatran. Currently available tests are not thought to be sufficiently sensitive to assess the anticoagulant status of patients on dabigatran. The action of dabigatran cannot be immediately reversed if it causes bleeding. Dabigatran has a predictable pharmacokinetic and pharmacodynamic profile; this eliminates the need for routine monitoring. The pivotal trials have shown that dabigatran is non-inferior to enoxaparin for preventing VTE post hip and knee replacement surgery. Both trials used large non-inferiority margins, which makes them underpowered to detect clinically significant differences between dabigatran and enoxaparin. These facets of the trial design reduce confidence in the conclusions that can be drawn about the relative efficacy of LMWH and dabigatran. The advantage of dabigatran is one of convenience, being an oral preparation rather than requiring injection as is the case for heparins. The selection of dabigatran over a LMWH will therefore depend on its cost and adverse event profile. The safety of dabigatran can only be established in trails with a larger number of patients than in the RE-MODEL and RE-NOVATE trials. The RE- VOLUTION trial programme 1 for the treatment, prevention and prophylaxis for several thromboembolic diseases is expected to involve more than 34,000 patients and should give a better picture of the safety of dabigatran.

3 Page 3 Background Venous thromboembolism (VTE) occurs when a blood clot (thrombus) forms in a vein and dislodges from its site of origin. 2 Most thrombi occur in the deep veins in the legs, and are called deep vein thrombosis (DVT). Dislodged thrombi can travel to the lungs and cause a pulmonary embolism (PE). DVT is associated with a number of risk factors, including surgical procedures, with the risk rising with an increased duration of the operation and period of immobility. Each year in England there are 25,000 deaths due to VTE. 2 Over 20% of patients having major surgery and over 40% having orthopaedic surgery will suffer from a DVT. 2 The condition can be asymptomatic, but it can also lead to sudden death due to PE, or cause long-term morbidity because of venous insufficiency and postthrombotic syndrome. 2;3 Over 130,000 total hip and total knee replacements, and femoral hip fractures occur annually and the personal and economic costs associated with VTE are significant. 2 The type of surgery determines the risk of major bleeding as well as the risk of VTE. 2 Data from the NHS Hospital Episode Statistics showed that procedures with the highest risks of VTE were cardiothoracic, major orthopaedic and vascular surgery. Comparisons between different categories of surgery are confounded by age, differences in prophylaxis, length of stay and immobility. 2 Hip and knee replacement surgery The most common post-operative complication after total hip replacement (THR) is DVT, and has been shown by venography in 50% to 60% of cases at any level, and above the knee joint in 10% to 20% of cases. 4 Evidence suggests that the current prevalence of PE, in the absence of any prophylaxis (about 0.4%) is lower than in historical reports. There is debate regarding the precise incidence of VTE after total knee replacement (TKR) 5. It can be shown by venography in 30% to 60% of cases at any level, and in 10% to 20% of cases proximally. Few of these develop a clinical event causing death or morbidity. 4;5 PE can occur more than six weeks after THR surgery and prolonged prophylaxis may be necessary in high risk patients. 4 To be effective, prophylaxis should be given as near to the time of surgery as possible, but avoid bleeding risk. 4 Low molecular weight heparins (LMWH) and warfarin can reduce radiological DVT by 40% to 60%, but bleeding complications may put the surgical wound or implant or patient at risk. 4;5 The Global Orthopaedic Registry records inhospital treatment and clinical outcomes of patients who have undergone elective THR and TKR: data from over 15,000 patients worldwide are available and that from patients undergoing elective THR and TKR have been analysed. 6 Out of 6639 THR patients, 76 experienced a DVT within 3 months of surgery at a mean of 22.5 days (range 6 to 37), whilst 11 had a PE at a mean of 14.3 days (range 2 to 31). The mean time to VTE post THR was 21.5 days (range 5 to 36). Five days after surgery 15% of patients had stopped receiving thromboprophylaxis. Of the 8236 TKR patients, 134 had a DVT within 3 months of surgery (mean 9.5 days, range 3 to 8), whilst 18 had a PE (mean 10.7 days, range 3 to 11). The mean time to VTE post TKR was 9.7 days (range 3-9). Four days after surgery 10% of patients were no longer taking thromboprophylaxis. In total, 98% of patients received pharmacological or mechanical prophylaxis. This data show that prophylaxis is sometimes shorter than recommended and that the increased risk of VTE extends beyond the usual period of hospitalisation. NICE Guidance recommends that all patients undergoing surgery are given thigh length compression/anti-embolism stockings (mechanical prophylaxis) from the time of admission to hospital, unless contra-indicated. 2 Patients having orthopaedic surgery should be offered mechanical prophylaxis and either a LMWH or fondaparinux. Patients having hip replacement surgery with one or more risk factors for VTE should have their LMWH or fondaparinux continued for 4 weeks. The American College of Chest Physicians recommend that thromboprophylaxis with either a LMWH, fondaparinux or a vitamin K antagonist is given for a minimum of 10 days following hip or knee replacement, and continued for up to 35 days following hip replacement. 7

4 Page 4 Coagulation cascade Once a vessel wall has been injured, tissue factor interacts with plasma factor VII and activates the coagulation cascade (see Figure 1 in Appendix 1). Thrombin is produced after activation of a number of proenzymes. Thrombin converts soluble fibrinogen to fibrin, activates factors V, VIII and XI, which generate more thrombin, and stimulates platelets. In addition, the activation of factor XIII leads to clot stabilisation. 8 Natural anticoagulants, such as tissue factor pathway inhibitor, protein C and protein S, and antithrombin, regulate the cascade and help restrict the formation of the haemostatic plug to the site of injury. Current therapy Anticoagulant therapy, such as warfarin, heparin and low molecular weight heparins (LMWHs) lower the incidence of VTE, as shown in numerous clinical trials. 3 They can reduce the risk of VTE by more than 60% irrespective of the type of surgery. 9 There are, however, limitations with these therapies. For example, warfarin has a narrow therapeutic index and variable anticoagulant effect due to interactions with some foods and medications. 3;10 Coagulation monitoring is essential and dose adjustment necessary to avoid serious adverse effects. Parenteral anticoagulants, such as heparin and fondaparinux are inconvenient to use after discharge. 3 Warfarin reduces the functional levels of factors II (prothrombin), VII, IX and X. 10 Direct thrombin inhibitors (DTI) Direct thrombin inhibitors, such as dabigatran etexilate, bind directly to the active catalytic site of thrombin (factor IIa 10 ) that is responsible for biological activities. This blocks thrombin s capacity to activate platelets, convert fibrinogen to fibrin and amplify its own generation by activating factors V, VIII and XI. 3;10 [See Appendix 1]. DTIs also block the activation of protein C and thrombin-activatable fibrinolysis inhibitor by the thrombin/ thrombomodulin complex. 10 Other available DTIs (also known as hirudins) are bivalirudin and lepirudin but, unlike dabigatran which is given orally, both of these are given by parenteral injection only. 11 DTIs have potential advantages in relation to heparin and warfarin, such as: 3 The ability to inhibit clot-bound thrombin. Resistance to neutralisation by platelet factor 4. Lack of heparin-induced thrombocytopenia (HIT). The possibility of avoiding the requirement for coagulation monitoring by providing a more predictable dose response. As with all anticoagulants, the balance between antithrombotic efficacy and the risk of bleeding is critical. Ximelagatran was the first oral DTI licensed for use in a number of European states, for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. 12 In February 2006, the European marketing authorisation application for a new indication for ximelagatran (for the prevention of stroke and other thromboembolic events associated with atrial fibrillation) was withdrawn. 12 This was due to reports of severe liver injury during long term use (more than 11 days treatment). Abnormal hepatic laboratory values had previously been reported during shorter term use. AstraZeneca voluntarily withdrew all marketed melagatran- and ximelagatran-containing medicinal products. This hepatotoxicity has prompted intense scrutiny of the potential hepatic side effects of all new oral anticoagulants. 10 Dabigatran 13;14 Dabigatran etexilate is a small molecule prodrug which does not have any pharmacological activity. After oral administration, it is rapidly absorbed and completely converted to dabigatran by esterase-catalysed hydrolysis in the plasma and liver. By inhibiting both free and fibrin-bound thrombin, dabigatran prevents the conversion of fibrinogen to fibrin and thrombus formation. Dabigatran also inhibits thrombininduced platelet aggregation. Dose 13;14 Dabigatran etexilate is licensed for primary prevention of VTEs in adult patients who have undergone elective total hip or knee replacement surgery. The recommended dose is 220mg once daily (2x110mg capsules). Treatment should be initiated with one 110mg cap-

5 Page 5 sule taken within 1-4 hours of completing surgery and continued with two capsules once daily thereafter. Treatment should continue for 10 days following knee replacement surgery and days following hip replacement surgery. For both surgeries, if haemostasis is not secured, treatment should be delayed. If treatment is not started on the day of surgery, it should be initiated with two capsules daily. Pharmacokinetics 13;14 The absolute bioavailability of dabigatran following oral administration is 6.5%. Peak plasma concentrations are obtained at 6 hours after administration in a post-operative setting, taking into account factors such as anaesthesia, gastrointestinal paresis and surgical effects independent of the oral medicinal product formulation. Food does not affect the absorption of dabigatran but delays the time to peak plasma concentration by 2 hours. The pharmacokinetics of dabigatran are not affected by body weight, gender, smoking or alcohol consumption. Plasma concentrations fall to less than 25% of the maximum concentrations within 12 hours of a single dose, and to approximately 30% of the maximum concentration 8 hours once in steady state. This suggest that in patients requiring surgery, a wait of only 12 hours after the last dabigatran dose would be required. 15 Special populations 13;14 There is limited clinical experience in patients with moderate renal impairment (creatinine clearance 30-50ml/min) and the elderly (>75 years): the dose should be reduced to 150mg daily (2x75mg capsules). The treatment should be as above, but replacing the 110mg capsules with 75mg for both initiation and maintenance.. Although over 99% of the efficacy and safety data were carried out in Caucasians the SPC states that ethnic origin does not affect the pharmacokinetics of dabigatran in a clinically relevant manner. No pharmacokinetic data from black patients are available. aminotransferase (ALT) should be measured as part of the standard pre-operative evaluation. If switching from dabigatran etexilate to a parenteral anticoagulant, it is recommended to wait 24 hours after the last dabigatran etexilate dose. If switching from a parenteral anticoagulant to dabigatran etexilate, the dabigatran dose should be given after the next scheduled dose of the parenteral anticoagulation would be due. Interactions 13;14 Concomitant use with the following medications is not recommended with dabigatran etexilate: other parenteral and oral anticoagulants, GPIIb/IIIa receptor antagonists, clopidogrel, dextran, sulfinpyrazone and vitamin K antagonists. Unfractionated heparin can be used at a dose to maintain a patent central venous or arterial catheter. Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 enzyme system and have no effect on the CYP450 enzymes. Amiodarone inhibits the efflux transport P-glycoprotein and dabigatran etexilate is a substrate of this transporter. Concomitant administration increases the maximum concentrations of dabigatran etexilate. The dose should be reduced to 150mg daily in patients who are also receiving amiodarone treatment, and consideration of the long-half life of amiodarone must be taken into account as the potential for drug interactions may persist after such treatment has been discontinued. Caution should be exercised when administering with strong P-glycoprotein inhibitors such as verapamil, clarithromycin and others as systemic exposure of dabigatran may be increased; use with the strong P-glycoprotein inhibitor quinidine is contraindicated. Potent P-glycoprotein inducers, such as St John s Wort, may reduce systemic exposure of dabigatran. No changes on digoxin or dabigatran exposure were noted when both were use concomitantly. Patients with elevated liver enzymes (>2x upper limit of normal) were excluded from the trials: the use of dabigatran etexilate in this population is not recommended. Alanine

6 Page 6 Clinical efficacy Three main phase III studies were conducted: RE-NOVATE 16 (total hip replacement), RE- MODEL 17 (total knee replacement), and RE- MOBILIZE 18 (total knee replacement) (see table 1). The first two studies were pivotal studies conducted in Europe. RE-MOBILIZE was a supportive study conducted in North America and used the US-approved enoxaparin dosing regime, which differs from that in Europe (i.e. 30mg twice daily instead of 40mg once a day), randomised patients post-surgery and administered dabigatran with a longer post-surgical delay compared to the other phase III studies (12-25 hours post surgery). 18 This dosing schedule is not recommended in the Summary of Product Characteristics (SPC). Aims The aim of the RE-NOVATE 16 and RE- MODEL 17 studies was to assess the efficacy and safety of two doses of dabigatran etexilate ( dabigatran ) (150mg and 220mg once daily) based on a non-inferiority design in comparison with enoxaparin 40mg daily, for the prevention of VTE after total hip and total knee replacement respectively. [See Appendix 2 for details of non-inferiority trials]. Patients There was a wide range of exclusion criteria, including any history of bleeding, haemorrhagic stroke, severe liver disease, ALT or aspartate aminotransferase (AST) over twice the upper limit of normal (ULN) and severe renal impairment. In the RE-NOVATE study, patients with coronary artery disease, chronic heart failure, history of VTE or history of malignancy were excluded. The choice of exclusion criteria limited the at-risk patient population and ensured that that enrolled was more homogenous. An observational cohort study including patients with moderate renal impairment or elderly is to be carried out. 18 A large proportion of the patients (63% in RE- NOVATE and 70% in RE-MODEL) had never smoked and more than 90% were abstinent at the time of surgery. 18 A small percentage of patients with concomitant diseases known to increase the risk of DVT were included. Treatment All patients received one active and one placebo treatment. 16,17 The first dabigatran dose was halved (110mg or 75mg) and given 1-4 hours after surgery providing there was good haemostasis. If administration was delayed until the day after surgery, the full dose was given fol- Table 1: Phase III studies of dabigatran etexilate for VTE prevention. 18 Study Design Key endpoints Treatment groups RE-NOVATE (n=3494) [pivotal European study] RE-MODEL (n=2101) [pivotal European study] RE-MOBILIZE (n=2615) [supportive US study] Randomised, double-blind, parallel group. Total hip replacement Randomised, double-blind, parallel group. Total knee replacement. Randomised, double-blind, parallel group. Total knee replacement. Primary: total VTE (confirmed PE, confirmed symptomatic DVT, or DVT detected by venography) and all cause mortality. Secondary: Major VTE (at least one of the following: confirmed PE, confirmed symptomatic proximal DVT or proximal DVT detected by venography) and VTE-related mortality. Dabigatran 220mg (n=1157) Dabigatran 150mg (n=1174) Enoxaparin 40mg (n=1162) All treatments given once daily (od) for days. Dabigatran 220mg (n=693) Dabigatran 150mg (n=708) Enoxaparin 40mg (n=699) All treatment given once daily for 6-10 days. Dabigatran 220mg od (n=862) Dabigatran 150mg od (n=877) Enoxaparin 30mg twice daily [US dose] (n=876)

7 Page 7 lowed by a second dose at least 12 hours later. Enoxaparin was given the evening before surgery (though in some countries it was started post-operatively to reflect local practice). Subcutaneous heparins can more commonly cause bleeding at the injection site than subcutaneous placebo and could unblind the treatment. 19 The investigators state that, although they agree with the issue, in individual cases it would be difficult to differentiate between treatments owing to a wide variation in patients responses. 20 Treatment was continued for days in the RE-NOVATE study and 6-10 days in the RE-MODEL study, until mandatory bilateral venography, which was done within 24 hours of the last dose. 16;17 [In the UK the dose of enoxaparin, for prophylaxis of DVT after orthopaedic surgery in high risk patients, is 40mg daily for 7-10 days 11 ]. Concomitant low-dose aspirin (less than 160mg) and selective COX-2 inhibitors were allowed during treatment, as were elastic compression stockings. Similar proportions of patients in each treatment group were taking aspirin or using compression stockings in the RE-NOVATE study. 20 Study design and endpoints The RE-MODEL and RE-NOVATE studies were therapeutic exploratory trials. Total VTE (venographic (asymptomatic) or symptomatic DVT or PE) and all-cause mortality were chosen as the primary endpoint for the pivotal trials. 18 Since the European marketing application for dabigatran, the CHMP Guideline has been revised and acknowledges total VTE as a primary endpoint. Major VTE and VTE-related mortality was chosen as secondary endpoints. Other secondary efficacy outcomes were proximal (nearer to the hip joint) and distal (further from the hip joint) DVT, incidence of total VTE and all-cause mortality during follow-up. 16;17 The most clinically relevant endpoint in therapeutic confirmatory trials is considered to be a composite endpoint consisting of proximal DVT (asymptomatic and symptomatic), symptomatic non-fatal PE and VTE-related death or death due to any cause. 21 Even though the dabigatran development programme included over 8000 patients, the individual studies could not be powered adequately to reliably assess efficacy for this composite endpoint. 18 Very large study populations are needed in order to show non-inferiority to LMWH, because the use of these has significantly reduced the overall frequency of major VTE and VTE-related mortality. The Full Analysis Set (FAS) population comprised of those patients who were randomised, had surgery, received at least one dose of study medication and had evaluable data for VTE, or who died during treatment, and were included in the primary efficacy analysis. The per protocol (PP) population was the FAS who did not have relevant protocol deviations, and would be used if the FAS fell below 90% of the primary efficacy analysis population. 18;22 Both populations provided similar results. 18 Patients with missing or inadequate bilateral venography who neither died nor suffered with a VTE, were excluded from the efficacy analyses. 16;17 The studies were powered for separate comparisons between enoxaparin and each dabigatran dose. For non-inferiority trials the per-protocol and intention-to-treat (ITT) populations are usually analysed. The per-protocol analysis is usually the primary form of analysis with the ITT acting as a sensitivity analysis. The ITT tends to reduce the size of any difference between 2 groups, and when the trial is designed not to find a difference it provides a less robust comparison. Non-inferiority margin The non-inferiority margin was based on existing trials where enoxaparin or placebo was given for days, rather than days as used in the RE-NOVATE study. For the RE- NOVATE study it was an absolute difference of 7.7%: a study with 720 assessable patients per group would have 95% power to reject the hypothesis that the primary outcome with dabigatran would be 7.7% higher than with enoxaparin; in other words the rate of VTE with dabigatran could be as high as 27.7% compared to a rate with enoxaparin of 20%, yet would be considered non-inferior. The size of the noninferiority margin should be clinically insignificant, but many would argue that an absolute difference of 7.7% is too large to be clinically insignificant. In this case the margin was chosen purely on statistical grounds (derived from the difference between placebo and enoxaparin [See Appendix 2] 16 ). A large non-inferiority margin reduces the sample size but increases the risk of failing to detect a smaller but clinically significant margin of inferiority. The non-inferiority margin for the RE-MODEL study was similarly high at 9.2% resulting in a sample size of 500 assessable patients per group with a 90% power to reject the hypothesis that the primary outcome with dabigatran would be an absolute increase of 9.2% com-

8 Page 8 pared to enoxaparin when the VTE rate with enoxaparin was as high as 48%. 17 Safety outcomes The primary safety outcome in both RE- NOVATE and RE-MODEL was the occurrence of bleeding events during treatment. 16;17 Bleeding was classified according to the International Society on Thrombosis and Haemostasis (ISTH) Guidelines for medical patients: 21 Fatal bleeding Clinically overt bleeding associated with a decrease in haemoglobin of more than 20g/L compared with baseline. Clinically overt bleeding leading to transfusion of two or more units of blood or packed cells. Critical bleeding (intracerebral, intraocular, intraspinal, pericardial or retroperitoneal). Bleeding requiring treatment cessation. Bleeding at the surgical site leading to reoperation or unusual medical intervention. Main results In the pivotal studies non-inferiority to enoxaparin of both doses of dabigatran for both the primary and secondary endpoints was shown. 16;17 The absolute difference in the rate of major VTE and VTE-related mortality with either dose of dabigatran vs. enoxaparin during the treatment period was not statistically significant. There was a clear dose-response for dabigatran: a trend towards higher efficacy with the 220mg dose was seen, but with an increase in bleeding risk. 18 The advantage of dabigatran is that it is orally administered and, like enoxaparin, does not need laboratory monitoring. Very few patients used concomitant aspirin [at a dose up to 160mg/day within 7 days of surgery: 4.1% in the RE-NOVATE study and 3.3% in the RE-MODEL study]. NSAIDs with a half life >12 hours were not allowed within 7 days of surgery: overall 55.2% in the RE-NOVATE study and 63.7% in the RE-MODEL study used NSAIDs concomitantly. 18 The effects of aspirin on bleeding events cannot be evaluated, though the authors state that no significant difference in efficacy or safety among patients using either therapy alone or in combination was seen. 20 There was no statistically significant difference in the rates of bleeding events during the treatment periods. In the RE-NOVATE study there were numerically more patients with major bleeding events in the dabigatran 220mg group (23, vs. 15 on 150mg and 18 on enoxaparin). More patients in this group had a fall in haemoglobin of 20g/L or more (18, vs. 12 and 12 respectively) and more transfusions of two or more units of blood were given (21 vs. 8 and 16 respectively). In the RE-MODEL study three transfusions of two or more units of blood were given in the dabigatran 220mg group compared with enoxparin (8 vs. 5). [See Appendix 3]. The use of transfusions is difficult to assess as no strict rules on when to transfuse were given. 18 Transfusions in a clinical setting are normally based on haemodynamic parameters, but these are not stated in the trials. 18 The incidence of liver enzyme elevation >3x ULN occurring with dabigatran was comparable to enoxaparin. All levels returned to baseline or the ULN with follow up. The frequency of acute coronary events (ACS) (unstable angina, myocardial infarction and cardiac death) was low and did not differ significantly between the groups. This suggests no evidence of any rebound effect on coagulation after stopping treatment. Further details of the individual trials follow and full details of the results are in Appendix 3. RE-NOVATE Study Of the 3494 adult patients (average age 64 years) undergoing total hip replacement randomised into the RE-NOVATE study, 2651 (76%) were included in the primary efficacy analysis. 16 It was assumed that 35% of patients would not have assessable venograms. Most patients had neuraxial anaesthesia (66% in the dabigatran 150mg group, 66% in 220mg group and 68% in the enoxparin group). General anaesthesia alone was used in 26%, 24% and 24% respectively, and a combination was used in 8%, 10% and 8% respectively. The duration of surgery was, on average, 85 minutes. Median duration of treatment was 33 days, with 87% receiving treatment for days. The primary efficacy outcome (total VTE and all-cause mortality during treatment) was seen

9 Page 9 in 8.6% of the dabigatran 150mg group, 6.0% of the dabigatran 220mg group and 6.7% of the enoxaparin group. Both doses of dabigatran were statistically non-inferior to enoxaparin (p< for both) according to the investigators definition. The absolute risk difference (ARD) between enoxaparin and dabigatran 220mg was 0.7%, meaning that for every 1000 patients treated with dabigatran, 7 will not suffer with a VTE (95% CI -2.9 to 1.6%). The ARD between enoxaparin and dabigatran 150mg was -1.9%, indicating that more patients treated with this dose of dabigatran will suffer with a VTE than those treated with enoxaparin (95% CI -0.6 to 4.4%). Extending the treatment with dabigatran from 7 days (as used in the dose ranging study) to 33 days, reduced the occurrence of VTE by approximately 50%. The low occurrence of symptomatic events (1% and 0.8% in the dabigatran 220mg and 150mg groups, and 0.3% in the enoxaparin group) should be interpreted with caution, since the study was not powered to investigate these lowfrequency events. Twenty four percent of the patients were not available for assessment for the primary outcome (dabigatran 220mg, 23.9%; dabigatran 150mg, 25.6% and enoxaparin 22.8%). 20 There were no significant differences in the numbers not assessed between the treatment groups. The authors state that large proportions of non-assessable patients are an unavoidable result of the use of venography, due to inadequate venograms or patients unable to undergo the procedure. 16 The number in this study is consistent with that reported in previous studies that used venographic DVT as an endpoint, and lower than the 35% anticipated at study initiation. Using venographic DVT as an endpoint could be considered a weakness of the trial. Both the European Health Authorities and the American College of Chest Physicians recommend the use of a composite endpoint of clinical events with asymptomatic venographic DVT. Asymptomatic and symptomatic VTEs were roughly equally split into proximal and distal independent of the treatment group. 16 Slightly more patients in the dabigatran 220mg group suffered with symptomatic DVT or PE compared with those in the enoxaparin group. There was no significant difference in the absolute difference of major VTEs and VTE-related mortality with either dose of dabigatran compared with enoxaparin (0.4% with 150mg, p=0.33; -0.8% with 220mg, p=0.71). During follow-up one patient in each group developed symptomatic events. Moderate increases in ALT (>3 times the ULN) occurred in more patients in the enoxaparin group (60/1122, 5%) compared with dabigatran 220mg (34/1117, 3%, p=0.0081) or 150mg (34/1124, 3%, p=0.0061). No clinical signs or symptoms were attributable to these abnormalities apart from one patient with cholangitis who was treated with dabigatran. All ALT concentrations returned to baseline or the ULN with additional follow up (in one case this took over 2 years). At all time points during treatment the occurrence of raised liver enzymes with either dabigatran dose was consistently lower than with enoxaparin. ACS events occurred in five patients in the dabigatran 220mg group, eight in the 150mg group and nine in the enoxaparin group during treatment and in three patients in the enoxaparin group during follow up. The RE-NOVATE results show that dabigatran is not inferior to enoxaparin in reducing the risk of VTEs after hip replacement therapy. There were limitations to this trial. High drop-out rates are a particular problem in non-inferiority trials as they make it more likely that the trial will fail to detect a real difference and erroneously confirm non-inferiority. The sensitivity analysis assumes that either all or none of those with missing data had the outcomes. 23 Despite the authors argument for robust results, it still stands that three times as many patients had missing data as there were patients with events. Even a small imbalance between the groups could have an important effect. What must be recognised is that the effects of these missing data are unknown. When patients drop out of the study, for example because of missing data, results of using the full analysis set may be biased towards demonstrating equivalence. 22 As dabigatran was noninferior on efficacy, it is the safety considerations that will be the dominant factor in selecting therapy. 23 Similar safety profiles were reported across the groups; however tens of thousands of patients will be required to provide definitive comparisons.

10 Page 10 RE-MODEL In the RE-MODEL study a total of 2101 adult patients (average age 68 years) undergoing total knee replacement were randomised to treatment and 1541 patients (73%) were included in the primary efficacy analysis. 17 It was assumed that 25% of the patients would not have evaluable venograms. The mean duration of therapy was 8 days, with 92% treated for 6-10 days. Most patients had neuraxial anaesthesia (49% in the dabigatran 150mg group, 47% in 220mg group and 48% in the enoxparin group). General anaesthesia alone was used in 22%, 24% and 22% respectively, and a combination was used in 29%, 29% and 30% respectively. The duration of surgery was, on average, 90 minutes. The primary outcome (total VTE and death) occurred in 40.5% in the dabigatran 150mg group, 36.4% in the dabigatran 220mg group and 37.5% in the enoxaparin group. 17 This rate is consistent with incidences seen in other knee replacement studies using the same venogram technique (44%-46%). The ARD between the groups was -1.3% for dabigatran 220mg (95% CI -7.3 to 4.6%) and 2.8% for dabigatran 150mg (95% CI -3.1 to 8.7%). As in the RE-NOVATE study, the incidence of symptomatic VTE was low whilst the incidence of asymptomatic VTE was higher. The majority of VTEs (both asymptomatic and symptomatic) were distal in all three groups. There was no significant difference in the incidence of major VTEs and VTE-related mortality with either dose of dabigatran compared with enoxaparin (3.8% and 2.6% with dabigatran 150mg and 220mg respectively and 3.5% with enoxaparin). Adverse events leading to treatment discontinuation occurred in 3.7% (both dabigatran groups) and 4.6% (enoxaparin group) of patients. ALT levels >3 x ULN were seen in 2.8%, 3.7% and 4.0% of the dabigatran 220mg and 150mg, and enoxaparin groups respectively. One patient in the dabigatran group also had raised bilirubin levels (2 x ULN); the changes in the liver enzymes were seen following subsequent surgery during which dabigatran was not used. In all cases, levels returned to normal range during followup. During treatment there were three cases of acute coronary events in the dabigatran 220mg group, seven in the 150mg group and four in the enoxaparin group. During follow-up there were three cases (one in the 150mg group and two in the enoxaparin group). No other adverse events were reported by the investigators. The RE-MODEL study showed that oral dabigatran was non-inferior to enoxaparin at preventing VTE following total knee replacement surgery, according to the investigators definition. There was no difference between the two dabigatran doses and enoxaparin with respect to bleeding and adverse events. The sensitivity analysis assumed that either all or none of those with missing data had the outcomes this amounted to a quarter of the number of patients randomised. As in the RE-NOVATE trial, the non-inferiority of dabigatran to enoxaparin means that the adverse event profile will be important in choosing treatment. Risk management plan The marketing authorisation application to the EMEA included a risk management plan (RMP). 18 There were two safety concerns: Bleeding. The proposed risk minimisation activities are an updated RMP which included a prescriber guide to educate them of the methods and interpretation of coagulation testing for dabigatran.* An observation cohort study on the risk of bleedings is to be conducted in the general population of patients with an increased risk of bleeding. Hepatotoxicity. The proposed risk minimisation activities are that the SPC will state a contraindication for hepatic impairment or liver disease and that increase of hepatic enzymes is an undesirable effect. The SPC will also state that patients with liver enzymes >3xULN were excluded in controlled trials and therefore dabigatran should not be used in these patients. ALT should be measured as part of the standard pre-operative evaluation. The CHMP did not consider any additional risk minimisation activities would be required. 18 *The CHMP states in the European Public Assessment Report that there is no assay sufficiently sensitive and standardised to assess routinely the anticoagulant status of patients following dabigatran administration. Commercially available thrombin time (TT) test kits developed for measuring TT after administration of direct thrombin inhibitors, such as hirudin, will be validated for measuring the TT of dabigatran. 18

11 Page 11 Cost The NHS list prices of dabigatran etexilate are: 75mg: 10 capsules 21.00; 60 capsules mg: 10 capsules 21.00; 60 capsules These prices do not take into account any local purchasing arrangement. The initial dose is 110mg within 1-4 hours of completed surgery, then 220mg once daily. In moderate renal impairment (Cr Cl ml/min) or patients >75 years the dose should be reduced: initial dose 75mg, then 150mg once daily. After knee replacement surgery continue treatment for a total of 10 days; after hip replacement surgery for days. The following table shows the costs of LMWH and fondaparinux, but do not take into account any local purchasing arrangements. Drug Dose [for prophylaxis of DVT by subcutaneous Cost 11 injection in high risk surgical patients] 11 Bemiparin (Zibor) Dalteparin (Fragmin) Enoxaparin (Clexane) 3500units 2 hours before or 6 hours after surgery then 3500units every 24 hours for 7 10 days 2500units 1 2 hours before surgery, then 2500units 8 12 hours later (or 5000units on the evening before surgery, then 5000units on the following evening), then 5000units every 24 hours for 5 7 days or longer (5 weeks in hip replacement) 40mg (4000units) 12 hours before surgery then 40mg (4000units) every 24 hours for 7 10 days 0.2-mL (3500-unit) prefilled syringe = mL (2500-unit) syringe = mL (5000-unit) syringe = mL (40-mg, units) syringe = 4.20 Fondaparinux (Arixtra) 2.5mg 6 hours after surgery then 2.5mg once daily for 5 9 days (longer after hip surgery) 0.3-mL (1.5-mg) prefilled syringe = 6.67 Tinzaparin (Innohep) 50units/kg 2 hours before surgery, then 50units/kg every 24 hours for 7 10 days or 4500units 12 hours before surgery, then 4500units every 24 hours for 7 10 days 4500-unit (0.45-mL) syringe = 3.83

12 Page 12 Reference List (1) Further phase III data shows dabigatran etexilate, a new oral anticoagulant, is effective and safe in preventing venous thromboembolism after orthopaedic surgery. July 11th Boehringer Ingelheim Limited press_releases/detail.asp?id=4734 (2) Venous thromboembolism. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. NICE clinical guideline 46. NICE Issue date: April (3) Eriksson BI, Dahl OE. Prevention of venous thromboembolism following orthopaedic surgery. Clinical potential of direct thrombin inhibitors. Drugs 2004; 64(6): (4) Primary total hip replacement: A guide to good practice. British Orthopaedic Association (5) Knee replacement: A guide to good practice. British Association for Surgery of the Knee (6) Warwick D, Friedman RJ, Agnelli G et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events. Findings from the Global Orthopaedic Registry. J Bone Joint Surg Am 2007; 89(B): (7) Geets WH, Bergqvist D, Pineo GF et al. Prevention of venous thromboembolism. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008; 133:381S-453S. (8) Di Nisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005; 353: (9) Committee for Medicinal Products for Human Use (CHMP). Guideline on the choice of the non-inferiority margin. January European Medicines Agency (EMEA) Doc ref: EMEA/CPMP/ EWP/2158/99 Adoption by Committee: July (10) Eikelboom JW, Weitz JI. A replacement for warfarin. The search continues. Circulation 2007; 116: (11) Joint Formulary Committee. British National Formulary, 55th edition. London. BMJ Group and RPS Publishing (12) Press release. AstraZeneca withdraws its application for Ximelagatran 36-mg film-coated tablets. European Medicines Agency (EMEA) Doc ref: EMEA/57827/2006 (13) Pradaxa 110mg hard capsules. Boehringer Ingelheim Limited Date of first authorisation/renewal of the authorisation: 18th March 2008 Date of access: 12/05/08 (14) Pradaxa 75mg hard capsules. Boehringer Ingelheim Limited Date of first authorisation/renewal of the authorisation: 18th March Date of access: 12/05/08. (15) Stangier J, Rathgen K, Stahle H et al. The pharmaokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64(3):

13 Page 13 (16) Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, doubleblind, non-inferiority trial. Lancet 2007; 370: (17) Eriksson BI, Dahl OE, Rosencher N et al. Oral dabigatran etexilate vs.subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5: (18) CHMP Assessment Report for Pradaxa. European Medicines Agency (EMEA). Ref: EMEA/174363/ pradaxa.htm Date of access: 12/05/08. (19) Pechlaner C, Marschang P. Dabigatran versus enoxaparin after total hip replacement. Lancet 2007; 370:2002. (20) Eriksson BI, Hantel S, on behalf of the RE-NOVATE Investigators. Author's reply. Lancet 2007; 370:2003. (21) Guideline on clinical investigation for medicinal products for prophylaxis of high intra- and post-operative venous thromboembolic risk. Committee for Medicinal Products for Human Use (CHMP) Ref: CPMP/EWP/707/98 Rev.1 corr Adoption by the CHMP: 15 November (22) ICH Topic E9. Statistical Principles for Clinical Trials. Note for guidance on statistical principles for clinical trials. September European Medicines Agency (EMEA) Doc ref: CPMP/ ICH/363/96. (23) Norrie J. Trials of venous thromboembolism prevention. Lancet 2007; 370: (24) Chapter 134. Hemostasis. In: Beers MH, Porter RS, Jones TV, et al. (editors). The Merck Manual of Diagnosis and Therapy. Eighteenth edition. New Jersey: Merck Research Laboratories., qt=hemostasis&alt=sh (25) Committee for Proprietary Medicinal Products (CPMP). Points to consider on switching between superiority and non-inferiority. European Medicines Agency (EMEA). 27 July Doc ref: CPMP/ EWP/482/99 (26) British HIV Association guidelines for the treatment of HIV-1 infected adults with antiretroviral therapy Pre-press version. BHIVA This document was written by the London New Drugs Group. The LNDG would like to thank Mr Simon Mellor, Consultant Orthopaedic Surgeon, Barnet General Hospital, Robin Offord, Director of Clinical Pharmacy, ULC Hospitals NHS Foundation Trust, Gary Masterman, Clinical Lead Pharmacist (Musculoskeletal)/Pharmacy Manager and Catrina Stewart, Musculoskeletal Pharmacist, Wrightington Hospital for their comments on the review. Boehringer Ingelheim have been given the opportunity to comment on this review.

14 Page 14 Appendix 1: Hemostasis 24 Plasma coagulation factors interact to produce thrombin, which converts fibrinogen to fibrin (see figure 1). Fibrin combines with platelets to form a clot and strengthens it by radiating from and anchoring it. There are two pathways involved: Intrinsic pathway: Factor XII, kininogen, prekallikrein and activated factor XI (XIa) produce factor IXa from factor IX. Factor IXa then combines with VIIIa and procoagulant phospholipid to form a complex that activates factor X. Extrinsic pathway: Factor VIIa and tissue factor directly activate factor X. Activation of either pathway activates the common pathway and results in clot formation. There are three steps: 1. A prothrombin activator, consisting of factor Xa, Va and procoagulant phospholipid, is produced. 2. This activator cleaves prothrombin into thrombin. 3. Thrombin induces the generation of fibrin polymers from fibrinogen. Thrombin also activates factor XIII, an enzyme which catalyses formation of stronger bonds between fibrin molecules, as well as factors VIII and XI. Calcium ions are needed for most thrombin-generating reactions. Clotting factors II, VII, IX and X are vitamin-k dependent and cannot normally bind to phospholipid surfaces or function in blood coagulation when made in the absence of vitamin K. Figure 1: Thrombin generation 4 XIa IXa + VIIIa Activated protein C + Protein S Thrombomodulin Tf-VIIa Xa + Va Thrombin (IIa) Fibrin Plasmin Fibrinolysis Tissue factor pathway inhibitor Antithrombin Thrombin Dabigatran Activation pathway Inhibitory pathway Tf: tissue factor Plasma factors: Va, VIIa, VIIIa, IXa, Xa, XIa