Medicine Review (Adopted by the CCG until review and further notice) Medicine

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1 East & South East England Specialist Pharmacy Services East of England, London, South Central & South East Coast East Anglia Medicines Information Service Medicine Review (Adopted by the CCG until review and further notice) Medicine Dabigatran etexilate Product /manufacturer Pradaxa, Boehringher Ingelheim Document status Agreed at NHS Suffolk Drug & Therapeutics Committee meeting on March 18 th Date of last revision 6 January 2010 Traffic Light decision DOUBLE RED (pending NICE) -Prescribing not supported in either general practice or secondary/tertiary care Prescribers rating A real advance - The product is an important therapeutic innovation but has certain limitations. Mechanism of action Medicine class Proposed indication Dosage Treatment alternatives Dabigtatran etexilate is converted to its active form dabigatran by a serum esterase which is independent of cytochrome P450. Dabigatran is a specific and reversible direct thrombin inhibitor. Thrombin is a key enzyme in blood clot formation at the end of the coagulation cascade. [1-3] Orally active antithrombotic agent Stroke prevention in patients with atrial fibrillation (AF) 150mg twice daily or 110mg twice daily Warfarin, aspirin, clopidogrel People at low risk of stroke should be offered aspirin, people at high risk of stroke should be offered warfarin and those at moderate risk of stroke should be offered aspirin or warfarin depending on risk factors. [4] In patients with AF, warfarin prevents 64% of strokes, however due to several factors it is prescribed to only two thirds of appropriate candidates. Factors include drug and dietary interactions, inconvenience of INR monitoring and risk of haemorrhage.[5] Place in therapy The National Prescribing Centre (NPC) have produced a review of the RE- LY study and suggest that dabigatran may be an appropriate option for those patients who cannot take warfarin, or undergo the monitoring required, or where control of anticoagulant status is poor, despite best efforts. Dabigatran has the considerable advantage that, unlike warfarin, it does not require regular anticoagulant monitoring and it has fewer clinically important food and drug interactions. [6, 7] An editorial in the New England Journal of Medicine relating to the RE-LY study reasons that because of dabigatrans twice daily dosing and a greater risk of non-haemorrhagic side effects, patients already taking warfarin with excellent INR control have little to gain by switching to dabigatran. However, many other patients who have AF and at least one additional risk factor for stroke could benefit from dabigatran. [5] Future alternatives Evidence for use Rivaroxaban oral factor Xa inhibitor The PETRO study was a 12 week, phase II, randomised, open label, active

2 control study which compared several fixed doses of dabigatran (50mg, 150mg or 300mg twice daily) with and without aspirin (81mg or 325mg daily) to warfarin alone in patients with AF to establish a dose response for bleeding events and an upper limit of tolerability based on the frequency of major and clinically significant bleeding events. [8] Dabigatran 300mg with aspirin had significantly more clinically relevant major bleeding events than dabigatran 300mg without aspirin (p=0.03). Dabigatran 50mg had significantly fewer bleeding events than warfarin (p=0.044). Increasing dabigatran dose was associated with increased bleeding. The results also showed that based on bleeding rates and anticoagulant activity, dabigatran 150mg twice daily was well tolerated and effective. Serious liver toxicity was not seen. The RE-LY study was a Phase III clinical trial with a prospective, randomized, open-label, blinded endpoint (PROBE) design. It evaluated the non-inferiority of two doses of dabigatran (110mg and 150mg twice daily) compared with warfarin in people with AF who were at moderate to high risk of stroke. The primary efficacy endpoint of the trial was incidence of stroke (including haemorrhagic) and systemic embolism. The primary safety endpoint was major bleeding. [7] Over a median two-year follow-up, the study found that the lower dose of dabigatran was non-inferior to warfarin at reducing the risk of stroke and systemic embolism in people with AF. The higher dose was found to be statistically significantly more effective than warfarin. Low dose dabigatran was associated with a reduced risk of major bleeding, whereas there were no significant differences between the high-dose dabigatran and warfarin. The PETRO and RE-LY trials are detailed in table 1. The NPC review of the RE-LY study provides a critical appraisal of the trial [6]: The studies main limitation, in terms of design, is its open-label nature. Both patients in the study, and the physicians allocating treatment, were aware of the treatment allocated (although allocation of dabigatran doses was blinded); this has potential to introduce considerable bias into the study. The independent blinded assessment of outcomes which took place mitigates this effect to some degree, at least for the objective outcomes. More patients discontinued treatment with dabigatran than warfarin during the study, which might be due to poorer tolerability. A higher incidence of discontinuations that were a result of serious side effects supports this view. However, as patients and physicians knew which treatment (dabigatran or warfarin) were being received this may have raised their perception of possible side effects from the newer drug, and decisions to discontinue may have been taken more readily. The RE-LY study aimed to demonstrate non-inferiority for dabigatran compared with adjustable dosed warfarin. The design allowed for superiority to be tested once non-inferiority was identified, which it was for the primary endpoint. All statistical analyses were conducted according to intention-to-treat principles. A per-protocol analysis, which includes patients who dropped out of the study, may have provided support to the non-inferiority status. Dabigatran was shown to be at least as effective as warfarin in preventing strokes, particularly haemorrhagic strokes, in people with AF

3 who are at moderate or high risk of strokes. This finding, taken together with no greater risk of major bleeding, suggests a possible role as an alternative to warfarin in such patients. The results of this study are not directly applicable to those patient groups who were excluded from the study (e.g. those with recent strokes). In general, the patients included, who were at moderate to high risk of stroke, are the types of patients for which warfarin can be considered according to the NICE AF clinical guideline. [9] In the study, the INR was within the therapeutic range for 64% of the time. Although this seems low, this is similar to other contemporary trials of warfarin and, in this trial, may reflect the high proportion of people in the study who had not received warfarin previously. Nevertheless, some patients will have been more controlled than others, and the study does not address the issue of whether dabigatran would be as effective as warfarin in those people who were well controlled on warfarin. Although, major bleeding was no more frequent between groups overall, the higher risk of GI side effects (both doses) and GI bleeding with dabigatran at the 150mg dose compared with warfarin raises questions about its use in people who are at high risk of these effects. The study only considered dabigatran treatment for a median period of two years, and thus long-term safety is unclear. Serious hepatic sideeffects were the reason for the withdrawal of the license for ximelegatran (another thrombin inhibitor) for a similar indication. Although there were no indications of a difference between treatments with regard to hepatic side effects in the present study, patients with a creatinine clearance of less than 30ml/min were excluded. It is not known whether monitoring of liver enzymes will be required with longterm use of dabigatran. The significantly greater rate of MIs with high-dose dabigatran serves as a signal of potential long-term safety which will need to be considered. The absolute differences in this study were small; nevertheless, this raises particular concerns about the use of dabigatran in people who are at high risk of coronary heart disease. NNT The following NNTs are based on the twice daily 150mg dabigatran dose in the RE-LY study [7]: Prevent 1 systemic embolism or stroke (inc. haemorrhagic stroke) = 172 Prevent 1 non-haemorrhagic stroke = 357 Prevent 1 haemorrhagic stroke = 357 Prevent 1 major bleed = 400 The following NNTs are based on the twice daily 110mg dabigatran dose in the RE-LY study [7]: Prevent 1 systemic embolism or stroke (inc. haemorrhagic stroke) = 625 Prevent 1 non-haemorrhagic stroke = 714 Prevent 1 haemorrhagic stroke = 384 Prevent 1 major bleed = 154 Cautions / contraindications Contraindications & cautions (taken from the current Summary of Product Characteristics which is for primary prevention of venous thromboembolic events (VTE) post total hip and knee replacement surgery, [2]) Hypersensitivity to the active substance or to any of the excipients Patients with severe renal impairment (CrCl < 30 ml/min) Active clinically significant bleeding Organic lesion at risk of bleeding Spontaneous or pharmacological impairment of haemostasis

4 Hepatic impairment or liver disease expected to have any impact on survival Concomitant treatment with quinidine Exclusions from the RE-LY study included - Presence of a severe heart-valve disorder Stroke within 14 days or severe stroke within 6 months Pregnancy There is no experience of dabigatran use in children or adolescents, therefore it can not be recommended due to lack of data on safety and efficacy. Women of child bearing potential should avoid pregnancy during treatment with dabigatran. Studies in animals have shown reproductive toxicity. There are no clinical data on the effect of dabigatran on infants during breast feeding. Breast feeding should be discontinued during treatment with dabigatran. There is no antidote to dabigatran. If an overdose is taken, the patient will be exposed to an increased bleeding risk. Treatment should be discontinued. Drug interactions / side effects Taken from the current Summary of Product Characteristics. [2] The following treatments are not receommedned for concomitant use with dabigatran - unfractionated heparins and heparin derivatives, low molecular weight heparins (LMWH), fondaparinux, desirudin, thrombolytic agents, GPIIb/IIIa receptor antagonists, clopidogrel, ticlopidine, dextran, sulfinpyrazone and vitamin K antagonists. Dabigatran is not metabolised by the cytochrome P450 system and has no effect on human cytochrome P450 enzymes. There is not a pharmacokinetic interaction with diclofenac. However due to the risk of haemorrhage with both dabigatran and NSAIDs, if they are used together, patients should be observed for signs of bleeding. Amiodarone, verapamil and clarithromycin are inhibitors of the efflux transporter P-glycoprotein and dabigatran etexilate is a substrate of this transporter. If dabigatran is co-administered with verapamil or amiodarone, the dose should be reduced to 150mg daily. Rifampicin and St Johns wort are P-glycoprotein inducers and may reduce the systemic exposure of dabigatran, caution is advised if these products are taken together. The following adverse events were noted in the RE-LY study [7] Very common ( 1/10): Dyspepsia Common ( 1/100, <1/10): dizziness, dyspnoea, peripheral oedema, fatigue, cough, chest pain, back pain, arthralgia, nasopharyngitis, diarrhoea, atrial fibrillation, urinary tract infection, upper respiratory tract infection, ALT or AST >3 times upper limit of normal, non serious hepatobiliary disorder NNH The following NNHs are based on the twice daily 150mg dabigatran dose in the RE-LY study [7]: Cause 1 myocardial infarction = 476

5 Cause 1 major GI bleed = 204 Cause 1 serious adverse event leading to discontinuation = 100 Cause 1 serious GI adverse event leading to discontinuation = 67 Cause 1 case of dyspepsia = 19 The following NNHs are based on the twice daily 110mg dabigatran dose in the RE-LY study [7]: Cause 1 myocardial infarction = 526 Cause 1 major GI bleed = 1000 Cause 1 serious adverse event leading to discontinuation = 100 Cause 1 serious GI adverse event leading to discontinuation = 63 Cause 1 case of dyspepsia = 17 Cost within PbR tariff? Cost (price from MIMS Dec 2009) Cost of other drugs & associated services (prices from Jan 2010 Drug Tariff) Yes The cost of dabigatran etexilate for this indication is yet to be determined. Dabigatran for the prevention of VTE costs 4.20 per day, 118 per month & 1529 per year. Drug Dose Cost per 28 days Cost per year Warfarin 3mg daily Aspirin 75mg daily Clopidogrel 75mg daily As dabigatran does not require regular anticoagulant monitoring, there could be a reduction in non-drug costs associated with use of the medicine. However, the costs associated with the current warfarin service will continue due to the need to maintain the existing infrastructure for patients well established on warfarin. The NPC suggest that it seems unlikely that there will be real cost savings until the evidence for alternatives to warfarin becomes more established. [6] The cost of running primary/secondary care anticoagulant clinics varies from per patient per year. [10] Potential number of patients & usage AF is the most common sustained cardiac arrhythmia in the UK. More than 46,000 new cases of AF are diagnosed each year. The prevalence of AF increases with age - at years of age, the prevalence is around 0.5%, by years of age, the prevalence is around 9%. More men than women have AF, when data are adjusted for age. In UK hospitals, 3 6% of people admitted with acute medical conditions have AF. [4] The prevalence of AF is about 1,300 per 100,000 population. The NICE clinical guideline on AF estimated that about 47% of people with AF receive anticoagulant therapy, however another 30% are eligible for therapy but do not receive treatment. [9] Applying these figures to NHS Suffolk (approximate population 610,887), there could be about 8000 people with AF, of which 3,760 are receiving warfarin and another 2,400 are eligible for treatment. Stroke and thromboembolism are the main complications of AF. People with AF have a five-fold greater risk of stroke and thromboembolism than people without AF. The incidence of stroke attributable to AF increases from 1.5% in people years of age to 23.5% in people years of age. Stroke risk is influenced by associated co morbidities, not by the type of AF. Co morbidities include hypertension; diabetes mellitus, congestive heart failure and prior stroke, and the risks are cumulative. [1, 4]

6 Stroke effects between 174 and 216 people per 100,000 population in the UK each year. This equates to between 94,000 and 117,000 people in England and Wales. It is estimated that of these strokes up to 20% are likely to be a complication of AF. About 10% of all people with acute ischaemic strokes will die within 30 days of stroke onset, of those who survive the acute event, about 50% will experience some level of disability after 6 months. When strokes occur in association with AF, patients may experience a greater level of mortality, morbidity, disability and longer hospital stays than with patients without AF. [1] Applying this data to NHS Suffolk there could be people affected by stroke each year and of these, up to may be as a complication of AF. A report by the National Audit Office in 2005 Reducing Brain Damage: Faster Access to better stroke care, stated that the financial cost of treating a person who has suffered a stroke is in the region of 15,000 over 5 years, which increases to 29,000 when informal care costs are included. Cost analysis Based on the figures above, the following may apply: Current annual expenditure on AF patients at risk of stroke - 3,760 people on warfarin at a cost of 14/yr = 52,640 3,760 people attending an anticoagulant clinic = 259, ,200 Total costs = 312, ,840 If the additional 30% of patients with AF who are currently not receiving warfarin were to receive dabigatran, annual expenditure might be 2,400 x 1,529 = 3,669,600 To prevent 1 systemic embolism or stroke (including haemorrhagic stroke), 172 patients need to be treated with dabigatran = 262,988

7 Points for consideration The aadvantages in efficacy and safety in the RE-LY study were small in absolute terms. It is not clear which dose of dabigatran should be prescribed. The RE-LY study followed up patients for a median of 2 years, treatment for AF may be life long and currently long term safety data for dabigatran is lacking. Dabigatran has fewer clinically important food and drug interactions compared to warfarin. It is not known whether monitoring of liver enzymes will be required with long-term use of dabigatran. No antidote is currently available for dabigatran. This may be of concern for patients who are at high risk of bleeding. What should clinicians do if the patient requires cardioversion is treatment with warfarin then necessary? Will clinicians (and patients?) feel confident in the treatment if the anticoagulant effect is not monitored? The cost effectiveness of dabigatran in comparison to drug and nondrug costs for warfarin needs to be considered carefully. NICE will make a national recommendation about use of dabigatran later in the year (see below). Warfarin and anticoagulant clinics will still be required as warfarin has a number of uses (treatment of deep-vein thrombosis and pulmonary embolism, atrial fibrillation, cardioversion, dilated cardiomyopathy, mural thrombus, symptomatic inherited thrombophilia, coronary artery thrombosis, paroxysmal nocturnal haemoglobinuria [11) and dabigatran is currently only licensed for stroke prevention in patients with AF. Decisions from other bodies NICE are due to start work on a TA on dabigatran for AF to be available at or around the launch of dabigatran in Cambridgeshire JPG not assessed Norfolk TAG Double Red SMC not assessed AWMSG not assessed Decision review date When Pradaxa launched for use in AF / NICE publish TA References 1. Dabigatran etexilate (Pradaxa) for stroke prevention in atrial fibrillation. National Horizon Scanning Centre, August Pradaxa for_stroke_prevention.pdf 2. Summary of Product Characteristics Pradaxa 110mg hard capsules. Boehringer Ingelheim, last revised 28 October Camm AJ. The RE-LY study: Randomised Evaluation of Long-term anticoagulant therapy: dabigatran vs. warfarin. Eur Heart J 2009; 30: Atrial Fibrillation. Clinical Knowledge Summary, last revised August Gage BF. Can we rely on RE-LY? (Editorial) N Engl J Med 2009; 361 (12): Dabigatran vs. warfarin for prevention of stroke in atrial fibrillation: the RE-LY study. NPCi blog, 27 Oct Connolly SJ, Ezekowitz MD et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12): Ezekowitz MD, Reilly PA et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100:

8 9. National Institute for Health and Clinical Excellence. Atrial Fibrillation. Clinical Guideline, June Miller PSJ, Drummond MF et al. Economic factors associated with antithrombotic treatments for stroke prevention in patients with atrial fibrillation. Eur Heart J 2005; 7 (suppl C): Joint Formulary. British National Formulary. 58 th ed. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain; September 2009 p131-2

9 Table 1 Summary of clinical trials for use of dabigatran etexilate Ref Trial Design Trial Population Treatment Results & Primary Outc 5 12 week, phase II, randomised, open label, active control study Conducted in Europe & USA 6 2 year, phase III, prospective, randomized, openlabel, blinded endpoint study Conducted worldwide 502 adults with paroxysmal persistent or permanent nonrheumatic AF with 1 or more of: hypertension, diabetes, heart failure, previous stroke or TIA, age > 75 yrs, left ventricular dysfunction Mean age = 71 yrs 81.9% were men 18,113 adults with AF and at least one other risk factor for stroke (see above) Mean age = 71 yrs 64% were men Warfarin alone, n=70 Dabigatran 50mg, n=59 Dabigatran 50/aspirin 81mg, n= 21 Dabigatran 50/aspirin 325mg, n=27 Dabigatran 150mg, n=100 Dabigatran 150/aspirin 81mg, n=36 Dabigatran 150/aspirin 325mg, n=33 Dabigatran 300mg, n=105 Dabigatran 300/aspirin 81mg, n=34 Dabigratran 300/aspirin 325mg, n=30 Dabigatran given twice daily Dabigatran 110mg, n=6015 Dabigatran 150mg, n=6076 Dabigatran given twice daily, blinded treatment Warfarin, n=6022, adjusted to INR of 2 to 3, unblinded treatment Aspirin used by ~20% of patients in all 3 groups. Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this - [Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008] Discontinuations: 38 pa warfarin]. 29 (all dabigatr Primary outcome: frequ Major bleeding: 4/64 dab dabigatran 300mg alone; Major + clinically relevan Total bleeding episodes: Major bleeding: 0/69 dab 150mg alone Major + clinically relevan Total bleeding episodes: Major bleeding: 0/48 dab 50mg alone Major + clinically relevan Total bleeding episodes: Major bleeding: 0/70 war Major + clinically relevan Total bleeding episodes: Discontinuations: 17% dabigatran (n=2539) Primary efficacy outcom Dabigatran 110mg: n=18 inferiority to warfarin sho Dabigatran 150mg: n=13 inferiority and superiority Warfarin: n=199; 1.69%/y Primary safety outcome Dabigatran 110mg: 2.71% Dabigatran 150mg: 3.11% Warfarin: 3.36% per year

10 Rank Methodology Description Meta-analysis: A statistical analysis that combines or integrates t clinical trials considered by the analyst to be "combinable" usuall original data, also sometimes called: pooling, quantitative synthe 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit me explicit criteria to assess their quality. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group Otherwise the two groups are identical for any significant variable end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, a look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at on 6 Case reports A report based on a single patient or subject; sometimes collecte 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor 2 Medium Quality of evidence in the papers reviewed Magnitude of effect inferred from trials reviewed Low Medium Are trial end-points surrogate markers or clinical outcomes? Clinical outcomes Clinical usefulness of trial end-points Known Side Effect Profile High Medium Known Interactions High Medium Concern re Possible Side Effects Not Yet Uncovered High Medium Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium NNT High Medium Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Same Condition Severity of Condition to be Treated Trivial Medium Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) novel 90% of warfarin use

11 Is the drug to be used in Suffolk? Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire) To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Experience Of The Condition Specific Specific Specific Diagnosis Specific Specific Specific Monitoring Progress Of Treatment Difficult Specific General Therapy Patient Selection Difficult Specific Specific Initiation Of Treatment Difficult Difficult Easy Dose Titration Difficult Specific Easy Monitoring Of Side Effects Complex Easy Easy Method Of Administration Complex Normal Normal Discontinuation Of Treatment Complex Complex Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2