prodigy study: duration of dual antiplatelet therapy under review In BrIef In Brief NPS RADAR AuguSt 2012

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1 3 In BrIef A digest of news items about NPS RADAR, new drugs and changes to PBS listings prodigy study: duration of dual antiplatelet therapy under review Dual antiplatelet therapy with aspirin and clopidogrel prevents more thrombotic events after acute coronary syndrome (ACS) than aspirin alone 1,2, but the optimal duration of therapy is unknown. Current guidelines specify that dual antiplatelet therapy be continued for 12 months after percutaneous coronary intervention (PCI) for people with ACS 3, but the evidence supporting this recommendation is not robust. The PRODIGY study compared the effects of 6- and 24-month courses of dual antiplatelet therapy on cardiovascular outcomes and bleeding at 2 years. The study found no improvement in ischaemic events but more bleeding with the longer duration of treatment. 4 similar effectiveness and more bleeding with prolonged dual antiplatelet therapy The PRODIGY study enrolled patients with ACS (including non-st-segment-elevation and ST-segment-elevation myocardial infarction [MI]) or chronic stable coronary artery disease (74% and 26%, respectively) and followed them for 2 years after coronary stent insertion. All patients (about 2000) received clopidogrel and aspirin therapy for the first 30 days and were then randomised to receive an additional 5 or 23 months of clopidogrel therapy together with indefinite aspirin therapy. At entry the study also randomised patients to receive one of four types of coronary stents: bare-metal, paclitaxel-eluting, zotarolimuseluting or everolimus-eluting. Two years after stent insertion, clopidogrel therapy for 24 months compared with 6 months had no significant effect on cardiovascular outcomes but doubled rates of major bleeds and blood transfusions (Table 1). 4 reassess benefits and risks of dual antiplatelet therapy at 12 months The PRODIGY study builds on findings from other studies that suggest there may be no benefit in continuing dual antiplatelet therapy beyond 12 months for people with drug-eluting stents. 5 However, the PRODIGY study was not blinded (other than for outcome assessment) and not powered to rule out a small benefit with prolonged therapy (that is, not enough patients to discount an absolute difference in the primary outcome smaller than 3.5%). 4,6 In addition, the findings do not exclude the possibility that clopidogrel therapy for 12 months may have a more favourable balance of benefits and risks than stopping the drug at 6 months. 7 Despite these uncertainties, the findings from the PRODIGY study indicate that there is an increased risk of a major bleed, and possibly little benefit, from indefinite dual antiplatelet therapy. Reassess a person s ongoing need for dual antiplatelet therapy 12 months after insertion of a coronary stent. This should be done either by the patient s cardiologist or in consultation with them do not discontinue antiplatelet therapy without first consulting the cardiologist. 8 Risk factors for thrombotic events (e.g. the type, number and length of stents; diabetes; renal failure; left ventricular dysfunction) and risk factors for bleeding (e.g. recent history of bleeding, severe anaemia, renal insufficiency, age > 75 years, Table 1. Effect of clopidogrel duration on outcomes after coronary stent insertion Outcome 6 months* (n = 983) 24 months (n = 987) Hazard ratio (95% confidence interval) Death, MI or stroke 10.0% 10.1% 1.02 (0.78 to 1.35) Fatal bleeding 0.5% 0.9% 1.78 (0.60 to 5.26) Major bleeding 0.6% 1.6% 2.63 (1.03 to 6.67) Red blood cell transfusion 1.3% 2.6% 2.00 (1.02 to 3.85) * 12% stopped clopidogrel therapy at 30 days (allowable under the study protocol for people in this treatment arm if they had stable coronary artery disease and received a bare-metal stent) Primary endpoint Bleeding Academic Research Consortium (BARC) classification (type 5) Thrombolysis in Myocardial Infarction (TIMI) trials classification

2 PCI with stent for people without ACS clopidogrel 75 mg daily Unspecified 4 In Brief * In key clinical trials, prasugrel was studied in people with ACS with or without STsegment elevation who were scheduled for PCI 10, while ticagrelor was studied in people with ACS with or without STsegment elevation. 9 female sex, history of stroke or TIA) need to be assessed to determine if the balance of benefits and risks of continuing clopidogrel (or other P2Y 12 antagonist) is favourable for the individual. 3,8 Some guidelines recommend indefinite dual antiplatelet therapy for people at high risk of ischaemic events and low risk of bleeding 8, although there is limited evidence to support this (see below). duration of therapy for people at high risk of ischaemic events In a subgroup analysis of the PRODIGY study, outcomes were similar regardless of diabetes status, stent type, stability of cardiovascular disease, number of lesions or the complexity of lesions. 4 However, the study was not powered to compare outcomes between people at low and high risk of ischaemic events and so does not rule out improved outcomes with prolonged dual antiplatelet treatment for people at high risk of ischaemic events (such as those with long stents, bifurcation stents, kidney disease or diabetes). other p2y 12 antagonists have different benefit risk profiles It is uncertain whether the findings of the PRODIGY study may apply to the newer P2Y 12 antagonists, prasugrel and ticagrelor, which are more potent inhibitors of platelet aggregation than clopidogrel. Prasugrel or ticagrelor in combination with aspirin are more effective than clopidogrel with aspirin in reducing ischaemic events in people with ACS at 14.5 months and 12 months, respectively*; however, they increase the risk of non-procedure-related bleeding, and less is known about the long-term safety and efficacy of these drugs. 9,10 Prasugrel or ticagrelor are only recommended for people at low risk of bleeding (Table 2), so patient characteristics may differ from those in the PRODIGY study. See the NPS RADAR reviews on prasugrel and ticagrelor for more information about the place in therapy of these drugs. Table 2. Guideline recommendations for dual antiplatelet therapy in ACS or after PCI 3,15 Indication Acute coronary syndromes (ACS) ST-segmentelevation MI After fibrinolytic therapy PCI (with or without stent/s) Antiplatelet therapy (in addition to aspirin mg daily) clopidogrel 75 mg daily Duration 1 month clopidogrel 75 mg daily or if person is at high risk of recurrent ischaemic events (e.g. diabetes, stent thrombosis) and not at high bleeding risk: prasugrel 10 mg daily or ticagrelor 90 mg twice daily 12 months Unspecified* Unspecified Non-ST-segment-elevation high-risk ACS Low risk of bleeding: prasugrel 10 mg daily or ticagrelor 90 mg twice daily Unspecified* Unspecified High risk of bleeding: clopidogrel 75 mg daily 12 months if PCI with stent; otherwise, unspecified * Median duration in a key clinical trial (TRITON-TIMI 38) was 14.5 months 10 TGA-approved product information specifies at least 12 months 17 ; median exposure in a key clinical trial (PLATO) was 9 months 9 This indication is not addressed in guidelines but is covered by PBS listing

3 5 * Definite, probable or possible stent thrombosis. Clopidogrel versus placebo loading dose. no difference between bare-metal and drug-eluting stents In the PRODIGY study the type of stent made no difference to the overall findings. In addition there was no difference in rates of late stenosis between the 24-month and 6-month treatment groups (2.6% and 2.9%*, respectively; hazard ratio 1.07, 95% confidence interval 0.64 to 1.83). 4 These findings are consistent with those of two studies (REAL-LATE and ZEST-LATE) that compared dual therapy (aspirin and clopidogrel) with aspirin monotherapy in people who had received a drug-eluting stent 12 months previously. In these studies involving about 2700 people in total, aspirin and clopidogrel treatment for months was no more effective than aspirin monotherapy in reducing rates of MI or cardiac death. 5 While these trials suggest that prolonged dual antiplatelet therapy may not protect people with drug-eluting stents from late stenosis, the findings should be regarded with caution. Current guidelines are informed by observational studies that suggest premature stopping of clopidogrel therapy may trigger MI and death, possibly due to late stent thrombosis among people with drug-eluting stents Neither the PRODIGY study nor the LATE studies were blinded (other than assessment), which limits their reliability. The results from a larger blinded study (> 15,000 people; the DAPT study) of dual anti-platelet therapy in people after coronary stent insertion are expected to be available in ,14 This study will compare cardiovascular and bleeding outcomes at 12 months and 30 months in people with drug-eluting stents and receiving dual antiplatelet therapy (aspirin and clopidogrel or prasugrel), and should provide more conclusive evidence to support an optimal duration of therapy. 14 guideline recommendations Current Australian guidelines recommend dual antiplatelet therapy for at least 12 months after PCI, including stent insertion for people with ST-segment-elevation MI (see Table 2). 3,15 These recommendations are based on earlier studies that compared 1 month with 9 12 months of clopidogrel therapy among people with non- ST-segment-elevation ACS (CURE study), and after elective PCI with insertion of bare-metal stents (CREDO study). 2,16 These studies had other differences in treatment protocols, which may have biased findings in favour of longer treatment with dual antiplatelet agents. However, the results of the PRODIGY study give no cause to change the current recommendations. REFERENcES 1. Sabatine MS, et al. N Engl J Med 2005;352: Yusuf S, et al. N Engl J Med 2001;345: Chew DP, et al. Heart Lung Circ 2011;20: Valgimigli M, et al. Circulation 2012;125: Park SJ, et al. N Engl J Med 2010;362: Valgimigli M, et al. Am Heart J 2010;160: Kleiman NS. Circulation 2012;125: Jackowski L, et al. Aust Fam Physician 2008; 37:721 3, Wallentin L, et al. N Engl J Med 2009;361: Wiviott SD, et al. N Engl J Med 2007;357: Pfisterer M, et al. J Am Coll Cardiol 2006; 48: Eisenstein EL, et al. JAMA 2007;297: Ho PM, et al. JAMA 2008;299: Mauri L, et al. Am Heart J 2010;160: Med J Aust 2006;184:S Steinhubl SR, et al. JAMA 2002;288: AstraZeneca Pty Ltd. Brilinta product information. June 2011.

4 6 In Brief Changes to pbs listings of synthetic infant formulas for protein intolerances From 1 July 2012 there are several changes to the PBS Authority-required listings for synthetic infant formulas: protein hydrolysate formula with mediumchain triglycerides (Alfaré, Karicare Aptamil Pepti-Junior Gold) amino acid synthetic formula (EleCare, Neocate Advance, Neocate Advance Vanilla, Neocate Advance Tropical Flavour) amino acid synthetic formula with long-chain polyunsaturated fatty acids (Neocate LCP, EleCare LCP) amino acid synthetic formula with long-chain polyunsaturated fatty acids and medium-chain triglycerides (Neocate Gold). Depending on the indication, there are changes relating to the need to consult with, or refer to, a specialist before prescribing. In addition, the definitions of combined intolerance and severe intolerance to cows milk protein have been revised. The listing changes come after increases in the number of prescriptions of synthetic infant formulas and a larger-than-expected proportion of infants with protein intolerances who start on an amino acid formula without first trying a protein hydrolysate formula. 1 protein hydrolysate formula listing changes The listings of protein hydrolysate formulas for protein intolerances now require general practitioners (GPs) to prescribe in consultation with a specialist allergist, clinical immunologist, paediatrician or specialist paediatric gastroenterologist. Consultation may be by telephone. For children older than 24 months, the existing requirement that the child must be seen by the specialist is unchanged. The listings are intended for children who have failed to respond to a strict cows -milkprotein-free diet using soy formula. Protein hydrolysate formulas are no longer listed for severe intolerance to cows milk protein. See below for details of the revised listings of amino acid synthetic formulas for severe intolerance these may be applicable. Listings for other indications (e.g. cystic fibrosis) remain unchanged. amino acid synthetic formula listing changes Along with the specific changes described further below, the following overall changes have been made to the listings of amino acid synthetic formulas for protein intolerances: clinical immunologists have been added to the list of specialists who may be consulted, along with specialist allergists and specialist paediatric gastroenterologists the length of initial treatment has changed from 3 months to 6 months when the listing requires a specialist assessment, the name of the specialist must be included in the authority application for children aged up to 24 months, continuing treatment can be authorised if the child has an appointment and is waiting to be assessed by a specialist. Listings for other indications (e.g. severe intestinal malabsorption) remain unchanged. Combined protein intolerance As previously, the listings of amino acid synthetic formulas for combined protein intolerance require that the child has tried a strict diet using protein hydrolysate as the principal formula (i.e. free of cows milk protein and soy protein) and failed to respond. The definition of combined intolerance has been revised to specify cows milk protein enteropathy that is not isolated colic or reflux.

5 7 Initial treatment for infants up to 24 months of age must now be in consultation with a specialist, as for the severe intolerance restriction. For a child aged over 24 months, the requirement remains that a specialist must see the child before the initial prescription. Continuing treatment requires repeat specialist assessment at least every 12 months (this was previously every 6 months). Severe intolerance The definition of severe cows milk protein intolerance has been revised to specify a diagnosis of severe cows milk protein enteropathy with failure to thrive (not isolated infant colic or reflux). Unlike the old severe intolerance restriction, it does not apply to children older than 24 months. New listing for cows milk anaphylaxis Amino acid synthetic formulas are now listed for cows milk anaphylaxis. Treatment must be in consultation with a specialist allergist or clinical immunologist. Consultation may be by telephone. The listing is for infants up to 24 months of age, and anaphylaxis is defined as a severe and/or potentially life-threatening allergic reaction. REFERENcE Bone mineral density T-score cut-off changed in denosumab (prolia) osteoporosis pbs listing The Authority required (Streamlined) listing of denosumab for osteoporosis in women aged 70 years has changed from 1 August The required bone mineral density T-score has been changed from 3.0 to 2.5. The T-score cut-off is now the same as applies to alendronate for osteoporosis. 1 The Pharmaceutical Benefits Advisory Committee recommended the change in listing on the basis that, in this patient group, denosumab 60 mg once every 6 months has a similar effect to that of alendronate 70 mg once weekly, at a similar cost. 1 Previously denosumab was listed on the basis of a comparison with zoledronic acid. 2 For more information about the place of denosumab in treating postmenopausal osteoporosis see the NPS RADAR review Denosumab (Prolia) for postmenopausal osteoporosis. REFERENcES 1. Australian Government Department of Health and Ageing. Drug Utilisation Subcommittee (DUSC) review of PBS listed nutritional products. October Australian Government Department of Health and Ageing. March 2012 PBAC outcomes: positive recommendations. internet/main/publishing.nsf/content/pbacrecmarch12-positive (accessed 5 June 2012). 2. Australian Government Department of Health and Ageing. Public summary document for denosumab, injection, 60 mg in 1 ml, single use pre-filled syringe, Prolia, July main/publishing.nsf/content/pbac-psd-denosumabjuly10 (accessed 5 June 2012).