Antiplatelet therapy:

Transcription

1 Balanced information for better care Antiplatelet therapy: Aggregating the latest evidence Evaluating the choices for a preventive therapy with impressive benefits and important risks

2 Antiplatelet agents have a proven role in the primary and secondary prevention of cardiovascular events FIGURE 1. Risk reductions from selected trials of antiplatelet regimens in patients with acute coronary syndrome A. Aspirin alone B. Clopidogrel + C. Prasugrel + D. Ticagrelor + 0% Reduction in risk of major vascular events -10% -20% -30% -40% -50% -60% -70% -20% -20% -19% -16% A. Data on the risk of compared to placebo are taken from the Antithrombotic Trialists Collaboration (ATT). 1 B. The added impact of clopidogrel plus compared to alone was derived from the CURE study. 2 C. The impact of prasugrel plus compared to clopidogrel plus was derived from TRITON-TIMI D. The impact of ticagrelor plus compared to clopidogrel plus was derived from the PLATO study. 4 2 Antiplatelet therapy: Aggregating the latest evidence

3 Antiplatelet agents increase the risk of bleeding, so their use should be limited to patients whose clinical benefit is likely to outweigh that risk. FIGURE 2. Increase in major bleeding with selected antiplatelet drugs in patients with acute coronary syndrome 100% Increase in risk of major bleeding 90% 80% 70% 60% 50% 40% 30% 20% 31% 25% 32% 25% 10% 0% A. Aspirin alone* B. Clopidogrel + C. Prasugrel + D. Ticagrelor + * Data for A through D are based on the same clinical trials as Figure 1. Major bleeding is defined as intracranial bleeding, clinically overt signs of hemorrhage associated with a drop in hemoglobin of >= 5 g/dl, and/or bleeding that directly results in death within 7 days but which is unrelated to coronary artery bypass surgery. These drugs are sometimes overused. FIGURE 3. Clopidogrel use by indication 5 FDA-approved indications (e.g. acute coronary syndrome, recent stroke, peripheral artery disease) 39% 53% Clopidogrel prescribed without an evidencebased indication Additional evidence-based indications (e.g. hisory of coronary artery disease or stroke) 8% The histories in one cohort of 4,977 patients taking clopidogrel were assessed to find reasons for use of the drug. The segments in the pie chart above reflect the proportion of patients who had FDA-approved indications (39%) or additional evidence-based indications (8%). More than half (53%) were found to have neither category of indication. Balanced information for better care 3

4 Acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI): Use dual antiplatelet therapy in most patients. Clopidogrel plus is the best-tested regimen in this setting and has become the standard of care. FIGURE 4. Patients randomized to receive clopidogrel plus had a relative reduction of 20% in the rate of cardiovascular death, nonfatal MI, or stroke compared to patients treated with alone % relative risk reduction (P<0.001) Outcome rate clopidogrel Months of follow-up 4 Antiplatelet therapy: Aggregating the latest evidence

5 More intensive antiplatelet agents such as prasugrel and ticagrelor further reduce ischemic events, but cause more bleeding. FIGURE 5. Reduction in risk of major vascular events and increased risk of major bleeding with prasugrel plus and ticagrelor plus, compared to clopidogrel plus (baseline). 3,4 40% clopidogrel + Change in benefit and risk compared to clopidogrel + (%) 30% 20% 10% 0% -10% -20% -19% -16% 32% 25% prasugrel + ticagrelor + -30% Reduction in risk of major vascular events Increase in risk of major bleeding How long to continue therapy? In patients with ACS or elective PCI, there is good evidence for use of dual antiplatelet therapy for at least 1 year. Prolonged use beyond this time frame has not been adequately studied; several ongoing trials are seeking to evaluate the benefits and risks of continuing treatment beyond one year. Balanced information for better care 5

6 Stable coronary artery disease: Use alone in most patients. The value of dual antiplatelet therapy is less well established for patients with stable coronary artery disease, including those with stable angina and a history of MI. For these patients, alone (81 mg/day) is usually the most appropriate regimen. FIGURE 6. Adding clopidogrel to did not significantly reduce the risk of major vascular events. 7 Cumulative incidence of the primary composite end point (%) alone clopidogrel (Plavix) + 7% relative risk reduction (not statistically significant) Months 30 Incidence of myocardial infarction, stroke, or death from cardiovascular causes in the CHARISMA trial. The rate of events with combination therapy (6.8%) was quite close to that seen with alone (7.3%), p=0.22, but the combination produced significantly more moderate or severe bleeding than alone. 6 Antiplatelet therapy: Aggregating the latest evidence

7 Stroke or TIA: Use clopidogrel alone, or dipyridamole plus. In patients who have had a stroke or a transient ischemic attack, several trials have compared or clopidogrel alone with clopidogrel plus or dipyridamole plus TABLE 1. Antiplatelet agents for stroke prevention Dual therapy with: EFFICACY BLEEDING Compared to: dipyridamole + better than equal to alone equal to more than clopidogrel alone In patients with ischemic stroke or TIA in the prior 3 months, the evidence favors clopidogrel alone or dipyridamole plus. In this setting, avoid combination therapy with clopidogrel and unless a patient has additional indications, such as PCI. Use for most patients with a more remote history of stroke. Peripheral arterial disease (PAD): Use clopidogrel alone. The CAPRIE trial found clopidogrel alone to be more effective than alone for patients with severe PAD. 12 In the CHARISMA trial, the combination of clopidogrel plus was no better than alone. 7 FIGURE 7. Relative reductions in major vascular events by patient subgroup in the CAPRIE study 12 ASPIRIN BETTER CLOPIDOGREL BETTER Stroke MI PAD All patients Relative-risk reduction (%) Balanced information for better care 7

8 Choosing an optimal dose: Use low-dose. Whether used alone or in combination with another drug, low-dose (e.g. 81 mg) confers the same benefit with a lower risk of bleeding. Higher doses of (such as 325 mg per day) increase the risk of bleeding, but do not meaningfully increase benefit. FIGURE 8. Data from a meta-analysis and the CURE trial show that higher doses of do not decrease the rate of vascular events 13,14 16% Percent of patients who had a vascular event 14% 12% 10% 8% 6% 4% 2% 13.2% 14.2% 9.6% 11.7% low dose high dose 0% Meta-analysis 13 CURE trial FIGURE 9. Safety analyses in the CURE trial revealed a higher rate of bleeding complications with high-dose compared to low-dose % Percent of patients who had a bleeding event 4.0% 3.5% 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 2.4% 4.2% 0.0% Low dose High dose 8 Antiplatelet therapy: Aggregating the latest evidence

9 Primary prevention of cardiovascular disease: Use low-dose in selected patients. FIGURE 10. Effect of on vascular and nonvascular outcomes in primary prevention patients 15 ASPIRIN BETTER PLACEBO BETTER Outcome Odds ratio (95% CI) Non-fatal MI 0.80 ( ) Total CVD events 0.90 ( ) CVD mortality 0.99 ( ) Non-CVD mortality 0.92 ( ) Total bleeds 1.70 ( ) Odds ratio (95% CI) Because of the bleeding risk caused by any antiplatelet therapy, should be prescribed for primary prevention only in patients for whom its benefits are likely to outweigh its harms. Some patients who take for primary prevention (e.g. low-risk diabetes) may derive less benefit than formerly believed. TABLE 2. Risk vs. benefit in primary prevention with varies substantially by patient characteristics. 16 Risk level at which CVD events prevented (benefit) exceeds GI bleeding risk Men: 10-year CHD risk Women: 10-year stroke risk Age years 4% Age years 3% Age years 9% Age years 8% Age years 12% Age years 11% Shared decision making with the patient can help determine the best strategy. Taking 10 year cardiovascular risk into account can help clarify the decision (see Concurrent NSAID use and history of ulcers raise the risk of serious gastrointestinal bleeding. 16 Balanced information for better care 9

10 Matching the patient with the best regimen TABLE 3. Recommended antiplatelet medications for selected clinical indications Condition Recommended Treatment Evidence Primary prevention Acute coronary syndromes [unstable angina, non- ST-segment elevation MI (NSTEMI), and ST-segment elevation MI (STEMI)] alone for patients in whom benefits outweigh risks Undergoing PCI: clopidogrel + for 1 year For some patients, prasugrel + or ticagrelor + may be a superior choice Not undergoing PCI: clopidogrel + for some patients for 1 year For some patients, ticagrelor + may be a superior choice POPADAD, JPAD, USPSTF CURE, COMMIT, CLARITY TRITON, PLATO CURE, COMMIT, CLARITY PLATO Stable angina or past MI Antiplatelet Trialists Collaboration, CHARISMA, CAPRIE Elective PCI clopidogrel + for 1 year CREDO Recent stroke clopidogrel or + dipyridamole MATCH, CHARISMA, ESPS2, ESPRIT, PRoFESS, SPS3 Past stroke alone CHARISMA, ATT Peripheral artery disease clopidogrel CHARISMA, CAPRIE 10 Antiplatelet therapy: Aggregating the latest evidence

11 Costs vary widely for different regimens This is particularly important for drugs that have very similar risk-benefit profiles. FIGURE 11. Average monthly price for commonly used antiplatelet agents* ticagrelor (Brillinta) 90mg twice daily $ prasugrel (Effient) 5mg-10mg daily $ extended release dipyridamole (Aggrenox) 25mg-200mg twice daily $ clopidogrel (Plavix and/or generics) 75mg daily $ mg daily $1.30 $0.00 $50.00 $ $ $ $ $ * Prices from goodrx.com and epocrates.com, October References: (1) Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. The Lancet. May ; 373: (2) The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Investigators. Effects of clopidogrel in addition to in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. Aug : 345(7): (3) Wiviott SD, Braunwald E, McCabe CH, Montalescot G, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. Nov ; 357(20): (4) Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. Sep 2010; 361(11): (5) Choudhry NK, Levin R, Avorn J. The economic consequences of non-evidence-based clopidogrel use. Am Heart J. May 2008; 155(5): (6) Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. Aug ; 345(7): (7) Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and versus alone for the prevention of atherothrombotic events. N Engl J Med. Apr ; 354(16): (8) Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. Jul ;364(9431): (9) Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. Nov 1996;143(1-2):1-13. (10) Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. May ; 367(9523): (11) Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. Sep ;359(12): (12) A randomised, blinded, trial of clopidogrel versus in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. Nov ; 348(9038): (13) Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. January 12, ;324(7329): (14) Peters RJ, Mehta SR, Fox KA, et al. Effects of dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. Oct ;108(14): (15) Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Erqou S, Sattar N, Ray KK. Effect of on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. Feb (3): (16) Aspirin for the Prevention of Cardiovascular Disease, Topic Page. December U.S. Preventive Services Task Force. Additional references documenting these recommendations are provided in the evidence document accompanying this material, also available at Balanced information for better care 11

12 About this publication These are general recommendations only; specific clinical decisions should be made by the treating physician based on an individual patient s clinical condition. More detailed information on this topic is provided in a longer evidence document at The Independent Drug Information Service (IDIS) is supported by the PACE Program of the Department of Aging of the Commonwealth of Pennsylvania, and the Washington D.C. Department of Health. Additional support is provided by the Centers for Disease Control and Prevention and the Rx Foundation. This material is provided by the Alosa Foundation, a nonprofit education organization which is not affiliated with any pharmaceutical company. IDIS is a service of the Alosa Foundation. This material was produced by Niteesh K. Choudhry, M.D., Ph.D., Associate Professor of Medicine, Harvard Medical School; Nihar R. Desai, M.D., M.P.H., Clinical Fellow in the Division of Cardiovascular Medicine, Brigham and Women s Hospital; Michael A. Fischer, M.D., M.S., Associate Professor of Medicine, Harvard Medical School; Jerry Avorn, M.D., Professor of Medicine, Harvard Medical School. Drs. Avorn, Choudhry, Desai, and Fischer are all physicians at the Brigham and Women s Hospital in Boston. None of the authors accepts any personal compensation from any drug company Alosa Foundation, Inc. All rights reserved.