Prasugrel development – Claims and achievements

Victor Serebruany; Inna Shalito; Olga Kopyleva

doi:10.1160/TH08-07-0452

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(01): 14-22
DOI: 10.1160/TH08-07-0452

Viewpoint Article

Schattauer GmbH

Prasugrel development – Claims and achievements

Victor Serebruany

¹HeartDrug ^TM Research Laboratories, Johns Hopkins University, Towson, Maryland, USA

,

Inna Shalito

¹HeartDrug ^TM Research Laboratories, Johns Hopkins University, Towson, Maryland, USA

,

Olga Kopyleva

¹HeartDrug ^TM Research Laboratories, Johns Hopkins University, Towson, Maryland, USA

› Author Affiliations

Abstract

Summary

The priority task to develop better and safer antiplatelet agents is difficult to overestimate. In fact, oral antiplatelet agents, such as aspirin in ISIS-2 study, and clopidogrel in COMMIT mega trial in moderate doses are among the very few classes of drugs, which lead to the absolute mortality reduction benefit in patients after acute vascular thrombotic events. Prasugrel is an experimental thienopyridine, and irreversible antagonist of ADP P2Y₁₂ receptor leading to inhibition of platelet activation and aggregation. The recent TRITON trial, assessing head-to-head prasugrel versus standard of care clopidogrel, both on top of aspirin, reveals numerous controversies with regard to the trial design, definition of events, interpretation of the results, and suitability of the high maintenance prasugrel dose for chronic preventive human use. We critically review various aspects of prasugrel development, focusing on the discrepancies between claims and achievements. We conclude that the benefits of prasugrel are overestimated, and the risks, especially during chronic use are underestimated. Very careful maintenance-dose selection with the main focus on long-term safety profile for the new agents will become a key to success for the future oral antiplatelet drug development.

Keywords

Antiplatelet agents - atherothrombosis - clinical trials

Full Text

References

References
1 Cattaneo M. P2Y₍₁₂₎ Receptor Antagonists: A Rapidly Expanding Group of Antiplatelet Agents. Europ Heart J 2006; 27: 1010-1012.
2 Riley AB, Tafreshi MJ, Haber SL. Prasugrel: A novel antiplatelet agent. Am J Health Sys Pharm 2008; 65: 1019-1028.
3 Small DS, Farid NA, Payne CD. et al. Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. J Clin Pharmacol 2008; 48: 475-484.
4 Payne CD, Li YG, Small DS. et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007; 50: 555-562.
5 Wallentin L, Varenhorst C, James S. et al. Prasugrel achieves greater and faster P2Y₁₂receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 01: 21-30.
6 Brandt JT, Close SL, Iturria SJ. et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 05: 2429-2436.
7 Weerakkody GJ, Jakubowski JA, Brandt JT. et al. Greater inhibition of platelet aggregation and reduced response variability with prasugrel versus clopidogrel: an integrated analysis. J Cardiovasc Pharmacol Ther 2007; 12: 205-212.
8 Weerakkody GJ, Jakubowski JA, Brandt JT. et al. Comparison of speed of onset of platelet inhibition after loading doses of clopidogrel versus prasugrel in healthy volunteers and correlation with responder status. Am J Cardiol 2007; 100: 331-336.
9 Wiviott SD, Trenk D, Frelinger AL. et al. PRINCIPLE-TIMI 44 Investigators.. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.
10 Wiviott SD, Braunwald E, McCabe CH. et al. the TRITON-TIMI 38 Investigators.. Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2007; 357: 2001-2015.
11 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
12 Jakubowski JA, Matsushima N, Asai F. et al. A multiple dose study of prasugrel (CS-747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans. Br J Clin Pharmacol 2007; 63: 421-430.
13 Serebruany VL, Midei MG, Meilman H. et al. Platelet inhibition with prasugrel (CS-747) compared with clopidogrel in patients undergoing coronary stenting: the subset from the JUMBO study. Postgrad Med J 2006; 82: 404-410.
14 Cannon CP, Braunwald E, McCabe CH. et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators.. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495-1504.
15 Serebruany VL. Prasugrel, clopidogrel, and combining Swedish apples with American oranges. Eur Heart J 2006; 27: 1886-1887.
16 Cohen M, Diez JE, Levine GN. et al. ACC; AHA.. Pharmacoinvasive management of acute coronary syndrome: incorporating the 2007 ACC/AHA guidelines: the CATH (cardiac catheterization and anti-thrombotic therapy in the hospital) Clinical Consensus Panel Report--III. J Invasive Cardiol 2007; 19: 525-538.
17 Silber S, Richartz BM, Brilmayer M. The European Society of Cardiology (ESC).. The European Society of Cardiology (ESC) guidelines for percutaneous coronary interventions (PCI). Herz 2006; 31: 836-846.
18 Wiviott S, Antman E, Winters K. et al. Randomized comparison of prasugrel a novel thienopyridine P2Y₍₁₂₎ antagonist with clopidogrel in percutaneous coronary intervention. Circulation 2005; 111: 3366-3373.
19 Serebruany VL, Midei MG, Meilman H. et al. Case Report: Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial. Intern J Clin Pract 2006; 60: 83-86.
20 Serebruany VL, Hanley DF, Atar D. et al. Non – compliance in antiplatelet trials: The AGATE trial perspective. Stroke 2004; 35: 143-144.
21 Serebruany VL, Malinin AE, Bhatt D. Paradoxical rebound platelet activation after NSAIDS or COX-2 inhibitors withdrawal: Which patients are at higher risk for vascular events?. Am J Med 2006; 119: 11-16.
22 Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. J Am Med Assoc 2001; 286: 954-959.
23 Chew DP, Bhatt DL, Sapp S. et al. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001; 103: 201-206.
24 Serebruany VL, Malinin AI, O’Connor CM. et al. Roxifiban Oral Compound Kinetics Evaluation Trial-I Platelet Substudy, Effects of roxifiban on platelet aggregation and major receptor expression in patients with coronary artery disease for the Roxifiban Oral Compound Kinetics Evaluation Trial-I (ROCKET-I Platelet Substudy). Am Heart J 2003; 146: 91-98.
25 Serebruany VL, Gurbel PA, Shustov AR. et al. Heterogeneity of platelet aggregation and major surface receptor expression in patients with acute myocardial infarction. Am Heart J 1998; 136: 398-405.
26 Antman EM, Wiviott SD, Murphy SA. et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 2008; 51: 2028-2033.
27 Vinholt P, Poulsen TS, Korsholm L. et al. The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischaemic heart disease. Thromb Haemost 2005; 94: 438-443.
28 Serebruany VL, Malinin AI, Ziai W. et al. Effects of clopidogrel and aspirin in combination versus aspirin alone on platelet activation and major receptor expression in patients after recent ischaemic stroke. For the Plavix Use for Treatment of Stroke (PLUTO-Stroke) Trial. Stroke 2005; 36: 2289-2292.
29 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Lack of association between the P2Y₍₁₂₎ receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res 2005; 116: 491-497.
30 Serebruany VL, Midei MG, Malinin AI. et al. Absence of Interaction Between Atorvastatin and Clopidogrel in Prospective Data: The Interaction of Atorvastatin and Clopidogrel (INTERACTION Study). Arch Int Med 2004; 164: 2051-2057.
31 Serebruany VL, Atar D. Assessment of bleeding events in clinical trials – proposal of a new classification. Am J Cardiol 2007; 99: 288-290.
32 Serebruany VL. Bleeding risks with prasugrel in the TRITON Trial: The Good News… The Bad News. Cardiology 2008; 111: 265-267.
33 Cannon CP, McCabe CH, Wilcox RG. et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000; 102: 149-156.
34 Cannon CP, Battler A, Brindis RG. et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol 2001; 38: 2114-2130.
35 Stone GW, Bertrand M, Colombo A. et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004; 148: 764-775.
36 Wiviott SD, Antman EM, Gibson CM. et al. TRITON-TIMI 38 Investigators.. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J 2006; 152: 627-635.
37 Stone GW, McLaurin BT, Cox DA. et al. ACUITY Investigators.. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203-2216.
38 Wiviott SD, Braunwald E, Murphy SA. et al. TRITON-TIMI 38 Investigators.. A perspective on the efficacy and safety of intensive antiplatelet therapy in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Am J Cardiol 2008; 101: 1367-1370.
39 Stone GW, Ware JH, Bertrand ME. et al. ACUITY Investigators.. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. J Am Med Assoc 2007; 298: 2497-2506.
40 Serebruany V. Excess rates of nonfatal myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel: preventing clinical events or chasing enzymatic ghosts?. Am J Cardiol 2008; 101: 1364-1366.
41 Wiviott SD, Braunwald E, McCabe CH. et al. TRITON-TIMI 38 Investigators.. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a sub-analysis of a randomised trial. Lancet 2008; 371: 1353-1363.
42 Serebruany VL. Aggressive antiplatelet strategies: time to reconsider. Editorial. Eur Heart J 2007; 28: 2183-2184.
43 Westerhout CM, Hernández AV, Steyerberg EW. et al. Predictors of stroke within 30 days in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2006; 27: 2956-2961.
44 Smith EE, Cannon CP, Murphy S. et al. Risk factors for stroke after acute coronary syndromes in the Orbofiban in Patients with Unstable Coronary Syndromes--Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 study. Am Heart J 2006; 151: 338-344.
45 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).. CAPRIE Steering Committee. Lancet 1996; 348: 1329-1339.
46 Diener HC, Bogousslavsky J, Brass LM. et al. MATCH investigators.. 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 2004; 364: 331-337.
47 Diener HC, Cunha L, Forbes C. et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
48 ESPRIT Study Group. Halkes PH, van Gijn J, Kappelle LJ. et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665-1673.
49 Diener HC, Sacco R, Yusuf S. Steering Committee; PRoFESS Study Group.. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS). Cerebrovasc Dis 2007; 23: 368-380.
50 Sacco R, Diener HC, Yusuf S. for the PRoFESS Investigators Prevention Regimen For Effectively avoiding Second Strokes(PRoFESS). Trial: Comparison of a fixed-dose combination of extended-release dipyridamole plus aspirin with clopidogrel (Abstract). EuroStroke. P.34, Nice, France, 2008.
51 European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee.. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008; 25: 457-507.
52 Adams RJ, Albers G, Alberts MJ. et al. American Heart Association, American Stroke Association.. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischaemic attack. Stroke 2008; 39: 1647-1652.
53 ISIS-2 Trial Investigators.. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988; 02: 349-360.
54 COMMIT Collaborative Group.. Addition of clopidogrel to aspirin in 45852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005; 366: 1607-1621.