Correspondence
Prasugrel versus Clopidogrel
N Engl J Med 2008; 358:1298-1301March 20, 2008
- Article
To the Editor:
Wiviott et al. (Nov. 15 issue)1 report the pivotal results of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38. To better assess the advantage of prasugrel over clopidogrel with respect to the benefit:risk ratio, two important clinical issues should be clarified. Since the numbers of deaths were nearly identical in the prasugrel group (154 deaths) and the clopidogrel group (155 deaths), as were the numbers of strokes, and since for each death from cardiovascular causes prevented by the use of prasugrel, one additional episode of fatal bleeding occurs,2 the efficacy benefit of prasugrel in TRITON–TIMI 38 is driven by nonfatal myocardial infarction (with 475 events in the prasugrel group vs. 620 events in the clopidogrel group). However, it is not clear whether the numbers reported by Wiviott et al. represent real clinical scenarios or just the increase in cardiac ischemic biomarkers that is so common during successful reperfusion. It is also important to report how many documented cases of stent thrombosis occurred in each treatment group, and why there was no difference in mortality between the two groups, rather than just to provide the combined number of patients with “definite or probable thrombosis.” Considering that it may be a very close call for the regulatory approval of prasugrel, these clarifications are urgently needed for assessment of the drug's potential efficacy.
Victor Serebruany, M.D., Ph.D.
Johns Hopkins University, Baltimore, MD 21204
heartdrug@aol.com Dr. Serebruany reports being listed as a coinventor on and receiving compensation for a U.S. patent application for prasugrel and receiving grant support from Eli Lilly and Sanofi–Bristol-Myers Squibb and advisory fees from Sanofi–Bristol-Myers Squibb. No other potential conflict of interest relevant to this letter was reported.
2 References1
Wiviott SD ,Braunwald E ,McCabe CH , et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015
Full Text | Web of Science | Medline2
Bhatt DL . Intensifying platelet inhibition -- navigating between Scylla and Charybdis. N Engl J Med 2007;357:2078-2081
Full Text | Web of Science | Medline
To the Editor:
In TRITON–TIMI 38, Wiviott et al. found a reduction in the incidence of myocardial infarction but an increase in major bleeding with prasugrel as compared with clopidogrel. The study design involved a 300-mg loading dose of clopidogrel; in the majority of patients (74%), the loading dose of either study drug was given after the first coronary guidewire was placed and during percutaneous coronary intervention (PCI) or within 1 hour after PCI, although it is well known that a 300-mg dose of clopidogrel achieves good clinical efficacy only after 8 to 12 hours.1 We2 and others3 have found, in randomized trials, that a 600-mg loading dose of clopidogrel before PCI (which is associated with maximal platelet inhibition within 2 hours) significantly reduces the risk of periprocedural myocardial infarction, as compared with a 300-mg loading dose, with no additional risk of bleeding. Wiviott et al. report that data supporting the 600-mg dose “have been inconsistent”; however, the results of randomized trials have consistently supported the 600-mg loading regimen.2,3 Since the definition of myocardial infarction in TRITON–TIMI 38 includes an increase in the level of creatine kinase MB fraction to twice the upper limit of the normal range after intervention,4 the use of prasugrel might involve trading a reduction in the risk of small myocardial infarctions for an increase in the risk of major bleeding.
4 ReferencesVincenzo Pasceri, M.D.
Giuseppe Patti, M.D.
Germano Di Sciascio, M.D.
Campus Bio-Medico University, 00163 Rome, Italy
vpasceri@hotmail.com 1
Steinhubl SR ,Berger PB ,Brennan DM ,Topol EJ . Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006;47:939-943
CrossRef | Web of Science | Medline2
Patti G ,Colonna G ,Pasceri V ,Pepe LL ,Montinaro A ,Di Sciascio G . Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099-2106
CrossRef | Web of Science | Medline3
Cuisset T ,Frere C ,Quilici J , et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339-1345
CrossRef | Web of Science | Medline4
Wiviott SD ,Antman EM ,Gibson CM , et al. 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
CrossRef | Web of Science | Medline
To the Editor:
In his editorial accompanying the article by Wiviott et al., Bhatt1 pointed out the potential of individualized antiplatelet therapy based on monitoring of platelet function. Unfortunately, the lack of standards and of specific test systems significantly limits the use of platelet-function monitoring to date.2,3 Its potential is further limited by poor correlation of the results of available test systems such as collagen-induced aggregometry and the platelet-function analyzer PFA-100 for measuring the response to aspirin (Figure 1Figure 1
Platelet Aggregation in Blood Samples as Tested with the Platelet-Function Analyzer PFA-100 and Light-Transmission Aggregometry.). In this example, only 40 of 69 patients (58%) were consistently identified as either having a response or not having a response with the use of both tests. Accordingly, even if the adaptation of single dosages may seem too speculative at present, at least the prevention of therapy with an agent proved not to be effective in two or more independent in vitro tests in a given patient might be a realistic strategy in the near future.3 ReferencesFriederike von Lewinski, M.D., Ph.D.
Joachim Riggert, M.D.
Walter Paulus, M.D.
University of Göttingen, 37075 Göttingen, Germany
wpaulus@med.uni-goettingen. de 1
Bhatt DL . Intensifying platelet inhibition -- navigating between Scylla and Charybdis. N Engl J Med 2007;357:2078-2081
Full Text | Web of Science | Medline2
Gurbel PA ,Becker RC ,Mann KG ,Steinhubl SR ,Michelson AD . Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol 2007;50:1822-1834
CrossRef | Web of Science | Medline3
Harrison P ,Frelinger AL III ,Furman MI ,Michelson AD . Measuring antiplatelet drug effects in the laboratory. Thromb Res 2007;120:323-336
CrossRef | Web of Science | Medline
Author/Editor Response
Serebruany and Pasceri et al. ask for clarification of the data from TRITON–TIMI 38. Pasceri et al. have misstated our definition of periprocedural myocardial infarction. The prespecified published definition was far more stringent: two separate samples, each with a level of creatine kinase MB fraction that was more than three times the upper limit of the normal range or a single sample with a level that was more than five times the upper limit of the normal range, provided it was the last sample obtained. The risks of both procedural myocardial infarction and nonprocedural myocardial infarction were significantly reduced in the prasugrel group, as was the risk of new ST-elevation myocardial infarction. Even if data for procedural myocardial infarction were excluded from the analyses, both the primary end point and the secondary end point of a net clinical benefit still would significantly favor prasugrel. Similarly, the risk of definite stent thrombosis was significantly reduced by the use of prasugrel.
Serebruany states that the number of deaths was identical in each treatment group, citing 154 deaths in the prasugrel group and 155 in the clopidogrel group; those numbers are apparently the result of summing the numbers of deaths from cardiovascular causes and cases of fatal bleeding (from Tables 2 and 3, respectively, in our article). However, in Table 2, we report the number of deaths from any cause as 188 in the prasugrel group and 197 in the clopidogrel group. The footnote to Table 2 states that death from cardiovascular causes and death from fatal hemorrhage were not mutually exclusive, with intracranial hemorrhage and death after cardiovascular procedures that were complicated by fatal bleeding included in both end points, which therefore cannot be summed without double-counting. To clarify, death from nonhemorrhagic cardiovascular events occurred in 121 subjects in the prasugrel group, as compared with 145 subjects in the clopidogrel group, and the composite of death from cardiovascular causes or fatal hemorrhage occurred in 142 subjects in the prasugrel group and 151 in the clopidogrel group.
We agree with Pasceri et al. that doses of clopidogrel that are higher than 300 mg result in more rapid onset of platelet inhibition,1 and a reduction in the rate of procedural myocardial infarction was found with 600 mg of clopidogrel in small studies, including the Antiplatelet Therapy for Reduction of Myocardial Damage during Angioplasty (ARMYDA-2) trial.2 However, enough equipoise exists regarding the relative merits of standard and high-dose clopidogrel to support a large, ongoing phase 3 trial (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions [CURRENT/OASIS 7]; ClinicalTrials.gov number, NCT00335452) comparing standard-dose clopidogrel and higher-dose clopidogrel. The prasugrel dose used in TRITON–TIMI 38 resulted in much greater and more rapid platelet inhibition than the higher-dose clopidogrel (600-mg loading dose, followed by 150 mg daily) used in the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation (PRINCIPLE)–TIMI 44 trial.3
3 ReferencesStephen D. Wiviott, M.D.
Eugene Braunwald, M.D.
Elliott M. Antman, M.D.
Brigham and Women's Hospital, Boston, MA 02115
eantman@rics.bwh. harvard. edu 1
Montalescot G ,Sideris G ,Meuleman C , et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48:931-938
CrossRef | Web of Science | Medline2
Patti G ,Colonna G ,Pasceri V ,Pepe LL ,Montinaro A ,Di Sciascio G . Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099-2106
CrossRef | Web of Science | Medline3
Wiviott SD ,Trenk D ,Frelinger AL , et al. 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
CrossRef | Web of Science | Medline
Author/Editor Response
As von Lewinski et al. point out, there are many limitations of monitoring platelet function at the present time. I agree with their observation that there is no universal standard and that the various tests that are available often give different results. Evidence of a lack of response or antiplatelet “resistance” does appear to be a marker of risk in several studies. I hope that future research will determine the optimal method of assessing response to antiplatelet therapy. More important than just refinement of the measuring technique is the need for prospective clinical-trial data to support the measurement of platelet function and subsequent modification of the therapeutic regimen.1,2 Unless and until this happens, the usefulness of measuring platelet function in an effort to improve clinical outcomes remains speculative.
TRITON–TIMI 38 provides substantial evidence that potent antiplatelet blockade reduces the risk of ischemic events and also increases the risk of bleeding. In fact, the trial validates the hypothesis that intense platelet inhibition through a particular pathway does result in a reduction of important thrombotic events. What remains to be determined is whether this is a threshold effect or a continuous effect. That is, is it necessary to get just above a certain level of inhibition of platelet aggregation to obtain clinical efficacy while balancing safety, or is it a more linear relationship, in which greater platelet inhibition generally results in better efficacy? Is the appropriate analogy warfarin or statins? The study of the relationship between platelet function and ischemic events, as well as bleeding, will most likely remain a fertile area of investigation for years to come.
2 ReferencesDeepak L. Bhatt, M.D.
Cleveland Clinic, Cleveland, OH 44195
bhattd@ccf.org 1
Bhatt DL . Aspirin resistance: more than just a laboratory curiosity. J Am Coll Cardiol 2004;43:1127-1129
CrossRef | Web of Science | Medline2
Wang TH ,Bhatt DL ,Topol EJ . Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J 2006;27:647-654
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Giuseppe Patti, György Bárczi, Dejan Orlic, Fabio Mangiacapra, Giuseppe Colonna, Vincenzo Pasceri, Emanuele Barbato, Béla Merkely, István Édes, Miodrag Ostojic, William Wijns, Germano Di Sciascio. (2011) Outcome Comparison of 600- and 300-mg Loading Doses of Clopidogrel in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction. Journal of the American College of Cardiology 58:15, 1592-1599
CrossRef
