Fluent Essays

12 Journal Club Template Journal Article Citation Introduction: Background · Information regarding the topic discussed in the article (medication, treatment, etc.) – why is this relevant? · Previous relevant trials should be reviewed by presenter to provide greater understanding of the topic being discussed – can summarize previous literature on the topic and point out any gaps in knowledge · Include any funding disclosures Objective · State the article’s main objective for the study Methods: Study Methods · Design of the trial (e.g. prospective/retrospective, RCT, case series, open-label, double-blinded, etc.) · Setting of the trial: (e.g. multicenter/single center study) · Time frame of the study conducted · Method of randomization, if applicable · Study design - any specifics about the study method (e.g. questionnaires, follow-up time frame, monitoring parameters, etc.) Patient Population Inclusion Criteria: · As stated in the article Exclusion Criteria: · As stated in the article Baseline Characteristics · Comparison of the baseline characteristics between the groups · Explanation of significant differences/similarities between the study groups Endpoints Primary Endpoints · As stated in the article · As stated in the article Secondary Endpoints · As stated in the article · As stated in the article Statistical Analysis · Explain each statistical test used in the analysis · Determine whether the test is appropriate for the type of data analyzed (example) Statistical Analysis Data Appropriate? Results: Primary Outcomes · Utilize graphs/charts to explain the outcomes · Highlight important outcomes and explain the significance Secondary Outcomes · Utilize graphs/charts to explain the outcomes · Highlight important outcomes and explain the significance Critique: Strengths · Analyze various parts of the article thoughtfully and carefully to establish the article’s strengths · Explore the article thoroughly and evaluate more persuasively by presenting a balanced view · Determine whether the study or work discussed the objective/purpose of the research Limitations · Same as above 1 Conclusions: Author’s Conclusion · Summarize the author’s major findings and conclusions My Conclusions · Incorporate your criticisms of the article to formulate your own conclusion · Discuss how the findings can be used in clinical practice References 1. 2. 3. Appendix: (can include other tables/charts or background information that can help explain the article) 1 n engl j med 357;20 www.nejm.org november 15, 2007 2001 The new england journal of medicine established in 1812 november 15, 2007 vol. 357 no. 20 Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes Stephen D. Wiviott, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Gilles Montalescot, M.D., Ph.D., Witold Ruzyllo, M.D., Shmuel Gottlieb, M.D., Franz-Joseph Neumann, M.D., Diego Ardissino, M.D., Stefano De Servi, M.D., Sabina A. Murphy, M.P.H., Jeffrey Riesmeyer, M.D., Govinda Weerakkody, Ph.D., C. Michael Gibson, M.D., and Elliott M. Antman, M.D., for the TRITON–TIMI 38 Investigators* A b s t r a c t From Brigham and Women’s Hospital and Harvard Medical School, Boston (S.D.W., E.B., C.H.M., S.A.M., C.M.G., E.M.A.); Institut de Cardiologie and INSERM Unit 856, Pitié–Salpêtrière University Hospital, Paris (G.M.); Instytut Kardiologii, Warsaw, Poland (W.R.); Bikur Cholim Hospital, Jerusalem, Israel (S.G.); Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany (F.-J.N.); Azienda Ospedaliero–Universi- taria di Parma, Parma, Italy (D.A.); Azien- da Ospedaliera Civile di Legano, Legano, Italy (S.D.S.); and Eli Lilly Research Labo- ratories, Indianapolis ( J.R., G.W.). Address reprint requests to Dr. Antman at the Car- diovascular Division, Brigham and Wom- en’s Hospital, TIMI Study Group, 350 Longwood Ave., 1st Fl., Boston, MA 02115, or at [email protected] *The members of the Steering and Oper- ations Committees of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38 are listed in the Appendix. The TRITON–TIMI 38 Investigators are listed in the Supple- mentary Appendix, available with the full text of this article at www.nejm.org. This article (10.1056/NEJMoa0706482) was published at www.nejm.org on Novem- ber 4, 2007. N Engl J Med 2007;357:2001-15. Copyright © 2007 Massachusetts Medical Society. Background Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treat- ment to prevent thrombotic complications of acute coronary syndromes and percu- taneous coronary intervention. Methods To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with sched- uled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleed- ing was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also great- er in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Conclusions In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591.) The New England Journal of Medicine Downloaded from nejm.org on August 30, 2021. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 357;20 www.nejm.org november 15, 20072002 The short-term and long-term ben-efits of dual-antiplatelet therapy with aspi-rin and clopidogrel have been established for patients with acute coronary syndromes1-3 and those undergoing percutaneous coronary interven- tion (PCI).4,5 Despite these benefits, many patients continue to have recurrent atherothrombotic events while receiving standard dual antiplatelet therapy.1 In addition, important limitations of clopidogrel remain, such as only a modest antiplatelet effect, with substantial interpatient variability 6,7 and a de- layed onset of action.5 Small clinical studies have suggested that patients with a reduced pharma- cologic response to clopidogrel may be at increased risk for adverse clinical events, including myocar- dial infarction and coronary-stent thrombosis.8-11 Prasugrel — a novel thienopyridine — is a pro- drug that, like clopidogrel, requires conversion to an active metabolite before binding to the plate- let P2Y12 receptor to confer antiplatelet activity. 12 At the currently studied doses, prasugrel inhibits adenosine diphosphate–induced platelet aggrega- tion more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers13 and in pa- tients with coronary artery disease,14,15 including those undergoing PCI.16 Phase 2 testing of prasu- grel, as compared with clopidogrel, in patients undergoing elective or urgent PCI showed a trend toward fewer ischemic events, with an acceptable safety profile.17 Thus, we designed the Trial to As- sess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction (TRITON– TIMI) 38, a phase 3 trial involving patients with acute coronary syndromes with scheduled PCI, comparing a regimen of prasugrel with the stan- dard-dose regimen of clopidogrel approved by the Food and Drug Administration.18 Although our trial was designed to compare regimens of prasu- grel and clopidogrel, it also tests the hypothesis that the use of an agent producing a higher level of inhibition of adenosine diphosphate–induced platelet aggregation and a less-variable response than standard-dose clopidogrel reduces ischemic events. M e t h o d s TRITON–TIMI 38 was designed as a collaboration between the TIMI Study Group, the sponsors — Daiichi Sankyo and Eli Lilly — and a steering committee of investigators (see the Appendix). Quintiles Corporation provided data- and site-man- agement services. All key prespecified and explor- atory analyses were performed by the TIMI Study Group, using an independent copy of the complete database. The academic authors wrote all drafts of the manuscript and vouch for the veracity and com- pleteness of its content. The database was locked on September 22, 2007; the analyses reported here- in were completed on October 26, 2007. Study Population We enrolled 13,608 patients with acute coronary syndromes (representative of the entire spectrum of those syndromes) with scheduled PCI. Patients were randomly assigned to the clopidogrel group or the prasugrel group in two strata: 10,074 pa- tients with moderate-to-high-risk unstable angi- na or non–ST-elevation myocardial infarction and 3534 patients with ST-elevation myocardial infarc- tion. The inclusion criteria for patients with un- stable angina or non–ST-elevation myocardial infarction were ischemic symptoms lasting 10 minutes or more and occurring within 72 hours before randomization, a TIMI risk score19 of 3 or more, and either ST-segment deviation of 1 mm or more or elevated levels of a cardiac biomarker of necrosis. Patients with ST-elevation myocardial infarction could be enrolled within 12 hours after the onset of symptoms if primary PCI was planned or within 14 days after receiving medical treat- ment for ST-elevation myocardial infarction.18 Full exclusion criteria have been published pre- viously.18 Key exclusion criteria included an in- creased risk of bleeding, anemia, thrombocyto- penia, a history of pathologic intracranial findings, or the use of any thienopyridine within 5 days before enrollment.18 The protocol was approved by the institutional review boards associated with all participating centers, and written informed consent was provided by all patients. Study Protocol A loading dose of study medication (60 mg of pra- sugrel or 300 mg of clopidogrel) was administered, in a double-blind manner, anytime between ran- domization and 1 hour after leaving the cardiac catheterization laboratory. Since the protocol was designed as a trial of patients with acute coronary syndromes who were undergoing PCI, the coro- nary anatomy had to be known to be suitable for PCI before randomization in all patients with un- stable angina or non–ST-elevation myocardial in- farction, or in those enrolled after medical treat- The New England Journal of Medicine Downloaded from nejm.org on August 30, 2021. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. Pr a sugr el vs. Cl opid ogr el in Patien t s w i th Acu te Corona r y S y ndromes n engl j med 357;20 www.nejm.org november 15, 2007 2003 ment for ST-elevation myocardial infarction. If the coronary anatomy was previously known or pri- mary PCI for ST-elevation myocardial infarction was planned, pretreatment with the study drug was permitted for up to 24 hours before PCI. Random- ization was to occur before PCI was performed, and the study drug was to be administered as soon as possible after randomization. The choice of vessels treated, devices used, and adjunctive medication administered to support PCI was left to the discretion of the treating physician. After PCI, patients received maintenance doses of either prasugrel (10 mg) or clopidogrel (75 mg) daily. Use of aspirin was required, and a daily dose of 75 to 162 mg was recommended. Study visits were conducted at hospital discharge, at 30 days, at 90 days, and at 3-month intervals thereafter, for a total of 6 to 15 months.18 End Points The primary efficacy end point was a composite of the rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke during the follow-up period. Key secondary end points at 30 and 90 days were the primary com- posite end point and a composite of death from cardiovascular causes, nonfatal myocardial infarc- tion, or urgent target-vessel revascularization. Key secondary end points for the entire follow-up pe- riod were stent thrombosis and a composite of death from cardiovascular causes, nonfatal myo- cardial infarction, nonfatal stroke, or rehospital- ization due to a cardiac ischemic event. Addition- al prespecified analyses included an analysis of the rates of the primary end point from randomization to day 3 and a landmark analysis of those data from day 3 to the end of the study. Key safety end points were TIMI major bleeding not related to coronary-artery bypass grafting (CABG), non– CABG-related TIMI life-threatening bleeding, and TIMI major or minor bleeding, as previously de- fined.18 Stent thrombosis was defined as definite or probable stent thrombosis according to the Academic Research Consortium.20 All components of the primary, secondary, and key safety end points were adjudicated by members of an independent clinical events committee that was unaware of the group assignments. Statistical Analysis Efficacy comparisons were performed on the ba- sis of the time to the first event, according to the intention-to-treat principle. Safety analyses were carried out on data from patients who received at least one dose of the study drug. The Gehan–Wil- coxon test was used to compare the treatment groups with regard to the primary efficacy end point18; the log-rank test was used in a prespeci- fied sensitivity analysis for the primary end point and in all analyses of key secondary and safety end points. Because of the substantial overlap between the cohort of patients with unstable angina or non– ST-elevation myocardial infarction and the over- all population of patients with acute coronary syn- dromes, and to preserve the statistical power to detect a difference between the two treatment groups, we used a closed testing procedure. The primary efficacy end point was analyzed in the cohort with unstable angina or non–ST-elevation myocardial infarction first, and only if there was a statistically significant difference between the treatment groups was this end point analyzed in the overall cohort.18 Rates of the end points are expressed as Kaplan–Meier estimates at 15 months and were compared with the use of hazard ratios and two-sided 95% confidence intervals. An inde- pendent data monitoring committee monitored the safety and efficacy of the study drugs. P val- ues of less than 0.05 were considered to indicate statistical significance. We calculated that a total of 875 primary end points would be required for the study to have a 90% power to detect a 20% reduction in the rela- tive risk of the primary end point among patients with unstable angina or non–ST-elevation myocar- dial infarction receiving prasugrel, as compared with clopidogrel. It was estimated that 9500 pa- tients with unstable angina or non–ST-elevation myocardial infarction would need to be enrolled to achieve this number of end points.18 A pre- specified assessment conducted when 650 patients had had a primary end point found a slightly lower-than-expected aggregate rate of the end point, which led us to increase the number of pa- tients in the cohort with unstable angina or non– ST-elevation myocardial infarction to approximate- ly 10,100.18 R e s u l t s We randomly assigned 13,608 patients (10,074 with unstable angina or non–ST-elevation myocardial infarction and 3534 with ST-elevation myocardial infarction), from 707 sites in 30 countries, to a treatment group between November 2004 and Jan- uary 2007. The baseline characteristics were sim- The New England Journal of Medicine Downloaded from nejm.org on August 30, 2021. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 357;20 www.nejm.org november 15, 20072004 ilar to those in contemporary studies of patients with acute coronary syndromes who were under- going PCI and were well matched between the treatment groups (Table 1). The median duration of therapy was 14.5 months. A total of 14 patients (0.1%) were lost to follow-up. Nearly all patients (99%) had PCI at the time of randomization, 94% received at least one in- tracoronary stent, and 47% received at least one drug-eluting stent. The study drug was adminis- tered before the first coronary guidewire was placed in 25% of patients, after the first coro- nary guidewire was placed and during the PCI or within 1 hour after PCI in 74%, and more than 1 hour after PCI in 1%. Efficacy End Points The rate of the primary efficacy end point was significantly reduced in favor of prasugrel among the patients with unstable angina or non–ST-eleva- tion myocardial infarction (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P = 0.002); therefore, as prespecified, the analysis was also performed in the overall cohort of patients with acute coronary syndromes. A significant benefit of prasugrel was also observed in the ST-elevation myocardial infarction cohort alone (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02), and there was no significant interaction between treatment group and enrollment stratum (unstable angina or non–ST-elevation myocardial infarction vs. ST- elevation myocardial infarction). In the overall cohort, a total of 781 patients (12.1%) in the clopidogrel group had the primary end point, as compared with 643 patients (9.9%) in the prasugrel group (hazard ratio, 0.81; 95% CI, 0.73 to 0.90; P<0.001) (Table 2 and Fig. 1A), sup- porting the primary hypothesis of superior effi- cacy. A significant reduction in the primary end point was seen in the prasugrel group by the first prespecified time point, 3 days (5.6% in the clopi- dogrel group vs. 4.7% in the prasugrel group; hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P = 0.01) (Fig. 1B), and persisted throughout the follow-up period. From 3 days to the end of the study, the primary end point had occurred in 6.9% of pa- tients receiving clopidogrel and in 5.6% of pa- tients receiving prasugrel (hazard ratio, 0.80; 95% CI, 0.70 to 0.93; P = 0.003) (Fig. 1C). The difference between the treatment groups with regard to the rate of the primary end point was largely related to a significant reduction in myocardial infarc- tion in the prasugrel group (9.7% in the clopido- grel group vs. 7.4% in the prasugrel group; haz- ard ratio, 0.76; 95% CI, 0.67 to 0.85; P<0.001). The rate of myocardial infarction with subsequent death from cardiovascular causes (including ar- rhythmia, congestive heart failure, shock, and sudden or unwitnessed death) was also reduced in the prasugrel group (0.7% in the clopidogrel group vs. 0.4% in the prasugrel group; hazard ratio, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). There was no significant difference between the two treatment groups in the rate of stroke or of death from cardiovascular causes not preceded by re- current myocardial infarction. Prasugrel showed superior efficacy in major prespecified subgroups (Fig. 2), without signifi- cant interactions between the characteristics of the patients and the treatment group. A benefit with prasugrel with regard to the primary end point was found both with the use of glycoprotein IIb/IIIa–receptor antagonists during the index hos- pitalization (hazard ratio for prasugrel vs. clopi- dogrel, 0.79; 95% CI, 0.69 to 0.91; P<0.001) or without such use (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = 0.03). The benefit tended to be greater among the 3146 patients with diabetes (17.0% of whom had the primary end point in the clopido- grel group, vs. 12.2% in the prasugrel group; haz- ard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001) than among the 10,462 patients without diabetes (10.6% of whom had the primary end point in the clopi- dogrel group, vs. 9.2% in the prasugrel group; hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P = 0.02). There was no significant interaction between treat- ment effect and diabetes status (P = 0.09) or the timing of the study-drug administration (P = 0.40). Similar significant reductions were seen for prasugrel in the overall cohort with regard to the prespecified secondary end point of death from cardiovascular causes, nonfatal myocardial infarc- tion, or urgent target-vessel revascularization at 30 days (hazard ratio, 0.78; 95% CI, 0.69 to 0.89; P<0.001) and at 90 days (hazard ratio, 0.79; 95% CI, 0.70 to 0.90; P<0.001). A significant reduction in the rate of urgent target-vessel revasculariza- tion alone was also found in the prasugrel group by the end of the follow-up period (hazard ratio, 0.66; 95% CI, 0.54 to 0.81; P<0.001) (Table 2). A reduction in favor of prasugrel was also seen by the end of the follow-up period for the end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or rehos- The New England Journal of Medicine Downloaded from nejm.org on August 30, 2021. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. Pr a sugr el vs. Cl opid ogr el in Patien t s w i th Acu te Corona r y S y ndromes n engl j med 357;20 www.nejm.org november 15, 2007 2005 pitalization for ischemia (hazard ratio, 0.84; 95% CI, 0.76 to 0.92; P<0.001) (Table 2). The rate of definite or probable stent thrombosis, as defined by the Academic Research Consortium, was sig- nificantly reduced in the prasugrel group as com- pared with the clopidogrel group, with 68 patients (1.1%) and 142 patients (2.4%), respectively, hav- ing at least one occurrence (hazard ratio, 0.48; 95% CI, 0.36 to 0.64; P<0.001). The significant re- duction in the rate of stent thrombosis was also found among patients receiving prasugrel in com- bination with bare-metal stents alone (hazard ra- tio, 0.52; 95% CI, 0.35 to 0.77; P<0.001) and among those receiving prasugrel in combination with at least one drug-eluting stent (hazard ratio, 0.43; 95% CI, 0.28 to 0.66; P<0.001). Safety End Points Among patients treated with prasugrel, 146 (2.4%) had at least one TIMI major hemorrhage that was not related to CABG, as compared with 111 pa- tients (1.8%) treated with clopidogrel (hazard ra- tio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03) (Table 3). This excess of TIMI major bleeding included a higher rate of life-threatening bleeding in the pra- sugrel group (1.4%, vs. 0.9% in the clopidogrel group; hazard ratio, 1.52; 95% CI, 1.08 to 2.13; P = 0.01) at the end of the study, as well as from the time of randomization to day 3 (0.4% vs. 0.3%; hazard ratio, 1.38; 95% CI, 0.79 to 2.41; P = 0.26) and from day 3 to the end of the study (1.0% vs. 0.6%; hazard ratio, 1.60; 95% CI, 1.05 to 2.44; P = 0.03). Fatal TIMI major bleeding occurred in significantly more patients treated with prasugrel (0.4%) than those treated with clopidogrel (0.1%) (P = 0.002) (Table 3), and more patients in the pra- sugrel group had nonfatal life-threatening bleed- ing (1.1%, vs. 0.9% in the clopidogrel group; hazard ratio, 1.25; 95% CI, 0.87 to 1.81; P = 0.23). A higher rate of TIMI major bleeding related to instrumentation and a significantly higher rate of spontaneous TIMI major bleeding were seen in the prasugrel group than in the clopidogrel group (Table 3). Intracranial hemorrhage was reported in 19 patients (0.3%) receiving prasu- grel and 17 patients (0.3%) receiving clopidogrel (P = 0.74). The combination of non–CABG-related TIMI major or minor hemorrhage was more fre- quent among patients receiving prasugrel than among those receiving clopidogrel (hazard ratio, 1.31; 95% CI, 1.11 to 1.56; P = 0.002) (Table 3). Few patients underwent CABG; among them, the rate of TIMI major bleeding was also greater with prasugrel than with clopidogrel (Table 3). More patients treated with prasugrel (2.5%, vs. 1.4% of patients treated with clopidogrel; P<0.001) discontinued the study drug owing to adverse events related to hemorrhage. When the rates of certain efficacy and bleed- ing end points — death from any cause, nonfa- tal myocardial infarction, nonfatal stroke, and TIMI major hemorrhage — were included in a prespecified analysis of net clinical benefit, the findings favored prasugrel (13.9% of patients in the clopidogrel group vs. 12.2% in the prasugrel group; hazard ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.004). Death from cardiovascular causes (in- cluding death related to intracranial hemorrhage or to bleeding related to a cardiovascular proce- dure) or fatal hemorrhage occurred in 151 patients (2.4%) receiving clopidogrel and in 142 patients (2.2%) receiving prasugrel (hazard ratio, 0.94; 95% CI, 0.75 to 1.18; P = 0.59). As a result of the discordance between the ef- ficacy results (lower rates of ischemic end points in the prasugrel group than in the clopidogrel group) and the safety results (higher rates of bleeding end points with prasugrel than with clopidogrel) during the entire follow-up period, we performed a series of post hoc exploratory analyses to iden- tify the subgroups of patients who did not have a favorable net clinical benefit (defined as the rate of death from any cause, nonfatal myocardial in- farction, nonfatal stroke, or non–CABG-related nonfatal TIMI major bleeding) from the use of prasugrel or who had net harm. There were three specific groups of interest; patients who had a previous stroke or transient ischemic at- tack had net harm from prasugrel (hazard ratio, 1.54; 95% CI, 1.02 to 2.32; P = 0.04), patients 75 years of age or older had no net benefit from prasugrel (hazard ratio, 0.99; 95% CI, 0.81 to 1.21; P = 0.92), and patients weighing less than 60 kg had no net benefit from prasugrel (haz- ard ratio, 1.03; 95% CI, 0.69 to 1.53; P = 0.89). In both treatment groups, patients with at least one of these three risk factors had higher rates of bleeding than those without them (Table 4). Patients with a history of cerebrovascular events had no evidence of a clinical benefit from prasu- grel (as compared with clopidogrel), as evaluated by the primary efficacy end point, and had a strong trend toward a greater rate of TIMI major bleeding (P = 0.06), including intracranial hemor- The New England Journal of Medicine Downloaded from nejm.org on August 30, 2021. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e n engl j med 357;20 www.nejm.org november 15, 20072006 Table 1. Baseline Characteristics of the Patients.* Characteristic Prasugrel (N = 6813) Clopidogrel (N = 6795) Unstable angina or NSTEMI (%) 74 74 STEMI (%) 26 26 Age Median (yr) 61 61 25th percentile, 75th percentile (yr) 53, 69 53, 70 ≥75 yr (%) 13 13 Female sex (%) 25 27 BMI† Median 28 28 25th percentile, 75th percentile 25, 31 25, 31 White race (%)‡ 92 93 Region of enrollment (%) North America 32 32 Western Europe 26 26 Eastern Europe 24 25 Middle East, Africa, or Asia–Pacific region 14 14 South America 4 4 Medical history (%) Hypertension 64 64 Hypercholesterolemia 56 56 Diabetes mellitus 23 23 Tobacco use 38 38 Previous MI 18 18 Previous CABG 8 7 Creatinine clearance <60 ml/min (%)§ 11 12 Index procedure (%) PCI 99 99 CABG 1 1 Stent 94 95 Bare-metal stent only 48 47 ≥1 Drug-eluting stent 47 47 Multivessel PCI 14 14 Antithrombin use to support PCI (%) Heparin 66 65 LMWH 9 8 Bivalirudin 3 3 Other or multiple therapies 22 23 Glycoprotein IIb/IIIa–receptor antagonist use during index hospitalization (%) 54 55 Timing of study-drug administration (%)¶ Before PCI 26 25 During PCI 73 74 After PCI 1 1 The New England Journal of Medicine Downloaded from nejm.org on August 30, 2021. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. Pr a sugr el vs. Cl opid ogr el in Patien t s w i th Acu te Corona r y S y ndromes n engl j med 357;20 www.nejm.org november 15, 2007 2007 rhage in six patients (2.3%) in the prasugrel group, as compared with none in the clopidogrel group (P = 0.02). As a result, there was a significant inter- action between a history of cerebrovascular events and the degree of net clinical benefit of prasu- grel as compared with clopidogrel (Table 4), indi- cating a significant harm from prasugrel among patients with a history of cerebrovascular events (518 patients), as compared with a significant ben- efit from prasugrel among patients without such a history (13,090 patients). There was also a sig- nificant interaction between the presence or ab- sence of any of these three risk factors and the degree of net clinical benefit for prasugrel as com- pared with clopidogrel (P = 0.006), though no sig- nificant harm was evident. Among patients with- out any of these three risk factors, there was greater efficacy with prasugrel (hazard ratio, 0.74; 95% CI, 0.66 to 0.84; P<0.001), no significant dif- ference in the rate of major bleeding in the pra- sugrel group and the clopidogrel group (hazard ratio, 1.24; 95% CI, 0.91 to 1.69; P = 0.17), and a substantially favorable net clinical benefit for the use of prasugrel (Table 4). The rate of serious adverse events not related to hemorrhage was similar in the prasugrel group and the clopidogrel group (occurring in 22.5% and 22.8% of patients, respectively; P = 0.52). The study drug was discontinued owing to adverse events not related to hemorrhage in 4.7% of patients treat- ed with prasugrel and in 5.0% of patients treated with clopidogrel (P = 0.37). The adverse events re- ported included severe thrombocytopenia in 17 patients in the prasugrel group (0.3%) and 18 patients in the clopidogrel group (0.3%) (P = 0.86); neutropenia in 2 patients (<0.1%) and 10 patients (0.2%) (P = 0.02), respectively; and colonic neo- plasms in 13 patients (0.2%) and 4 patients (0.1%) (P = 0.03). Known gastrointestinal bleeding pre- ceded the diagnosis of colonic neoplasms in nine patients (seven in the prasugrel group and two in the clopidogrel group). D i s c u s s i o n The risk of myocardial ischemic events in patients with acute coronary syndromes has been shown to be reduced by means of platelet inhibition with the use of aspirin21 and, even more effectively as compared with the use of aspirin alone, dual-anti- platelet therapy with aspirin and …