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EXPEDITED REVIEW

Patients With Prior Myocardial Infarction, Stroke, or Symptomatic Peripheral Arterial Disease in the CHARISMA Trial

Deepak L. Bhatt, MD, FACC^_*,_*, Marcus D. Flather, MD, Werner Hacke, MD, Peter B. Berger, MD, FACC, Henry R. Black, MD^||, William E. Boden, MD, FACC^¶, Patrice Cacoub, MD^#, Eric A. Cohen, MD^_**, Mark A. Creager, MD, FACC, J. Donald Easton, MD, Christian W. Hamm, MD, FACC, Graeme J. Hankey, MD^||||, S. Claiborne Johnston, MD, PhD^¶¶, Koon-Hou Mak, MD, FACC^##, Jean-Louis Mas, MD^_***, Gilles Montalescot, MD, PhD, Thomas A. Pearson, MD, FACC, P. Gabriel Steg, MD, FACC, Steven R. Steinhubl, MD, FACC^||||||, Michael A. Weber, MD, FACC^¶¶¶, Liz Fabry-Ribaudo, MSN, RN^_*, Tingfei Hu, MS^_*, Eric J. Topol, MD, FACC^###, Keith A.A. Fox, MBChB^_**** for the CHARISMA Investigators

^_* Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, United Kingdom
Department of Neurology, University of Heidelberg, Heidelberg, Germany
Geisinger Center for Health Research, Danville, Pennsylvania
^|| New York University School of Medicine, New York, New York
^¶ Division of Cardiology, Kaleida Healthcare, Buffalo, New York
^# Department of Internal Medicine, Hopital Pitie-Salpetriere, Paris, France
^_** Division of Cardiology, Sunnybrook and Women’s College Health Science Centre, Toronto, Canada
Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
Department of Neurology, Rhode Island Hospital and Brown University, Providence, Rhode Island
Department of Cardiology, Kerckhoff-Klinik Center, Bad Nauheim, Germany
^|||| Department of Neurology, Royal Perth Hospital and School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia
^¶¶ Department of Neurology, University of California San Francisco, San Francisco, California
^## Gleneagles Medical Centre, Singapore
^_*** Department of Neurology and Stroke Unit, Sainte-Anne Hospital, Paris, France
Institut de Cardiologie — Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France
Department of Community & Preventive Medicine, University of Rochester School of Medicine, Rochester, New York
Service de Cardiologie, Hôpital Bichat, Paris, France
^|||||| Division of Cardiology, University of Kentucky, Lexington, Kentucky
^¶¶¶ SUNY Downstate Medical Center College of Medicine, Brooklyn, New York
^### Case Western Reserve University, Cleveland, Ohio
^_**** University and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Manuscript received December 4, 2006; revised manuscript received March 16, 2007, accepted March 20, 2007.

^_* Reprint requests and correspondence: Dr. Deepak L. Bhatt, Associate Director, Cardiovascular Coordinating Center, Staff, Cardiac, Peripheral, and Carotid Intervention, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk F25, Cleveland, Ohio 44195. (Email: bhattd{at}ccf.org).

	Abstract

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Objectives: The purpose of this study was to determine the possible benefit of dual antiplatelet therapy in patients with prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease (PAD).

Background: Dual antiplatelet therapy with clopidogrel plus aspirin has been validated in the settings of acute coronary syndromes and coronary stenting. The value of this combination was recently evaluated in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, where no statistically significant benefit was found in the overall broad population of stable patients studied.

Methods: We identified the subgroup in the CHARISMA trial who were enrolled with documented prior MI, ischemic stroke, or symptomatic PAD.

Results: A total of 9,478 patients met the inclusion criteria for this analysis. The median duration of follow-up was 27.6 months. The rate of cardiovascular death, MI, or stroke was significantly lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.72 to 0.96, p = 0.01). Additionally, hospitalizations for ischemia were significantly decreased, 11.4% versus 13.2% (HR 0.86, 95% CI 0.76 to 0.96, p = 0.008). There was no significant difference in the rate of severe bleeding: 1.7% versus 1.5% (HR 1.12, 95% CI 0.81 to 1.53, p = 0.50); moderate bleeding was significantly increased: 2.0% versus 1.3% (HR 1.60, 95% CI 1.16 to 2.20, p = 0.004).

Conclusions: In this analysis of the CHARISMA trial, the large number of patients with documented prior MI, ischemic stroke, or symptomatic PAD appeared to derive significant benefit from dual antiplatelet therapy with clopidogrel plus aspirin. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA]; http://clinicaltrials.gov/ct/show/NCT00050817?order=1; NCT00050817 [ClinicalTrials.gov] )

Abbreviations and Acronyms   CI = confidence interval   HR = hazard ratio   MI = myocardial infarction   PAD = peripheral arterial disease

The CHARISMA study enrolled a stable population with either established atherothrombotic disease or multiple risk factors for atherothrombotic events (5). In a prespecified analysis of the CHARISMA trial, the 12,153 patients enrolled with established disease (documented cardiovascular, cerebrovascular, or peripheral arterial disease [PAD]) seemed to derive a significant benefit from combination therapy, while the 3,284 patients without documented disease but with multiple risk factors did not derive any benefit (4).

The CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial had previously demonstrated in a stable secondary prevention population that clopidogrel monotherapy was superior to aspirin monotherapy for reducing the composite of vascular death, MI, or stroke, as well as hospitalization for ischemic events (6,7), and that this benefit was further amplified in higher-risk subgroups from the CAPRIE trial such as those with prior ischemic events (8). We hypothesized that if the CHARISMA trial had examined only a "CAPRIE-like" high-risk secondary prevention population instead of a broader and overall lower-risk population, as was actually done, greater benefit of dual antiplatelet therapy over aspirin might have been evident.

	Methods

Top Abstract Methods Results Discussion Appendix References

 
The design of the CHARISMA trial has been published previously (9). Briefly, patients with documented coronary artery disease, cerebrovascular disease, or PAD, or with multiple risk factors for atherothrombosis were enrolled and randomized in double-blind fashion to clopidogrel plus aspirin or placebo plus aspirin and followed for a median of 28 months. Patients were excluded if they had indications for open-label clopidogrel use or were at high risk of bleeding.

For the purposes of this post hoc analysis, patients were identified as "CAPRIE-like" if they were enrolled with a documented prior MI, documented prior ischemic stroke, or symptomatic PAD. Symptomatic PAD was defined as either current intermittent claudication with an ankle brachial index 0.85 or a history of intermittent claudication with a previous related intervention (amputation, peripheral bypass surgery, endovascular procedure). In the CAPRIE trial, the time limit for entry for stroke was 1 week to 6 months after the event and 35 days for MI; unlike the inclusion criteria in the CAPRIE trial, for the current analysis, no time limit was set with respect to the occurrence of the prior ischemic event.

The primary efficacy end point was cardiovascular death (including hemorrhagic death), MI, or stroke (from any cause). The primary safety end point was severe bleeding as defined by the GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries) criteria, which includes fatal bleeding, primary intracranial hemorrhage, or bleeding that causes hemodynamic compromise and requires blood or fluid replacement, inotropic support, or surgical intervention (10). These events were validated by the Cleveland Clinic Clinical Events Adjudication Committee. The secondary efficacy end point consisted of cardiovascular death, MI, stroke, or rehospitalization for unstable angina, transient ischemic attack, or a revascularization procedure (coronary, cerebral, or peripheral). Moderate bleeding as determined by the GUSTO criteria was the secondary safety end point; this end point captures bleeding that leads to transfusion but that does not lead to hemodynamic compromise that requires intervention (10).

Statistical analysis.   The efficacy of clopidogrel plus aspirin versus placebo plus aspirin was assessed using a 2-sided log-rank test. Treatment effect, as measured by the hazard ratio (HR) (relative risk) and its associated 95% confidence interval (CI), was estimated using Cox’s proportional hazards model. Cumulative Kaplan-Meier estimates of the event rates were also calculated. Statistical comparisons of the safety event rates in the 2 treatment groups were performed using a 2-sided log-rank test. No adjustments for multiple comparisons were made. Multivariate analysis incorporating baseline demographics, concomitant medications, and time from enrolling ischemic event was performed to examine any independent effect of the randomized treatment. The instantaneous hazard functions of primary efficacy and safety end points were estimated by the life-table method as the first 30 days, 30 to 90 days, 90 to 180 days, and then every 180 days. All analyses were performed using SAS version 8.2 (SAS Institute Inc., Cary, North Carolina).

	Results

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A total of 9,478 patients fulfilled the "CAPRIE-like" criteria for this analysis. A total of 3,846 patients had prior MI, with a median time from the qualifying event to randomization of 23.6 months; 3,245 patients had prior stroke, with a median time from event of 3.5 months; 2,838 patients had symptomatic PAD, with a median time from diagnosis of 23.6 months. Note that 443 (4.7%) patients fell into multiple categories because they actually had more than 1 prior event or disease location. The baseline characteristics of these patients in the 2 randomized arms were well matched, with no significant differences (Table 1). Concomitant medication use was also similar in the 2 arms of the study except nitrate use, which was 25.8% in the aspirin plus placebo arm and 23.5% in the aspirin plus clopidogrel arm (p = 0.008) (Table 2).

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Kaplan-Meier Curves for Cardiovascular Death, MI, or Stroke for Clopidogrel + ASA Versus Placebo + ASA Kaplan-Meier event curves for the primary end point of cardiovascular death, myocardial infarction (MI), or stroke. ASA = aspirin; CI = confidence interval; RRR = relative risk reduction.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Hazard Ratio for the Primary End Point in Patients Enrolled With Prior MI, Stroke, or PAD Hazard ratio (HR) and 95% CI for the composite of cardiovascular death, MI, or stroke for patients randomized to placebo plus aspirin versus clopidogrel plus aspirin that were enrolled with a prior MI, prior ischemic stroke (IS), or symptomatic peripheral arterial disease (PAD). Abbreviations as in Figure 1.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Kaplan-Meier Curves for the Primary End Point in Patients With CAD Either With or Without Prior MI (A) Kaplan-Meier curves for the primary end point of cardiovascular death, MI, or stroke in patients enrolled with prior MI. (B) Kaplan-Meier curves for the primary end point in patients enrolled with coronary artery disease without prior MI. Abbreviations as in Figures 1 and 2.

Multivariate analysis revealed treatment with clopidogrel plus aspirin to be an independent predictor of freedom from cardiovascular death, MI, or stroke; the HR for cardiovascular death, MI, or stroke in patients randomized to clopidogrel plus aspirin instead of placebo plus aspirin was 0.84 (95% CI 0.73 to 0.97, p = 0.019). The effect of time from the ischemic event or diagnosis to randomization was included in the model and there was no significant effect of time with regard to outcome, although such testing may have been underpowered. Therefore, the primary end points at various times from the ischemic event are presented (Table 4); these data are also presented as an instantaneous hazard function from the time of randomization (Fig. 4). Besides randomization to clopidogrel, other predictors of decreased risk of cardiovascular death, MI, or stroke were female gender, concomitant statin use, and concomitant use of other lipid-lowering therapies. Significant predictors of cardiovascular death, MI, or stroke were increasing age, history of congestive heart failure, history of stroke, diastolic blood pressure 80 mm Hg, increasing neutrophil count, concomitant anticoagulants, concomitant antidiabetic medications, and current smoking.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Instantaneous Hazard for Cardiovascular Death, MI, or Stroke or for Severe or Moderate Bleeding (A) Instantaneous hazard for cardiovascular death, MI, or stroke. (B) Instantaneous hazard for severe or moderate bleeding. Abbreviations as in Figure 1.

	Discussion

Top Abstract Methods Results Discussion Appendix References

Thus, there appears to be a gradient of benefit for dual antiplatelet therapy depending on the risk of thrombotic events of the patient. A reduction in all-cause mortality with short-term clopidogrel given in addition to aspirin was observed in the COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction) trial (11), with significant 2% to 3% absolute risk reductions in composite ischemic end points seen in the CURE and CREDO trials (20 to 30 ischemic events prevented per 1,000 patients treated for about 1 year). In comparison, the CAPRIE-like cohort from the CHARISMA trial shows a more modest degree of benefit, with 14.4 episodes of cardiovascular death, MI, or stroke averted over the course of an average of 27.6 months per 1,000 patients treated, at a cost of 1.7 severe bleeds. Of note, there was no statistically significant increase in severe bleeding, including fatal bleeding or intracranial hemorrhage. Additionally, during the median of 27.6 months, 17.5 hospitalizations for ischemic events (unstable angina, transient ischemic attack, worsening PAD) or revascularization were prevented at the cost of an additional 7.6 moderate bleeds (essentially, transfusions).

The benefit on ischemic outcomes started soon after randomization with increasing separation of the event curves as duration of therapy increased. Examination of the actual event rates showed that the largest absolute benefit appeared to be in patients whose ischemic event was within the prior month, with a lower absolute benefit seen between 30 days and 30 months, with further attenuation of observed benefit beyond 30 months; it is biologically plausible that the greatest degree of benefit would be in those whose ischemic event was most recent, although this analysis was underpowered to detect any definite time-related effect. Several patterns emerge upon examination of this data set. The benefit in preventing ischemic events is greatest early after randomization. The benefit in preventing ischemic events is less in patients who are further removed from the last previous ischemic event at the time of randomization. The bleeding excess is also "front-loaded," with more bleeding seen with dual antiplatelet therapy compared with aspirin plus placebo in the first few months of therapy and little difference afterward. All of these patterns are not statistically significant per se, as the study lacks power to make a definitive statement regarding these observations.

Based on the findings in the subgroup of 2,675 patients who were excluded from the original CHARISMA group of "established cardiovascular disease" to derive the current study population, it appears that patients with angina and documented multivessel coronary artery disease, a history of remote percutaneous coronary intervention, a history of coronary artery bypass surgery, or those with transient ischemic attacks may not benefit from dual antiplatelet therapy. Thus, it seems that it is those patients who have had plaque rupture and thrombosis in the past that are most likely to derive benefit from an extended duration of dual antiplatelet therapy.

There are evident limitations to this analysis. As a post hoc subgroup analysis, it can only be considered hypothesis generating. Even large subgroup analyses may be misleading and provide spurious results. Nevertheless, with over 9,000 patients, it is a large subgroup that consists of a logical cohort to analyze given the initial findings of the CAPRIE trial. Furthermore, in this subgroup, the baseline characteristics of the clopidogrel plus aspirin and placebo plus aspirin groups were well matched without any significant differences, and the results persisted after multivariable analysis.

In conclusion, patients with documented prior MI, stroke, or symptomatic PAD in the CHARISMA trial appeared to have significant benefit from a reduction in ischemic events from dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin, which was somewhat offset by an increase in moderate, although not severe, bleeding. Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate.

	Appendix

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For complete author disclosure information, please see the online version of this article.

	Acknowledgments

 
The executive committee would like to acknowledge the efforts of Bernard Job, MD, and Christophe Gaudin, MD, from Sanofi-Aventis, and Mel Blumenthal, MD, and Ravi Saini, MD, from Bristol-Myers Squibb on behalf of the CHARISMA trial.

	Footnotes

 
The CHARISMA study was funded by Sanofi-Aventis and Bristol-Myers Squibb. Please see the for complete author disclosure information.

	References

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1. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Lancet 2001;358:527-533.[CrossRef][ISI][Medline]
2. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001;345:494-502.[Abstract/Free Full Text]
3. Steinhubl SR, Berger PB, Mann 3rd JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial JAMA 2002;288:2411-2420.[Abstract/Free Full Text]
4. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 2006;354:1706-1717.[Abstract/Free Full Text]
5. Bhatt DL, Fox KA, Hacke W, et al. A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial Am Heart J 2005;150:401.e1-401.e7.
6. CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Lancet 1996;348:1329-1339.[CrossRef][ISI][Medline]
7. Bhatt DL, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin Am Heart J 2000;140:67-73.[CrossRef][ISI][Medline]
8. Ringleb PA, Bhatt DL, Hirsch AT, Topol EJ, Hacke W. Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events Stroke 2004;35:528-532.[Abstract/Free Full Text]
9. Bhatt DL, Topol EJ. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial Am Heart J 2004;148:263-268.[CrossRef][ISI][Medline]
10. The GUSTO Investigators An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction N Engl J Med 1993;329:673-682.[Abstract/Free Full Text]
11. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial Lancet 2005;366:1607-1621.[CrossRef][ISI][Medline]

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This Article Abstract Figures Only Full Text (PDF) View Appendix All Versions of this Article: j.jacc.2007.03.025v1 49/19/1982    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (35) Citing Articles via Google Scholar Google Scholar Articles by Bhatt, D. L. Search for Related Content PubMed Articles by Bhatt, D. L.