Clopidogrel For High Atherothrombotic Risk And Ischemic Stabilization, Management And Avoidance Research Articles

Generalisability of trials on antithrombotic treatment intensification in patients with cardiovascular disease

ObjectiveAssessment of generalisability of guideline-informing trials on antithrombotic treatment intensification to real-world patients with cardiovascular disease (CVD).MethodsInclusion and exclusion criteria of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS),...

Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease: Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Trial

Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease: Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Trial

Letter by Aboyans et al Regarding Article, “Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease”

HomeCirculationVol. 122, No. 3Letter by Aboyans et al Regarding Article, “Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Aboyans et al Regarding Article, “Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease” Victor Aboyans, MD, PhD, Alexandre Le Guyader, MD and Philippe Lacroix, MD Victor AboyansVictor Aboyans Department of Thoracic and Cardiovascular Surgery and Vascular Medicine, Dupuytren University Hospital, Limoges, France Search for more papers by this author , Alexandre Le GuyaderAlexandre Le Guyader Department of Thoracic and Cardiovascular Surgery and Vascular Medicine, Dupuytren University Hospital, Limoges, France Search for more papers by this author and Philippe LacroixPhilippe Lacroix Department of Thoracic and Cardiovascular Surgery and Vascular Medicine, Dupuytren University Hospital, Limoges, France Search for more papers by this author Originally published20 Jul 2010https://doi.org/10.1161/CIRCULATIONAHA.109.931212Circulation. 2010;122:e394To the Editor:Berger and colleagues1 are commended for their interesting and hypothesis-generating posthoc analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial published recently in Circulation. To better understand the potential pathways leading to an enhanced protective effect of clopidogrel in smokers, several issues need further discussion and analysis.First, the protective effect of clopidogrel in smokers in this report contrasts with the lack of interaction between smoking and antiplatelet strategies in the subgroups analysis in the first Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial report.2 This difference might be explained by a different definition of smoking in the current article1 (≥1 cigarette a day) compared with the original publication (>15 cigarettes a day). The authors should explain why they changed their definition and whether the number of cigarettes smoked daily may affect the beneficial effects of clopidogrel, as suggested recently by others.3Second, the authors repeatedly called the 2 therapeutic arms of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial the “clopidogrel” group and the “placebo” group, even though both groups were also taking low-dose (75 to 160 mg) aspirin. Another hypothesis that has not been considered by the authors is that the protective effect observed in smokers in the “aspirin plus clopidogrel” group (compared with the “aspirin alone” group) might be related to the antiplatelet effect of clopidogrel in patients resistant to aspirin, the latter condition being strongly associated with smoking.4Last, the authors report higher rates of bleeding in smokers taking clopidogrel plus aspirin, but they did not detail the different localizations of bleeding. Smoking (along with aspirin) is a risk factor for gastrointestinal ulcers and their hemorrhagic complications.5 The higher rates of bleeding while taking clopidogrel in smokers versus nonsmokers not only might be related to a greater platelet inhibition by this drug in smokers, as suggested by the authors, but also may be due to an increased incidence of smoking-related gastrointestinal complications revealed by dual antiplatelet therapy. Similarly, the higher incidence of different types of cancers in smokers may contribute to this increased hemorrhagic risk.DisclosuresNone. References 1 Berger JS, Bhatt DL, Steinhubl SR, Shao M, Steg PG, Montalescot G, Hacke W, Fox KA, Lincoff AM, Topol EJ, Berger PB, for the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) Investigators. Smoking, clopidogrel, and mortality in patients with established cardiovascular disease. Circulation. 2009; 120: 2337–2344.LinkGoogle Scholar2 Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, for the CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006; 354: 1706–1717.CrossrefMedlineGoogle Scholar3 Desai NR, Mega JL, Jiang S, Cannon CP, Sabatine MS. Interaction between cigarette smoking and clinical benefit of clopidogrel. J Am Coll Cardiol. 2009; 53: 1273–1278.CrossrefMedlineGoogle Scholar4 Mirkhel A, Peyster E, Sundeen J, Greene L, Michelson AD, Hasan A, Domanski M. Frequency of aspirin resistance in a community hospital. Am J Cardiol. 2006; 98: 577–579.CrossrefMedlineGoogle Scholar5 Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet. 2009; 374: 1449–1461.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 20, 2010Vol 122, Issue 3 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.931212PMID: 20644023 Originally publishedJuly 20, 2010 PDF download Advertisement SubjectsEpidemiologySecondary Prevention

Effect of Clopidogrel on the Rate and Functional Severity of Stroke Among High Vascular Risk Patients

Disabling stroke is costly and considered by some patients a fate worse than death. We aimed to determine whether clopidogrel reduces the rate and functional severity of stroke among high vascular risk patients, including patients with previous transient ischemic attack or ischemic stroke, who were enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial. We randomly assigned 15,603 high vascular risk patients to receive clopidogrel (75 mg daily) or placebo in addition to background acetylsalicylic acid and followed them for a median of 28 months. The main outcome of this prespecified substudy was the functional severity of stroke outcome events as measured by the modified Rankin Scale (mRS) score at 3 months after the stroke outcome. During follow-up, 436 (2.8%) patients had a definite adjudicated stroke and a follow-up assessment of the mRS at 3 months poststroke, of whom 202 had been randomly assigned clopidogrel and 234 placebo (relative risk reduction 14%, 95% CI: -4% to 29%, P=0.12). There was no significant difference between the mean mRS scores at 3 months after stroke among patients assigned clopidogrel compared with placebo (mean mRS 3.6 [SD 2.4] clopidogrel versus 3.3 [SD 2.1] placebo; P=0.15). There was also no significant difference between the various categories of the mRS score at 3 months after stroke among patients assigned to clopidogrel compared with placebo. Among 4320 patients with a qualifying diagnosis of transient ischemic attack or ischemic stroke, 233 (5.4%) experienced a stroke during follow-up, of whom 103 were randomly assigned clopidogrel and 130 placebo (relative risk reduction 20%, 95% CI: -3% to 38%). There was no significant difference between the mean mRS scores at 3 months after stroke among patients with a qualifying transient ischemic attack or ischemic stroke who were assigned clopidogrel compared with placebo (3.4 [SD 2.1] clopidogrel versus 3.3 [SD 1.9] placebo; P=0.48). The addition of clopidogrel to acetylsalicylic acid did not significantly alter the rate and functional severity of stroke outcome events among high vascular risk patients enrolled in the CHARISMA trial.

Role of Dual Antiplatelet Therapy in Symptomatic Patients with Established Vascular Disease: Putting the CHARISMA Trial into Therapeutic Perspective

The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial has spurred debate over subgroup analysis interpretation and prompted renewed consideration of the long-term role of dual aspirin and clopidogrel therapy (DAPT) in patients with established vascular disease. Previous DAPT studies consistently demonstrated greater efficacy but an increased risk of bleeding compared with aspirin alone in patients with acute coronary syndromes or undergoing percutaneous coronary intervention. However, CHARISMA data were inconclusive and difficult to interpret. The principal subgroup analysis showed a significant benefit for clopidogrel plus aspirin in the 80% of patients with documented vascular disease, but unexpectedly showed potential harm in the approximately 20% of asymptomatic patients. Hypothesizing that dual antiplatelet therapy would provide benefit across the broad spectrum of atherothrombotic disease was plausible. In retrospect, it is apparent that by combining such a heterogeneous population, CHARISMA failed to show a clear treatment effect for DAPT and potentially masked important benefits in specific populations. Given the inherent clinical and biological variability among patients and disease states, difficult-to-interpret clinical data should not be dismissed. The current challenge is identifying clinically useful data from CHARISMA to determine the role of DAPT in contemporary clinical practice.

Smoking Interaction with Clopidogrel; Another Smoker's Paradox?

The American Heart Association estimates that one in five deaths from cardiovascular disease are directly linked to cigarette smoking. Individuals who smoke are two to six times more likely to develop coronary artery disease than nonsmokers. However, individuals who quit smoking will reduce their risk to levels equivalent to those of a nonsmoker within three years. Refer to the page 119-124 Exposure to cigarette smoke is an established risk factor for coronary heart disease in both Western and Asian countries. The multivariate relative risk of coronary heart disease mortality for current smokers was 1.8-3.7 compared to nonsmokers.1) Poor prognosis in smokers results from: 1) induction of hypercoagulability due to increased platelet activation, dyslipidemia, and endothelial dysfunction; 2) increased catecholamine release leading to increased heart rate, blood pressure, coronary vasoconstriction, and even arrhythmogenic effect; and 3) reduction in oxygen delivery due to increased carbon monoxide levels.2) The term of smoker's paradox has been coined by Barbash et al.3) who reported better outcomes among the smokers receiving thrombolytic therapy for acute myocardial infarction. Similarly, Cohen et al.4) reported that cigarette smoking was associated with a lower rate of subsequent target lesion revascularization in patients undergoing percutaneous coronary intervention (PCI). Hasdai et al.5) reported that current smokers during an index percutaneous intervention had fewer adverse events in the univariable analysis than the nonsmokers and former smokers. This improved can be explained in part by better covariables such as younger age or a more favorable clinical and angiographic profile. Therefore, this term may be misleading.6) Clopidogrel, an inhibitor of the platelet P2Y12 adenosine diphosphate receptor, improves prognosis in patients with acute coronary syndrome (ACS). However, there is significant response variability and a diminished clopidogrel response is associated with an increased risk of ischemic events.7) Smoking induces cytochrome P450 1A2 (CYP1A2), a hepatic enzyme involved in the metabolism of clopidogrel. Clopidogrel shows better inhibition of platelet aggregation in smokers than nonsmokers,8) and smokers are less likely to be hyporesponders than nonsmokers.9) In this issue of the Journal, Cho et al.10) investigated the association between smoking status and post-clopidogrel platelet reactivity in patients with acute myocardial infarction. Differences in the clinical situation and timing of the platelet test could explain the differences with the Bliden study.8) The decreases in CYP1A2 activity induced by smoking may also disappear after three days. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial compared long-term clopidogrel 75 mg/day vs. placebo in patients at high risk for cardiovascular events, and clopidogrel significantly reduced mortality in smokers but not in former or never-smokers.11) In addition to CYP1A2 activation by smoking, smokers may simply be a higher-risk group because of enhanced platelet activity and therefore benefit more from antithrombotic intervention. The Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28) trial compared the effect of clopidogrel on angiographic and clinical outcomes in 3,429 ST elevation myocardial infarction patients by smoking intensity: not current smokers (n=1,732), and smokers of 1 to 9 (n=206), 10 to 19 (n=354), 20 to 29 (n=715), and ≥30 cigarettes/day (n=422). Clopidogrel reduced the primary end point of a closed infarct-related artery or death/myocardial infarction, particularly among those who smoked ≥10 cigarettes/day.12) The CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) trial, which tested high-dose vs. usual-dose clopidogrel in ACS patients undergoing PCI, showed that smokers (vs. nonsmokers) had significant benefit with the higher clopidogrel dose. Smoking increases the risk for cardiovascular events and mortality in patients with established cardiovascular disease, but clopidogrel treatment may be more effective in smokers. Therefore, the interaction of smoking with acute myocardial infarction deserves further study in more patients using designs that show fewer time limitations.

Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease

Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown. We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15). Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility.

Cost-Effectiveness of Clopidogrel plus Aspirin versus Aspirin Alone for Secondary Prevention of Cardiovascular Events: Results from the CHARISMA Trial

To determine the incremental cost-effectiveness of clopidogrel plus aspirin (C + A) compared with aspirin (A) alone during the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial from a US payer perspective. Although the CHARISMA trial did not find a benefit of adding clopidogrel to aspirin in its overall study cohort, a benefit was suggested in a prespecified subgroup of patients with established cardiovascular (CV) disease. The cost-effectiveness of dual antiplatelet therapy in this population is unknown. Medical resource utilization was assessed prospectively, and costs for hospitalizations, physician services, outpatient care, and medications were assigned using 2007 US dollars. Life expectancy was estimated contingent on fatal and nonfatal CV events using statistical models of long-term survival from the Saskatchewan Health database. C + A was associated with a 12.5% relative reduction in CV death, myocardial infarction, or stroke compared with A alone (6.9% vs. 7.9%, P = 0.048) over a median 28 months of follow-up. Severe or moderate bleeding events were higher in patients receiving C + A versus A alone (3.6% vs. 2.5%, P < 0.001). Mean cost/patient was $2607 higher for C + A, while projected life expectancy increased by an average of 0.072 years due to fewer in-trial events. The resulting incremental cost-effectiveness ratio (ICER) for C + A was $36,343/year of life gained. Findings were insensitive to discount rate, life expectancy projections, post-event costs, and indirect costs from lost productivity; the ICER was most sensitive to the cost of clopidogrel. Bootstrap analysis demonstrated that the ICER for C + A remained <$50,000/life-year gained in 70.6% of bootstrap replicates and <$100,000/life-year gained in 87.4%. Among patients with established CV disease, adding clopidogrel to aspirin appears to increase life expectancy modestly at a cost generally considered acceptable within the US health-care system.

Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid

Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B(2) concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B(2) concentrations that could thereby reduce cardiovascular risk. Urinary 11-dehydro thromboxane B(2) concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B(2) concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B(2), whereas aspirin dose > or =150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B(2) levels. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B(2) are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.

Stroke and atherothrombosis: An Update on the Role of Antiplatelet Therapy

Atherothrombosis is responsible for most acute ischemic manifestations of atherosclerotic disease, including stroke. Individuals with evidence of atherothrombotic disease in one vascular bed have a significant risk of recurrence and show increased vulnerability over time for other manifestations elsewhere in the vasculature. Ischemic event rates for asymptomatic patients with multiple atherothrombotic risk factors appear to be similar to those in patients with documented cardiovascular disease. For example, diabetes mellitus and obesity are found at alarmingly high rates in patients with prior cardiovascular events, including stroke or transient ischemic attacks. Antiplatelet therapy is a key component of atherothrombotic event prevention. The results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) study showed that while dual antiplatelet therapy with aspirin and clopidogrel may not play a role in primary prevention, post hoc analysis alluded to the possibility of benefit for dual antiplatelet therapy in certain populations of stroke patients. We examined current recommendations for the prevention of atherothrombotic events, focusing on the role of oral antiplatelet agents in patients with ischemic stroke.

Is there a role for combinations of antiplatelet agents in stroke prevention?

Antiplatelet medications are the agents of choice for secondary prevention of noncardioembolic ischemic strokes. Multiple clinical trials have proven their reliable albeit modest clinical benefits and relatively good safety profile. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are aspirin, clopidogrel, and the combination of aspirin and extended-release dipyridamole. Because of the multiple pharmacologic mechanisms available for platelet inhibition, combination antiplatelet agents have the potential for synergistic effects. However, combinations of antithrombotic agents do not necessarily improve clinical efficacy and are typically associated with increased toxicity. Clopidogrel and aspirin have been used in combination in patients with diverse arterial vascular diseases. Combination antiplatelet therapy with clopidogrel and aspirin has established clinical benefits, particularly in coronary disease and in patients who have undergone coronary stenting. Although it is tempting to extrapolate the benefits of clopidogrel and aspirin to the setting of secondary stroke prevention, recent clinical trials have failed to document significant clinical benefits in cerebrovascular patients. This failure has occurred because of a lack of significant efficacy for prevention of vascular events and a substantial increase in bleeding risk. Therefore, the clopidogrel and aspirin combination is not recommended for recurrent stroke prevention. In general, when clopidogrel is used for cerebrovascular patients, the addition of aspirin should be avoided unless there is a specific cardiac indication such as recent acute coronary syndrome or a coronary stent. The combination of aspirin and extended-release dipyridamole is supported by Class I data from two large studies demonstrating superiority over aspirin alone for recurrent stroke prevention. Although dual antiplatelet therapy with clopidogrel and aspirin has never been directly compared with the combination of aspirin and extended-release dipyridamole, clinical trial results favor the latter for secondary stroke prevention. Currently, there are no data for primary stroke prevention with dual antiplatelet agents regarding aspirin and extended-release dipyridamole. Limited data from the recent Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance (CHARISMA) trial indicate that the combination of clopidogrel and aspirin may be harmful, compared with aspirin alone.

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

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

Clinical Trials Update from the Annual Scientific Session of the American College of Cardiology 2006

The results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial showed that the addition of clopidogrel to standard, low-dose aspirin did not significantly reduce the combined rate of death, heart attack, or stroke when compared with aspirin alone in a broad population of secondary prevention and high-risk primary prevention patients.1 However, the CHARISMA data also suggested that combination therapy may be useful in patients with established cardiovascular disease, with no apparent benefit in those with multiple risk factors alone. The CHARISMA study design and baseline characteristics are described in detail elsewhere in this supplement.2 Briefly, the study enrolled 15,603 patients at risk for atherothrombotic events caused by documented cardiovascular disease (including documented coronary artery disease, cerebrovascular disease, or peripheral arterial disease) or multiple risk factors alone. Patients were randomly assigned to clopidogrel 75 mg/day or placebo, in addition to low-dose aspirin (75‐162 mg/day), and were observed for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction (MI), stroke, or death from cardiovascular causes, with the secondary end point additionally including hospitalization for ischemia. In the overall population of patients, there was no statistically significant difference in the rate of the primary efficacy end point in the clopidogrel group (6.8%) compared with the placebo group (7.3%; relative risk, 0.93; 95% confidence interval [CI], 0.83‐1.05; p 0.22). For the secondary end point, clopidogrel reduced the combined risk from 17.9% in the placebo group to 16.7% in the clopidogrel group (relative risk, 0.92; 95% CI, 0.86‐0.995; p 0.04). There was no significant difference in the rate of severe bleeding between the clopidogrel and placebo groups (1.7% vs 1.3%; relative risk, 1.25; 95% CI, 0.97‐1.61%; p 0.09). Moderate bleeding, however, was increased from 1.3% in the placebo group to 2.1% in the clopidogrel group (relative risk, 1.62; 95% CI, 1.27‐2.10; p 0.001). In a subgroup analysis of asymptomatic patients (N 3,284) with multiple risk factors alone (meant to represent a high-risk primary prevention population), the primary end point rate was 6.6% with clopidogrel and 5.5% with placebo (relative risk, 1.2; 95% CI, 0.91‐1.59; p 0.20; Figure 1). In the 12,153 symptomatic patients (meant to represent a stable secondary prevention population), there was a suggestion of a benefit; the primary end point rate was 6.9% with clopidogrel plus aspirin and 7.9% with placebo plus aspirin (relative risk, 0.88; 95% CI, 0.77‐0.998; p 0.046). The investigators concluded that dual antiplatelet therapy with clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the primary end point in the broad population tested. Some benefit was noted in a subgroup of patients with prior evidence of cardiovascular disease. Further analysis of different patient groups should help provide insights into the outcomes with single antiplatelet therapy versus dual antiplatelet therapy.

Identification of and Management Approaches for the High-Risk Patient

Atherothrombosis is a systemic disease that often involves the coronary, cerebrovascular, and peripheral arterial circulations. The presence of multiple risk factors, even in asymptomatic patients, greatly increases the risk of future cardiovascular disease. Antiplatelet therapy potentially has a valuable role across the full spectrum of atherothrombotic disorders. The role of aspirin is well established, and the benefits of clopidogrel have been demonstrated in clinical trials. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial is currently under way to determine whether the combination of clopidogrel plus aspirin is superior to aspirin plus placebo in >15,000 patients with stable atherothrombosis. The results of the CHARISMA trial are expected to provide further information on the optimal management of patients with stable atherothrombosis with respect to both antiplatelet therapy and overall management.