Prevalence of diabetes and impact on cardiovascular events and mortality in patients with chronic coronary syndromes, across multiple geographical regions and ethnicities.

BACKGROUND: In contrast with the setting of acute myocardial infarction, there are limited data regarding the impact of diabetes mellitus on clinical outcomes in contemporary cohorts of patients with chronic coronary syndromes. We aimed to investigate the prevalence and prognostic impact of diabetes according to geographical regions and ethnicity. METHODS AND RESULTS: CLARIFY is an observational registry of patients with chronic coronary syndromes, enrolled across 45 countries in Europe, Asia, America, Middle East, Australia, and Africa in 2009-2010, and followed up yearly for 5 years. Chronic coronary syndromes were defined by ≥1 of the following criteria: prior myocardial infarction, evidence of coronary stenosis >50%, proven symptomatic myocardial ischaemia, or prior revascularization procedure.Among 32 694 patients, 9502 (29%) had diabetes, with a regional prevalence ranging from below 20% in Northern Europe to ∼60% in the Gulf countries. In a multivariable-adjusted Cox proportional hazards model, diabetes was associated with increased risks for the primary outcome (cardiovascular death, myocardial infarction, or stroke) with an adjusted hazard ratio of 1.28 (95% confidence interval 1.18, 1.39) and for all secondary outcomes (all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and coronary revascularization). Differences on outcomes according to geography and ethnicity were modest. CONCLUSION: In patients with chronic coronary syndromes, diabetes is independently associated with mortality and cardiovascular events, including heart failure, which is not accounted by demographics, prior medical history, left ventricular ejection fraction, or use of secondary prevention medication. This is observed across multiple geographic regions and ethnicities, despite marked disparities in the prevalence of diabetes. CLINICALTRIALS IDENTIFIER: ISRCTN43070564.

A B-spline approach to phase unwrapping in tagged cardiac MRI for motion tracking.

A novel B-Spline based approach to phase unwrapping in tagged magnetic resonance images is proposed for cardiac motion tracking. A bicubic B-spline surface is used to model the absolute phase. The phase unwrapping problem is formulated as a mixed integer optimization problem that minimizes the sum of the difference between the spatial gradients of absolute and wrapped phases, and the difference between the rewrapped and wrapped phases. In contrast to the existing techniques for motion tracking, the proposed approach can overcome the limitation of interframe half-tag displacement and increase the robustness of motion tracking. The article further presents a hybrid harmonic phase imaging-B-spline method to take the advantage of the harmonic phase imaging method for small motion and the efficiency of the B-Spline approach for large motion. The proposed approach has been successively applied to a full set of cardiac MRI scans in both long and short axis slices with superior performance when compared with the harmonic phase imaging and quality guided path-following methods.

A VR simulator for intracardiac intervention.

A VR simulator provides low-cost, realistic training for intracardiac techniques for determining the heart's mechanical and electrical activities. A geometric method models interaction between a catheter and the heart wall. Boundary-enhanced voxelization accelerates detection of catheter-heart interaction. A tactile interface incorporates a VR catheter unit to track the catheter's movement.

Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials.

OBJECTIVE: Oral direct thrombin and anti-Xa inhibitors have been shown to be efficacious in the prevention and treatment of venous thromboembolism, and prevention of embolic events in atrial fibrillation. Recent studies showed that dabigatran may be associated with increased rates of myocardial infarction (MI). Coronary risk for the other agents was unclear. The aim of the study is to determine the coronary risk among four novel antithrombotic agents. DESIGN: Mixed treatment comparison meta-analysis. DATA SOURCES AND STUDY SELECTION: Randomised controlled trials (RCTs) on ximelagatran, dabigatran, rivaroxaban and apixaban were obtained from PubMed search (February 2012) and major scientific meeting in 2011. The random-effects model was used to evaluate the effect of these agents on MI or acute coronary syndrome (MI/ACS), major bleeding complication and all-cause mortality. RESULTS: From 28 RCTs (n=138 948), the risk for MI/ACS was higher for dabigatran (OR 1.30; 95% CI 1.04 to 1.63; p=0.021) but lower for rivaroxaban (OR 0.78; 95% CI 0.69 to 0.89; p<0.001). Ximelagatran showed a higher risk for MI/ACS, which was not statistically significant, while apixaban demonstrated a non-significant lower likelihood. Among the RCTs for MI/ACS among the four agents, only those pertaining to ximelagatran showed heterogeneity. Major bleeding complication rates varied considerably among different agents. Importantly, these agents were associated with a lower all-cause mortality, without heterogeneity among the studies. CONCLUSIONS: The risk for coronary events was significantly higher for dabigatran but not significantly higher for ximelagatran. Conversely, this risk was lower among anti-Xa inhibitors. All-cause mortality was lower among those receiving novel antithrombotic agents. This information may be useful in selecting agents for specific subsets of patients requiring anticoagulation.

The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study.

AIMS: Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. METHODS AND RESULTS: A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. CONCLUSION: No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov number, NCT00050817.

High-sensitivity C-reactive protein and clopidogrel treatment in patients at high risk of cardiovascular events: a substudy from the CHARISMA trial.

AIMS: This study investigated the effect of clopidogrel treatment on inflammatory activity as evidenced by the change in high-sensitivity C-reactive protein (hsCRP) levels in a broad population of patients who are at high risk of atherothrombotic events. The predictive value of hsCRP levels for a treatment benefit of clopidogrel was also explored. METHODS: The study included 8021 patients with established atherosclerotic disease or multiple cardiovascular risk factors enrolled in the CHARISMA trial. Patients were randomly assigned either to clopidogrel plus aspirin or placebo plus aspirin. HsCRP was measured at study entry and at study termination (median 28 months). The predefined primary composite endpoint was myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: There was a stepwise increase in the event rate of the combined primary endpoint with increasing quartiles of hsCRP at baseline (4.0%, 6.1%, 7.4% and 8.7% for the highest quartile). In both treatment groups the changes in hsCRP levels over time were identical. In patients with low hsCRP levels (<3 mg/l) clopidogrel treatment was associated with a lower event rate compared with placebo (4.0% vs 6.0%, log rank p=0.005). In contrast no treatment effect was observed in patients with high hsCRP levels (8.1% vs 8.0%, ns). CONCLUSIONS: In this broad population, hsCRP is a powerful predictor of ischaemic events. Compared with placebo, clopidogrel was without effect on inflammatory markers. The reduction in cardiovascular events by antiplatelet treatment with clopidogrel was isolated to patients with low levels of hsCRP.

Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial.

BACKGROUND: The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial reported no statistically significant benefit of adding clopidogrel to acetylsalicylic acid in the long-term management of a broad population of patients with stable vascular disease. However, a subanalysis raised the hypothesis that dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid may be more effective than aspirin in patients with prior ischaemic stroke, myocardial infarction of symptomatic peripheral arterial disease. We aimed to determine whether the possible benefits of clopidogrel plus acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke may be 'front-loaded', and maximal within the first 30-days of randomisation, without being unduly hazardous. METHODS: This was a subanalysis of a randomised, double-blind, placebo-controlled trial of clopidogrel vs. placebo, in addition to background therapy with low-dose acetylsalicylic acid (CHARISMA trial), restricted to all patients with transient ischaemic attack or ischaemic stroke. The primary efficacy outcome was stroke, and safety outcome severe bleeding, during the follow-up period. RESULTS: Among all transient ischaemic attack and ischaemic stroke patients randomised to placebo (n=2163), 131 (6·1%) experienced a stroke during follow-up compared with 105 (4·9%) of 2157 patients assigned clopidogrel (hazard ratio: 0·80, 95% confidence intervals: 0·62-1·03). There was no significant difference in severe bleeding (1·7% placebo vs. 1·9% clopidogrel, hazard ratio: 1·11, 95% confidence intervals: 0·71-1·73). Among all patients randomised within 30-days of their qualifying transient ischaemic attack or ischaemic stroke to placebo (n=667), 46 (6·9%) experienced a stroke compared with 34 (5·1%) of 664 patients assigned clopidogrel (hazard ratio: 0·74, 0·46-1·16). There was no significant difference in severe bleeding (1·6% placebo vs. 1·4% clopidogrel, hazard ratio: 0·83, 95% confidence intervals: 0·34-2·01). CONCLUSION: The data are consistent with, but do not prove the hypothesis that early addition of clopidogrel to acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke of arterial origin may be more effective and acceptably safe compared with acetylsalicylic acid alone. Adequately powered clinical trials that are dedicated to exploring this hypothesis are needed.

Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin versus aspirin alone (a post hoc analysis of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance [CHARISMA] trial).

No prospective randomized trial has specifically examined the long-term outcomes of clopidogrel use in patients with chronic kidney disease. This study aimed to determine the risks and benefits of long-term clopidogrel administration in patients with diabetic nephropathy, the most common form of chronic kidney disease. We performed a post hoc analysis of the CHARISMA trial, which randomly assigned patients without active acute coronary syndrome, but with established atherosclerotic disease (symptomatic) or multiple risk factors for atherosclerotic disease (asymptomatic), to clopidogrel plus aspirin versus placebo plus aspirin. All CHARISMA patients (n = 15,603) were separated into the 3 groups: nondiabetic patients, diabetic patients without nephropathy, and diabetic patients with nephropathy. Within each group, outcomes of patients randomly assigned to clopidogrel were compared with those of patients randomly assigned to placebo. Outcomes in the prespecified CHARISMA subgroups of asymptomatic and symptomatic patients were also compared with respect to study drug assignment and nephropathy status. Patients with nephropathy who received clopidogrel had no difference in bleeding, but experienced significantly increased cardiovascular (CV) and overall mortality compared with those randomly assigned to placebo. There were no differences in bleeding, overall mortality, or CV mortality for nondiabetic or diabetic patients without nephropathy who received clopidogrel versus placebo. In the asymptomatic cohort, patients with nephropathy randomly assigned to clopidogrel had significantly increased overall and CV mortality compared with placebo, whereas asymptomatic patients without nephropathy randomly assigned to clopidogrel had no significant mortality difference compared with placebo. In conclusion, this post hoc analysis suggested that clopidogrel may be harmful in patients with diabetic nephropathy. Additional studies are needed to investigate this possible interaction.

Ethnic variation in adverse cardiovascular outcomes and bleeding complications in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study.

BACKGROUND: Atherothrombosis is a common condition affecting individuals worldwide. Its impact on different ethnic groups receiving evidence-based therapy is unclear. We aimed to determine if ethnicity is an independent predictor for cardiovascular events and bleeding complications in a contemporary clinical trial on antiplatelet therapy. METHODS: This was a prospective observational study of 15,603 patients enrolled in the CHARISMA trial followed up every 6 months for a median of 28 months. The primary efficacy end point was the first occurrence of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was bleeding. RESULTS: The cohort comprised 12,502 (80.1%) white, 486 (3.1%) black, 775 (5.0%) Asian, and 1,613 (10.3%) Hispanic patients. There was no difference in the occurrence of the primary composite end point among the 4 ethnic groups. Compared with Asians, cardiovascular and all-cause mortality occurred more frequently among black (adjusted hazard 2.19 and 2.04) and Hispanic (adjusted hazard, 1.83 and 1.69) patients. Although the occurrence of severe bleeding was similarly low among the 4 ethnic groups, Asian (adjusted hazard, 2.21) and black (adjusted hazard, 3.06) patients were more likely to have moderate bleeding complications than Hispanic patients. CONCLUSION: In this trial of individuals at risk of vascular events, ethnicity was not a significant, independent predictor of the primary composite cardiovascular event. However, ethnicity was a significant, independent predictor of the secondary outcomes, cardiovascular and all-cause mortality (blacks and Hispanics), and moderate bleeding complications (blacks and Asians).

The influence of body mass index on mortality and bleeding among patients with or at high-risk of atherothrombotic disease.

AIMS: We aimed to determine the relationship between body mass index (BMI) and cardiovascular events among individuals with or at-risk of atherothrombotic disease. METHODS AND RESULTS: This was a prospective observational study of 15 532 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who were randomly assigned to clopidogrel or placebo, and followed-up for a median of 28 months for the occurrence of the primary endpoint (cardiovascular death, myocardial infarction, or stroke), all-cause mortality, and bleeding complications. Compared with the highest BMI quartile, the primary endpoint, cardiovascular, and all-cause mortality all occurred more frequently among patients in the lowest BMI quartile (about a third lower). The relationship between continuous BMI and adverse cardiovascular outcomes were presented as two linear spline terms with 29 kg/m(2) as the cut-point for all-cause mortality. Lower BMI was associated with an increase in moderate and severe bleeding complications, largely accounted for by those receiving dual-antiplatelet agents with the highest tertile aspirin dose. CONCLUSION: Adverse cardiovascular events and bleeding complications occurred more frequently among individuals with or at-risk for atherothrombotic disease and low BMI. Further studies should be directed to these patients to improve outcomes.

Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial.

AIMS: To examine the unanticipated, excess mortality observed in patients randomized to clopidogrel and aspirin vs. aspirin alone in the prespecified 'asymptomatic' subgroup of CHARISMA, we investigated whether dual-antiplatelet therapy may be associated with adverse cardiovascular (CV) events in a primary prevention population. METHODS AND RESULTS: Of 15 603 patients enrolled, 3284 were initially categorized as asymptomatic with CV risk factors, but 995 had a prior CV event, leaving 2289 patients to represent the primary prevention cohort. This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding. A multivariate analysis analysed predictors of CV death in this group. No post mortem data were available. Compared with aspirin alone, a significant increase in CV death (P = 0.01) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population. Within the primary prevention cohort, this excess CV death was not significant (P = 0.07). Multivariate analysis of the primary prevention group showed a trend towards excess CV death (P = 0.054; HR 1.72; CI 0.99-2.97) with dual-antiplatelet therapy (aspirin plus clopidogrel). Other independent predictors of CV death included increasing age, hypertension, atrial fibrillation, and a history of heart failure. There was a non-significant increase in moderate or severe bleeding (P = 0.218) with dual-antiplatelet therapy; thus, bleeding was an unlikely explanation for the excess event rate. CONCLUSION: These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population. In this subgroup analysis, CV death occurred more frequently than anticipated. The cause of this apparent harm is not elucidated, may represent play of chance, but requires further prospective evaluation.

Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial.

OBJECTIVES: The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up. BACKGROUND: There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy. METHODS: The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non-CYP3A4-MET). RESULTS: Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non-CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non-CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates. CONCLUSIONS: Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.

Impact of sex, metabolic syndrome, and diabetes mellitus on cardiovascular events.

Although cardiovascular events occur more frequently among patients with metabolic syndrome (MS) or diabetes mellitus (DM), the impact of gender is unclear. We aimed to determine the relation of MS and DM on cardiovascular events between men and women. The National Health Survey of 1992 provided information on outcomes for 3,414 Singaporeans aged 18 to 69 years without cardiovascular diseases. Definition of MS was based on the National Cholesterol Education Program criteria. Cardiovascular events included hospital admissions for coronary heart disease, stroke, and cardiovascular mortality. The proportion of subjects with MS was 12.4%. After 10 years, the annual cardiovascular event rates (per 1,000 person-years) for men without DM were 3.0 and 15.9 among subjects without and with MS, respectively, and the respective rates for men with DM were 22.5 and 21.4. The corresponding rates for women were 0.9, 3.7, 5.3, and 21.5, respectively. Among nondiabetic subjects, cardiovascular events occurred more frequently among men than women among subjects with MS (adjusted hazard ratios [HRs] 4.71, 95% confidence interval [CI] 1.56 to 14.2) and those without MS (HR 3.35, 95% CI 1.78 to 6.31). Among patients with DM, cardiovascular events occurred more commonly among men than women without MS (HR 6.04, 95% CI 1.43 to 25.6). Rates for cardiovascular events were comparable between men and women with DM and MS (HR 0.98, 95% CI 0.48 to 1.99). In conclusion, the adverse impact of MS or DM was greater among men, and the presence of both conditions increases the risk substantially for cardiovascular events among women.

Routine functional testing after percutaneous coronary intervention: results of the aggressive diagnosis of restenosis in high-risk patients (ADORE II) trial.

BACKGROUND: It is unclear whether routine or selective functional testing is optimal following percutaneous coronary intervention (PCI) in high-risk patients. OBJECTIVES: The aim of this trial was to compare exercise endurance, functional status, and quality of life (QOL) among high-risk patients randomized to either routine or selective functional testing following PCI. METHODS: We randomized 84 patients to either routine or selective functional testing. Patients had one or more of the following: multivessel PCI, diabetes mellitus, left ventricular ejection fraction < 35%, and/or PCI of the proximal left anterior descending artery. Patients in the routine arm (n = 41) underwent maximum endurance exercise treadmill testing (ETT) with nuclear perfusion imaging at 1.5 and 6 months. Patients in the selective arm (n = 43) only underwent functional testing for a clinical indication. All patients underwent a maximum endurance ETT at 9 months. Exercise endurance, functional status, and QOL were assessed at 9 months. RESULTS: Most patients were middle-aged men (58 +/- 10 years old; 87% male) who underwent PCI with stenting (94%). Among routine functional testing patients, 27.0% and 41.9% had a positive functional test at 1.5 and 6 months, respectively. Exercise endurance was improved in the routine vs. selective arm at 9 months (metabolic equivalents: 10.3 +/- 2.6 vs. 8.6 +/- 3.0, P = 0.013). There was no difference in improvement from baseline for the Duke Activity Status Index, the Seattle Angina Questionnaire, or the SF-36. Nine-month cumulative incidences of cardiac procedures and clinical events were not significantly different. CONCLUSIONS: Routine functional testing following PCI in high-risk patients may lead to improved exercise endurance but not improved QOL.

Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial.

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).