High Atherothrombotic Risk Research Articles

Datos al año de seguimiento del registro REACH en España

Atherothrombosis is one of the main causes of death worldwide. In Spain, as in other countries, this disease is a major public health problem, constituting a healthcare priority. The aim of the REduction of Atherothrombosis for Continued Health (REACH) registry is to analyze the long-term risk of atherothrombotic episodes in the at-risk population, evaluate the importance of cross risk, and define the prognostic factors of atherothrombotic episodes. More than 68,000 patients in more than 5,000 centers in 44 countries have been included in the REACH registry, of which 2,252 live in Spain. As observed internationally, in Spanish patients the complication rate at only 1-year of follow-up was high. The annual overall mortality rate in patients with established vascular disease or under primary prevention but with high atherothrombotic risk, represented by patients with risk factors only, was 3.57% and 1.98%, respectively, while that of cardiovascular mortality was 2.69% and 0.62%. In the subgroups of coronary artery disease (CAD), cerebral vascular disease (CVD) and peripheral artery disease (PAD) rates according to the affected territory were 3.47%, 2.78% and 1.46%, respectively. Involvement of more than one territory was clearly a poor prognostic factor: the annual complications rate increased according to whether 0, 1, 2, or 3 vascular beds were diseased for cardiovascular mortality (0.62%, 2.46%, 3.55% and 4.32%, respectively, p < 0.05) and for cardiovascular mortality, plus myocardial infarction, plus stroke, plus hospitalization for cardiovascular reasons these rates were 5.50%, 4.18%, 20.59% and 19.40%. Importantly, these patients have a poor prognosis even in the short-term, especially those with established vascular disease; furthermore, the greater the number of diseased vascular beds, the poorer the prognosis. This situation must therefore be improved by earlier identification of at-risk individuals and by optimizing both primary and secondary preventive measures.

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.

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

We aimed to determine the relationship between body mass index (BMI) and cardiovascular events among individuals with or at-risk of atherothrombotic disease. 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. 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.

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

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. 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. 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. 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).

Mounting Evidence for Safety and Improved Outcomes of Drug-Eluting Stenting

Mounting Evidence for Safety and Improved Outcomes of Drug-Eluting Stenting

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.

Combination Antiplatelet Agents for Secondary Prevention of Ischemic Stroke

Stroke is a leading cause of death and the primary cause of serious, long-term disability in the United States. Joint guidelines from the American Heart Association (AHA) and American Stroke Association (ASA), as well as recent guidelines from the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Antiplatelet Therapy, recommend aspirin, clopidogrel, or extended-release dipyridamole plus aspirin as acceptable first-line options for secondary prevention of ischemic events in patients with a history of ischemic stroke or transient ischemic attack (TIA). The ACCP strongly recommends the combination of extended-release dipyridamole plus aspirin over aspirin monotherapy (highest level of evidence) and suggests clopidogrel monotherapy over aspirin monotherapy (lower level of evidence). The AHA-ASA guidelines suggest that either extended-release dipyridamole plus aspirin or clopidogrel monotherapy should be used over aspirin monotherapy. Both guidelines recommend avoiding the combination of clopidogrel and aspirin for most patients with previous stroke or TIA. Results from recent trials evaluating combination antiplatelet therapy have been published that enhance the AHA-ASA recommendations and provide the foundation for the updated ACCP guideline. To identify pertinent combination antiplatelet trials, a MEDLINE search of the literature from 1967-2007 was performed. Two trials were identified--the European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA). The ESPRIT compared aspirin monotherapy with the combination of aspirin plus extended-release dipyridamole for prevention of secondary ischemic events in patients with a history of TIA or minor stroke. The CHARISMA trial compared aspirin plus clopidogrel with aspirin alone in a population at high risk for atherothrombotic events using the composite outcome of myocardial infarction, stroke, and death from cardiovascular causes. Data from ESPRIT add to evidence that the combination of aspirin plus extended-release dipyridamole is superior to aspirin alone. The findings of the CHARISMA trial reinforce recommendations from both AHA-ASA and ACCP that the combination of aspirin and clopidogrel be reserved for special populations requiring this antiplatelet combination (e.g., those who have had coronary artery stenting).

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.

Dual antiplatelet therapy with clopidogrel and aspirin

Dual antiplatelet therapy with clopidogrel and aspirin is reviewed. Several studies have evaluated the effectiveness of clopidogrel, aspirin, or the combination of these agents in a variety of patient populations. The results of these studies have helped determine the role of clopidogrel and aspirin in evidence-based medicine. Investigators in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance trial concluded that patients with multiple atherothrombotic risk factors who have stable cardiovascular disease (CVD) or no history of CVD or documented vascular disease should not receive combination clopidogrel and aspirin due to an increase in death. Patients with established vascular disease being treated with clopidogrel and aspirin may benefit from the combination through a reduction in the rate of myocardial infarction, stroke, or death from cardiovascular causes. The combination should not be used longer than one year since the benefits past one year have not been established by clinical trials, though consideration for longer treatment may be warranted in patients with stent implantation. One of the inherent risks associated with using clopidogrel and aspirin is the risk for increased bleeding. If a patient is started on combination therapy, it is imperative to monitor for signs and symptoms of bleeding. Dual antiplatelet therapy with clopidogrel and aspirin should be used in certain patients, such as those with any type of acute coronary syndrome or stent implantation, if there are no contraindications to combined therapy. The risk of bleeding should be considered in patients receiving the combination.

INTERPRETING THE CHARISMA STUDY: What is the role of dual antiplatelet therapy with clopidogrel and aspirin?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study (N Engl J Med 2006; 354:1706-1717, J Am Coil Cardiol 2007; 49:1982-1988) assessed the effect of dual antiplatelet therapy with clopidogrel (Plavix) and aspirin in patients at risk of atherothrombotic events. At a median of 28 months, the rate of the primary efficacy end point (a composite of myocardial infarction, stroke, and death from cardiovascular causes) was not significantly lower in the group receiving clopidogrel plus aspirin than in the group receiving placebo plus aspirin. However, one subgroup may have derived some benefit from the combination: those at higher risk owing to a history of myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease.

Role of Antiplatelet Agents in the Primary and Secondary Prevention of Atherothrombotic Events in High Risk-Patients

Atherothrombosis describes the superimposition of a thrombus on a ruptured atherosclerotic plaque, and is the primary cause of acute ischemic events. Atherothrombosis is a generalized and progressive process with an inflammatory component. Patients with disease in one vascular bed are at risk of disease in another, a concept known as "cross-risk." Platelet adhesion, activation, and aggregation in the final stage of atherothrombosis are ultimately responsible for arterial occlusion and consequent ischemia. Therefore, antiplatelet therapy is an effective treatment choice for secondary prevention. Clopidogrel, an adenosine diphosphate receptor antagonist, given alone or in combination with aspirin, may benefit secondary prevention of ischemic events. Current treatment guidelines suggest the use of a combination of these two agents for secondary prevention where appropriate. However, data conflict regarding the efficacy of antiplatelet therapy for primary prevention. A recent meta-analysis demonstrated that aspirin significantly reduces the risk of first myocardial infarction in both men and women. The recent Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, which evaluated the effects of clopidogrel plus aspirin compared with aspirin alone, seems to support the use of dual antiplatelet therapy in secondary prevention, but suggests that it may not be more effective than aspirin alone in primary prevention.

Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Stroke in Patients with a History of Atrial Fibrillation: Subgroup Analysis of the CHARISMA Randomized Trial

Background: Aspirin offers modest reduction in stroke in patients with atrial fibrillation. Whether combination of aspirin with clopidogrel offers additional protection is unclear. Methods: Post-hoc subgroup analysis of 593 participants with a history of atrial fibrillation in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) randomized trial testing clopidogrel 75 mg per day plus aspirin (75–162 mg per day) vs. aspirin alone in patients with stable cardiovascular disease or multiple cardiovascular risk factors. Results: Mean patient age was 70 years, 78% were men, and hypertension, heart failure and diabetes were present in 78, 20 and 44%, respectively. During a median follow-up of 2.3 years, stroke (ischemic and hemorrhagic) occurred in 15 of 298 assigned to clopidogrel plus aspirin and in 14 of 285 given aspirin alone (hazard ratio, HR, 1.03, 95% CI 0.49–2.1). There was no difference in all-cause mortality (HR 1.1, 95% CI 0.6–1.9) or in the composite of stroke, myocardial infarction, or vascular death (HR = 1.2, 95% CI 0.7–2.0). Severe/fatal extracranial hemorrhage occurred in 6 patients with combination vs. 3 with aspirin alone. Conclusions: This post-hoc subgroup analysis does not support the use of this combination over aspirin alone in patients with a history of atrial fibrillation pending results of ongoing larger randomized trials.

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.

Poststroke Care

See related article, pages 1899–1904. “Thinking is easy, acting is difficult, and to put one’s thoughts into action is the most difficult thing in the world”. — —Goethe (1749–1832) Major advances in acute stroke management have been seen over the past decade, including the use of thrombolysis, antithrombotic therapy, and organized in-hospital stroke care. However, relatively few studies have evaluated the effectiveness of these interventions in routine clinical practice, or have assessed issues related to delivery of services, access to care, and long-term care after discharge from stroke. In this issue of Stroke , Bravata et al1 contribute to our understanding of outcomes after stroke by analyzing readmissions and deaths in the first 5 years after a hospitalization for stroke. The target population included stroke survivors aged over 65 years who were Medicare beneficiaries and who were discharged from Connecticut acute care hospitals in 1995. This population was followed from discharge in 1995 through 2000 using Medicare claims and Social Security Administration mortality data. Among 2603 patients discharged alive, 40% were readmitted at least once within the first year of discharge, 53% had died or been readmitted within 1 year and only 15% survived admission-free for 5 years. Leading causes for readmission included pneumonia (8.2% to 9.0%), stroke (3.9% to 6.1%) and acute myocardial infarction (4.2% to 6.0%). There was no apparent association between length of hospital stay and readmission rate (unreported data kindly provided by the authors, 2007), and no information was available on potential patient and system factors associated with higher hospital readmission rates. Lower readmission rates of 25% to 27% within 1 year have been previously reported.2,3 These studies found that the average number of days of rehospitalization was 23.2 Stroke was the single most frequent reason for readmission followed by cardiac disease, …

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).

CHARISMA: The Antiplatelet Saga Continues

To the Editor: We read with interest the Editorial by Norris and Barnett1 on the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. They conclude that aspirin is still the first choice in the secondary prevention of stroke, that clopidogrel is only marginally more effective than aspirin in secondary prevention of vascular end points, and that there is no convincing evidence that clopidogrel (either alone or combined with aspirin) improves the outcome in patients presenting with TIA or stroke with a cost that is 80 times that of aspirin alone.1 The Canadian Cooperative Study Group already in 1978 had observed that among men the fewest events occurred …

Stroke and the statistics of the aspirin/clopidogrel secondary prevention trials

Four randomized trials have investigated the combination of clopidogrel plus aspirin for secondary prevention of vascular outcomes in 54,949 patients. Here we argue that attempts to translate the results of these trials into clinical practice have proven frustrating because of the following statistical considerations: differences in study populations and study design make comparisons difficult (comparisons of 'apples and oranges'), incomplete factorial designs prevent proper contrasts (examining 'bits and pieces' of a larger picture), results concern widely different vascular diseases ('puzzling subgroups'), and negative results are easily misinterpreted. Between 1996 and 2004 three major randomized trials assessed combinations of aspirin and clopidogrel, finding: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) in favor of clopidogrel alone versus aspirin alone, Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) in favor of clopidogrel plus aspirin versus aspirin alone, and Management of Atherothombosis with Clopidogrel in High-risk Patients (MATCH) in favor of clopidogrel plus aspirin versus clopidogrel alone. A recently completed fourth trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance; CHARISMA) was a 'negative study' comparing aspirin alone to aspirin plus clopidogrel. Even after four large randomized trials we still do not know the optimal treatment for secondary prevention of stroke. We suggest that subsequent trials should focus on a particular vascular disease and test hypotheses that relate to a specific mechanism.

Evolving Perspectives on Clopidogrel in the Treatment of Ischemic Stroke

Antiplatelet therapy is indicated for the treatment of ischemic stroke or transient ischemic attack (TIA). Aspirin reduces subsequent occlusive vascular events, including recurrent stroke, by about 25%. In such patients, clopidogrel has been evaluated in an effort to further reduce risk. In the Management of Atherothrombosis with Clopidogrel in High-risk Patients trial, the combination of clopidogrel plus aspirin was compared with clopidogrel alone, and the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial tested the addition of clopidogrel to aspirin. Combination therapy with aspirin plus clopidogrel provided no significant incremental benefit compared with aspirin or clopidogrel alone. In addition, combination therapy increased the risk of serious bleeding. On the basis of the current totality of evidence for long-term treatment of survivors of ischemic stroke or TIA, clopidogrel is an effective alternative for patients who are intolerant to aspirin.

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.