Clopidogrel In Unstable Angina To Prevent Recurrent Events Research Articles

Demystifying the Contemporary Role of 12-Month Dual Antiplatelet Therapy After Acute Coronary Syndrome.

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS.

Economic Evaluation of Clopidogrel in Acute Coronary Syndrome Patients without ST-Segment Elevation in Greece

Current guidelines recommend treatment with antiplatelet and anticoagulant therapy for the secondary prevention of atherothrombotic events among patients with non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA). The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial has shown that clopidogrel alone or in combination with aspirin is more effective in reducing the risk of atherothrombotic events than aspirin alone in NSTEMI or UA patients. However, in the current climate of financial constraints, the effectiveness of a treatment should be considered in conjunction with its long-term economic costs to determine the best possible care. To evaluate the cost effectiveness of 1 year of treatment with clopidogrel in addition to aspirin in NSTEMI or UA patients from the third-party-payer perspective in Greece. An existing Markov model consisting of six states (NSTEMI/UA/no event, first year with stroke, history of stroke, first year with myocardial infarction [MI], history of MI and death) was adapted and extended to the Greek healthcare setting for year 2012. Utility values obtained from a Greek national study were assigned to each health state in order to estimate the quality-adjusted life-years (QALYs). Costs assigned to each health state included antiplatelet treatment cost, cost for the management of adverse events and the costs for concomitant medication, hospitalization, outpatient visits, rehabilitation and nursing. Cost effectiveness and cost utility was expressed as the cost per life-year (LY) gained and QALY gained, respectively. A probabilistic sensitivity analysis was conducted. The Markov analysis predicts a discounted survival of 8.27 years in the aspirin treatment group and 8.41 years in the aspirin plus clopidogrel treatment group. The corresponding discounted QALYs were 6.88 and 7.00, respectively. The cumulated lifetime costs per patient were € 18 779 and € 19 191, for the aspirin and aspirin plus clopidogrel treatment arms, respectively. The incremental cost-effectiveness ratio (ICER) with the addition of clopidogrel was &U20AC;2951 for each LY saved and &U20AC;3541 for each QALY saved. Finally, clopidogrel plus aspirin was found to be cost effective in more than 95% of simulated samples at a threshold of &U20AC;7000 per discounted QALY gained. One-year treatment with clopidogrel in addition to aspirin is a cost-effective treatment option for secondary prevention in patients with acute coronary syndrome without ST-segment elevation in Greece.

Clopidogrel Efficacy and Cigarette Smoking Status

RECENT ANALYSES OF LARGE-SCALE TRIALS SUGGEST either a reduced or complete lack of clinical benefit from clopidogrel therapy in nonsmokers. Importantly, this observation is not explained by an enhanced prothrombotic state (a condition in which P2Y12 inhibitor therapy may be expected to be most effective) in smokers relative to nonsmokers as evidenced by variable event rates in smokers and nonsmokers treated with placebo. Cigarette smoking induces the activity of cytochrome P450 (CYP) 1A2, an isoenzyme involved in the metabolic activation of clopidogrel but less recognized in importance than CYP2C19. Nonsmokers have greater platelet reactivity than smokers during clopidogrel treatment. A recent additional important analysis of the CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) trial revealed a significant interaction based on smoking status (P=.01 for interaction). Specifically, patients in the clopidogrel-treated nonsmoker group (a combination of the neversmoker group and former-smoker group) had no reduction in the incidence of the primary outcome of ischemic stroke, myocardial infarction (MI), or vascular death compared with the aspirin-treated nonsmoker group (10.4% vs 10.6%, respectively; hazard ratio [HR], 0.98 [95% CI, 0.88-1.09]), whereas patients in the clopidogrel-treated currentsmoker group had a significantly lower incidence of the primary outcome compared with the aspirin-treated currentsmoker group (8.3% vs 10.8%, respectively; HR, 0.76 [95% CI, 0.64-0.90]). To our knowledge, the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events [N=12 562]) trial investigators have not presented a similar adjusted analysis of nonsmokers and smokers. However, an abstract based on CURE trial data reported that in the largest smoking status subgroup—never smokers—clopidogrel treatment was not associated with a significant reduction in the primary outcome (a composite of death from cardiovascular causes, nonfatal MI, or stroke) compared with never smokers treated with placebo (10.2% vs 10.9%, respectively; HR, 0.93 [95% CI, 0.79-1.11]), whereas current smokers treated with clopidogrel had a significantly lower incidence of the primary outcome compared with placebo (6.1% vs 9.4%, respectively; HR, 0.63 [95% CI, 0.48-0.83]). In the CREDO (Clopidogrel for the Reduction of Events During Observation) trial, there was no difference in the occurrence of the primary composite end point (1-year death, MI, and stroke) in clopidogrel-treated nonsmokers relative to placebo-treated nonsmokers, whereas a significant benefit was observed in clopidogrel-treated smokers compared with placebo-treated smokers (6.3% vs 13.8%, respectively; HR, 0.44 [95% CI, 0.23-0.83]). Desai et al attempted to refine the relation between smoking status and clinical outcomes based on previous pharmacodynamic findings. These investigators conducted a post hoc analysis of patients with ST-segment elevation MI, based on the quantification of the number of cigarettes smoked at baseline, in the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28) trial. They reported an adjusted analysis based on smoking status for both the primary end point (angiographic outcome) and the secondary end point (30-day clinical outcome), revealing a significant smoking status interaction for both end points (P=.04 and P=.006, respectively, for interaction in patients who smoked at least 10 cigarettes/d). In that trial, clopidogrel therapy was associated with an overall 36% and 20% reduction in the rate of the primary and secondary end points, respectively, relative to placebo. The reduction in the primary end point was enhanced among clopidogrel-treated patients who smoked 10 or more cigarettes per day relative to placebo (adjusted odds ratio [OR], 0.49; P .0001). In addition, clopidogreltreated patients who smoked zero cigarettes per day or less than one-half pack per day had no significant benefit in 30-day clinical end point occurrence compared with patients treated with placebo (13.7% vs 14.3%, respectively; OR, 0.98 [95% CI, 0.75-1.28]), whereas clopidogrel-treated patients who smoked 10 or more cigarettes per day exhibited a 46% reduction in the 30-day clinical end point relative to the placebo group (8.0% vs 14.3%, respectively; OR, 0.54 [95% CI, 0.38-0.76]).

Cardiovascular Pharmacogenomics: Current Status and Future Directions—Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on January 7, 2011, at George Washington University in Washington, DC, to provide recommendations to the NHLBI that would guide informed decisions on research directions and priorities in the field of cardiovascular

Measurement of Hemoglobin A1c from Filter Papers for Population-Based Studies

Stability and transport challenges make hemoglobin (Hb) A(1c) measurement from EDTA whole blood (WB) inconvenient and costly for large-scale population studies. This study investigated Hb A(1c) measurement from WB blotted on filter paper (FP) in a Level I National Glycohemoglobin Standardization Program (NGSP)-accredited laboratory. Three Bio-Rad Variant™ II HPLC instruments and WB and FP specimens were used. Precision, accuracy, linearity, and readable total area of the 6.5-min (β-thalassemia method) Variant II HbA(2)/HbA(1c) Dual Program were assessed. Hb A(1c) stability was measured using in-house FP QC samples. The INTERHEART (a study of the effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries) and CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) studies provided chromatographs for morphometric analyses and interoperator variability experiments. Statistical analyses were performed to assess long-term sample stability, WB vs FP agreement, and significance of Hb A(1c) peak integration. Intra- and interassay CVs were ≤2.00%. Total area counts between 0.8 and 5.5 × 10(6) μV/s produced accurate Hb A(1c) results. The regression equation for agreement between WB(x) and FP(y) was as follows: y = 0.933x + 0.4 (n = 85). FP QC samples stored at -70 °C and tested over approximately 3 years yielded CVs of 1.72%-2.73% and regression equations with slopes of -1.08 × 10(-4) to 7.81 × 10(-4). The CURE study, with better preanalytical preparation, achieved a 97% reportable rate, and the reportable rate of the INTERHEART study was 85%. The FP collection method described provided accurate, robust, and reproducible measurement of Hb A(1c) using the Bio-Rad Variant II HPLC autoanalyzer when FP specimens were prepared according to standardized protocols, and analyses were performed in an NGSP-certified laboratory, supporting the use of FP collection cards in large multinational studies.

Pharmacogenetics and Clopidogrel Response in Patients Undergoing Percutaneous Coronary Interventions

Pharmacogenetics and Clopidogrel Response in Patients Undergoing Percutaneous Coronary Interventions

Incidence of Bleeding in ‘Real-Life’ Acute Coronary Syndrome Patients Treated with Antithrombotic Therapy

Objective: Randomized clinical trials have reported low risks of bleeding in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients receiving triple antithrombotic treatment (aspirin, clopidogrel and heparin). As trial patients often differ substantially from unselected patients treated in routine clinical settings, we compared the incidence of bleeding in ‘real-life patients’ with the incidence in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial. Methods: We conducted a historical follow-up study based on 195 nonselected patients diagnosed with NSTE-ACS admitted to a Danish hospital. Data were obtained through systematic review of medical records. Bleeding complications were registered for 6 months after the event. Results: One hundred and nineteen (61.0%) patients fulfilled the inclusion and exclusion criteria of the CURE trial and were treated with triple antithrombotic therapy. Eleven (9.2%) of the 119 patients suffered a life-threatening bleeding. Their relative risk of life-threatening bleeding was 4.3 (95% CI 2.4–7.7) compared with the CURE study population. There was no difference in minor bleeding. Among patients not eligible according to the CURE criteria, but receiving intensive antithrombotic treatment, the relative risk of life-threatening bleeding was 6.4 (95% CI 3.1–12.9). Conclusions: When triple antithrombotic therapy is used in clinical practice in NSTE-ACS patients, the risk of bleeding may exceed that reported in trials. Assessment of the bleeding risk in the individual patient is warranted.

CHARISMA

Ever since the Antithrombotic Trialists reported a clear benefit from aspirin in the secondary prevention of vascular disease in patients with a variety of cardiovascular events,1 there has been a search for more effective antithrombotic agents. The first relatively nontoxic drug to undergo randomized clinical trial was clopidogrel in the CAPRIE study2 (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) where 3 groups of patients (myocardial ischemia (MI), ischemic stroke or peripheral arterial disease) were given either aspirin or the drug. The compound end point of MI, ischemic stroke and vascular death was significantly reduced by clopidogrel compared with patients taking aspirin. However, the substantial benefit on vascular outcome evident in the peripheral vascular group was not shared by either the stroke patients or those with MI. Because aspirin and clopidogrel have different biochemical pathways inhibiting platelet adhesiveness, a combination of the 2 drugs might be even more effective in secondary prevention of vascular events. In CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) the dual antiplatelet therapy was found even more beneficial …

Clopidogrel

Clopidogrel (Plavix) is a selective inhibitor of adenosine diphosphate-induced platelet aggregation. In patients with acute coronary syndromes (ACS) [unstable angina or non-ST-segment elevation myocardial infarction], clopidogrel plus aspirin (acetylsalicylic acid) for up to 1 year significantly reduced the risk of cardiovascular events relative to placebo plus aspirin in the well designed clinical trial CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) and its substudy in patients undergoing percutaneous coronary intervention (PCI) [PCI-CURE]. In pharmacoeconomic evaluations based on data from these trials conducted in a number of countries that used a variety of models, methods and/or type of costs, clopidogrel plus aspirin was consistently predicted to be cost effective relative to aspirin alone in the management of patients with ACS, including those undergoing PCI. Clopidogrel plus aspirin in patients with ACS reduced the incremental cost per cardiovascular event prevented and/or life-year gained (LYG) relative to aspirin alone in analyses using within-trial data (including longer-term analyses incorporating life-expectancy estimates) from the CURE or PCI-CURE studies. In Markov models of cost effectiveness with a lifetime horizon from a healthcare payer perspective based on the CURE trial, relative to aspirin alone, clopidogrel plus aspirin for 1 year was predicted to have incremental costs per LYG of 8132Euro in Spain (2003 values) and 1365Euro in Sweden (2000 values). In similar Swedish analyses from a healthcare payer perspective, clopidogrel plus aspirin for 1 year was predicted to have incremental costs per LYG of 10,993Euro (2004 values) relative to aspirin alone based on data from the PCI-CURE substudy. Broadly similar results have also been reported in modelled analyses from other countries. Cost-utility analyses based on the CURE trial suggest that, relative to lifelong aspirin alone, clopidogrel plus aspirin for 1 year followed by aspirin alone is associated with incremental costs per QALY gained that are below the traditional threshold of cost utility in Spain, the UK and the US. In patients with ACS, including those undergoing PCI, the addition of clopidogrel to standard therapy with aspirin is clinically effective in preventing cardiovascular events. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of clopidogrel plus aspirin for up to 1 year as a cost-effective treatment relative to aspirin alone in this patient population.

Total first-year costs of acute coronary syndrome in a managed care setting.

There is a limited amount of literature examining the burden and cost of illness of acute coronary syndrome (ACS) in the managed care population. The goal of this study was to estimate the total cost of health care utilization (health plan plus patient) in the 12-month period following newly onset ACS. The demographic and health characteristics of these patients are compared with the similar data from 2 large clinical trials: CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) and PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy--Thrombolysis in Myocardial Infarction 22). A retrospective claims analysis was conducted for the 2-year period from July 1, 1999, through June 30, 2001. ACS was defined as an emergency room visit or hospitalization with a primary International Classification of Diseases, 9th Edition/Revision (ICD-9) diagnosis of 410.xx (acute myocardial infarction) or 411.1x (intermediate coronary syndrome). Patients were required to be free of any ACS claim in the previous 6 months. Patients without 6 months of prior continuous enrollment or those patients younger than 18 years were excluded. Patients were followed up to 12 months to identify total medical and pharmacy costs, revascularization procedures, and medication use. A total of 13,731 patients met the inclusion criteria, yielding 133,814 months of follow-up (mean: 9.75 months per patient) and representing approximately 0.4% of the managed care members in the database during the study period. The mean age was 54 years and 68% were male. The total direct cost incurred by the health plan and patients was dollar 309 million (dollar 2,312 per patient-month of follow-up); 72% of total costs were attributable to hospitalizations. The majority of costs were medical (dollar 286 million, 93%), and dollar 23 million (7%) were pharmacy costs. Fifty-one percent of patients had a revascularization procedure, which was typically performed during the index hospitalization (median time to revascularization was 0 days). Coronary artery stent implantation was the most common revascularization procedure (68%). During follow-up, 490 patients (3.6%) had a detectable death, 58% of patients received a beta-blocker, 60% received one or more cholesterol-lowering medications, and 36% of patients received clopidogrel therapy. Aspirin therapy was not measured. These managed-care patients with newly onset ACS incurred substantial costs in the 12 months following initial presentation. Revascularization was a common therapeutic intervention for these patients. There appear to be opportunities to improve medication therapy after an acute ACS event. There were some demographic and health characteristics that were different in these commercially insured patients from those in 2 large clinical trials.

Aspirin and clopidogrel in acute coronary syndromes: therapeutic insights from the CURE study.

Platelet adhesion, activation, and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and causes acute coronary syndromes. Aspirin and clopidogrel exert their antiplatelet effects by inhibiting thromboxane A2 production and adenosine diphosphate-induced platelet aggregation pathways, respectively. Aspirin has proven benefits in primary and secondary prevention of coronary artery disease. Clopidogrel, an alternative antiplatelet agent used in patients with aspirin intolerance, is especially useful in combination with aspirin after coronary stent procedures. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study demonstrates for the first time the benefit of adding clopidogrel to aspirin rather than using aspirin alone in patients having acute coronary syndromes without ST-segment elevation myocardial infarction. Patients who are resistant to aspirin (up to 10%) have higher rates of cardiovascular events and may derive special benefit from the combination therapy. Aspirin resistance can be assessed through platelet aggregometry testing, measurement of urinary thromboxane metabolites, and, possibly, genomic testing in the future.