Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial

Background

Clopidogrel is a more potent antiplatelet agent than aspirin, resulting in greater clinical efficacy in patients with atherothrombotic disease. Furthermore, the combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin alone in the treatment of patients with acute coronary syndromes and after coronary stenting. Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention and secondary prevention is unknown.

Methods and results

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study was designed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established coronary, cerebral, or peripheral arterial disease or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event. This randomized, international, multicenter, double-blinded, placebo-controlled study has finished enrolling patients worldwide. A total of 15,603 patients will be followed long term. The primary end point will be the composite of vascular death, myocardial infarction, or stroke. Rates of severe bleeding will also be compared between the two arms of the study.

Conclusions

This large-scale trial of patients at high risk for atherothrombotic events will allow determination of the value of a strategy of adding clopidogrel to the current standard of care, including low-dose aspirin, for a wide spectrum of patients with atherothrombosis.     

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).     

Prevention of vascular events in patients with cerebrovascular disease: efficacy and appropriate duration of antiplatelet therapy

Antiplatelet therapy has shown consistent benefit in the prevention of secondary stroke. The paucity of head-to-head studies of different antiplatelet regimens, assessment of comparative efficacy, and optimal treatment duration requires evaluation and comparison of clinical studies that vary extensively in design and follow-up. Evidence for aspirin benefit in secondary stroke prevention is strong, but existing studies provide little guidance with regard to treatment duration. The efficacy of clopidogrel in secondary event prevention is significantly greater than that of aspirin for patients with a history of peripheral artery disease, but does not differ from that of aspirin for patients with a history of stroke or myocardial infarction. Relative to clopidogrel alone, the addition of aspirin to clopidogrel results in increased risk for life-threatening bleeding episodes similar in absolute magnitude to the reduction of secondary event risk in patients with stroke. Benefits associated with clopidogrel occur early in the course of therapy; few data support clopidogrel use for longer than 1 year after stroke. Monotherapy with extended-release dipyridamole (ER-DP) provides reduction in secondary stroke risk similar to aspirin; however, the combination of aspirin plus ER-DP significantly reduces risk relative to either agent alone. Compared with placebo and monotherapy with either agent, risk reduction for the aspirin plus ER-DP combination continued through 24 months, with no concomitant increase in bleeding risk. Additional clinical studies should provide needed comparisons of efficacy and guidance with regard to optimal duration of therapy.     

Secondary stroke prevention with antiplatelet therapy with emphasis on the cardiac patient: a neurologist's view

The prevention of secondary vascular events is of paramount importance in patients with a history of stroke or transient ischemic attack (TIA). Most cardiologists are aware of the benefits of clopidogrel plus aspirin versus those of other antiplatelet regimens in patients with acute coronary syndrome. Using a representative post-stroke patient as an example, this article reviews data evaluating the effectiveness of antiplatelet regimens in preventing secondary vascular events in stroke and TIA patients. These results differ from those seen in clinical trials of acute coronary syndrome patients. Clinical studies provide little evidence that clopidogrel, with or without aspirin, is more efficacious in this setting than aspirin alone. Moreover, the increased risk of bleeding episodes with clopidogrel and aspirin in combination probably outweighs any small reductions in secondary event risk. In contrast, extended-release dipyridamole (ER-DP) plus aspirin reduces secondary stroke risk to a significantly greater extent (23% relative risk reduction) than aspirin alone. Currently available clinical trial data support the use of ER-DP plus aspirin, but not clopidogrel plus aspirin, to prevent secondary vascular events after stroke or TIA.     

MATCH results: implications for the internist

The long-awaited results of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack (MATCH) study, a large-scale trial undertaken to evaluate the safety and efficacy of clopidogrel + aspirin for secondary prevention of stroke, have been published. The efficacy of any antiplatelet therapy, including aspirin, is modest when it is used as monotherapy, and combination therapy with 2 antiplatelet agents has shown promise in reducing the risk for secondary stroke in patients who have had a previous transient ischemic attack (TIA) or ischemic stroke. However, unlike the Second European Stroke Prevention Study (ESPS-2), which demonstrated a significant reduction in risk for secondary stroke with aspirin + extended-release dipyridamole versus aspirin alone the results of the MATCH trial indicated that the reduction in risk achieved by adding aspirin to clopidogrel is not significantly greater than that achieved with clopidogrel alone. Furthermore, a significant increase in life-threatening bleeding complications was associated with the combination of clopidogrel + aspirin. Given these findings, clopidogrel + aspirin cannot be recommended at this time for the secondary prevention of stroke in patients who have had a previous ischemic stroke or TIA.     

Antiplatelet therapy in the treatment of atherothrombotic disease: considering the evidence

Aspirin should be used to treat patients with acute myocardial infarction (MI) and continued indefinitely to reduce vascular death, nonfatal MI, and nonfatal stroke. Clopidogrel added to aspirin is beneficial in the treatment of patients with acute ST-elevation MI. Patients with unstable angina or non-ST-elevation MI should be treated with aspirin plus clopidogrel for at least 9 months to reduce the risk vascular death, nonfatal MI, and nonfatal stroke. Patients with prior MI should be treated indefinitely with aspirin and with clopidogrel if aspirin is contraindicated. Patients with ischemic stroke should be treated with either aspirin or clopidogrel indefinitely. Extended-release dipyridamole plus low-dose aspirin is more efficacious than low-dose aspirin but is associated with an insignificant increase in nonfatal MI and vascular death than low-dose aspirin. Clopidogrel is more effective than aspirin in reducing the risk of vascular death, nonfatal MI, and nonfatal stroke in patients with peripheral arterial disease.     

Antiplatelet therapy in the prevention of ischemic vascular events: literature review and evidence-based guidelines for drug selection.

BACKGROUND: New antiplatelet drugs are being developed and many clinical trials evaluating the benefits of antiplatelet drugs for the secondary prevention of ischemic events in patients with atherosclerotic vascular disease have been performed. HYPOTHESIS: An updated systematic review and evidence-based guidelines for the appropriate selection of antiplatelet drugs may be beneficial to physicians and healthcare organizations attempting to create or update current clinical practice guidelines or clinical pathways aimed at caring for these patients. METHODS: (1) A systematic review of the recent literature on the relative efficacy and safety of aspirin, ticlopidine, and clopidogrel was undertaken; (2) an evidence-based, expert panel approach using a modified Delphi technique to create explicit guidelines for prescribing antiplatelet therapy was instituted; and (3) the recommendations of an expert panel were summarized. RESULTS: Consensus guidelines were developed for the utilization of aspirin, ticlopidine, or clopidogrel for the prevention of ischemic events in patients with manifestations of atherosclerotic vascular disease (prior myocardial infarction, prior ischemic stroke, or established peripheral arterial disease) who are at increased risk for recurrent ischemic events. Based on efficacy and safety, clopidogrel was recommended as the drug of choice for patients with established peripheral arterial disease; aspirin or clopidogrel should be considered in patients with prior myocardial infarction (with clopidogrel favored for patients who have had a recurrent event while on aspirin or in whom aspirin is contraindicated); aspirin or clopidogrel should be considered as first-line treatment in patients with prior ischemic (nonhemorrhagic) stroke--however, clopidogrel is the favored drug in patients in whom other antiplatelet drugs are either contraindicated or who have had recurrent events while on therapy. CONCLUSIONS: Myocardial infarction, ischemic stroke, and peripheral arterial disease are all clinical manifestations of the same underlying disease process (atherosclerosis), with thrombus formation on the disrupted atherosclerotic plaque (atherothrombosis) being a common precipitating factor of ischemic events in patients suffering from these disorders. An evidence-based approach was used to develop a practice guideline, based on available published evidence, for the appropriate utilization of antiplatelet agents (aspirin, ticlopidine, or clopidogrel). These guidelines may be of use to multidisciplinary teams wishing to create or update clinical guidelines or clinical pathways which address the care of patients with atherosclerotic vascular disease. New antiplatelet agents such as clopidogrel may be more effective and associated with lower risk of selected adverse effects (such as gastrointestinal distress, gastrointestinal hemorrhage, and neutropenia) than those previously used to prevent thrombus formation in the setting of atherosclerotic arterial disease. Combination antiplatelet therapy is being evaluated as an option for those patients who experience recurrent events on a single antiplatelet agent.     

Use of antiplatelet drugs in secondary prevention in older persons with atherothrombotic disease

Unless there are contraindications to the use of aspirin, aspirin should be used in treating patients with acute myocardial infarction (MI) and continued indefinitely to reduce vascular death, nonfatal MI, and nonfatal stroke. Clopidogrel added to aspirin has been shown to be beneficial in the treatment of patients with acute ST-elevation MI. Patients with unstable angina or non-ST-elevation MI should be treated with aspirin plus clopidogrel for at least 9 months to reduce vascular death, nonfatal MI, and nonfatal stroke. Patients with prior MI should be treated indefinitely with aspirin and with clopidogrel if aspirin is contraindicated. Patients with ischemic stroke should be treated with either aspirin or clopidogrel indefinitely. Extended release dipyridamole plus low dose aspirin has been shown to be more efficacious than low dose aspirin in only one large study, and is associated with an insignificant increase in nonfatal MI and vascular death over low dose aspirin alone. Clopidogrel is significantly more effective than aspirin in reducing vascular death, nonfatal MI, and nonfatal stroke in patients with peripheral arterial disease.     

Efficacy and safety of clopidogrel and/or aspirin for ischemic stroke/transient ischemic attack: An overview of systematic reviews and meta-analysis

Objective:Patients experiencing acute ischemic stroke or transient ischemic attack are commonly treated with clopidogrel and/or aspirin (mono- and dual-antiplatelet therapy) to minimize the risk for recurrent stroke. Updated data from systematic studies can be used to guide practice. The present study aimed to compare findings from systematic reviews and meta-analyses addressing the efficacy and safety of clopidogrel or aspirin – alone or in combination – in patients experiencing acute ischemic stroke or transient ischemic attack.Methods:The Cochrane Library, PubMed, Ovid, Scopus, EBSCO, and CINAHL databases were searched for relevant studies published from inception to 2020. Data from each study were extracted independently using a predefined data abstraction form. The Risk of Bias in Systematic Reviews tool and A Measurement Tool to Assess Systematic Reviews 2 were used to evaluate risk of bias and the quality of the included studies.Results:Seven studies, published between 2010 and 2020, were eligible for analysis. The included studies evaluated a wide range of outcomes, including recurrent stroke, myocardial infarction, recurrent ischemic stroke, vascular mortality and vascular events, bleeding events, all-cause mortality, functional disability, and quality of life. The risk of bias and methodological validity of the included studies ranged from low to high according to ROBIS and AMSTAR 2 parameters. Results revealed that clopidogrel plus aspirin was more effective than aspirin alone in reducing the risk for recurrent stroke (ischemic or hemorrhagic), with high-quality evidence. However, compared with aspirin, dual treatment increased major bleeding events (intracranial bleeding and extracranial bleeding), supported by high-quality evidence.Conclusions:High-quality evidence suggested that clopidogrel plus aspirin was more efficient than monotherapy, although the risk for hemorrhagic stroke was relatively higher in combined therapy regimens lasting >1 month.     

Preventing atherothrombotic events in peripheral arterial disease: the use of antiplatelet therapy

Patients with peripheral arterial disease (PAD) are at increased risk of generalized atherothrombotic events. Epidemiologic data shows a high rate of co-prevalence of PAD and atherosclerosis in other vascular beds. Aggressive risk-factor modification and antiplatelet therapy has become the cornerstone of treatment to prevent ischaemic events associated with PAD. Recent clinical trials have confirmed the clinical benefit of clopidogrel and ticlopidine in patients with PAD, agents that irreversibly inhibit the binding of adenosine diphosphate to its platelet receptor. In the clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) trial, clopidogrel was associated with an overall risk reduction of 8.7% (compared with aspirin, P=0.043) in myocardial infarction (MI), ischaemic stroke and vascular death. These results demonstrated that long-term administration of clopidogrel was effective in preventing ischaemic events in patients with atherosclerotic vascular disease including PAD. Aspirin and/or clopidogrel are the antiplatelet agents of choice for the reduction of atherothrombotic events in patients with PAD.     

The Challenge of Antiplatelet Therapy in Patients with Atrial Fibrillation and Heart Failure

Antiplatelet therapy is the cornerstone of secondary prevention in cardiovascular disease. This review focuses on the role of antiplatelet therapy in atrial fibrillation (AF) and heart failure (HF). Aspirin has a limited role in stroke prevention among most patients with AF, being of limited efficacy and not any safer than warfarin, especially in the elderly. For HF patients with AF, cardioembolism is a major cause of stroke, and antiplatelet alone would be insufficient thromboprophylaxis. Aspirin plus clopidogrel rather than aspirin alone is preferred for those AF patients who have refused any form of oral anticoagulation. For AF patients undergoing percutaneous coronary intervention, triple antithrombotic therapy (aspirin, clopidogrel, and warfarin) is recommended for the initial period (1–6 months) based on the stent type, followed by vitamin K antagonists (VKA) and clopidogrel or, alternatively VKA and aspirin for up to 12 months. In AF patients with stable vascular disease, VKA monotherapy would suffice.     

The Role of Clopidogrel in the Management of Patients with Ischemic Heart Disease

Antiplatelet therapy plays a pivotal role in the treatment of patients across the entire spectrum of coronary artery disease. Platelets are believed to be integrally involved in both the development and progression of atherosclerotic heart disease, as well as in its acute thrombotic complications. While aspirin remains the traditional antiplatelet agent in patients with CAD, adverse vascular events continue to occur in patients on aspirin therapy. Clopidogrel is a relatively new antiplatelet agent and is currently one of the most widely prescribed drugs for the treatment of symptomatic coronary artery disease. As a member of the class of drugs known as the thienopyridines, clopidogrel irreversibly prevents platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors on its surface. The findings of a number of seminal clinical trials have expanded the indications for the use of clopidogrel in patients with coronary artery disease. When used in conjunction with aspirin, these studies have demonstrated an incremental benefit of clopidogrel above and beyond that of aspirin alone. This article reviews the data supporting the use of clopidogrel in patients with atherosclerotic heart disease, and makes recommendations for its use based on the available evidence.     

Economic evaluation of clopidogrel plus aspirin for secondary prevention of cardiovascular events in Canada for patients with established cardiovascular disease: Results from the CHARISMA trial

Background

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial found a statistically significant reduction in cardiovascular events when clopidogrel was added to aspirin in a prespecified subgroup of patients with established cardiovascular disease. However, the economic implications of such a strategy for the Canadian health care system are unknown.

Methods

For each patient in the CHARISMA trial with established cardiovascular disease, costs were estimated by multiplying resource utilization by unit costs derived from populations of Canadian patients in 2008 dollars. Changes in life expectancy due to nonfatal events were estimated with parametric regression models based on the Saskatchewan Health database.

Results

For patients with established cardiovascular disease, a strategy of clopidogrel plus aspirin for median duration of 28 months was associated with a 12.5% relative reduction in cardiovascular death, myocardial infarction, or stroke compared with aspirin alone (6.9% vs 7.9%, P =.048). Mean cost per patient was CAD$1,488 higher for clopidogrel plus aspirin, and life expectancy increased by 0.057 years. The resulting incremental cost-effectiveness ratio for adding clopidogrel was CAD$25,969 per life-year gained or CAD$21,549 per quality-adjusted life-year. These results were sensitive to the cost of clopidogrel but relatively insensitive to plausible variations in discount rate, costs other than clopidogrel, and the prognostic impact of nonfatal events.

Conclusion

Among the subgroup of patients with established cardiovascular disease in the CHARISMA trial, adding clopidogrel to aspirin increases life expectancy at a cost generally considered acceptable in Canada.     

New look at antiplatelet agent-related peptic ulcer: an update of prevention and treatment

Patients taking antiplatelet agents for the prevention of cardiovascular diseases who develop gastrointestinal bleeding represent a serious challenge in clinical practice. The initial step in reducing gastrointestinal risk of antiplatelet therapy is to assess whether the patient has a continued need for antiplatelet therapy. The next step is to eliminate the risk factors that may place the patient at increased gastrointestinal risk. In the management of bleeding ulcer patients with high-risk stigmata of recent hemorrhage, resuming antiplatelet agents at 3-5 days after the last dosing is a reasonable strategy. However, patients with low-risk stigmata can keep taking antiplatelet agents immediately following endoscopy. In the management of aspirin-related uncomplicated peptic ulcers in patients requiring antiplatelet therapies, continuing aspirin plus a powerful proton pump inhibitor is the choice of treatment. Patients who require antiplatelet agents for the prevention of cardiovascular diseases should be tested and treated for Helicobacter pylori infection before starting antiplatelet therapy. Additionally, those with high risks for upper gastrointestinal bleeding should receive co-therapy with a gastroprotective drug, preferably a proton pump inhibitor at standard dose. H2-receptor antagonist can significantly reduce upper gastrointestinal bleeding risk in patients taking low-dose aspirin but it is ineffective in the prevention of upper gastrointestinal bleeding in clopidogrel users. Although several retrospective studies reported that patients prescribed clopidogrel who also took proton pump inhibitors had significant increases in cardiovascular events, the current evidence from a prospective randomized trial does not justify a conclusion that proton pump inhibitors are associated with cardiovascular events among clopidogrel users.     

Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination

Management of peripheral arterial disease (PAD) requires standard atherosclerotic risk management interventions. However, PAD is often complicated by walking pain (intermittent claudication [IC]), which requires symptom-specific therapies as well. Thus, all PAD patients are encouraged to take antiplatelet agents to reduce the associated risks of major cardiovascular events, and those with IC may also require treatment with cilostazol, an agent proven to increase exercise capacity and enhance quality of life in these patients. Although it was initially thought that cilostazol's antiplatelet properties might render it unsafe to use in combination with other platelet inhibitors because of possible additive effects, a recent study has dispelled such concerns. There is evidence that in a crossover trial of 21 patients with PAD and IC, aspirin alone, or clopidogrel alone, significantly increased bleeding times, but cilostazol alone did not. The combination of aspirin and clopidogrel had a greater effect on increasing bleeding time than either monotherapy, and no further bleeding time prolongation was observed, when cilostazol was added to any aspirin/clopidogrel regimen. These findings suggest that PAD patients with IC may be safely managed with both cilostazol and standard antiplatelet therapy, without increasing the risk of adverse bleeding effects.     

A review of therapeutic strategies for risk reduction of recurrent stroke

Although cardiovascular disease (CVD) is a major source of morbidity and mortality in the United States, a relatively small percentage of deaths related to CVD result from ischemic stroke. However, the impairment and costs associated with stroke are large--and largely preventable. Large-scale trials have demonstrated benefit with antihypertensive therapy for secondary prevention, showing significantly reduced rates of stroke and cardiovascular events. Statins have shown efficacy in primary stroke prevention, and one trial showed reduced incidence of stroke and cardiovascular events in patients with recent stroke or transient ischemic attack (TIA). The merits of antiplatelet therapy in primary and secondary stroke prevention have been demonstrated across numerous trials and meta-analyses. Trials assessing aspirin plus clopidogrel or aspirin plus extended-release dipyridamole for preventing secondary stroke have produced somewhat contradictory findings. This review discusses the relationship between CVD and risk of secondary stroke or TIA and summarizes secondary prevention strategies, focusing on antiplatelet agents, to provide guidance for the practicing cardiologist. Certain combination therapies appear to be more effective for secondary prevention of stroke or TIA than therapy with single antiplatelet agents. The choice of agents may be important, based on results of several trials. The ongoing, large-scale, comparative Prevention Regimen for Effectively Avoiding Second Strokes (PR. FESS) trial should provide cardiologists with more definitive recommendations.     

Aspirin and Clopidogrel: Efficacy, Treatment, and Resistance in Coronary Artery Disease

Oral antiplatelet therapy is a key element of the continuously evolving treatment of acute coronary syndromes. As part of this evolution, resistance to oral antiplatelet therapy has emerged as a new challenge adversely affecting patients’ clinical risk and outcome. This review addresses the role of two oral antiplatelet therapy agents, aspirin and clopidogrel, their mechanism of action, and the evidence supporting their use in the setting of coronary artery disease. Unfortunately, clinically relevant resistance to aspirin and clopidogrel exists. Resistance may indicate a higher risk for major adverse events. An established safe and reliable treatment alternative is lacking at this point; further research is needed to evaluate the efficacy of any alternative treatments that can be offered to decrease cardiovascular risk and improve clinical outcomes.     

Patients with peripheral arterial disease in the CHARISMA trial

Aims: The aim of this study was to determine whether clopidogrel plusaspirin provides greater protection against major cardiovascularevents than aspirin alone in patients with peripheral arterialdisease (PAD). Methods and results: This is a post hoc analysis of the 3096 patients with symptomatic(2838) or asymptomatic (258) PAD from the CHARISMA trial. Therate of cardiovascular death, myocardial infarction (MI), orstroke (primary endpoint) was higher in patients with PAD thanin those without PAD: 8.2% vs. 6.8% [hazard ratio (HR), 1.25;95% CI 1.08, 1.44; P = 0.002]. Among the patients with PAD,the primary endpoint occurred in 7.6% in the clopidogrel plusaspirin group and 8.9% in the placebo plus aspirin group (HR,0.85; 95% CI, 0.66–1.08; P = 0.18). In these patients,the rate of MI was lower in the dual antiplatelet arm than theaspirin alone arm: 2.3% vs. 3.7% (HR, 0.63; 95% CI, 0.42–0.96;P = 0.029), as was the rate of hospitalization for ischaemicevents: 16.5% vs. 20.1% (HR, 0.81; 95% CI, 0.68–0.95;P = 0.011). The rates of severe, fatal, or moderate bleedingdid not differ between the groups, whereas minor bleeding wasincreased with clopidogrel: 34.4% vs. 20.8% (odds ratio, 1.99;95% CI, 1.69–2.34; P < 0.001). Conclusion: Dual therapy provided some benefit over aspirin alone in PADpatients for the rate of MI and the rate of hospitalizationfor ischaemic events, at the cost of an increase in minor bleeding.     

Platelet receptor redox regulation

A large number of patients require antiplatelet therapy (mainly aspirin and/or clopidogrel). Recent studies suggest that the combination of these agents is useful in patients with acute coronary syndrome and after percutaneous coronary intervention with stent placement. On the other hand, bleeding complications, most of which arise from the upper gastrointestinal (UGI) tract, can limit the use of antiplatelet drugs. Clopidogrel appears to be associated with fewer UGI side effects and bleeding compared with aspirin. However, a history of previous UGI bleeding is a major risk factor for clopidogrel-associated bleeding. The use of proton-pump inhibitors (PPIs) decreases the rate of UGI bleeding in patients receiving aspirin or clopidogrel. Furthermore, a recent study suggested that the administration of low-dose aspirin plus high-dose esomeprazole (a potent PPI) was associated with fewer episodes of UGI bleeding than clopidogrel alone in patients with a history of recent UGI haemorrhage. However, this study had several limitations and its results should be cautiously extrapolated into clinical practice. The combination of aspirin plus clopidogrel increases the risk of UGI bleeding. Unfortunately, there are no data on the effect of PPI prophylaxis in this setting. Available evidence suggests that where aspirin and/or clopidogrel are to be started or continued in patients with a recent history of UGI ulceration or bleeding (after ulcer healing and eradication of H. pylori infection), treatment with a PPI is a useful precaution. The patients should also be carefully monitored for recurrence of UGI bleeding.     

Dual Antiplatelet Therapy with Prasugrel or Ticagrelor Versus Clopidogrel in Interventional Cardiology

For several years, clopidogrel plus aspirin has been the dual antiplatelet therapy (DAPT) of choice for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with stent implantation. More recently, prasugrel and ticagrelor have demonstrated greater efficacy than clopidogrel. In TRITON-TIMI 38, the risk of TIMI major bleeding unrelated to coronary artery bypass graft (CABG) surgery was similar for prasugrel and clopidogrel after excluding subgroups with increased bleeding risk (previous stroke or transient ischemic event; age ≥75 years; weight <60 kg). In the PLATO trial, rates of TIMI major bleeding were similar for ticagrelor and clopidogrel, but ticagrelor was associated with a significantly higher rate of non-CABG-related TIMI major bleeding. Current evidence suggests that prasugrel or ticagrelor plus aspirin should be the DAPT of choice in patients with ACS undergoing PCI unless they are at particularly high risk of bleeding. No studies have yet compared prasugrel and ticagrelor in ACS patients, however prasugrel and ticagrelor have different side effect profiles, and the choice of agent should be made either as a default choice and/or on an individual patient basis. Ongoing trials in ACS patients will increase the evidence base for new P2Y₁₂ receptor inhibitors and help to establish the most effective DAPT regimens.