The role of aspirin in cardiovascular prevention: implications of aspirin resistance

Aspirin is well recognized as an effective antiplatelet drug for secondary prevention in subjects at high risk of cardiovascular events. However, most patients receiving long-term aspirin therapy still remain at substantial risk of thrombotic events due to insufficient inhibition of platelets, specifically via the thromboxane A2 pathway. Although the exact prevalence is unknown, estimates suggest that between 5.5% and 60% of patients using this drug may exhibit a degree of "aspirin resistance," depending upon the definition used and parameters measured. To date, only a limited number of clinical studies have convincingly investigated the importance of aspirin resistance. Of these, few are of a sufficient scale, well designed, and prospective, with aspirin used at standard doses. Also, most studies do not sufficiently address the issue of noncompliance to aspirin as a frequent, yet easily preventable cause of resistance to this antiplatelet drug. This review article provides a comprehensive overview of aspirin resistance, discussing its definition, prevalence, diagnosis, and therapeutic approaches. Moreover, the clinical implications of aspirin resistance are explored in various cardiovascular disease states, including diabetes mellitus, hypertension, heart failure, and other similar disorders where platelet reactivity is enhanced.     

A review of aspirin resistance; definition,possible mechanisms,detection with platelet function tests,and its clinical outcomes

Aspirin (acetylsalicylic acid) is one of the main therapeutics in prevention of thrombo-embolic vascular events. Its efficiency is proved in the prevention of cardiovascular events. However, antiplatelet effect of aspirin is not absolute in all patients and some patients experience thrombo-embolic events despite aspirin. These patients are clinically called as aspirin resistant or aspirin non-responders. Globally, a lot of people are affected by aspirin resistance according to the high prevalence of athero-thrombotic vascular diseases. A prevalence of 5.5–45% in patients with various cardiovascular disease by different laboratory methods has been reported for aspirin resistance. Clinical outcome of aspirin resistance has been demonstrated in patients with different vascular diseases. Detection of platelet function in patients treated with aspirin may be necessary in the prediction of clinical outcome. Point of care methods, which have correlated results with the standard light transmittance aggregometry may be appropriate choices in the detection of platelets’ response to antiplatelet therapy. Adequate additional therapies may reduce atherothrombotic risks and major cardiovascular events rate in aspirin resistant subjects. None of the current researches advised the cessation of aspirin therapy. There is need to investigate the efficacy of additional adenosine diphosphate receptor antagonists or newer antiplatelet agents in aspirin resistant subjects. The intent of this paper is to review the literature discussing possible mechanisms, determination techniques, and clinical effects of aspirin resistance.     

Patient-Specific Antiplatelet Therapy

Platelets are key players in thrombosis, and have thus become the main targets in the acute treatment of, as well as in the primary and secondary prevention against, thrombotic cardiovascular diseases. Three main classes of anti-platelet agents are currently available for clinical use: aspirin, the thienopyridines, and the intravenous GPIIb/IIIa antagonists. While these therapies are beneficial in the mean patient population, they may produce adverse effects in selected patient subgroups. In this article, we review the three main classes of antiplatelet drugs, discussing them in terms of the patient characteristics that are likely to influence their overall efficacy and safety.     

Antiplatelet therapy in secondary stroke prevention

This article focuses on recent data about the safety and effectiveness of antiplatelet therapies for secondary stroke prevention. Highlights include a discussion of changes in the professional labeling for aspirin and the results of a low- versus high-dose aspirin trial (Aspirin after Carotid Endarterectomy trial). Safety issues regarding aspirin also are considered. Other topics include a review of recent data on thrombotic thrombocytopenic purpura (TTP) associated with ticlopidine and a brief update on clopidogrel. A summary of discussions related to the European Stroke Prevention Study 2 data and Food and Drug Administration consideration of combination dipyridamole/aspirin therapy are presented.     

Antiplatelet treatment in primary and secondary stroke prevention in women

Stroke is a leading cause of death worldwide and the first cause of disability in the Western world. Over the last 20years, antiplatelet agents have reduced overall stroke rates in primary and secondary prevention in men. However, this has not been the case for women. In this narrative review, the most widely used antiplatelet therapies for primary and secondary prevention in stroke, excluding cardioembolic stroke, will be outlined. First, the largest randomised controlled trials will be analysed as well as the enrolment percentages of women. Second, analyses on sex-interaction effects in each study will be examined. Moreover, the Authors will discuss the need to develop targeted antiplatelet therapies specifically for women. Based on current results, the most randomised clinical trials and meta-analyses on antiplatelet agents in cerebrovascular disease have not performed sub-analyses on sex-related differences and this is mainly because women were underrepresented. Despite this, antiplatelet agents are considered to be equally effective for both sexes in primary and secondary stroke prevention. Finally, aspirin is the most widely studied antiplatelet in women and has been shown to provide greater benefit for women as primary prevention of ischemic stroke without a significant increased risk in haemorrhage.     

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.     

Antiplatelet therapy in cerebrovascular disease: implications of Management of Artherothrombosis with Clopidogrel in High-risk Patients and the Clopidogrel for High Artherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance studies' results for cardiologists

Cardiovascular disease is prevalent among patients with stroke; thus, cardiologists frequently treat patients at high risk for stroke. Results from recent clinical trials of antiplatelet medications, given alone or in combination, may be of special interest to cardiologists. The MATCH study demonstrated no significant difference between clopidogrel alone and clopidogrel plus aspirin in reducing risk of vascular events after stroke or transient ischemic attack. A 1.3% increased risk of major bleeding was associated with clopidogrel plus aspirin. In CHARISMA, clopidogrel plus aspirin did not reach statistical significance vs. placebo plus aspirin in reducing incidence of myocardial infarction (MI), stroke, or death from cardiovascular causes in patients with stable atherothrombotic disease; clopidogrel was associated with an increase in moderate bleeding. These results suggest that clopidogrel plus aspirin may be inappropriate as first-line therapy for secondary stroke prevention. In patients with established cardiovascular disease at risk for MI or other vascular events, physicians must weigh the benefits and risks before choosing this therapy. Selection of an antiplatelet agent must be based on patient history, including previous MI and stroke, susceptibility to bleeding, and other high-risk factors (e.g. advanced age and diabetes). Aspirin plus extended-release dipyridamole may be more effective than clopidogrel for preventing stroke in high-risk patients. This article strives to put MATCH and CHARISMA results into context by providing an overview of antiplatelet therapy, including relevant clinical trial results, a review of current practice guidelines, and a summary of an ongoing study that will improve clinical decision making.     

Antithrombotic Therapy in Peripheral Artery Disease: Risk Stratification and Clinical Decision Making

Patients with peripheral artery disease (PAD) are an underrecognised group with significant thrombotic risk. This risk is modifiable with the use of aggressive secondary preventative efforts, including optimisation of antithrombotic therapy. Appropriate antithrombotic selection for patients with PAD requires appropriate assessment of thrombotic and bleeding risk. Recent Canadian guidelines have recommended dual pathway therapy initiation for stable PAD and post-revascularisation patients. However, there is ongoing discussion about how to identify PAD patients who stand to benefit most from these therapies while trying to minimise harm from bleeding. Clinical equipoise also persists around questions such as the utility of dual antiplatelet therapy in conjunction with rivaroxaban after high-risk endovascular interventions and the optimal therapy for patients experiencing acute limb ischemia. In patients with chronic PAD and high-risk comorbidities or limb features, or in patients after revascularisation, dual pathway therapy with low-dose rivaroxaban and aspirin has emerged as the only regimen to reduce major adverse cardiovascular and limb events while maintaining an acceptable bleeding profile. After endovascular revascularisation, limited-duration (< 30 days) clopidogrel may be added to rivaroxaban and aspirin in selected high-risk patients at the provider’s discretion. After acute limb ischemia, the risk of another vascular event is exceptionally high, but there is no high-quality evidence to guide decision making for intensified antithrombotic therapy. Randomised investigations addressing this question are urgently needed to better serve this high-risk and vulnerable population.     

Clopidogrel: How good is it and how does it work?

Until recently, long-term antiplatelet therapy for the treatment and prevention of the complications of atherothrombotic disease was limited to aspirin. Although an incredibly costeffective therapy, in placebo-controlled clinical trials approximately 75% of patients at risk continue to experience thrombotic events despite chronic aspirin therapy. The availability of the thienopyridines, in particular clopidogrel, represents an important addition to the physician’s armamentarium. A number of clinical trials have confirmed the efficacy of the combination of clopidogrel and aspirin therapy compared with aspirin alone, with multiple other important largescale clinical trials currently ongoing. The exact mechanism of this benefit is still being elucidated but is clearly related to the inhibition of the many consequences of platelet activation—vascular inflammation, endothelial dysfunction, and localized angiogenesis/mitogenesis—and not just aggregation.     

Antiplatelet therapy for atherothrombotic disease: How can we improve the outcomes?

Platelets play a key role in hemostasis but are also responsible for the formation of pathogenic thrombi underlying the acute clinical manifestations of vascular atherothrombotic disease. Platelets are activated by multiple pathways, including adenosine diphosphate (ADP), thromboxane A₂ (TXA₂), and thrombin, ultimately leading to formation of platelet-rich thrombi that occlude the arterial lumen, resulting in ischemia and cardiovascular events. Current oral antiplatelet agents inhibit the TXA₂ (aspirin [ASA]) and ADP platelet activation pathways (P2Y₁₂ ADP receptor antagonists) and have demonstrated clinical efficacy for the reduction of morbidity and mortality in patients with atherothrombotic disease. However, these agents are associated with residual risk for thrombotic events, bleeding risk, and variability in response. Thus, there is a strong clinical need for novel antiplatelet therapies that decrease the risk of thrombotic events without exposing patients to increased risk of bleeding. This review describes the clinical safety and efficacy of ASA and P2Y₁₂ ADP receptor antagonists, the limitations of current antiplatelet therapy, and novel therapies in development, including newer P2Y₁₂ ADP receptor antagonists and protease-activated receptor (PAR-1) inhibitors.     

Antithrombotische Therapie

Platelet function is one of the main components in the development of atherosclerosis and atherothrombotic clinical events. Patients with diabetes mellitus in particular exhibit increased platelet activity and reduced inhibition in response to platelet inhibitors. The general administration of aspirin in all patients with diabetes mellitus type 2 is recommended by some scientific societies. In clinically stable patients, secondary prevention with clopidogrel is superior to the use of aspirin. In patients with diabetes mellitus, the relative risk reduction with clopidogrel is four times higher than the risk reduction in non-diabetics. Dual platelet inhibitor therapy has no clinical advantages in these stable patients. In contrast, dual antiplatelet therapy is significantly superior to monotherapy with aspirin in patients with acute coronary syndrome. Although the relative risk reduction in patients with diabetes mellitus is comparable to the rate in non-diabetics, the absolute number of events prevented in these patients is significantly higher due to the higher event rate. The results presented suggest that the clinical outcome in patients with diabetes mellitus is mainly determined by the degree of platelet activation and its effective inhibition by platelet inhibitors.     

Aspirin resistance: mechanisms and clinical implications

Acetylsalicylic acid (aspirin) has been shown to irreversibly interfere with platelet function, an effect that is associated with a reduction in morbid and mortal arterial thrombotic events in multiple clinical studies. This clinical benefit appears to be attenuated by resistance to the antiplatelet effects of aspirin in up to 35% of patients. The mechanisms for aspirin resistance are multifactorial and include noncompliance with aspirin therapy, diabetes mellitus, cell-cell and drug-drug interactions, genetic polymorphisms, and coronary artery disease. It has not been determined what the best laboratory procedure is to screen for aspirin resistance. Those individuals at high risk for aspirin resistance might best be treated with an additional oral antiplatelet drug (eg, clopidogrel) to achieve maximal protection against arterial thrombotic events.     

Aspirin “Resistance”

Recent clinical studies have shown that the expected antiplatelet effect of aspirin is not always achieved. From the laboratory point of view, resistance to aspirin is the inability to achieve the expected inhibition of platelet cyclooxygenase-(COX-)1 with prevention of platelet thromboxane (TX) A2 formation. The failure to prevent atherothrombotic events (treatment failure) must be distinguished from aspirin resistance. Nevertheless, different definitions of aspirin resistance complicate the assessment of published data, a problem aggravated by discordant results of the available diagnostic laboratory techniques.The pharmacological mechanisms of aspirin resistance are not completely understood. Potential causes include pharmacokinetic and pharmacodynamic issues, such as reduced bioavailability, increased platelet turnover, interactions with nonsteroidal anti-inflammatory drugs, comorbidities (hypercholesterolemia or diabetes mellitus), alternative pathways of platelet activation, and genetic polymorphisms. Clinical trials demonstrated a negative impact of aspirin resistance on the clinical outcome: an about fourfold increased risk of major atherothrombotic events has been found in aspirin nonresponders suffering from vascular disease.An individualized antiplatelet therapy with aspirin will have to consider the possibility of aspirin resistance. Thus, standardized and inexpensive diagnostic assays are needed. The identification of aspirin-resistant patients is essential to individually tailor antiplatelet treatment. For example, increasing the dosage of aspirin or alternative antiplatelet drugs are potential therapeutic concepts, but these require careful future investigation.     

Antiplatelet strategy in primary and secondary prevention of cardiovascular disease in patients with type 2 diabetes mellitus: A perspective from the guideline appraisal

Aims/IntroductionTo appraise guidelines on the antiplatelet strategy of prevention of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus, and highlight the consensuses and controversies to aid clinician decision‐making.Materials and MethodsA systematic search was carried out for guidelines regarding CVD prevention or focusing on type 2 diabetes patients. Appraisal of Guidelines for Research and Evaluation II instrument was utilized to appraise the quality of included guidelines.ResultsOf the 15 guidelines with discrepant Appraisal of Guidelines for Research and Evaluation II scores (66%; interquartile range 51–71%), 10 were defined as “strongly recommended” guidelines. For secondary prevention, >60% of guidelines advocated that the dual antiplatelet therapy was used within 12 months when the type 2 diabetes patients experienced acute coronary syndrome and/or post‐percutaneous coronary intervention or coronary artery bypass grafting, with subsequent long‐term aspirin use. For primary prevention, 80% of guidelines supported that aspirin should not be routinely used by patients with type 2 diabetes. No consensus on whether to prolong dual antiplatelet therapy in secondary prevention, and whether to use aspirin in type 2 diabetes patients with high CVD risk exists in current guidelines.ConclusionsPhysicians should use the recommendations from “strongly recommended” guidelines to make informed decisions and know the consensuses of current guidelines. Dual antiplatelet therapy should be used within 12 months when type 2 diabetes patients experience acute coronary syndrome and/or percutaneous coronary intervention/coronary artery bypass grafting, with subsequent long‐term aspirin use. In primary prevention, aspirin should not be routinely used by individuals with type 2 diabetes, but might be considered for those with high CVD risk.     

Aspirin and other antiplatelet drugs in the prevention of venous thromboembolism

While there is good evidence for a protective effect of aspirin against occlusive vascular events in individuals with arterial disease, its role in preventing venous thromboembolism (VTE) is unclear. In this article we review the role of aspirin and other antiplatelet drugs in prevention of venous thromboembolism in surgical patients, high risk medical patients requiring aspirin for other reasons, patients with myeloproliferative disorders, long distance travellers and patients receiving treatment with the IMiD class of drugs. Overall, data from the PEP study and Anti-Platelet Trialists' systematic review show that aspirin reduces the risk of VTE by around 25% in high risk surgical patients. Data from retrospective and before/after studies also suggest efficacy in reducing VTE in myeloma patients on IMiD drugs in combination with dexamethasone or chemotherapy. However, there has been no direct comparison with coumarins or heparin to indicate that aspirin is the optimal form of thromboprophylaxis. In patients who require aspirin because of high risk of arterial vascular occlusion (including patients with polycythaemia vera and essential thrombocythaemia), the additional small reduction in VTE risk is an added benefit with no additional risk associated. There is no evidence for a role of aspirin in prevention of travel-related thrombosis. At present there is no clear evidence that aspirin is the drug of choice for the prevention of VTE in any patient group.     

Antithrombotic therapy in peripheral artery disease: A review of the EUCLID trial results and current ongoing trials

In addition to risk‐factor modification, antithrombotic therapy is the hallmark of management to reduce cardiovascular ischemic events in patients with peripheral artery disease (PAD). Currently, the guidelines recommend long‐term antiplatelet therapy with aspirin or clopidogrel in this patient population to reduce myocardial infarction, stroke, and vascular death. Past outcomes studies have shown some benefit of ticagrelor, another antiplatelet agent, as compared with clopidogrel in patients with coronary disease and concomitant PAD. However, most recently, the Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial has shown no additional benefit of ticagrelor over clopidogrel. In this trial, a minority of patients had concomitant coronary artery disease, making it unique to previous studies. The EUCLID trial's evidence of neutrality between clopidogrel and ticagrelor sheds light into the complexity of studying the PAD population and the continued need to meticulously design trials to investigate the optimal therapies. The topics that will be discussed in this review include the role of antiplatelet therapy in the management of patients with PAD, a review of the EUCLID trial results and the important factors to be considered in interpreting the surprising results, and promising recent ongoing clinical trials assessing therapies in the treatment of patients with PAD.     

Aspirin in the Modern Era of Cardiovascular Disease Prevention

Aspirin’s antithrombotic effects have a long-established place in the prevention of cardiovascular disease (CVD), and its traditional use as a core therapy for secondary prevention of CVD is well recognized. However, with the advent of newer antiplatelet agents and an increasing understanding of aspirin’s bleeding risks, its role across the full spectrum of modern CVD prevention has become less certain. As a consequence, recent trials have begun investigating aspirin-free strategies in secondary prevention. For example, a contemporary metanalysis of trials that assessed P2Y₁₂ inhibitor monotherapy versus prolonged (≥ 12 months) dual antiplatelet therapy (which includes aspirin) after percutaneous coronary intervention reported a lower risk of major bleeding and no increase in stent thrombosis, all-cause mortality, myocardial infarction (MI), or stroke in the P2Y₁₂ monotherapy group.In contrast to secondary prevention, aspirin’s role in primary prevention has always been more controversial. While historical trials reported a reduction in MI and stroke, more contemporary trials have suggested diminishing benefit for aspirin in this setting, with no reduction in hard outcomes, and some primary prevention trials have even indicated a potential for harm. In this review, we discuss how changing population demographics, enhanced control of lipids and blood pressure, changes in the definition of outcomes like MI, evolution of aspirin formulations, and updated clinical practice guidelines have all impacted the use of aspirin for primary and secondary CVD prevention.     

Aspirin resistance and atherothrombotic disease.

Acute coronary syndromes and other manifestations of atherothrombotic disease are primarily caused by atherosclerotic plaque rupture or fissuring and subsequent occlusive or subocclusive thrombus formation. Platelets play a critical role in the pathophysiology of atherothrombotic disease, and aspirin is the most commonly used antiplatelet agent. Clinical trials have demonstrated the efficacy of aspirin in both primary and secondary prevention of myocardial infarction, stroke, and cardiovascular death. Despite its proven benefit, the absolute risk of recurrent vascular events among patients taking aspirin remains relatively high, an estimated 8% to 18% after two years. Therapeutic resistance to aspirin might explain a portion of this risk. Although formal diagnostic criteria and a validated method of measurement are lacking, aspirin resistance may affect between 5% and 45% of the population. Given the prevalence of cardiovascular disease, the potential impact of aspirin resistance is large. Currently, however, there are many unanswered questions regarding the biological mechanism, diagnosis, population prevalence, clinical relevance, and optimal therapeutic intervention for aspirin resistance.