Genomics and the efficacy of aspirin in the treatment of cerebrovascular disease

Opinion statement  Aspirin has been shown to reduce the risk of stroke, myocardial infarction, and death in patients with a history of cardiovascular disease or at high risk for cardiovascular disease. However, many individuals suffer a stroke or other cardiovascular event despite aspirin therapy. Data suggest that heritability contributes importantly to the antiplatelet and clinical responses to aspirin. Candidate genes for influencing aspirin response include those involved in platelet aggregation and in modulating cardiovascular disease risk and progression. Although several studies have examined genetic determinants of platelet responsiveness to aspirin, the results are largely inconsistent. Few studies have examined genetic association with clinical outcomes, including reductions in stroke risk, with aspirin. In perhaps the most significant pharmacogenomic study with aspirin to date, a large primary prevention trial showed that the apolipoprotein A genotype was associated with risk of stroke and other cardiovascular events in women and that aspirin eliminated this risk. These data suggest that ultimately, it may be possible to tailor aspirin therapy based on an individual’s genotype, at least for primary prevention of stroke and cardiovascular events in women. Data on genetic determinants of response to aspirin in secondary stroke prevention are far less advanced. Future pharmacogenomic studies should focus on elucidating the role of genotyping in choosing appropriate antiplatelet therapy (ie, aspirin alone versus a thienopyridine or combination antiplatelet therapy) for secondary disease prevention.     

Aspirin and clopidogrel resistance: an emerging clinical entity.

We read with interest the recent article which reviewed theissue of aspirin and clopidogrel resistance.¹ The authors reviewthe aspirin and clopidogrel clinical trial data and concludethat both therapies have emerged as efficacious in both theprimary and     

Cilostazol in secondary prevention of stroke: impact of the Cilostazol Stroke Prevention Study

According to recent epidemiological data in Japan, stroke affects roughly 5.3 males and 3.9 females per 1000 person-years and is the third leading cause of mortality. At present, management strategies for secondary prevention of stroke include aggressive treatment of cardiovascular risk factors (i.e., hypertension, smoking cessation, etc.). Antiplatelet drugs in Japan, namely aspirin and cilostazol, are utilized regularly for the prevention of secondary stroke. While aspirin is beneficial for a wide range of cardiovascular endpoints, including total and ischemic strokes, it is also associated with significantly increased risks for hemorrhagic infarction. Cilostazol, by contrast, has been shown to significantly reduce the risk of recurrent strokes without affecting the occurrence of intracranial hemorrhage. In the Cilostazol Stroke Prevention Study, a randomized double-blind, placebo-controlled trial involving more than 1000 Japanese patients, cilostazol was found to reduce the risk of secondary stroke by 41.7% compared with placebo, a statistically significant reduction (P = 0.015). The greatest risk reduction (43.4% in cilostazol versus placebo, P = 0.0373) was found in patients who initially had a lacunar infarction, suggesting that cilostazol has a specific effect against small-vessel disease. In addition, cilostazol achieved significant risk reductions on a number of combined endpoints (e.g., cerebral infarction, intracranial hemorrhage, myocardial infarction, or vascular death), and was associated with benefits in intent-to-treat analyses. These findings indicate that cilostazol may have a role as a vascular neuroprotectant, but the clinical implications are limited by the fact that patients were randomized to placebo instead of aspirin, which is the standard of care.     

Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials

ObjectiveLow-dose aspirin is a common strategy for preventing cardiovascular disease and associated mortality. A recent individual patient data meta-analysis of 8 trials of low- and high-dose aspirin, with long-term follow-up, found important reductions in cancer mortality. We aimed to determine whether cancer mortality also is reduced by low-dose aspirin in the shorter term.MethodsWe conducted a comprehensive search of 10 electronic databases up to December 2011. We conducted a meta-analysis using data from all randomized clinical trials evaluating low-dose (75-325 mg) daily aspirin. We extracted data on non-cardiovascular disease mortality and cancer mortality. We pooled studies using a random-effects model and conducted a meta-regression. We supplemented this with a cumulative meta-analysis and trial sequential monitoring analysis.ResultsTwenty-three randomized studies reported on nonvascular death. There were 944 nonvascular deaths of 41,398 (2.28%) patients receiving low-dose aspirin and 1074 nonvascular deaths of 41,470 (2.58%) patients not receiving aspirin therapy. The relative risk of nonvascular death was 0.88 (95% confidence interval [CI], 0.81-0.96, I² = 0%). Eleven trials included data evaluating cancer mortality involving 16,066 patients. There were 162 of 7998 (2.02%) and 210 of 8068 (2.60%) cancer deaths among low-dose aspirin users versus non-aspirin users, respectively, reported over an average follow-up of 2.8 years. The relative risk of cancer mortality was 0.77 (95% CI, 0.63-0.95, I² = 0%). Studies demonstrated a significant treatment effect after approximately 4 years of follow-up. The optimal information size analysis showed that a sufficient number of patients had been randomized to provide convincing evidence of a preventive role of low-dose aspirin in nonvascular deaths.ConclusionNonvascular deaths, including cancer deaths, are reduced with low-dose aspirin.     

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??In last century??aspirin became a standard drug for the secondary prevention of cardiovascular disease.In recent years??a number of clinical trial evidence has confirmed that aspirin had been used as the primary prevention of cardiovascular disease.The mechanism is to block the thromboxane A??2 formation by inhibiting cycloosygenase.Studies have shown that low-dose aspirin could effectively reduce coronary heart disease and ischemic stroke risk in males.However??for women??aspirin for primary prevention of coronary heart disease is unobvious.In this paper??we discuss the relationship between aspirin and heart health in females by retrospectively reviewing the mechanism of aspirin??its efficacy and primary prevention effect on cardiovascular disease.     

Aspirin in diabetic retinopathy. A systematic review.

Diabetes mellitus is a risk factor for eye disease that can lead to blindness. There have been both concerns that aspirin use might worsen diabetic retinopathy, as well as hopes that aspirin might be beneficial in treating it. We investigated whether there are beneficial effects of aspirin alone and in combination with other antiplatelet agents in the treatment of diabetic retinopathy, and the relative hazards for the development of high-risk proliferative retinopathy following aspirin treatment. We conducted a sensitive search for randomized controlled trials combined with index terms for identifying studies on aspirin treatment in diabetic retinopathy in the Cochrane Library (issue 4, 2001) and Medline (1966 to October, 2001). We examined randomized controlled clinical trials in diabetic patients with (non) proliferative diabetic retinopathy and aspirin treatment alone or in combination with dipyramidole versus placebo administration. Two independent reviewers judged trial eligibility, collected details of study population, interventions, and outcomes using a standard data extraction form. One reviewer assessed the quality of trial reporting. We identified six publications pertinent to our objective. Aspirin dosages ranged from 650 mg to 990 mg daily, the dose of dipyridamole, used in only one trial, was 225 mg per day. Studies lasted 8 weeks to 5 years. All trials showed that aspirin alone or in combination with dipyridamole neither lowered nor increased the risk of the development of diabetic retinopathy. The results suggest that there are no ocular contraindications to taking aspirin if required as part of a treatment for cardiovascular diseases or other medical indications.     

Aspirin for primary prevention of atherosclerotic disease in Japan

Atherosclerotic disease is the most prevalent cause of death worldwide. The ratio of coronary heart disease/cerebrovascular disease differs between Japan and Western countries and the incidence of hemorrhagic stroke and gastrointestinal bleeding is higher in Japan. Thus, the threshold for aspirin administration for primary prevention has been controversial in Japan. Much anecdotal data from Western countries and from Japan has implied that the threshold for administering aspirin to those with risk factors for coronary heart disease is higher than that recommended in Western countries, and that the potential candidates for primary prevention in Japan seem to be diabetic patients. The Japanese primary Prevention of atherosclerosis with Aspirin for Diabetes (JPAD) trial involving 2,530 patients with type 2 diabetes started in December 2002. Compared to other primary prevention trials, this trial offered an acceptable sample size, a standard aspirin dosage, and gender balance. Because stroke is the most significant component of all atherosclerotic diseases in Japan, the impact of primary prevention with aspirin on stroke should be understood. Thus, the JPAD trial should generate reliable data on primary prevention with aspirin for diabetic patients that would also be relevant to other countries.     

Antiplatelet therapy for stroke prevention

Recent trials of antiplatelet therapy for stroke prevention indicate that the combination of clopidogrel (75 mg/d) plus low-dose aspirin (75–162 mg/d) was not more effective than low-dose aspirin alone in the long-term prevention of major vascular events among patients at high risk of atherothrombotic events, nor was it more effective than oral anticoagulation in patients with atrial fibrillation. Furthermore, oral anticoagulation (International Normalized Ratio of 2.0–3.0) was not more effective than aspirin alone among patients with recent cerebral ischemia of presumed arterial origin. However, the addition of extended-release dipyridamole to aspirin was more effective than aspirin alone among patients with recent cerebral ischemia of presumed arterial origin. A large trial comparing clopidogrel with the combination of aspirin and extended-release dipyridamole in more than 20,000 patients with recent (< 120 days) atherothrombotic ischemic stroke is expected to report in 2008.     

Early decrease in coagulation activity after myocardial infarction is associated with lower risk of new ischaemic events: observations from the ESTEEM: reply

The ESTEEM trial was a phase II study evaluating the efficacyand safety of treatment with the first available oral directthrombin inhibitor ximelagatran together with aspirin, whencompared with aspirin only, after a recent myocardial infarction.¹In a subgroup of 518 (out of     

Effect of long-term aspirin use on embolic events in infective endocarditis.

BACKGROUND: In a recent clinical trial, aspirin therapy was initiated approximately 34 days after the onset of symptoms but did not reduce the risk of embolism in patients with endocarditis. However, it is possible that aspirin used early in the course of the disease may be beneficial. The purpose of the study is to assess the effect of long-term daily aspirin use on the risk of embolic events in patients with infective endocarditis. METHODS: The clinical characteristics and outcomes of patients excluded from the Multi-Centre Aspirin Trial in Infective Endocarditis because of long-term aspirin use (n = 84) were compared with the data for patients randomized to the placebo arm (n = 55). The former patients took aspirin before and during the early stages of infective endocarditis, whereas the latter patients were not exposed to aspirin before and during the entire hospitalization. Logistic modeling was used to assess the effect of long-term aspirin use on embolism and bleeding. RESULTS: There was a trend toward excess bleeding in long-term aspirin recipients, compared with placebo recipients (P = .065). Logistic modeling revealed that long-term aspirin use may be associated with excess bleeding (unadjusted odds ratio, 2.35 [P = .059]; adjusted odds ratio, 2.08 [P = .118]), but it had no impact on the risk of embolic events in either model. CONCLUSIONS: In patients with endocarditis, long-term daily use of aspirin does not reduce the risk of embolic events but may be associated with a higher risk of bleeding. In the acute phase of endocarditis, aspirin should be used with caution.     

Antithrombotic drugs in peripheral arterial diseases

The efficacy of antithrombotic drugs in the treatment of peripheral arterial disease remains a subject of discussion. A recent Dutch trial continues to question the value of anticoagulants in this indication. There is very little definitive data concerning anti-platelet agents. Controlled trials remain few in number and scarcely show spectacular results on the spontaneous course of arterial disease of the limbs. The hope aroused in certain studies of the use of prostaglandins in severe ischaemia remains to be confirmed in a well controlled trial. Practitioners of percutaneous angioplasty usually prescribe anticoagulants or anti-aggregants to decrease the risk of an early recurrence. There are also arguments which justify the administration of aspirin after endarterectomy.     

Preventing stroke in patients with atrial fibrillation: current treatments and new concepts

Atrial fibrillation (AF) is common, and it increases the risk of stroke. Placebo-controlled trials consistently showed that warfarin reduces the risk of stroke by two thirds, and a meta-analysis of trials of aspirin show a one-fifth reduction. Meta-analysis of trials directly comparing warfarin and aspirin shows that warfarin reduces the risk of stroke compared with aspirin by about one third. Major advisory bodies recommend risk stratification of patients with AF and prophylactic therapy with warfarin for patients at higher risk. There are several problems with warfarin therapy, which have resulted in a widely documented underuse. These problems include a narrow therapeutic window, marked variability in pharmacokinetics, and contraindications. There are new promising approaches to stroke prevention in AF. One of these is combination antiplatelet therapy. In a large randomized trial, the combination of dipyridamole and aspirin has been shown to have additive benefits against stroke. The combination of clopidogrel and aspirin results in additive benefits against vascular events, with only a modest increase in bleeding. A trial of combined antiplatelet therapy in AF is warranted. Occlusion of the left atrial appendage, either with a transvenous device or with surgery, is another strategy that is being explored. A direct thrombin inhibitor, ximelagatran, has been shown to have an excellent pharmacokinetic profile and is being developed as an oral agent for stroke prevention in AF, and it will not need regular monitoring. (Am Heart J 2003;145:418-23.)     

Antiplatelet therapy in prevention of cardio- and venous thromboembolic events

The contribution of platelets in the pathophysiology of low-shear thrombosis—specifically, in atrial fibrillation (AF) and venous thromboembolic events (VTE)—remains less clear than for arterial thrombosis. AF itself appears to lead to platelet activation, offering a potential target for aspirin and other antiplatelet agents. Randomized trial results suggest a small benefit of aspirin over placebo, and of dual antiplatelet therapy (aspirin plus clopidogrel) over aspirin alone, for prevention of cardioembolic events in AF. Antiplatelet therapy thus can represent an option for patients with AF who are unsuitable for therapy with warfarin or novel oral anticoagulant agents. For VTE, the rationale for antiplatelet therapy reflects the venous response to disrupted blood flow—interactions among monocytes, neutrophil extracellular traps, and platelets. Early randomized trials generally showed poorer performance of aspirin relative to heparins and danaparoid sodium in prevention of VTE. However, results from large placebo- and dalteparin-controlled randomized trials have spurred changes in the most recent practice guidelines—aspirin is now recommended after major orthopedic surgery for patients who cannot receive other antithrombotic therapies.     

Drug insight: cyclo-oxygenase 2 inhibitors and cardiovascular risk--where are we now?

Cyclo-oxygenase (COX) 1 mediates the production of thromboxane A2 in platelets, leading to platelet aggregation and vasoconstriction. Conversely, COX2 catalyzes endothelial prostacyclin synthesis, which effectively counteracts thromboxane A2, triggering vasodilation and platelet inhibition. Selective COX2 inhibitors decrease prostacyclin production, potentially disrupting homeostasis and creating a prothrombotic state. The VIGOR study findings of increased cardiovascular risk with rofecoxib were subsequently confirmed by large meta-analyses, observational studies and recent APPROVe trial publication. The APC trial findings of increased cardiovascular risk with Celebrex (celecoxib) conflict with those in the ADAPT trial, the upcoming PreSAP publication, a case-control study by Graham et al. and prior large clinical trials, meta-analyses and observational studies of this drug. Therefore, while an adverse class effect is a possibility for COX2 inhibitors, the published data are inconsistent. Baseline cardiovascular risk in patients might contribute significantly to these findings. In light of the negative Vioxx (rofecoxib) publicity, however, COX2 inhibitors might forever remain underinvestigated. The relative selectivity of these compounds for COX2 is extremely variable, casting significant doubt on the class-effect hypothesis. Improved endothelial function has also been reported with celecoxib, leading to endothelium-dependent vasodilation, and associated decreases in C-reactive protein and LDL cholesterol. The addition of meloxicam to low-dose aspirin and heparin has improved clinical outcomes after acute coronary syndromes. These are the first studies suggesting improvement in endothelial function and reduction of inflammation with COX2 inhibition. Thus, more randomized controlled trials are needed to study the relative cardiovascular effects of different COX2 inhibitors, alone and in combination with aspirin.     

Antithrombotic treatment and the incidence of angina pectoris

BACKGROUND: In primary prevention, anticoagulation with warfarin sodium to an international normalized ratio of 1.5 and 75 mg of aspirin per day each reduced the incidence of coronary heart disease (CHD). Effects on the development of angina pectoris and total CHD (resulting from angina, myocardial infarction, and coronary death) have been assessed, particularly in light of recent evidence that warfarin may have a "durable effect" on CHD through effects on the pathologic condition of the vessel walls involved. METHODS: The Thrombosis Prevention Trial was carried out in 5499 men aged 45 through 69 years who were at increased risk of CHD. The trial was factorial, with 1 group taking active warfarin and active aspirin, 1 taking active warfarin and placebo aspirin, 1 taking placebo warfarin and active aspirin, and 1 taking double placebo treatment. In addition to those with myocardial infarction and coronary death, men developing angina pectoris after entry to the trial were identified. RESULTS: Warfarin appeared to reduce the incidence of stable angina by 16% (95% confidence interval [CI], -14 to 38), although not significantly (P =.26), while aspirin increased the incidence by 39% (95% CI, 0 to 91) (P =.05). The incidence of stable angina was 37% (95% CI, -1 to 60) less in those taking warfarin than in those taking aspirin (P =.05). Warfarin reduced total CHD by 18% (95% CI, 4 to 30) (P =.01), while the reduction due to aspirin was 8% (95% CI, -10 to 22) (P =.36). CONCLUSIONS: The results are compatible with the concept of a durable effect of warfarin on the chronic pathologic conditions underlying angina, although this has not been established with certainty. Further research is needed to confirm or refute our findings, because they carry potentially important implications for the primary prevention of CHD with the use of antithrombotic agents.     

What's new in stroke? The top 10 studies of 2009-2011: part II

Five studies published between 2009 and 2011 are reviewed that importantly inform stroke prevention for patients with atrial fibrillation (AF) or with cervical carotid artery stenosis. Two large, phase III randomized trials tested novel oral anticoagulants for stroke prevention in patients with AF: the direct thrombin inhibitor dabigatran 150 mg twice daily was superior to adjusted-dose warfarin (RE-LY trial) and the direct factor Xa inhibitor apixaban was far superior to aspirin in patients deemed unsuitable for warfarin (AVERROES trial). For both novel anticoagulants, major bleeding rates were similar to the comparator treatment. Clopidogrel plus aspirin was more efficacious than aspirin alone for prevention of stroke in patients with AF deemed unsuitable for warfarin, but major bleeding was significantly increased with dual antiplatelet therapy (ACTIVE A trial). Two large randomized trials (CREST, ICSS) provide the best available data on the short-term risks of carotid artery stenting vs. endarterectomy. In both trials, periprocedural stroke was more frequent with stenting than with endarterectomy, but the increased risk was largely confined to patients >70 years old. For younger patients, periprocedural risks were comparable with stenting or endarterectomy, but long-term outcomes are required to assess the relative merits of the two procedures.     

Prospective Comparison of Patient Characteristics and Outcome of Non-prior Aspirin Users versus Aspirin Users with Unstable Angina or Non-Q-Wave Myocardial Infarction Treated with Combination Antithrombotic Therapy

The objective of this study was to determine if aspirin users presenting with acute coronary syndromes are at higher risk for subsequent clinical events. In a trial evaluating combination antithrombotic therapy in resting angina or non-Q-wave myocardial infarction (MI), patients were prospectively dichotomized on admission into nonprior versus recent aspirin users. Then 105 nonprior users and 144 users were randomized to treatment with aspirin plus heparin/warfarin for 12 weeks. Recurrent myocardial ischemia occurring during the 12-week follow-up period was defined as recurrent angina (with electrocardiographic changes or prompting coronary revascularization), MI, or death. Prior aspirin users had a significantly higher incidence of previous MI, prior bypass grafting, beta-blocker use, or hypertension (p 0.003) and were more likely to present with unstable angina as opposed to non-Q-wave MI. (p 0.008). The cumulative probability of recurrent ischemic endpoints for nonprior versus recent users was 10% versus 21% at 14 days (log rank p = 0.03), and 19% versus 29%, at 12 weeks (p = 0.06). Using the Cox model, adjusting for variables significantly associated with outcome, aspirin use remained a significant predictor of 14-day outcome (p = 0.04) but not of 12-week outcome (p = 0.06). In conclusion, even after adjusting for significant differences in baseline variables, aspirin users presenting with rest angina or non-Q-infarction have a worse short-term prognosis in spite of maximal medical therapy.