Aspirin dose for prevention of cardiovascular disease in diabetics

OBJECTIVE: To determine whether a specific dose of aspirin can be recommended for prevention of cardiovascular disease in patients with diabetes. DATA SOURCE: Biomedical literature was accessed through MEDLINE (1990-February 2002). Key terms included diabetes, cardiovascular protection, and aspirin. DATA SYNTHESIS: Pharmacologic and clinical studies focusing on the dose-response relationship of aspirin therapy were reviewed. Evidence supports the benefit of low-dose aspirin therapy in reducing vascular events in secondary and primary prevention trials in various patient populations; however, some studies suggest larger doses of aspirin may be needed in certain patients. CONCLUSIONS: Review of the evidence does not support a particular dose of aspirin for cardiovascular protection in diabetic patients. Clinical guidelines recommend aspirin therapy in the range of 81-325 mg/d. However, due to an increased prevalence of cardiovascular morbidity and disturbances in coagulation in diabetic patients, the dose of aspirin for prevention of cardiovascular disease in these individuals may be different from that in other populations and requires further evaluation.     

Clinical implications of aspirin resistance

Aspirin (acetylsalicylic acid) is one of the main therapeutic medications used in the prevention of thromboembolic vascular events. Aspirin exhibits its antiplatelet action by irreversibly inhibiting platelet cyclooxygenase-1 enzyme, thus preventing the production of thromboxane A2 (TXA2). Aspirin resistance, as measured in vitro, is the inability of aspirin to reduce platelet activation and aggregation by failure to suppress the platelet production of TXA2. Laboratory tests of platelet TXA2 production or platelet function dependent on TXA2 can detect aspirin resistance in vitro. The clinical implication of this laboratory definition has not yet been elucidated via prospective trials that have controlled for confounders, such as hypertension, diabetes and dyslipidemia. Large meta-analyses have found low-dose aspirin to be as effective as high-dose aspirin in preventing vascular events, making a dose-dependent improvement in laboratory response clinically irrelevant. Possible causes of aspirin resistance include poor compliance, inadequate dose, drug interactions, genetic polymorphisms of cyclooxygenase-1, increased platelet turnover and upregulation of non-platelet pathways of thromboxane production. However, there is currently no standardized approach to the diagnosis and no proven effective treatment for aspirin resistance. Further research exploring the mechanisms of aspirin resistance is needed in order to better define aspirin resistance, as well as to develop a standardized laboratory test that is specific and reliable, and can correlate with the clinical risk of vascular events. The intent of this paper is to review the literature discussing possible mechanisms, diagnostic testing and clinical trials of aspirin resistance and to discuss its clinical relevance as it pertains to cerebrovascular and cardiovascular disease.     

Clinical implications of aspirin resistance

Aspirin (acetylsalicylic acid) is one of the main therapeutic medications used in the prevention of thromboembolic vascular events. Aspirin exhibits its antiplatelet action by irreversibly inhibiting platelet cyclooxygenase-1 enzyme, thus preventing the production of thromboxane A₂ (TXA₂). Aspirin resistance, as measured in vitro, is the inability of aspirin to reduce platelet activation and aggregation by failure to suppress the platelet production of TXA₂. Laboratory tests of platelet TXA₂ production or platelet function dependent on TXA₂can detect aspirin resistance in vitro. The clinical implication of this laboratory definition has not yet been elucidated via prospective trials that have controlled for confounders, such as hypertension, diabetes and dyslipidemia. Large meta-analyses have found low-dose aspirin to be as effective as high-dose aspirin in preventing vascular events, making a dose-dependent improvement in laboratory response clinically irrelevant. Possible causes of aspirin resistance include poor compliance, inadequate dose, drug interactions, genetic polymorphisms of cyclooxygenase-1, increased platelet turnover and upregulation of nonplatelet pathways of thromboxane production. However, there is currently no standardized approach to the diagnosis and no proven effective treatment for aspirin resistance. Further research exploring the mechanisms of aspirin resistance is needed in order to better define aspirin resistance, as well as to develop a standardized laboratory test that is specific and reliable, and can correlate with the clinical risk of vascular events. The intent of this paper is to review the literature discussing possible mechanisms, diagnostic testing and clinical trials of aspirin resistance and to discuss its clinical relevance as it pertains to cerebrovascular and cardiovascular disease.     

Combined aspirin/ACE inhibitor treatment for CHF

OBJECTIVE: To review the literature evaluating the interaction between angiotensin-converting enzyme (ACE) inhibitors and aspirin in patients with congestive heart failure (CHF). DATA SOURCES: A literature search through MEDLINE (1966-March 2001) and EMBASE (1966-March 2001) identified randomized, double-blind, controlled trials evaluating the use of ACE inhibitors and aspirin in patients with CHF. DATA SYNTHESIS: No prospective study has evaluated the effects of aspirin and ACE inhibitors on clinical outcomes of patients with CHF. All have been short-term studies evaluating the effects on hemodynamic parameters only. CONCLUSIONS: While the potential for an interaction between ACE inhibitors and aspirin exists, the results from ongoing prospective trials will help determine the efficacy of using both agents in patients with CHF.     

Aspirin for the prevention of vascular death in women.

OBJECTIVE: To review current information relevant to the use of aspirin for preventing vascular death in women, and to provide recommendations based on this information. DATA SOURCES: References from pertinent articles are identified throughout the text. DATA SYNTHESIS: Based on current information, low-dose aspirin is not recommended as primary prevention for cardiovascular death in women; efforts are better focused at promoting risk-factor reduction. Low-dose aspirin is recommended for reducing further cardiovascular morbidity and mortality in women with known cardiovascular disease. Women presenting with unstable angina or myocardial infarction should receive aspirin 325 mg as soon as the diagnosis is confirmed, and this dosage should be continued on a chronic basis. Women who have experienced transient ischemic attacks or ischemic stroke should receive aspirin 1000 mg/d, with a subsequent dosage reduction to 325 mg/d in patients who do not tolerate the higher dose. CONCLUSIONS: Current recommendations are based on the results of studies that involved few women. Further investigation of antiplatelet agents for primary and secondary prevention of vascular death in women is needed.     

Safety of COX-2 inhibitors in asthma patients with aspirin hypersensitivity

OBJECTIVE: To review the safety of cyclooxygenase-2 (COX-2) inhibitors in asthma patients with aspirin hypersensitivity. DATA SOURCES: Clinical studies were identified using MEDLINE (1966-September 2002). Key search terms included cyclooxygenase inhibitors, aspirin, asthma, and hypersensitivity. English-language articles were identified and included. References from the identified articles were also reviewed. DATA SYNTHESIS: The literature provides information regarding the safety of COX-2 inhibitors in asthma patients with aspirin-exacerbated respiratory disease (AERD). The mechanism of AERD involves inhibition of cyclooxygenase, particularly COX-1. Inhibition of COX-1 causes an increased production of certain inflammatory mediators, which results in the reactions seen with AERD. Considering this mechanism, COX-2 inhibitors may be an alternative to aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) in a patient with AERD. This article analyzes 4 studies to evaluate the safety of COX-2 inhibitors in this population. RESULTS: The 4 studies evaluated included a total of 172 patients with AERD. All patients included demonstrated intolerance to aspirin or NSAIDs and tolerated the selective COX-2 inhibitor administered. CONCLUSIONS: COX-2 inhibitors provide a potentially safe alternative for treatment of inflammatory conditions in patients with AERD.     

A contemporary viewpoint on ‘aspirin resistance’

Abstract

Aspirin is an irreversible inhibitor of platelet prostaglandin synthase activity, and is the most widely prescribed drug for the secondary prevention of cardiovascular disease. In recent years, clinical and laboratory evidence has shown significant individual variability in the response to aspirin and its link to clinical outcome. The term ‘aspirin resistance’ has been introduced to describe situations when clinical or ex-vivo effects of aspirin are less than expected. The accumulating evidence of increased risk of major adverse clinical events (MACE) associated with ‘aspirin resistance’ in the settings of acute coronary syndrome (ACS), stroke, and peripheral arterial disease has stimulated the search for ways of overcoming aspirin resistance. Existence of the link between high on-treatment platelet reactivity and atherothrombotic events suggests the common mechanisms for atherosclerosis progression and thrombotic complications with the platelets, being a key cellular interface between coagulation and inflammation.

This review article provides a contemporary view on ‘aspirin resistance’ and discusses its definition, clinical importance, and possible mechanisms in light of recent data on the role of platelets in atherothrombosis.     

Aggrenox: a fixed-dose combination of aspirin and dipyridamole

OBJECTIVE: To describe the pharmacology, pharmacokinetics, efficacy, and safety of a fixed-dose combination of aspirin and extended-release (ER) dipyridamole indicated for the secondary prevention of stroke. DATA SOURCES: Published articles and abstracts were identified from a MEDLINE search (1966-December 1999) using the search terms dipyridamole, aspirin, antiplatelet, antiaggregation, and stroke prevention. Pertinent articles written in English were considered for review. Additional articles were identified from the references of retrieved literature. STUDY SELECTION AND DATA EXTRACTION: Studies including a combination of aspirin/dipyridamole in human subjects were evaluated. Emphasis was placed on randomized, controlled trials. DATA SYNTHESIS: Aspirin is a platelet inhibitor that works by inhibiting platelet cyclooxygenase, which reduces the production of thromboxane A2. Dipyridamole is a platelet inhibitor that is thought to work in part by inhibiting platelet cyclic-3',5'-adenosine monophosphate and cyclic-3',5'-guanosine monophosphate phosphodiesterase. The active metabolite of aspirin, salicylic acid, is highly bound to plasma protein and has a plasma half-life of two to three hours. Dipyridamole is also highly bound to plasma proteins, and the ER formulation has a plasma half-life of 13 hours. The first European Stroke Prevention Study (ESPS-1) found the combination of aspirin/dipyridamole to be superior to placebo in the prevention of stroke and transient ischemic attack (TIA). The ESPS-1, however, did not include an aspirin-only treatment arm. Therefore, it was unclear whether the combination of aspirin/dipyridamole was superior to aspirin alone. As a result, a second trial was conducted that included treatment arms of aspirin alone, ER dipyridamole alone, combination therapy, and placebo. The combination of aspirin 25 mg plus ER dipyridamole 200 mg twice daily was shown in the ESPS-2 to be significantly better than either agent given individually in preventing stroke and TIAs (p < 0.001). CONCLUSIONS: The American College of Chest Physicians (ACCP) recommends aspirin 50-325 mg/d to be the initial antiplatelet of choice for the prevention of atherothrombotic cerebral ischemic events. However, with the favorable results of the ESPS-2, it may be appropriate to substitute aspirin/ER dipyridamole for aspirin alone as the drug of choice. This combination appears to have a favorable adverse effect profile. The relative effectiveness of aspirin/ER dipyridamole compared with clopidogrel and ticlopidine has yet to be determined. If alternative antiplatelet therapy is needed, the ACCP recommends clopidogrel rather than ticlopidine because of its lower incidence of adverse effects. The ACCP further states that the combination of aspirin plus dipyridamole may be more effective than clopidogrel; these agents have a similarly favorable adverse effect profile.     

Risk of gastric injury with enteric- versus nonenteric-coated aspirin

OBJECTIVE: To evaluate through clinical trials the risk of various aspirin preparations on the gastric mucosa. DATA SOURCES: Articles reporting clinical research were accessed through MEDLINE (1980-November 1998). Key search terms included enteric-coated aspirin, buffered aspirin, and gastrointestinal (GI) bleeding. DATA SYNTHESIS: Aspirin products are known to cause GI bleeding. Enteric-coated aspirin may provide an additional protective effect on gastric mucosa compared with buffered aspirin. An evaluation of studies comparing various aspirin preparations and the risk of gastric mucosal injury was conducted. CONCLUSIONS: For long-term use, enteric-coated aspirin may provide a safer alternative than buffered aspirin; however, further studies are necessary.     

Role of C-reactive protein in cardiovascular disease

OBJECTIVE: To discuss the role of C-reactive protein (CRP) in cardiovascular disease as a predictor of vascular events and identify key factors that increase or decrease this inflammatory marker. DATA SOURCES: Articles were identified through searches of MEDLINE (1966-July 2003), International Pharmaceutical Abstracts (1970-June 2003), and bibliographies of selected articles. Search terms included C-reactive protein, HMG-CoA reductase inhibitors, fenofibrate, niacin, aspirin, estrogen, thiazolidinediones, and raloxifene. data selection and data extraction: All studies relevant to CRP and cardiovascular disease or the effects of pharmacologic and nonpharmacologic interventions on CRP levels were evaluated. All information deemed relevant to this review was included. DATA SYNTHESIS: Numerous studies have shown a strong association between CRP levels and future vascular events (i.e., coronary, cerebrovascular, peripheral vascular disease), with minimal correlation to low-density-lipoprotein cholesterol. Clinical guidelines have recently been published indicating that CRP levels of <1, 1-3, and >3 mg/L correspond to low, moderate, and high risk, respectively, for future vascular events. Drugs including statins, fibrates, niacin, thiazolidinediones, and antiplatelet agents, as well as weight loss and exercise, have demonstrated efficacy in lowering CRP levels. CONCLUSIONS: CRP appears to be a valuable tool for predicting future vascular events in patients striving for primary or secondary prevention of cardiovascular disease. While several pharmacologic and nonpharmacologic interventions have been shown to lower CRP levels, the impact on clinical outcomes requires further study.     

Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial

Summary. Objective: We aimed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin. Methods: We performed a randomized, double‐blind, placebo‐controlled, crossover trial, comparing clopidogrel 75 mg day^?1 versus placebo, in 36 aspirin‐treated patients with symptomatic objectively confirmed peripheral arterial disease. Results: The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid, urinary 11 dehydro thromboxane B₂ concentrations, or soluble markers of platelet activation markers (P‐selectin, CD40‐ligand) and inflammation (high sensitivity serum C‐reactive protein, interleukin‐6). Clopidogrel significantly inhibited platelet aggregation induced by ADP (reduction 26.2%; 95% CI: 21.3–31.1%, P < 0.0001) and collagen (reduction 6.2%; 95% CI: 3.2–9.3%, P = 0.0003). The greatest inhibition of collagen‐induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [lower tertile of arachidonic acid‐induced platelet aggregation: 2.8% (95% CI: ?0.8 to 6.3%) reduction in mean collagen‐induced aggregation by clopidogrel; middle tertile: 4.0% (95% CI: 0.4–7.6%); upper tertile 12.6% (95% CI: 4.5–20.8%); P‐value for interaction 0.01]. Conclusions: The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid‐induced platelet aggregation by aspirin. This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin. Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor, thereby overcoming the problem of laboratory aspirin resistance.     

Pharmacogenomics in cardiovascular disease: focus on aspirin and ADP receptor antagonists

Antiplatelet agents like aspirin and adenosine diphosphate receptor antagonists are effective in reducing recurrent ischemic events. Considerable inter‐individual variability in the platelet inhibition obtained with these drugs has initiated a search for explanatory mechanisms and ways to improve treatment. In recent years, numerous genetic polymorphisms have been linked with reduced platelet inhibition and lack of clinical efficacy of antiplatelet drugs, particularly clopidogrel and aspirin. Consequently, attempts to adjust antiplatelet treatment according to genotype have been made, but the clinical benefit has been modest in studies performed so far. The progress in genome science over the last decade and the declining cost of sequencing technologies hold the promise of enabling genetically tailored antiplatelet therapy. However, more evidence is needed to clarify which polymorphisms may serve as targets to improve treatment. The present review outlines the panel of polymorphisms affecting the benefit of aspirin and adenosine diphosphate receptor antagonists, including novel and ongoing studies evaluating whether genotyping may be beneficial in tailoring antiplatelet therapy.     

Identifying determinants of variability to tailor aspirin therapy

Once-daily, low-dose aspirin is a cornerstone in the prophylaxis and treatment of cardiovascular diseases. Aspirin ‘resistance’ still lacks definition, a standardized reference assay, underlying mechanisms, clinical impact or efficacy of alternative antiplatelet drugs. Aspirin response in several studies has been measured by different platelet function tests, not always reflecting aspirin pharmacodynamics, thus generating significantly heterogeneous results. The EMA indicated serum thromboxane B₂ as the only valid surrogate assay to study different aspirin formulations. Rather than resistance, recent studies focused on sources of intra- and inter-individual variability in response to aspirin, based on pharmacokinetic and/or pharmacodynamic mechanisms. Drug interactions, diabetes, conditions of increased platelet output, obesity and aging can potentially increase the variability of aspirin response. Preliminary studies testing different aspirin regimens showed that twice-daily low doses were more effective than once-daily higher aspirin doses on surrogate end points of platelet inhibition. Large studies are needed to test new disease-tailored, low-dose aspirin regimens.     

Relationship between endothelial dysfunction, oxidant stress and aspirin resistance in patients with stable coronary heart disease

OBJECTIVE: Interindividual variability of platelet inhibition after aspirin administration has been described. Additionally, aspirin resistance occurs in some individuals, but the mechanism for aspirin resistance is still unknown. The aim of the present study was to examine the role of endothelial dysfunction in aspirin resistance. METHODS: The antiplatelet effect of aspirin was studied prospectively in 54 consecutive patients with stable coronary heart disease. Platelet aggregation rate was measured and aspirin resistance was defined by a relative inhibition of adenosine diphosphate (5 micromol/L)-induced platelet aggregation of >or=70%. Thrombomodulin (TM) and free tissue factor pathway inhibitor (TFPI) were measured as endothelial dysfunction markers. Erythrocyte superoxide dismutase activity, plasma level of vitamin C, vitamin E and lipoperoxide were measured to estimate the oxidative stress. RESULTS: Platelet aggregation was positively correlated with TM (r = 0.277, P < 0.05) and TFPI (r = 0.288, P < 0.05) respectively. The TFPI level in aspirin-resistant patients (119.5 +/- 13.5 ng/mL) was significantly higher than that in aspirin-sensitive patients (107.8 +/- 18.9 ng/mL; P < 0.05). There were no statistically significant differences on any indicator of oxidative stress between two groups. CONCLUSIONS: Endothelial dysfunction is one of the mechanisms for aspirin resistance, whereas oxidative stress may not involve in the process of aspirin resistance.     

Aspirin resistance: effect of clinical, biochemical and genetic factors

Aspirin is one of the cornerstones of treatment for cardiovascular disease. However, some patients may be 'resistant' to its effect: this is associated with adverse cardiovascular outcomes and increased mortality. Measuring response to aspirin is often difficult and there is no accepted definition of aspirin resistance. Many assays are available to test aspirin sensitivity but most are not specific to aspirin and the degree of agreement between different assays is poor. Each assay has its own advantages and disadvantages, and there is currently no one assay that can be recommended for routine clinical practise. There are also many potential modifiers of aspirin response including aspirin dose, non-compliance, disease severity, genetic factors, inflammation, diabetes mellitus, hyperlipidaemia, smoking and interacting drugs. Treating the underlying cause may improve aspirin sensitivity but current data are contradictory with no large clinical trials that have addressed this. Further work is required in this area to determine whether and how aspirin resistance is important clinically, what the best measurement is phenotypically and how this should be used in clinical practise, and whether there are any genetic predisposing factors. This will require well designed prospective studies which take into account the numerous confounding factors that can modify aspirin resistance.     

Celecoxib as adjunctive therapy for treatment of colorectal cancer

OBJECTIVE: To describe the role of celecoxib as adjunctive therapy in the treatment of familial adenomatous polyposis (FAP), an inherited autosomal dominant predisposition syndrome for colorectal cancer. DATA SOURCES: Literature was evaluated through MEDLINE search (1995-March 2000) and through secondary sources, using the search terms celecoxib, cyclooxygenase-2 inhibitors, and familial adenomatous polyps. DATA SYNTHESIS: Observational studies have found a decreased rate of colorectal cancer in people who regularly took aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs). The Food and Drug Administration granted accelerated approval in December 1999 for the NSAID celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, for adjunctive therapy in patients with FAP, based on a six-month, randomized, controlled clinical trial. CONCLUSIONS: Aspirin and other NSAIDs reduce the incidence of colorectal cancer in the general population. Limited clinical studies in patients with FAP using nonaspirin NSAIDs have shown a reduction in polyp burden. A current clinical trial using celecoxib has also shown a reduction in polyp burden in patients with FAP. The long-term clinical impact of using a selective COX-2 inhibitor is not known, since celecoxib has not been studied beyond six months in patients with FAP. By reducing the polyp burden in FAP patients, celecoxib may be useful as adjunctive chemotherapy, in addition to routine endoscopic surveillance and surgery.     

Effect of glucosamine on glucose control

OBJECTIVE: To review the literature regarding the effect of glucosamine on glucose control. DATA SOURCES: English-language articles on the effects of administration of exogenous glucosamine on glucose control were identified through a search of MEDLINE (1966-March 2006), EMBASE (1988-March 2006), and International Pharmaceutical Abstracts (1970-March 2006) databases using the search terms glucosamine, blood glucose, and diabetes mellitus. Abstracts of articles were then reviewed to determine relevance to the topic. Bibliographies of selected articles were screened for other pertinent references. DATA SYNTHESIS: Theoretically, glucosamine may alter glucose metabolism. Insulin resistance has been noted following intravenous administration of glucosamine in animal studies; however, these findings have not been confirmed in humans. Alterations in glucose control have not been documented in long-term efficacy studies using oral glucosamine for osteoarthritis or in trials of short duration conducted in healthy or diabetic subjects. The long-term effects of glucosamine in patients with diabetes have yet to be established in well-controlled trials. CONCLUSIONS: Small, short-term studies suggest that glucosamine may be used in selected patients without affecting glucose control; however, data in patients with diabetes mellitus are limited, and close monitoring for potential changes in glucose control is recommended.     

Impact of nonsteroidal antiinflammatory drugs on the cardioprotective effects of aspirin

OBJECTIVE: To examine the evidence of a pharmacodynamic interaction between aspirin and nonsteroidal antiinflammatory drugs (NSAIDs); specifically, to determine whether a deleterious relationship exists with respect to the cardioprotective effects of aspirin. DATA SOURCES: Primary articles were identified by a MEDLINE search (1966-May 2004). Search terms included aspirin, nonsteroidal antiinflammatory drug, drug interaction, mortality, myocardial infarction, and stroke. STUDY SELECTION AND DATA EXTRACTION: All prospective and retrospective studies conducted in human subjects and investigating the potential interaction between aspirin and NSAIDs were included. DATA SYNTHESIS: Several controlled pharmacodynamic studies indicate that the sustained inhibition of cyclooxygenase activity by aspirin is blunted in the presence of some NSAIDs. While these data are fairly consistent, they are limited in that they rely on surrogate markers and not clinical outcomes. Observational studies have shown conflicting results regarding the effect of combination NSAID and aspirin therapy on mortality risk and incidence of myocardial infarction. CONCLUSIONS: Pharmacodynamic data indicating an interaction between aspirin and NSAIDs have not translated to a consistent clinical effect in observational studies. In the absence of a randomized, controlled, clinical outcomes study, there is insufficient evidence to dictate a change in therapy.     

Cyclooxygenase-1 haplotype modulates platelet response to aspirin

BACKGROUND: Aspirin (acetylsalicylic acid) irreversibly inhibits platelet cyclooxygenase (COX)-1, the enzyme that converts arachidonic acid (AA) to the potent platelet agonist thromboxane (TX) A2. Despite clear benefit from aspirin in patients with cardiovascular disease (CAD), evidence of heterogeneity in the way individuals respond has given rise to the concept of 'aspirin resistance.'AIMS: To evaluate the hypothesis that incomplete suppression of platelet COX as a consequence of variation in the COX-1 gene may affect aspirin response and thus contribute to aspirin resistance. PATIENTS AND METHODS: Aspirin response, determined by serum TXB2 levels and AA-induced platelet aggregation, was prospectively studied in patients (n = 144) with stable CAD taking aspirin (75-300 mg). Patients were genotyped for five single nucleotide polymorphisms in COX-1 [A-842G, C22T (R8W), G128A (Q41Q), C644A (G213G) and C714A (L237M)]. Haplotype frequencies and effect of haplotype on two platelet phenotypes were estimated by maximum likelihood. The four most common haplotypes were considered separately and less common haplotypes pooled. RESULTS: COX-1 haplotype was significantly associated with aspirin response determined by AA-induced platelet aggregation (P = 0.004; 4 d.f.). Serum TXB2 generation was also related to genotype (P = 0.02; 4 d.f.). CONCLUSION: Genetic variability in COX-1 appears to modulate both AA-induced platelet aggregation and thromboxane generation. Heterogeneity in the way patients respond to aspirin may in part reflect variation in COX-1 genotype.     

Dietary manipulation of platelet function

Activated platelets contribute to plaque formation within blood vessels in the early and late stages of atherogenesis, and therefore they have been proposed as risk factor for cardiovascular disease. Anti-platelet drugs, such as aspirin, are now the most prescribed pharmacological treatment in Europe. Certain dietary bioactives also beneficially affect platelet function, and with less side effects, albeit that effects are generally more subtle. Therefore, consumption of dietary bioactives could play a role in the prevention of atherothrombotic vascular disease. Here we review the efficacy of dietary treatment strategies, especially those involving certain dietary fatty acids and polyphenols, to modulate platelet function in healthy subjects or in patients with cardiovascular disease. Variation in study populations, small study sizes and lack of comparability between methods to assess platelet function currently limit robust evidence on the efficacy of dietary bioactives in healthy subjects or specific patient groups. Also, limited knowledge of the metabolism of dietary bioactives, and therefore of the bioavailability of bioactive ingredients, restricts our ability to identify the most effective dietary regimes to improve platelet function. Implementation of uniform point-of-care tests to assess platelet function, and enhanced knowledge of the efficacy by which specific dietary compounds and their metabolites affect platelet function, may enable the identification of functional anti-platelet ingredients that are eligible for a health claim, or combined treatment strategies, including both pharmacological anti-platelet treatment as well as dietary intervention, to tackle atherothrombotic vascular disease.