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Insufficient platelet function suppression by aspirin is a predictor of cardiovascular events in high-risk patients. The authors assessed the impact of obesity on platelet responsiveness before and after 2 weeks of aspirin 81 mg/d in 2014 people. Obese individuals had greater baseline platelet reactivity. Comparing obese and nonobese individuals after aspirin therapy, results for aggregometry to collagen were 6.7 vs 6.1 ohms, P=.008; aggregometry to adenosine diphosphate were 13.1 vs 11.8 ohms,P<.0001; aggregometry to arachidonic acid (AA) were 4.9% vs 8.3% nonzero aggregation, P=.002; urinary excretion of 11-dehydro-thromboxane B2 (Tx-M) were 4.9% vs 8.3% nonzero aggregation, P=.002; and aspirin resistance were 26.% vs 20.5%, P=.002; respectively. These remained significantly different for AA aggregation and Tx-M excretion after adjustment for covariates. Obese individuals have greater native platelet reactivity and retain greater reactivity after suppression by aspirin.
Prev Cardiol. 2010;13:56–62.©2009 Wiley Periodicals, Inc.
Most studies demonstrate a notable increase in cardiovascular risk in obese individuals,1 although the extent to which this is entirely independent of other risk factors remains unclear.2 Traditional coronary artery disease (CAD) risk factors, including hyperglycemia, hypertension, dyslipidemia, and impaired fasting glucose, all cluster strongly in obese adults.3 In addition, obesity appears to be associated with a prothrombotic state that may also enhance the susceptibility of obese people to acute cardiovascular disease events.4,5
Based on compelling evidence supporting a cardioprotective effect in persons at increased risk for a first CAD event, the United States Preventive Services Task Force currently recommends low-dose aspirin (at least 75 mg/d) for people with a projected CAD risk of ≥3% over the next 5 years.6 This recommendation is particularly relevant for individuals with clustered CAD risk factors, such as those with obesity and a strong family history of premature CAD.7
Aspirin exerts its protective effect by inhibiting platelet cyclooxygenase-1 (COX-1) and its production of thromboxane, a potent platelet activator.8 However, marked variability in aspirin’s suppressive effect on platelet function is reported for asymptomatic individuals9,10 and those with overt CAD.11,12 Furthermore, lesser suppression of collagen aggregation,4 adenosine diphosphate (ADP) and arachidonic acid (AA) aggregation,13 and urinary excretion of 11-dehydro-thromboxane B2 (Tx-M)14 is associated with increased risk of myocardial infarction, stroke, and cardiovascular death in patients with CAD.
Aspirin is commonly used in obese patients for primary and secondary cardiovascular protection, but the impact of obesity on platelet function and response to aspirin is poorly characterized. The purpose of this study was to characterize platelet responsiveness to low-dose aspirin in a large population of obese and nonobese men and women with a strong family history of premature CAD, a population at sufficiently increased risk to warrant aggressive primary prevention.15
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No large population-based studies to date have characterized the putative independent impact of obesity on in vivo and ex vivo platelet responsiveness to aspirin. In this study of low-dose aspirin in unaffected individuals from families with premature CAD, obese individuals had greater baseline platelet function than nonobese individuals in pathways directly and indirectly related to COX-1. After aspirin, residual platelet function remained greater for obese individuals both in vivo and ex vivo, and the association between obesity and platelet reactivity remained significant for direct COX-1 measures after adjusting for demographic and clinical covariates. Importantly, obese persons showed the same or even greater change in collagen-induced aggregation and Tx-M, respectively, with only a modest increment in ADP aggregation. This suggests that obese persons obtained a similar effect with low-dose aspirin, but it was not sufficient to overcome their higher levels of native platelet activation.
The finding that platelets from obese individuals were more reactive both at baseline and after aspirin suggests an innate hyperaggregable state in obesity that has been suggested in prior smaller studies.24–26 Although the absolute differences in platelet function between groups were generally small, they were consistent ex vivo and in vivo and across all platelet activation pathways. Furthermore, the differences between obese and nonobese individuals were sufficiently large to detect a significant difference in the proportion of individuals who met published aspirin resistance Tx-M criteria associated with clinical aspirin failure.14
Our results are consistent with those of a much smaller study involving 21 participants in which obese individuals had less suppression of platelet aggregation to AA and ADP after aspirin exposure.25 Two other smaller studies, one in patients with CAD26 and one in normal volunteers,24 demonstrated an association between participants’ weight and residual platelet function in response to enteric-coated low-dose aspirin. The authors suggested that reduced bioavailability from enteric coating may have mitigated aspirin’s suppressive effect and that this effect could lead to underdosing of obese individuals. In contrast, our findings using 81 mg/d of regular aspirin suggest that there is a threshold at the level of obesity after which platelet reactivity is higher both at baseline and after aspirin. Thus, the use of enteric-coated aspirin in the prior study cannot fully explain the differences in platelet function between obese and nonobese individuals.
Another potential explanation of post–aspirin-increased residual platelet function in obese individuals can be larger volume of distribution. However, although the design was not optimal and the sample size considerably smaller, we noted that the administration of a larger aspirin dose did not result in any further decrease in platelet function, which one would expect if the volume of distribution was the primary problem. The smaller subsample results highlight the fact that increasing the aspirin dosage above 81 mg/d to the maximal daily dose usually used clinically does not result in any further suppression of platelet function.
Previous work examining the relationship between obesity and platelet function has demonstrated higher levels of urinary Tx-M in obese women. After an average short-term weight loss of 15.3 kg, obese women had significantly lower levels of Tx-M.27 Thus, weight reduction may potentially be an effective nonpharmacologic strategy to decrease aspirin resistance in obese individuals.
Insufficient suppression of platelet function by aspirin is associated with increased future risk of myocardial infarction, stroke, and cardiovascular death in patients with atherosclerosis.12–14 Lesser suppression of in vivo platelet function is also associated with higher predicted risk of future CAD events in asymptomatic individuals. Our finding of lesser suppression of platelet function by aspirin in obese persons suggests that these individuals may receive decreased cardioprotection from low-dose aspirin. Further study is required to determine the clinical consequence of reduced platelet suppression by aspirin in patients with obesity and whether higher doses of aspirin are required in these individuals to achieve equivalent platelet suppression and/or cardioprotection than in nonobese people.
The biological mechanism for the obesity-related platelet function differences observed remains unresolved. Fibrinogen levels and all traditional known CAD risk factors are often more common in obese individuals,5 but they did not explain platelet function differences observed. Leptin is a protein hormone that regulates dietary energy intake and energy expenditure, influencing appetite and the metabolic substrate for obesity. The elevations of leptin observed in obese people are proatherogenic and have been shown to be associated with endothelial dysfunction, vascular smooth muscle cell proliferation, increased oxidative stress, and inflammation, all mechanisms involved in atherosclerotic vascular disease.28 Leptin receptors exist on human platelets,29 and in obese mice, increased leptin has been proposed as a mechanism responsible for a propensity to prothrombosis.30 Future studies will help to determine whether leptin enhances baseline platelet reactivity and diminishes aspirin responsiveness in obese individuals.
It should be noted that the highly potent impact of aspirin on platelet function, even among individuals who retain some residual platelet function post-aspirin, obviates the necessity for a control group. The COX-1 pathway is virtually totally suppressed in everyone, so that it is eminently possible to determine that aspirin has been taken. This is one of the few trial paradigms where there would be no benefit of a placebo-controlled study.