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Resistance to Aspirin Increases Cardiovascular Event Risk

Posted: Thursday, February 07, 2008

Patients ostensibly resistant to aspirin face significantly increased rates of life-threatening cardiovascular events, a meta-analysis has found. 

Michael R. Buchanan, Ph.D., of McMaster University, reported that, myocardial infarction, strokes, and acute coronary syndrome occurred in 39% of patients with putative aspirin resistance, versus 16% of those who respond normally to aspirin-based antithrombotic therapy (OR: 3.85, 95% CI: 3.08 to 4.80, P<0.001).

Their meta-analysis of 20 studies, involving 2,930 clinical study participants who received aspirin, also found that ostensibly aspirin-resistant patients did not fare any better when another antiplatelet drug, clopidogrel (Plavix) was added. Similar odds ratios for any cardiovascular event were seen in pooled data from 13 studies involving aspirin alone and from six studies of clopidogrel.

The meta-analysis aimed to determine whether "aspirin resistance is real and is clinically relevant -- that is, it significantly affects the risk of cardiovascular, cerebrovascular, and vascular-related events."

The researchers concluded that their findings support the idea that aspirin resistance, however it is defined, is clinically meaningful. But they acknowledged the results won't settle the associated controversy over how to define or test for aspirin resistance.

Overall, 28% of participants in these studies were identified as aspirin-resistant. It was more prevalent in women (OR: 2.08, P=0.001) and in patients with previous renal impairment (OR: 2.44, P=0.03).

The meaning and importance of aspirin resistance has been debated in the past few years. Dr. Buchanan and colleagues noted that in several prior publications, "aspirin resistance" has been characterized as probably a misnomer, with little clinical significance.

The group reviewed all studies published since 1966 in which participants received aspirin as an antithrombotic and in which they were classified as resistant or sensitive to the drug. To be included, studies also had to have blinded investigators and measurements of clinical outcomes.

The researchers found that aspirin-resistant patients had heightened risk for individual types of cardiovascular events as well as for all events lumped together:

· Death (four studies, 728 patients): OR: 5.99 (95% CI: 2.28 to 15.72, P<0.003)
· Acute coronary syndrome (nine studies, 1,275 patients): OR: 4.06 (95% CI: 2.96 to 5.56, P<0.001)
· Bypass graft failure (three studies, 420 patients): OR: 4.35 (95% CI: 2.26 to 8.37, P<0.001)
· New cerebral event (four studies, 340 patients): OR: 3.78 (95% CI: 1.25 to 11.41, P<0.02)

In most of the studies, aspirin compliance was monitored -- an important point, because one criticism of the concept of aspirin resistance has been that patients so identified may simply be noncompliant.

The analysis also found that aspirin doses seemed not to matter significantly, as there were similar cardiovascular risks in participants receiving 75 to 100 mg/day and in those on more than 100 mg up to 1,500 mg/day.

Dr. Buchanan and colleagues noted that the 20 studies used seven different assays to measure aspirin resistance, each targeting different aspects of platelet function.

"We were unable to determine which platelet function test best identifies aspirin-resistant patients," Dr. Buchanan and colleagues wrote. They suggested that "aspirin nonresponsiveness" may be a better term until the underlying mechanisms are more fully understood.

In an accompanying editorial, Giuseppe Biondi-Zoccai, M.D., of the University of Turin, and Marzia Lotrionte, M.D., of Catholic University in Rome, said doubt still remained as to whether the phenomenon is really a distinct condition. "We don't know whether aspirin resistance is a true abnormal response or whether it reflects normal variability in drug activity," they wrote. "We also aren't clear whether aspirin resistance has a negative prognostic effect independent of more traditional risk factors, such as diabetes or obesity."

They said some answers may be forthcoming from a randomized trial called TREND-AR, in which a regimen including clopidogrel, aspirin, and heparin will be compared to the same regimen plus the newer antiplatelet drug tirofiban. "This trial, among others, will show whether aspirin resistance is just a non-modifiable risk factor (like age or sex) or whether more aggressive antithrombotic regimens are beneficial in patients with aspirin resistance," Drs. Biondi-Zoccai and Lotrionte wrote.

Practice Pearl: Explain that the study found nearly a fourfold increase in risk of cardiovascular events among people identified as having aspirin resistance. 

Source: Diabetes In Control: Krasopoulos G, et al "Aspirin 'resistance' and risk of cardiovascular morbidity: systematic review and meta-analysis" BMJ 2008; DOI: 10.1136/bmj.39430.529549.BE. Additional source: BMJ, Biondi-Zoccai G, Lotrionte M, "Aspirin resistance in cardiovascular disease" BMJ 2008; DOI: 10.1136/bmj.39430.529549.BE.

 
 
 
 
 
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