Source: tuberose.com

"Our study emphasizes the importance of examining even the drugs we've been using for a long time, because they may not be as safe as we've assumed," lead author Dr Andrew Chan (Massachusetts General Hospital and Harvard Medical School, Boston, MA) told heartwire. "People are taking these products more often and for longer periods of time, and this is not something that should be undertaken lightly."

Dr Andrew Chan (Source: Massachusetts General Hospital)

The researchers point out that NSAIDs inhibit antithrombotic prostacyclins in much the same way as COX-2 selective inhibitors. Although nonselective NSAIDs also inhibit COX-1, which synthesizes the prothrombotic thromboxane A₂, the relative balance between COX-1 and COX-2 activity is critical for vascular homeostasis. They suggest that all NSAIDs may in fact shift the equilibrium toward thrombosis and vasoconstriction.

In the present analysis, Chan and his team examined the influence of NSAIDs and acetaminophen on the risk of major cardiovascular events, which they characterize as nonfatal myocardial infarction, fatal coronary heart disease, and stroke. They studied more than 70 900 women enrolled in the Nurses' Health Study who were free of known cardiovascular disease or cancer.

The women, aged 44 to 69, provided medication data biennially from 1990. During 12 years of follow-up, the investigators confirmed 2041 major cardiovascular events. After adjusting for risk factors, they found that women who frequently used NSAIDs had a relative risk for a cardiovascular event of 1.44 (95% CI 1.27-1.65) compared with nonusers.

Our study emphasizes the importance of examining even the drugs we've been using for a long time because they may not be as safe as we've assumed.

The women who frequently used acetaminophen had a relative risk for a cardiovascular event of 1.35 (95% CI 1.14-1.59). "Moreover," the researchers write, "we observed significant dose-response relations." Compared with nonusers, the relative risk for a cardiovascular event among women who used 15 or more tablets per week was 1.86 (95% CI 1.27-2.73) for NSAIDs and 1.68 (95% CI, 1.10-2.58) for acetaminophen.

The researchers also found that the elevated risk associated with frequent NSAID use was particularly evident among current smokers (relative risk 1.82, 95% CI 1.38-2.42) and was absent among never smokers.

The investigators found that women taking NSAIDs or acetaminophen only occasionally—roughly 1 to 21 days per month—did not experience a significant increase in the risk of cardiovascular events. During an interview with heartwire, Chan noted that infrequent casual analgesic use did not appear to pose a danger, but he said that patients using over-the-counter pain relievers on a more regular basis should consult a doctor.

He points to a number of strengths and limitations to the present study. His group looked at a large number of patients and followed them for a long period of time. But, he notes, the study is observational and analgesic use was self-selected.

"Despite the strong biological plausibility of our results," the researchers write, "it is possible that our findings could be related to the reason for which participants used NSAIDs or acetaminophen." But, they add, high doses of these agents, including aspirin, were primarily used for analgesia and did not appear to increase the risk of cardiovascular events among high-frequency aspirin users.

At this point, our understanding of the cardiovascular risks associated with analgesics is still fairly crude.

The investigators note that although they cannot completely exclude residual confounding by factors associated with frequent analgesic intake, their findings remained significant even after they carefully controlled for known cardiovascular risk indicators as well as common reasons for chronic analgesic use.

"At this point, our understanding of the cardiovascular risks associated with analgesics is still fairly crude," Chan said. "Moving forward, we will need more clarification on who the specific at-risk patient populations might be or what risk factors need to be taken into account."

Chan says he hopes this study will trigger enough questions in people's minds to help spur future research. "It is important that we continue to add to the body of literature and raise people's awareness."