May 15, 2011

Even Short-Term NSAID Use Risky in Cardiac Patients

Last week while perusing through Medscape News, I came across an outstanding article. It was not outstanding because of its brilliance, rather because of the implication of its content. I read with dismay the new observational data suggesting that in patients with prior MI, most NSAIDs even when taken for as little as 1 week, are associated with an increased risk for death and recurrent MI.

The findings of the study were reportedly published online on May 9 in Circulation journal. You may access the finding report here.

In summary, it reported that use of NSAIDs after a previous MI was associated with a 45% increased risk for death or recurrent MI in the first 7 days of treatment and a 55% increased risk if treatment continued to 3 months.

"We found that short-term treatment with most NSAIDs was associated with increased and instantaneous cardiovascular risk," first author Anne-Marie Schjerning Olsen, MB, from Copenhagen University in Hellerup, Denmark, told Medscape Medical News.

"Our results indicate that there is no apparent safe therapeutic window for NSAIDs in patients with prior MI and challenge the current recommendations of low-dose and short-term use of NSAIDs as being safe," she said.

These reports are quite troubling because a lot of patients fitting into the description are currently prescribed NSAIDs by their physicians.

Results 'Completely Consistent' With 2007 AHA Advisory

I was surprised to learn that in a previous 2007 scientific statement, the American Heart Association (AHA) advised clinicians about the risks of NSAID use among patients with known cardiovascular disease or those at risk for ischemic heart disease and provided a stepped-care approach for use of these agents in this patient population. I went in search of this stepped-care protocol, and have shared it below.

In the meantime, I note report by Medscape News about comments on the new study, of Elliott Antman, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and lead author of the 2007 advisory, who said, "Essentially, what this paper shows is that there is a gradient of risk among NSAIDs; some are associated with more risk than others; none appear to be completely safe, and the researchers could not identify a period that appeared to be safe, no matter how short."

"This is completely consistent with the advice that we put forward in 2007, which is to use the safest drug, in the lowest dose required to control musculoskeletal symptoms, for the shortest period of time," Dr. Antman told Medscape Medical News.

"We do have to be practical here," Dr. Antman said, "because despite very best efforts with physical therapy and nonpharmacologic treatments, there are individuals who have severe, debilitating arthritis, lupus, or rheumatoid arthritis and we do have to have a treatment plan for those patients." The AHA's stepped-care approach provides such a plan, Dr. Antman noted.

This last comment shows how practical and reasonable the medical community has to be about all this, and it also is the reason I became very keen to get myself acquainted with the AHA stepped-care approach for the use of NSAIDs in people with a history of MI. I have shared it below.

AHA stepped-care approach

Stepped care approach to management of musculoskeletal symptoms
Stepped care approach to management of musculoskeletal symptoms. In patients with known cardiovascular disease or who are at risk for ischemic heart disease, clinicians should use a stepped care approach to pharmacological therapy that focuses on agents with the lowest reported risk of cardiovascular events and then progress toward other agents with consideration of the risk/benefit balance at each step. Once the decision is made to prescribe an NSAID (below the horizontal line), additional considerations assume importance, as illustrated by the recommendations at the bottom left and right of the diagram. See text for further discussion. ASA indicates acetylsalicylic acid (aspirin); PPI, proton-pump inhibitor. Credit: AHA
Treatment Considerations.
Musculoskeletal symptoms should be categorized as those that result from tendonitis/bursitis, those that result from degenerative joint problems (eg, osteoarthritis), or those that result from inflammatory joint problems (eg, rheumatoid arthritis). Initial treatment should focus on nonpharmacological approaches (eg, physical therapy, heat/cold, orthotics).

For patients whose symptoms are not controlled by nonpharmacological approaches, pharmacological treatments should then be considered. When choosing any medication, both safety and efficacy should be considered. In general, the least risky medication should be tried first, with escalation only if the first medication is ineffective. In practice, this usually means starting with acetaminophen or aspirin at the lowest efficacious dose, especially for short-term needs. Despite the potential for abuse, a role remains for narcotic medications for short-term pain relief. It should be recognized that with the exception of aspirin, the “low-risk” medications mentioned above have not been subjected to randomized clinical trials to conclusively demonstrate their superior safety.

In patients who do not tolerate these simple interventions or who require long-term or high-dose therapy, the issues become more complex. Long-term or high-dose therapy with aspirin and other NSAIDs is associated with increased risk for GI bleeding. Occasionally, high-dose acetaminophen can result in hepatic toxicity, especially in patients who consume excess alcohol. When acetaminophen, aspirin, and perhaps even narcotic medications (for acute pain) are not effective, tolerated, or appropriate, it may be reasonable to consider an NSAID as the next step; however, this should be coupled with the realization that effective pain relief may come at the cost of a small but real increase in risk for cardiovascular or cerebrovascular complications (moving below the horizontal line in Figure above).

The scientific evidence to date indicates that important differences exist between these agents in terms of risk of major thrombotic events. Clinicians are cautioned against relying on meta-analyses that involve an incomplete set of trials, contain small numbers of events, and focus only on short-term follow-up when assessing the relative risks of various agents. Naproxen appears to be the preferred choice. Although the ADAPT study, which investigated prevention of development of Alzheimer’s disease with either naproxen or celecoxib compared with placebo, raised concerns about the safety of naproxen, the trial had major limitations. These include a very high rate of patients lost to follow-up (almost 10%), a large number of enrollees who did not receive their study medication, a lack of specified criteria for the cardiovascular events, and no central adjudication of the reported nonfatal events. The small number of reported cardiovascular deaths, myocardial infarctions, and strokes in the naproxen and placebo groups in ADAPT do not materially alter the relative risk and 95% CI for naproxen. As noted in Figure above, if symptoms are not adequately controlled by a nonselective NSAID, subsequent steps involve prescription of drugs with increasing degrees of COX-2–inhibitory activity, ultimately concluding with the COX-2–selective NSAIDs.

First Time-to-Event Analysis

Back to the Medscape News article. In a First Time-to-Event Analysis, Medscape News report that all NSAIDs, except naproxen, were associated with an increased risk for death or recurrent MI, with diclofenac having the highest risk (HR in the first week of treatment, 3.26; 95% CI, 2.57 - 3.86).

It quotes Dr. Olsen, "Particularly worrying was the fact that the widely used nonselective NSAID diclofenac was associated with early and higher cardiovascular risk than the selective COX-2 inhibitor rofecoxib, which was withdrawn from the market in 2004 due to its unfavorable cardiovascular risk profile. The accumulating evidence suggests that we must limit NSAID use to the absolute minimum in patients with established cardiovascular disease.

"If NSAID therapy is necessary for patients with known cardiovascular disease, the doctors should choose a more selective COX-1 inhibitor in minimum dose (eg, naproxen ≤ 500 mg daily or ibuprofen ≤ 1200 mg daily) for the shortest period of time," she added.

Dr. Antman said this paper provides a "good reminder" for clinicians and patients about the risks of NSAIDs in this patient population.

"Many of the drugs that we are talking about," he noted, "can be obtained over-the-counter, and it is the presumption of many patients that if it is a drug that they can get over-the-counter it must be 'safer.' Very often they don't report those medications to their physician when they go for an office visit."

Source:
The above article is reproduced from material entitled 'Even Short-Term NSAID Use Risky in Cardiac Patients' by Medscape Medical News. Retrieved 15.05.2011 from here. And also from material entitled 'Use of Nonsteroidal Antiinflammatory Drugs' by American Heart Association. Retrieved 15.05.2011 from here. Note: Materials may be edited for content and length.

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