Friday, May 13, 2011

NSAIDs Deadly for Heart Attack Survivors?

NSAIDs When heart attack survivors or those with heart disease take nonsteroidal anti-inflammatory drugs, or NSAIDs, it puts them at higher risk for recurring heart attack or death, according to a new study in Circulation, a journal of the American Heart Association. Results of the new research suggest that even short-term use of these pain relievers is unsafe for these patients with pain.

The research team in Denmark observed that, despite the fact that certain NSAIDs are contraindicated in patients with established cardiovascular disease, many still receive these analgesics for short periods of time [Olsen et al. 2011]. And, this may be especially so in countries like the United States where many NSAIDs are available without prescription. Therefore, the researchers conducted a large-scale study to assess the duration of NSAID treatment and cardiovascular mortality risks in a nationwide cohort of patients with prior myocardial infarction (MI, or heart attack).

Subjects included all patients >30 years of age who had a first-time MI during 1997 to 2006. Subsequent NSAID use was identified via nationwide registries of hospitalization and drug dispensing pharmacies in Denmark. Of the 83,677 patients included for analysis, 42.3% had received NSAIDs at some point following MI, and there were 35,257 deaths/recurrent MIs (29,234 were deaths) recorded in the entire study population during the 10-year follow-up period.

NSAID treatment overall was associated with a significantly increased risk of death/recurrent-MI at the beginning of treatment, and such risk persisted throughout the treatment course tracked for up to 14 weeks. The graph below shows composite death/re-MI incidence rates for the entire study population (red line) compared with all NSAIDs (black dots). The vertical bars represent 95% confidence intervals, none of which cross the red line and, therefore, are statistically significant increases at all time points. [Confidence intervals were discussed in a prior UPDATE here.]

NSAID Death Incidence

In total, hazard ratios indicated that use of NSAIDs in these patients was associated with a 45% increased risk of death and recurring heart attack within as little as one week of starting treatment and a 55% increased risk if the drugs were taken for about 3 months. The most commonly used NSAIDs — ibuprofen, diclofenac, and naproxen, and the selective COX-2 inhibitors celecoxib and rofecoxib — also were analyzed individually.

The nonspecific NSAID diclofenac was associated with the highest risk of death/re-MI; more than 3 times the risk compared with other agents during the first week of therapy, which persisted throughout the course of treatment. Rofecoxib was associated with an increased risk in the first week, whereas, celecoxib had an increased risk after 14 to 30 days. Ibuprofen showed an increased risk when used for >1 week, but its overall risk was less than the COX-2 inhibitors or diclofenac. Naproxen was not associated with a significantly increased risk of death or MI during the entire course of treatment; however, the authors caution that naproxen may significantly influence gastrointestinal bleeding that might adversely affect mortality in patients with prior MI.

The authors concluded that even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any amount of NSAID should be limited from a cardiovascular safety point of view.

COMMENTARY: In 2007, the American Heart Association recommended that practitioners prescribe NSAIDs at the lowest dose for the shortest period of time in persons with cardiovascular disease. Now, this study out of Denmark suggests that using NSAIDs even at those doses and short-term may be putting these patients at increased risk. In short, there appears to be no safe therapeutic window for NSAIDs — whether nonspecific or Cox-2-specific — in patients with prior MI.

In an ongoing series of Pain-Topics UPDATES [here] we have discussed various concerns about NSAID safety, including cardiovascular risks (eg, stroke, heart attack) [here]. This latest study confirms added risks following non-fatal MI. Across all studies, diclofenac and, secondarily, ibuprofen have been demonstrated to carry significant risks; whereas, naproxen has been relatively much safer. One of the medicines in the current study, rofecoxib (Vioxx®), was removed from the market in the U.S. because of increased risk of heart attack and stroke. The U.S. Food and Drug Administration also has issued warnings or expressed concerns about the health effects of other COX-2 inhibitor NSAIDs such as celecoxib (Celebrex®) and valdecoxib (Bextra®). For unknown reasons, simple aspirin is often omitted from studies of NSAID safety.

A significant failing of this Danish study is that daily dosing was roughly estimated to calculate number of days on NSAID therapy for each subject; however, specific doses were unknown and not a part of the analyses. Therefore, the presence of a dose-response relationship affecting risk could not be determined. Also, the data-mining approach used by the researchers lacked information about clinical parameters that might have been important, such as blood pressure, body mass index, smoking history, lipid levels, etc. Hence, unmeasured confounders might have been influences outcomes to some extent.

It must also be acknowledged that the incidence rates of death/re-MI in the studied population expressed as annual percentages were low, ranging roughly from 0.045% to 0.06% during the 14 week period investigated (data from graph above). In perspective, however, this is generally greater than rates of overdose fatalities even with high-dose opioid analgesic therapy, calculated in a recently reported study as 0.04% [see UPDATE here]

Mortality Trends In a prior UPDATE [here], using compiled data and conservative estimates, we had developed a proportional comparison of annual mortality rates attributable to acetaminophen, opioids, and NSAIDs (see graph). Clearly, NSAID-related mortality might be of much greater concern than the other two classes of analgesics. And, while acetaminophen may have a lower death rate, it is the greatest cause of acute liver failure in the U.S. and a source of considerable, albeit often treatable, morbidity. Very recently, we noted in an UPDATE [here] that acetaminophen overdoses lead to more than 78,000 emergency department (ED) visits each year in America, and the majority (70%) are due to intentional self-harm attempts.

Simply put… all analgesics carry risks, and all are misused or abused in some fashion. Readily available and/or commonly prescribed NSAIDs and acetaminophen are far from being safe and in many respects are much more hazardous than opioids. It is a great irony that these potentially dangerous analgesics, from a patient health perspective, are so easily obtainable for the asking at any pharmacy or grocery store in the U.S., while more effective and relatively safer opioids are among the most regulated and restricted drugs in all of medicine.  What’s your opinion? Comment below.

REFERENCES: Olsen A-MS, Fosbøl EL, Lindhardsen J, et al. Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction A Nationwide Cohort Study. Circulation. 2011(May 9 online before print);123:2226-2235 [article PDF here].