A large international study revealed that diclofenac-an anti-inflammatory agent found in scores of prescription and over-the-counter preparations such as Cataflam and Voltaren-raises the risk of cardiovascular 'events', including heart attack and stroke, by 40 per cent.
Vioxx, the arthritis drug pulled from the market in 2004 amidst evidence that it caused heart attacks, had only a slightly higher risk factor of 45 per cent. What's more, diclofenac can increase the risk of serious heart problems even at doses available without prescription (PLoS Med, 2011; 8: e1001098).
Both diclofenac and Vioxx (generically known as rofecoxib) belong to the non-steroidal anti-inflammatory drug, or NSAID, family-a group of drugs with analgesic, antipyretic (fever-reducing) and anti-inflammatory effects. Commonly used to treat back pain, arthritis and flu, NSAIDs are among the most widely used drugs around the world. In the UK, diclofenac was the most frequently prescribed NSAID last year, with almost six million prescriptions written for it-and this figure doesn't include those who bought the drug over the counter.
Such widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent. The main adverse drug reaction (ADR) associated with NSAIDs is related to its gastrointestinal effects, but there has been growing concern over their cardiovascular risks, too, a possibility first raised more than a decade ago (J Pharmacol Exp Ther, 1999; 289: 735-41). Since then, the risk of cardiovascular events during treatment with NSAIDs has become one of the most studied ADRs in history.
Reviewing the risks
The latest report, by Patricia McGettigan at the Hull York Medical School in Hull, UK, and David Henry at the Institute for Clinical Evaluative Sciences in Toronto, Canada, is a systematic review of the literature of controlled observational drug studies, involving more than 2.7 million people who were exposed to these drugs.
Unlike previous reviews, this one provides up-to-date cardio-vascular risk estimates for all of the currently available NSAIDs (as well as the recalled drug Vioxx) and directly compares the risk with each drug. The review also includes an analysis of the cardiovascular risk at low doses of the relevant drugs to approxi-mate the likely effects of over-the-counter use of NSAIDs.
The results revealed that, out of the most extensively studied drugs, Vioxx had the highest overall cardiovascular risk, but it was closely followed by diclofenac. Alarmingly, even low doses of diclofenac were associated with a 22-per-cent increased risk of having a cardiovascular event, a rate that rose as the doses increased.
In addition, ibuprofen, a popular over-the-counter painkiller, was associated with an 18-per-cent overall greater risk of heart attack or stroke, although further analyses showed that only the higher doses of the drug (in general, those above 1200 mg/ day), elevated the risk.
However, the researchers also noted that "the higher doses of ibuprofen (with higher risk) may be reached relatively easily, particularly with the 400-mg strength preparations that are available in some countries".
In fact, ibuprofen at doses above 1200 mg/day increased cardiovascular risk by a relative 78 per cent. In contrast, naproxen, also available over the counter, was associated with a 9-per-cent greater cardiovascular risk overall, with no change in risk at higher doses.
Among the less studied NSAIDs is etoricoxib, a newer type of drug known as a cyclo-oxygenase-2 (COX-2) inhibitor. This was associated with a two-fold greater risk of heart problems. Although the data for this drug are sparse, even its lower confidence limit (LCL)-in other words, how small the effect might plausibly be-exceeded that of the other drugs. Indeed, based on the LCL, etoricoxib increased the risk of having a cardiac event by 45 per cent-equivalent to the risk seen with the deadly Vioxx (rofecoxib), which was also a COX-2 inhibitor.
Interestingly, Vioxx manufacturer Merck Sharp & Dohme (MSD) also makes etoricoxib, which is marketed as Arcoxia and widely touted as Vioxx's successor. Although it's already been approved for use in some 70 countries worldwide, including the UK, the US Food and Drug Administration (FDA) has just issued MSD with a non-approval letter for Arcoxia, indicating that the company needs to provide additional data in support of the drug's risk-benefit profile if it wants to gain approval.
The FDA's concerns appear to be supported by the results of the present review, which show that the drug might be even more dangerous than the already discredited Vioxx.
The risks are real
Although the new analyses are based on observational studies rather than on randomized controlled trials, the authors of the review believe that the results are meaningful because "the large sizes of the studies reviewed here, the presence of consistent dose-response relationships, and general agreement with the results of randomised trials give us confidence in the results".
In addition, they said, "In our view, the results are sufficiently robust to inform clinical and regulatory decisions."
But what exactly are the implications of these results for our health?
According to McGettigan, while young, healthy people who take these drugs don't have much to worry about, those with an already increased risk of heart problems do: "A patient with previous heart problems, high blood pressure and diabetes has an annual background risk of heart attack of over five per cent," she said. "Use of diclofenac will increase that by 40 per cent, giving an annual risk of over seven per cent. In other words, one in 50 such patients might suffer an avoidable heart attack.
"In contrast, a healthy young woman has an annual risk of heart attack of less than 0.1 per cent-she will experience a negligible increase in cardiovascular risk with any of the commonly used NSAIDs."
Just how risky NSAIDs are for people with preexisting heart problems was highlighted in a recent Danish study published in Circulation, the official journal of the American Heart Association. The study analyzed data from nearly 84,000 heart-attack survivors, 42 per cent of whom were taking a prescription NSAID. The researchers, from the University of Copenhagen in Gentofte, found that even short-term treatment with most NSAIDs was associated with an increased risk of death and recurrent heart attack.
However, in this report, diclofenac was associated with the highest risk. Those taking the drug were more than three times more likely to suffer another heart attack within a week of the first. As the researchers concluded, "Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view" (Circulation, 2011; 123: 2226-35).
Yet another study, this time in patients with coronary heart disease and high blood pressure in the US, found that the chronic self-reported use of NSAIDs was associated with a dramatically increased risk of death, heart attack and stroke (Am J Med, 2011; 124: 614-20).
Efficacy vs safety
The evidence linking popular NSAIDs with heart risks is now undeniable, with the risks posed by diclofenac and etoricoxib being particularly worrying.
Ultimately, the research so far highlights the serious failure of our drugs 'watchdogs' to protect our public health, while underlining the importance of adequately assessing drug safety in proper clinical trials.
To avoid yet another Vioxx disaster, establishing the safety, rather than efficacy, of all drugs should be given top priority.
For alternative ways to beat chronic pain, see WDDTY vol 20 no 6 (pages 6-9).
Factfile: Heart-risky NSAIDs
- Etoricoxib (Arcoxia)
- Etodolac (Lodine, Etopan)
- Rofecoxib (Vioxx)
- Diclofenac (Voltaren, Anuva, Diclon, Clofast)
- Indomethacin (Indocin, Indocid)
- Meloxicam (Movalis, Melox)
- Ibuprofen (Advil, Nurofen)
WDDTY VOL 22 NO 8, November 2011