Common Painkillers + heart attacks or strokes
FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes
The U.S. Food and Drug Administration (FDA) is strengthening an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke. Based on our comprehensive review of new safety information, we are requiring updates to the drug labels of all prescription NSAIDs. As is the case with current prescription NSAID labels, the Drug Facts labels of over-the-counter (OTC) non-aspirin NSAIDs already contain information on heart attack and stroke risk. We will also request updates to the OTC non-aspirin NSAID Drug Facts labels.
Patients taking NSAIDs should seek medical attention immediately if they experience symptoms such as chest pain, shortness of breath or trouble breathing, weakness in one part or side of their body, or slurred speech.
NSAIDs are widely used to treat pain and fever from many different long- and short-term medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu. NSAIDs are available by prescription and OTC. Examples of NSAIDs include ibuprofen, naproxen, diclofenac, and celecoxib (see Table 1 for a list of NSAIDs).
The risk of heart attack and stroke with NSAIDs, either of which can lead to death, was first described in 2005 in the Boxed Warning and Warnings and Precautions sections of the prescription drug labels. Since then, we have reviewed a variety of new safety information on prescription and OTC NSAIDs, including observational studies,1 a large combined analysis of clinical trials,2 and other scientific publications.1 These studies were also discussed at a joint meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee held on February 10-11, 2014.
Based on our review and the advisory committees’ recommendations, the prescription NSAID labels will be revised to reflect the following information:
- The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.
- The risk appears greater at higher doses.
- It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.
- NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.
- In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.
- Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.
- There is an increased risk of heart failure with NSAID use.
In addition, the format and language contained throughout the labels of prescription NSAIDs will be updated to reflect the newest information available about the NSAID class.
Patients and health care professionals should remain alert for heart-related side effects the entire time that NSAIDs are being taken. We urge you to report side effects involving NSAIDs to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page
Source : FDA (July 2015)
Nonsteroidal Anti-inflammatory Drugs and Risk of Atrial Fibrillation: Is There a Relationship?
Nonsteroidal anti-inflammatory drugs (NSAIDs), including nonselective NSAIDs and cyclooxygenase-2 (COX-2) inhibitors, frequently are prescribed for the management of pain associated with musculoskeletal conditions and injuries, as well as other sources of mild to moderate pain and inflammation. In fact, an estimated 5% of all physician appointments in the United States involve a prescription for NSAIDs.1 A recent meta-analysis of 31 trials enrolling 116,429 patients examined the risk of cardiovascular events associated with NSAIDs.1 When compared to placebo, significantly increased risks of myocardial infarction, stroke, cardiovascular mortality, and death were attributed to NSAID use.1 Of the NSAIDs studies, naproxen was associated with the lowest risk of adverse cardiovascular events.1
The relationship between the use of NSAIDs and risk of atrial fibrillation (AF) is not yet clearly understood, although the adverse renal effects associated with NSAIDs, such as fluid retention, electrolyte imbalances, and blood pressure variations, are thought to play a role in AF.2 A meta-analysis that examined the relationship between COX-2 inhibitors and risk of AF evaluated data from 114 trials and reported that rofecoxib was associated with a significantly higher rate of cardiac arrhythmias (relative risk [RR], 2.90; 95% CI, 1.07-7.88). However, the analysis was limited by a low number of arrhythmia events.3
A recent analysis of approximately 3 million patients in the United Kingdom General Practice Research Database revealed that current use of NSAIDs was associated with a RR of 1.44 (95% CI, 1.08-1.91) for chronic AF. Risk declined as more time elapsed since last use of NSAIDs, while risk increased with longer duration of use. The RR for chronic AF was 1.57 (95% CI, 1.15-2.15) for patients taking NSAIDs for more than 30 days, compared with 1.80 (95% CI, 1.20-2.72) among those who used NSAIDs for more than 1 year. No relationship between NSAID therapy and risk of paroxysmal AF was observed, with the exception of patients who used NSAIDs for more than 1 year (RR, 1.74; 95% CI, 1.11-2.71).4
A population-based, case-control study further evaluated whether NSAIDs increased the risk of AF or flutter. The analysis included 32,602 individuals with a first inpatient or outpatient hospital diagnosis of AF or flutter and 325,918 population controls. Compared with no use of NSAIDs, the adjusted incidence rate ratio (IRR) among cases was 1.17 (95% CI, 1.10-1.24) for current nonselective NSAID use. The IRR increased to 1.27 (95% CI, 1.20-1.34) for those who used COX-2 inhibitors, with no significant differences in risk associated with newer versus older COX-2 inhibitors.2
Notably, new users of nonselective NSAIDs and COX-2 inhibitors were at highest risk of AF or flutter. The IRR for new users of nonselective NSAIDs was 1.46 (95% CI, 1.33-1.62) and 1.71 (95% CI, 1.56-1.88) for COX-2 inhibitors. Evaluation of the incidence of AF or flutter by type of NSAID for new users revealed that the risk was greatest for celecoxib (1.83; 95% CI, 1.44-2.34) and lowest for ibuprofen (1.43; 95% CI, 1.28-1.59) and naproxen (1.44; 95% CI, 0.97-2.12).2 Importantly, elderly patients taking NSAIDs were at greatest risk of AF or flutter. In addition, those with chronic kidney disease were at increased risk, with an adjusted IRR of 2.87 (95% CI, 1.53-5.38) for new users of COX-2 inhibitors and 1.75 (95% CI, 1.11-2.77) for long-term users of nonselective NSAIDs. Similarly, the adjusted IRR for patients with rheumatoid arthritis who were new users of a COX-2 inhibitor was 2.49 (95% CI, 1.40-4.42) and 1.44 (95% CI, 1.01-2.03) for long-term users of nonselective NSAIDs.2
As we review these findings, it is important to acknowledge the potential for methodological limitations of these case-control studies, including the possible effects of unmeasured confounders that might affect study results. In addition, the specific biologic mechanism to explain the association between NSAIDs and risk of AF is not yet understood, although one proposed explanation suggests that an underlying inflammatory condition increases both the risk of AF and the use of NSAIDs. Alternatively, it has been suggested that NSAIDs provoke disorders such as heart failure and hypertension, which can lead to AF.5
With these cautions in mind, evidence from these studies suggest that AF is an additional cardiovascular risk associated with NSAIDs,2,5 with the strongest association evident for new users and individuals who take NSAIDs for longer periods of time. These findings have clinically significant implications due to the high rate of administration of NSAIDs to treat pain and inflammation associated with a wide variety of musculoskeletal and other conditions. This is particularly important for older adults, who are at increased risk of AF by virtue of their advanced age. Of greatest concern, of course, are older patients who have been diagnosed with hypertension or heart failure and are already at increased risk for the adverse effects of NSAIDs because of these conditions.5
- 1. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.
- 2. Schmidt M, Christiansen CF, Mehnert F, et al. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ. 2011;343:d3450.
- 3. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA. 2006;296:1619-1632.
- 4. De Caterina R, Ruigómez A, Rodríguez LA. Long-term use of anti-inflammatory drugs and risk of atrial fibrillation. Arch Intern Med. 2010;170:1450-1455.
- 5. Gurwitz JH. NSAIDs and atrial fibrillation. BMJ. 2011;343:d2495.
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NSAIDs and Cardiovascular Risk Explained
After nearly 13 years of study and intense debate, a pair of new papers from the Perelman School of Medicine, at the University of Pennsylvania have confirmed exactly how a once-popular class of anti-inflammatory drugs leads to cardiovascular risk for people taking it.
It has been almost eight years since Vioxx® was withdrawn by Merck from the market, provoking an intense controversy about the role inhibitors of the enzyme COX-2 play in causing heart attacks and strokes. Since then, other drugs in the class from Pfizer, Novartis, and Merck have been withdrawn (Bextra®); have failed to be approved (Arcoxia®, Prexige®); or have been retained on the market in the US with a “black box” warning on the label (Celebrex®).
COX-2 is one of two similar enzymes that churn out short-lived fats called prostaglandins. The other, COX-1, works in platelets -- cells in the blood that stick together in the first stages of clotting. COX-2 is active in the cells that line blood vessels. These enzymes have diverse, potent, and often contrasting effects in the body. For example, low-dose aspirin protects against heart attacks and strokes by blocking COX-1 from forming a prostaglandin called thromboxane A2 in platelets. On the other hand, COX-2 is the more important source of prostaglandins, particularly one called prostocyclin, which causes pain and inflammation.
COX-2 inhibitors are a subclass of nonsteroidal anti-inflammatory drugs (NSAIDs), among the most common drugs consumed on the planet. Older NSAIDs include drugs like Naprosyn, which inhibits mostly COX-1; Advil®, which inhibits COX-1 and COX-2; and Voltaren® and Mobic®, which mostly inhibit COX-2. The newer drugs were developed because targeting COX-2 reduced serious gastrointestinal side effects like bleeding ulcers. However, aggressive direct-to-consumer advertising meant that drugs like Vioxx and Celebrex were taken mostly by patients who had never had the GI problems with the older, cheaper NSAIDs.
Just before Celebrex and Vioxx were approved and launched, a group led by Garret FitzGerald, MD, chair of the department of Pharmacology, and director of the Institute for Translational Medicine and Therapeutics at Penn, observed that both drugs suppressed prostacyclin in humans, as reflected by its major metabolite in urine, PGI-M. Based on the potentially cardioprotective properties of prostacyclin, which relaxes blood vessels and unglues platelets in test tube experiments, the team predicted that shutting down this protection with inhibitors would cause heart attacks and strokes. More than 10 years later, it is now clear what the COX inhibitors do in the body. Eight placebo-controlled, randomized trials, performed to find new uses of these drugs, showed that they posed a cardiovascular hazard, similar in magnitude to that resulting from being a smoker or a diabetic, notes FitzGerald. “Despite this, controversy has continued about how all this came about, until now.”
Arguments against the proposed mechanism were threefold. First, it was proposed that COX-2 didn’t exist under normal circumstances in the blood-vessel lining and PGI-M came from some other source. The kidneys were suggested as the source by some researchers. Second, even if blood-vessel prostacyclin was blocked, other protective mechanisms, especially formation of nitric oxide (NO) would take over. And third, although NSAIDs elevate blood pressure, it was proposed that this observation was unrelated to COX-2 and treating high blood pressure would deal with the problem.
FitzGerald’s group has now “closed the loop” with its earlier clinical studies and answered these questions in a paper just published in Science Translational Medicine. In it, they confirm that COX-2 is expressed in cells lining blood vessels and that selectively removing it predisposes mice to blood clotting and high blood pressure. These mice, just like humans taking COX-2 inhibitors, also see a fall in PGI-M. What’s more, the Penn group discovered that COX-2 in lining cells controls the expression of eNOS, the enzyme that makes NO in the body. “So, rather than replacing the missing prostacyclin, as others have proposed, NO is lost and amplifies the effects of COX-2 inhibition on the cardiovascular system,” says FitzGerald.
Indeed, the lost NO may not be the only step that magnifies the effects of losing prostacyclin. In a second paper, published in April 2012, in the Proceedings of the National Academy of Sciences, FitzGerald’s group shows that arachidonic acid, the fat broken down by COX-2 to make prostacyclin, can be shunted down another pathway to make a new series of dangerous fats called leukotrienes when COX-2 is disrupted.
Clinical studies have shown that those most at risk from COX-2 inhibitors are patients who already have heart disease. However, the Penn group now suggests broader implications. Here, the group resolves one aspect of the controversy, showing that COX-2 disruption causes hardening of the arteries in mice. This result is provocative because randomized trials of Vioxx and Celebrex in patients at low risk of heart disease detected an increase in heart attacks after patients had been taking the drugs for more than a year. These current Penn studies raise the disturbing prospect that heart-healthy patients taking NSAIDs for prolonged periods might be gradually increasing their risk of heart attacks and strokes by progressively hardening their arteries.
“However, it’s not all bad news,” says FitzGerald. This risk of hardening of the arteries was diminished in mice by reducing leukotriene formation, via blocking a critical protein called the 5-lipoxygenase activating protein, or FLAP. Inhibitors of FLAP are already in trials in humans to see if they work in asthma. Perhaps, FitzGerald concludes, they can now find an additional use -- protecting the heart from NSAIDs.
Source : Newswise
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Common Painkillers increases risk of heart attacks or strokes
Taking certain commonly used painkillers for long periods or in high doses increases the risk of heart attacks or strokes, a study has suggested. The report by researchers from Bern University, published in the British Medical Journal, looked at 31 clinical trials on more than 116,000 patients to examine the effects of painkillers on people’s health.
The team studied data from existing large-scale studies comparing use of non-steroidal anti-inflammatory drugs (NSAIDs) as well as new-generation anti-inflammatory medicines (COX-2 inhibitors) – naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib and lumiracoxib – with other drugs or placebos.
Anti-inflammatory drugs are widely used to manage pain in patients with osteoarthritis and other painful conditions.
“There is little evidence to suggest that any of the investigated NSAIDs included in these studies are safe in cardiovascular terms,” Peter Jüni, professor of clinical epidemiology at Bern University, told swissinfo.ch.
While the absolute risk of cardiovascular problems among people taking painkillers was low, the team found that relative to a placebo the drugs carried "important risks".
The scientists found that compared with a placebo or dummy pill, rofecoxib and lumiracoxib were associated with twice the risk of heart attack, while ibuprofen was associated with more than three times the risk of stroke.
Etoricoxib and diclofenac were linked with around four times the risk of cardiovascular death. Naxproxen seemed the least harmful, but should be weighed against potential side effects including stomach problems, they noted.
Jüni stressed that the findings did not relate to people taking anti-inflammatories occasionally for symptoms such as period pain or sports injuries.
The problematic patients are typically elderly people who may be obese with high cholestoral levels or hypertension or have musculoskeletal conditions like osteoarthritis, and be using the drugs “chronically”.
Without drugs, such people have a one per cent risk over one year of heart attack or stroke, but when taking NSAIDs, the risk is up to four per cent, Jüni said.
“I still think the risks are underestimated by the medical profession,” he said. “Many patients are not aware of the issues. I think more information is necessary. It would be reasonable to have more prominent warnings so people take the drugs now and again rather than daily and not several times a day.”
No immediate changes
But the Swiss Agency for Therapeutic Products (Swissmedic), responsible for checking drug compliance, believes drug information for painkillers is “prominent, detailed and clear”.
And it does not envisage making any immediate changes in the light of this study.
“Discussions about the analysis and results first have to be carried out among experts and regulators at the scientific level,” said Swissmedic spokesman Joachim Gross.
Several groups of researchers became concerned about the toxicity issue from 2001 onwards but this was largely ignored by the medical community, Jüni said.
In 2004, Vioxx, a COX-2 inhibitor, was withdrawn from the market after a trial showed it increased the risk of heart disease.
The researchers said that since then there has been much debate about the heart safety of COX-2 inhibitors and NSAIDs, but various studies have failed to give clear results.
Commenting on the findings, Simon Maxwell, a professor of clinical pharmacology at Edinburgh University, said it was important to see them in context.
"Most users of these drugs will only take them for a relatively brief duration to treat short-lasting episodes of pain and are at minimal risk," he said.
He added that patients with chronic pain may need to use painkillers for longer periods and while the study suggested they might be exposed to some excess risk, the alternatives "may be less acceptable".
Professor Bernhard Meier, chief cardiologist at Bern's Inselspital Hospital, echoed this, adding that patients often faced a dilemma.
“When it’s necessary to take medication like Voltaren or Naproxen, then [patients should] continue to do so, but try to reduce the dose and see if it’s possible to go without,” he told Swiss national television.
Source : swissinfo.ch
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