Current NSAID Use Linked to Increased Risk of Heart Failure, Large European Analysis Shows

The use of nonsteroidal anti-inflammatory drugs (NSAIDs), including the popular painkillers ibuprofen, naproxen, and diclofenac, is associated with an increased risk of hospital admission for heart failure, a large European study shows.

In a real-world study of nearly 10 million people taking NSAIDs in the Netherlands, Italy, Germany, and United Kingdom, individuals currently taking the medications had a 19% higher risk of heart failure when compared with past users. The risk varied among the individual NSAIDs, with nine drugs—indomethacin, diclofenac, ketorolac, piroxicam, ibuprofen, naproxen, rofecoxib, etoricoxib, and nimesulide—all associated with significantly higher risks of heart failure among current users compared with past users.  

The risk of heart failure among users was highest for those taking ketorolac, with individuals having a two-fold higher risk for heart failure compared with past users. For those taking rofecoxib and etoricoxib, which are selective COX-2 inhibitors, the risk of heart failure was increased 34% and 55%, respectively. For those taking ibuprofen, naproxen, and diclofenac, which are nonselective NSAIDs, the risk of heart failure was 15%, 19%, and 21% higher, respectively, than for past users.

In their paper published September 28, 2016, in the BMJ, investigators led by Andrea Arfé, PhD (University of Milan, Italy), who are part of the Safety of Nonsteroidal Anti-Inflammatory Drugs (SOS) Project Consortium say the study confirms previous reports showing NSAIDs increase the risk of heart failure and that the magnitude of effect varies among individual agents and dose used. “The effect of individual NSAIDs could depend on a complex interaction of pharmacological properties, including duration and extent of platelet inhibition, extent of blood pressure increase, and properties possibly unique to the molecule,” according to the researchers.

Confirms Previous Findings

In 2013, members of the Coxib and Traditional NSAID Trialists’ (CNT) collaboration analyzed 639 randomized trials and showed that high-dose NSAIDs increased the risk of vascular events by approximately 33%, although naproxen appeared to be the exception. As reported by TCTMD, the use of COX-2 inhibitors, diclofenac, ibuprofen, and naproxen all increased the risk of heart failure.   

Gunnar Gislason, MD (Copenhagen University Hospital, Denmark), who wrote an editorial accompanying the BMJ paper with Christian Torp-Pedersen, MD (Aalborg University, Denmark), told TCTMD the findings confirm previous analyses. While the results are not surprising, he said, the study is very large and includes multiple countries and healthcare databases.

The European Society of Cardiology (ESC) recommends against using NSAIDs in patients with existing cardiovascular disease, but for those who absolutely require the drugs, low-dose naproxen is an option, he said. The ESC advises cardiovascular patients against taking any of the COX-2 inhibitors and diclofenac, a commonly used NSAID that appears to carry greater risk than other agents, added Gislason.

“The problem, as expected, is that these drugs are sold over-the-counter without any advice on side effects or the harmful effects,” said Gislason. “And even though they are sold in low dosages, the message is wrong. If you have an average individual, somebody who doesn’t have this knowledge [about the risks], they’re trusting the healthcare authorities or regulators that the drugs are safe to use. That’s the problem. It gives a misconception that the drugs are safe.”

The lack of knowledge about the risk of heart failure and other vascular events is particularly problematic for a patient with cardiovascular disease, he added. “It’s not like these drugs are only sold at drug stores, where they might be able to get professional advice,” said Gislason. “They’re also sold at convenience stores and gas stations.”

In 2005, the US Food and Drug Administration first required manufacturers of marketed prescription NSAIDs to revise their labeling to include a boxed warning highlighting the potential for cardiovascular events with the drugs as well as the increased risk of serious, life-threatening bleeding, such as gastrointestinal bleeding. In 2015, the FDA strengthened the existing label to warn that non-aspirin NSAIDs increase the risk of MI and stroke. The “drug facts” labels of the over-the-counter NSAIDs also contain information on MI and stroke risks.

The FDA stated the risk of MI and stroke can occur early, increases with longer use of NSAIDs, and appears greater at higher doses. Although the agency noted the risk does not appear to be similar for all NSAIDs, the data were insufficient to make recommendations on one drug over another.

In 2015, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee warned of a small increased risk of MI and stroke in patients taking high doses of ibuprofen (2,400 mg per day or higher). Two years earlier, the EMA had updated safety information for diclofenac, warning the NSAID is associated with an increased risk of MI and stroke at high doses (150 mg per day) and when used for long periods. As part of the 2013 review, the EMA recommended physicians take the same cardiovascular precautions with diclofenac as they would with selective COX-2 inhibitors. 

Nearly 10 Million Patients

In their study, the SOS consortium obtained data from five population-based healthcare databases, including 7,680,181 new users of NSAIDs between 2000 and 2010. Among the new users of NSAIDs, there were 92,163 hospital admissions for heart failure; these individuals were matched with 8,246,403 controls. The most frequently used traditional NSAIDs were diclofenac, nimesulide, and ibuprofen.   

In addition to observing the higher risk of heart failure with current NSAID use, the researchers report that for the nine individual NSAIDs linked with heart failure, the association existed regardless of whether or not the patients had a prior heart failure hospitalization. They also found that the estimated risk of heart failure with current use of nimesulide, etoricoxib, and indomethacin among women was lower in magnitude than among men. When investigators looked at dose, they found that users taking very high doses of diclofenac, indomethacin, piroxicam, and rofecoxib had a “more than two-fold higher risk of heart failure than past users.”

In addition, the researchers showed traditional NSAIDs provided no protection compared with celecoxib. Compared with current users of the COX-2 inhibitor, the current users of other NSAIDs did not have a lower risk of heart failure admissions. The data did not show celecoxib increased the risk of heart failure at commonly used doses, but investigators say they “cannot exclude an increase in risk” when the drug is used at high doses, given the wide confidence intervals for that dose class.

To TCTMD, Gislason said NSAIDs do have a role for certain patients, but that given their uptake they are too frequently used as an “easy way out.” The drugs, he said, should be the last resort for a patient in pain. Milder painkillers, including paracetamol, are options, but other “alternatives like exercise and physiotherapy, even weight loss, could help some of these patients,” he suggested.

In terms of study limitations, Gislason noted the nested case-control study only provided information on the relative risk of heart failure among current users compared with past users. Data on the absolute risks of NSAIDs would be more helpful to physicians. “If you have a very low-risk patient, a 20% increased risk in something that is very low is quite small,” he said. “If you have high risk—such as a patient with cardiovascular disease or if they have many risk factors for cardiovascular disease—then a 20% risk can have a considerable impact. We need to consider the individual risk of the patient when we’re recommending or prescribing drugs.”   

In the editorial, as well as to TCTMD, Gislason said that what with the widespread use of NSAIDs, even a small increase in cardiovascular risk is worrisome. “It’s a public health issue,” he said. “It raises an issue about public health safety and therefore we need to reduce use of those drugs and consider some other ways of relieving pain in patients that need it.”

Sources:

• Arfé A, Scotti L, Varas-Lorenzo C, et al. Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ. 2016; Epub ahead of print.
• Gislason GH, Torp-Pedersen C. NSAIDs and the failing heart. BMJ. 2016; Epub ahead of print.

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