Heart disease is the leading cause of death for both men and women. According to the US Centers for Disease Control and Prevention (CDC), there are about 735,000 annual cases of heart attack in the US; about 610,000 people die of heart disease every year, accounting for 1 in every 4 deaths.

Stroke statistics are less overwhelming but still dramatic. Stroke kills almost 130,000 Americans each year, corresponding to 1 out of every 20 deaths. Nevertheless, every year, more than 795,000 people in the US have a stroke, with about 87% of all strokes being ischemic strokes, due to blockage of blood flow to the brain. Stroke is a leading cause of serious long-term disability.

The traditional risk factors for heart attack and stroke include hypertension, diabetes, smoking, and high levels of cholesterol and triglycerides in the blood. But the U.S. Food and Drug Administration (FDA) has added a new item to this list.

The FDA issued a safety announcement on July 9^th stating that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke.

This adds to the long-running list of NSAIDs’ adverse side-effects that include an increased risk of serious gastrointestinal, hepatic, and renal damage, for example. Even though the existing label warning in non-aspirin NSAIDs already contained information on heart attack and stroke risk, it only stated that these drugs ‘may’ cause an increased risk of such events. The FDA is now strengthening this warning to a more assertive version.

Non-aspirin NSAIDs is a widely used class of drugs available both in prescription and over the counter (OTC) forms that includes, for example, diclofenac (eg. Voltaren), naproxen (eg. Aleve, Naprosyn), and ibuprofen (eg. Advil, Motrin, and Nurofen). The OTC variety of these drugs is mostly used to treat pain or fever, with ibuprofen being among the most widely used. The prescription forms are usually stronger and are used to treat chronic disease, namely rheumatic diseases and other painful conditions.

The pharmacological effects of NSAIDs are mediated through blockade of COX enzymes, responsible for the synthesis of various prostaglandins, such as thromboxane, and prostacyclin. Since these molecules act on vascular function, platelet aggregation, and smooth muscle proliferation, NSAIDs can affect these functions by altering the balance of these molecules.

NSAIDs can generally be distinguished by their level of selectivity for different types of COX, specifically for COX-1 and COX-2. COX-1 is ubiquitous in most tissues, while COX-2 is primarily upregulated in inflammatory states. Those NSAIDs that affect both COX-1 and COX-2 in varying degrees are referred to as nonselective agents; selective COX-2 inhibitors act primarily on COX-2, which is strongly associated with inflammation and pain.

The reason why aspirin is distinguished from other NSAIDs (and not included in FDA’s warning) is that it is a selective COX-1 inhibitor; COX-1 plays a role in regulating angiogenesis in endothelial cells, being beneficial from a cardiovascular standpoint. The use of aspirin in the prevention of cardiovascular events is well established.

Selective COX-2 inhibitors are generally better tolerated than non-selective inhibitors, though the rates of serious adverse events are similar. Prostacyclin is one of the primary products of COX-2 and is responsible for vasodilation, inhibition of smooth muscle cell proliferation, and platelet inhibition. The imbalance of relative COX-2 to COX-1 effects is the most widely disseminated theory for the harmful effects of NSAIDs, but emerging data suggest this concept may not be completely accurate.

Various factors may contribute to this association between NSAIDs, heart attack and stroke. For example, all NSAIDs can potentially, and to varying degrees, affect vasoconstriction and sodium excretion, which can lead to hypertension, a risk factor for cerebrovascular events.

The adverse effects of NSAIDs may even be observed after a relatively short-term use, particularly when other risk factors come into play. A recent study demonstrated an increased risk of stroke, specifically ischemic stroke, among hypertensive subjects after using NSAIDs for only 30 days.

The FDA’s safety announcement sums it all up:

• 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 […].
• NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. […]
• 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.

As the FDA suggests, all 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. They also advise patients and health care professionals to remain alert for heart-related side effects the entire time that NSAIDs are being taken.

Better safe than sorry.

References

Catella-Lawson F, & Crofford LJ (2001). Cyclooxygenase inhibition and thrombogenicity. The American journal of medicine, 110 Suppl 3A PMID: 11173047

Chang CH, Shau WY, Kuo CW, Chen ST, & Lai MS (2010). Increased risk of stroke associated with nonsteroidal anti-inflammatory drugs: a nationwide case-crossover study. Stroke; a journal of cerebral circulation, 41 (9), 1884-90 PMID: 20671253

Chuang SY, Yu Y, Sheu WH, Tsai YT, Liu X, Hsiung CA, & Tsai HJ (2015). Association of short-term use of nonsteroidal anti-inflammatory drugs with stroke in patients with hypertension. Stroke; a journal of cerebral circulation, 46 (4), 996-1003 PMID: 25737315

Dhillon N, & Liang K (2015). Prevention of stroke in rheumatoid arthritis. Current treatment options in neurology, 17 (7) PMID: 25981388

Mozaffarian D, Benjamin EJ, Go AS, et al. (2015) Heart disease and stroke statistics — 2015 update: a report from the American Heart Association. Circulation. pp29-322.

Park K, & Bavry AA (2014). Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Vascular health and risk management, 10, 25-32 PMID: 24421643

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