Is There a Role for NSAIDs in Patients With Cardiovascular Disease?
The recent action by the US Food and Drug Administration (FDA) to strengthen the warning label of nonsteroidal anti-inflammatory drugs (NSAIDs) to reflect an increase risk of heart attack or stroke raises questions about how safe are these medications for patients with pre-existing cardiovascular disease (CVD).1
NSAIDs are commonly the first-line treatment for pain, especially for pain caused by musculoskeletal disorders. A recent report on prescription use in the United States stated that ibuprofen was prescribed to 35.1 million persons in 2013.2 There have been many studies showing a direct increased risk of adverse cardiovascular effects due to NSAIDs. The recent FDA announcement is based on the agency’s comprehensive review of new safety information.3 The FDA will also request updates to the over-the-counter non-aspirin NSAID Drug Facts labels, according to a release from the FDA (Table 1).
The risk of heart attack and stroke with NSAIDs was first described in 2005 in the Boxed Warning and Warnings and Precautions sections of the prescription drug labels. Since then, FDA reviewed a variety of new safety information on prescription and OTC NSAIDs, including observational studies, a large combined analysis of clinical trials, and other scientific publications. 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, 2014.4
CVD is widely prevalent in the general population today, with the deaths contributed to CVD increasing from 14.4 million in 1990 to 17.5 million in 2005.5 According to the World Health Organization, this number will only increase and is estimated to reach close to 20 million by 2015.6 CVD comprises primarily of coronary heart disease (CHD), cerebrovascular disease, peripheral artery disease, and aortic atherosclerosis and thoracic/abdominal aortic aneurysm.
It is estimated that over half of the patients with CVD are also concurrently affected by disorders of the musculoskeletal system, including arthritis, with a recent study confirming an increased rate of CVD contributed to patients with inflammatory arthritis.7 This article will review the literature to help physicians decide if NSAIDs are safe to use in patients with CVD.
NSAIDs: Mechanism of Action
The primary function of NSAIDs is to inhibit cyclo-oxygenase (COX), which will ultimately inhibit the transformation of arachidonic acid to prostaglandins, prostacyclin, and thromboxane in the inflammatory cascade. There are 2 types of COX enzymes: COX-1 and COX-2. NSAIDs can either target one or both COX enzymes. Of these 2 isomers, COX-1 is constantly expressed in most tissues in variable amounts and helps regulate normal cellular processes (including cytoprotection, hemostasis, and platelet aggregation).8
Thromboxane A2 (TXA2) is the predominant derived product due to COX-1 and is a known vasoconstrictor and modulator of platelet aggregation. COX-2, on the other hand, is largely expressed during a state of inflammation and is a catalyst for the formation of prostaglandin I2 (PGI2) and prostaglandin E2 (PGE2). PGI2 is a vasodilator and prevents formation of a platelet plug by inhibiting platelet activation.9,10
The vascular implications of NSAIDs stem from the inhibition of TXA2 and PGI2.11 As a vasoconstrictor, TXA2 increases renal salt and fluid retention, thereby increasing blood pressure leading to myocardial and vascular remodeling. As a vasodilator, PGI2 assists in renal salt and fluid excretion, thereby decreasing blood pressure and preventing any vascular or cardiac remodeling.11 Normally, there exists a fragile equilibrium between TXA2 and PGI2, which is disrupted when NSAIDs are introduced into the equation leading to an increased risk of cardiovascular complications.
Non-selective NSAIDs inhibit both COX-1 and COX-2 and include ibuprofen (Advil, Motrin, others), naproxen (Aleve, Naproxyn, others), diclofenac (Voltaren, others), indomethacin (Indocin, others), and ketorolac (Sprix, others). This class of NSAIDs is often prescribed for a short-term and at the lowest effective dose to help limit any adverse effects. Inhibition of COX-1 is thought to be largely responsible for some of the adverse events (AEs) associated with NSAIDs, including gastrointestinal bleeding. Major cardiovascular adverse events noted with these agents have included myocardial infarction, stroke, heart failure, and arrhythmias.7 Table 2 list non-selective and selective NSAIDs.
In a meta-analysis when non-selective NSAIDs are compared to placebo, diclofenac was been found to cause an increase in vascular events by 33% (RR 1.41, C1 1.12–1.78), of which roughly 75% of the morbidity and mortality is largely associated to an increase in myocardial infarctions (RR 1.70, CI 1.19–2.41). The same study also found that ibuprofen was associated with an increase in coronary events (RR 2.22, CI 1.10–4.48), but not major vascular events (RR 1.44, CI 0.89–2.33). The analysis also disclosed an increase in cerebrovascular events in both diclofenac (RR 1.18, CI 1.12-1.78) and Ibuprofen (RR 0.97, CI 0.42-2.24). Naproxen appears to have fared the best, as it did not significantly increase coronary events (RR 0.84, 0.52–1.35) or major vascular events (RR 0.93, CI 0.69–1.27).12
In patients with low cardiovascular risk, the excess absolute risk for a major vascular event or death due to diclofenac and ibuprofen have resulted in an excess of 2 events per 1,000 persons per year. This risk is only further increased in patients with high cardiovascular risk: an excess of 7 to 8 events per 1000 persons per year. Naproxen does not increase risk in either groups, noted the authors.13
The risk of heart failure, including exacerbation of preexisting heart failure, is approximately doubled by the use of all NSAIDs.7 A Danish study compared patients with heart failure who used NSAIDs with controls with heart failure who did not use NSAIDs. The study found an increased risk of rehospitalization for heart failure in patients who used diclofenac (RR 1.85, CI 1.17-2.94) or ibuprofen (RR 2.49, CI 1.19-5.20) compared with controls. This study also established that naproxen also increased the risk for heart failure exacerbation (RR 1.87, CI 1.10-3.16). Of note, the study further established a dose-dependent increased risk for death with the use of non-selective NSAIDs, with the highest risk contributed to diclofenac for doses >100 mg per day (RR 5.54, CI 5.08-6.03) and the lowest risk for naproxen for doses <500 mg per day (RR 0.88, CI 0.73-1.05). Ibuprofen also conferred a lower risk when dosage was limited to <1,200 mg per day (RR 0.99, CI 0.94-1.04).14