Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used effectively for the treatment of pain conditions and inflammation over the past 100 years and are among the most commonly used drugs worldwide. However, during the last decade there have been increased concerns regarding the cardiovascular safety profile of NSAIDs. These concerns have primarily been related to results from studies demonstrating increased cardiovascular risk with cyclooxygenase-2 (COX-2) inhibitors. Recently, there has been accumulating evidence from several large observational studies and meta-analyses that nonselective NSAIDs are also associated with increased cardiovascular risk.
The main action of NSAIDs is inhibition of the COX enzyme that facilitates synthesis of prostaglandins from arachidonic acid. The prostaglandins are mediators of several physiologic functions, including inf lammation, thrombosis, body salt and water homeostasis, blood pressure, and gastric protection.1 COX has two main isoforms, COX-1 and COX-2, both of which are inhibited by NSAIDs, but in varying degrees.
The vascular effect of NSAIDs is mainly mediated by two products of COX prostaglandin synthesis: thromboxane A2 (TXA2), a vasoconstrictor and potent stimulator of platelet aggregation modulated by the COX-1 isoform, and prostaglandin I2 (PGI2), a potent vasodilator and inhibitor of platelet function predominantly regulated by the COX-2 isoform. TXA2 increases renal salt and fluid retention, increases blood pressure, and enhances myocardial and vascular remodeling, whereas PGI2 facilitates renal salt and fluid excretion and lowers systemic blood pressure. Equilibrium between TXA2 and PGI2 exists in the healthy vascular system, and it has been proposed that NSAIDs, in varying degrees, tip the TXA2/PGI2 balance, thereby increasing cardiovascular risk.
Although studies have demonstrated increased cardiovascular risk with rofecoxib2 (not available in the United States) and other COX-2 inhibitors,3–7 traditional nonselective NSAIDs have been used uncritically for decades with a lack of randomized studies regarding cardiovascular safety. However, several large observational studies and meta-analyses have demonstrated increased cardiovascular risk with nonselective NSAIDs.5,6,8–10
Risk profiles of NSAIDs vary depending on the degree to which individual formulations inhibit the COX-1 or COX-2 isoforms. Hence, nonselective NSAIDs with high COX-2 inhibition (e.g., diclofenac [Cataflam]) seem to have higher cardiovascular risk, whereas nonselective NSAIDs with high COX-1 inhibition (e.g., naproxen [Naprosyn], aspirin, ibuprofen) seem to have higher gastrointestinal risk.1
The primary focus of discussions on cardiovascular risk has been on thrombotic risk. However, NSAIDs can increase the risk of fluid retention and edema, and destabilize and worsen preexisting heart failure. Accordingly, international guidelines have advocated caution when using NSAIDs in persons with heart failure.11 Furthermore, NSAIDs have been shown to influence renal function by decreasing renal perfusion and glomerular filtration rate; cause interstitial nephritis; increase blood pressure; and, in persons with preexisting hypertenion, destabilize blood pressure control.12 Several studies have demonstrated that, in persons with established cardiovascular disease or increased cardiovascular risk, NSAIDs are even more harmful with regards to cardiovascular adverse events.7–9,13
Although current evidence points to increased cardiovascular risk with NSAIDs, a total abandonment of NSAID use is not likely or possible. There will always be groups of patients with pain conditions who must take NSAIDs. Nevertheless, there is a need to focus on the balance between risk and benefit before initiating NSAID treatment. This is especially important in persons with established cardiovascular disease in whom alternative pain treatment with lower cardiac risk (e.g., acetaminophen, weak opiates) should always be the first choice. In persons needing NSAID treatment, NSAIDs with the highest COX-1 selectivity (e.g., naproxen, ibuprofen, aspirin) should be preferred and used in the lowest dosages and for the shortest durations possible. For stronger analgesic effect, a combination with other types of analgesics should be considered.
It is also important to consider the value of nonpharmacologic therapeutic measures, such as physiotherapy and physical exercise, as supplements to analgesic therapy.
Epidemiologic studies have demonstrated extensive use of prescription NSAIDs in the general population, as well as in persons with established cardiac disease.8,9,14 Also, in many countries, NSAIDs are sold without a prescription, expert advice, limits on their use, or information on potential adverse effects. This indicates the need for reevaluation of current treatment strategies regarding NSAID use and the misconception that NSAIDs are harmless for everyone.15