View Full Version : Cardiovascular Risk Associated With NSAIDs and COX-2 Inhibitors

Sat 11th October '14, 7:56pm
Laura A. Perry, RPh, PharmD, BCPS, Charles Mosler, RPh, PharmD, CGP, FASCP, Ashton Atkins, PharmD, Megan Minehart, PharmD
DisclosuresUS Pharmacist. 2014;39(3):35-38.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain associated with a variety of medical conditions. Nonselective NSAIDs reversibly inhibit the enzyme cyclooxygenase (COX) in both of its isoforms, COX-1 and COX-2. An increased risk of cardiovascular events has been associated with the use of NSAIDs, especially of COX-2 selective NSAIDs. Current evidence suggests that naproxen, a nonselective NSAID, is associated with the lowest risk of cardiovascular events. Therefore, naproxen is the NSAID of choice in patients with high cardiovascular risk.

Cardiovascular disease is defined as any disease that involves the heart, blood vessels, or both, many of which are related to the process of atherosclerosis. Approximately 83 million American adults are affected by one or more types of cardiovascular disease, and of these patients, 40 million are 60 years of age or older.[1] Many patients of varying ages utilize OTC and prescription anti-inflammatory drugs to manage pain. Approximately 30 million Americans use nonsteroidal anti-inflammatory drugs (NSAIDs) daily for reasons ranging from cardioprotection and everyday aches and pains to more serious complications such as rheumatoid arthritis, acute gout (http://emedicine.medscape.com/article/329958-overview?src=wgt_edit_news_lsm&lc=int_mb_1001), and other comorbid conditions.[2]

Patients at an increased risk for cardiovascular events with concurrent usage of NSAIDs include patients with recent bypass surgery, unstable angina, myocardial infarction (MI), ischemic cerebrovascular events, or any other active athlerosclerotic process. Patients who have cardiovascular disease and are taking NSAIDs, especially cyclooxygenase-2 (COX-2) selective agents, are at a much higher risk of having an MI than patients not taking these drugs. Therefore, understanding the potential danger of the use of NSAIDs in patients who have cardiovascular risk factors is essential.[1,3]

NSAIDs and Adverse Effects

As with any medication, NSAIDs are not without adverse effects. The most commonly experienced side effects are nausea, vomiting, diarrhea, constipation, decreased appetite, rash, dizziness, headache, and drowsiness. The more severe side effects seen with NSAID use are fluid retention, renal failure (associated with more chronic use), liver failure, gastric ulcers, and increased or prolonged bleeding following an injury or surgical procedure.[1,3]

Many of the adverse effects associated with NSAID use can be explained by their effect on phospholipid metabolism. Membrane phospholipids are broken down by phospholipase A[2] to arachidonic acid, the substrate for the COX enzymes. COX-1 is constitutively expressed in the stomach, kidneys, and intestinal endothelium, where it leads to vasoconstriction and platelet aggregation. COX-2 is upregulated during time s of inflammation, where it causes vasodilation and inflammation via the migration of macrophages, leukocytes, and fibroblasts. It is this balance between the two enzymes that is ultimately disrupted upon administration of NSAIDs (Figure 1).[1,4]


The decision about which NSAID to use will vary among patients, and COX selectivity is one of the determining factors. NSAIDs target both COX-1 and COX-2 enzymes. The rationale for the use of selective COX-2 inhibitors stemmed from the negative gastrointestinal (GI) effects of nonselective NSAIDs and aspirin. Selectivity for the COX-2 enzyme proves to be gastroprotective, which is a major benefit for pain management in patients with GI complications such as peptic ulcer disease (http://emedicine.medscape.com/article/181753-overview?src=wgt_edit_news_lsm&lc=int_mb_1001) (PUD), gastroesophageal reflux disease (GERD), and GI bleeding. However, the COX-2 selective inhibition exhibited by certain NSAIDs can increase the risk of cardiovascular events in patients with preexisting cardiovascular disease. This prothrombotic risk results from thromboxane A[2]–mediated vasoconstriction and platelet aggregation, which will remain unbalanced and unopposed when prostacyclin activity is suppressed via COX-2 inhibition.[1,4]

On the other end of the spectrum, irreversible COX-1 inhibition has been shown to be cardioprotective, which is apparent with low-dose aspirin. Nonselective NSAIDs inhibit both COX-2 and COX-1. Because COX selectivity varies among the nonselective NSAIDs, so will the NSAID-associated cardiovascular risk.[1,4]


Source: Medscape: Medscape Access (http://www.medscape.com/viewarticle/828262)

Sat 11th October '14, 8:00pm
American Heart Association StanceIn 2007, the American Heart Association (AHA) addressed the concern that selective COX-2 inhibition may potentiate a cardiovascular event in patients who are at an increased risk. The AHA states that physicians and patients must weigh the risks and benefits of each agent before choosing a treatment plan for pain relief. Patients should be treated only for the shortest amount of time and with the lowest dosage of drug necessary to gain symptom relief.[13,17]

A stepwise approach is suggested, beginning with the agents that have the lowest associated cardiovascular risk and moving to the agents with higher risk if treatment failure occurs. Non-NSAID products, such as acetaminophen or nonacetylated salicylates, are the preferred agents in patients with high cardiovascular risk. If these treatments are not tolerated or fail to control pain, the use of NSAIDs may be warranted. Patients beginning NSAID therapy should start with a nonselective NSAID, such as ibuprofen or naproxen. However, the literature suggests naproxen as the nonselective NSAID of choice for these patients. If pain control is not established with nonselective NSAIDs, the next trial should be with an agent that is semiselective for COX-2, such as meloxicam or diclofenac.[17]

Finally, if all the above treatments have failed, the patient may consider treatment with the selective COX-2 inhibitor celecoxib. Celecoxib use in patients at risk for thrombotic events should be reserved for patients who have no other appropriate alternatives.[17]

Concurrent use of nonselective NSAIDs with aspirin may decrease the cardioprotective profile normally seen with aspirin use. This is due to competitive inhibition of the receptor binding site of the COX-1 enzyme. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) concluded that ibuprofen was shown to negate the cardioprotective effects of aspirin.[7] Although no cardiovascular interaction has been seen with concomitant use of celecoxib and aspirin, administration of aspirin with a selective COX-2 inhibitor may negate the gastroprotective effects of selective COX-2 inhibition. Despite these concerns, patients using low-dose aspirin for cardioprotection may take NSAIDs. Aspirin's cardioprotective profile may help to decrease the cardiovascular risk associated with NSAID or COX-2 inhibitor use. Furthermore, the addition of a proton pump inhibitor (PPI) may be warranted in certain patients with high GI risk to prevent ulcers and other GI side effects associated with concurrent aspirin and NSAID or COX-2 inhibitor use.[14,17,18]

During treatment with NSAIDs, patients should be closely monitored for increases in blood pressure, signs of edema, decreasing renal function, and GI bleeding. If any of these adverse effects occur, a decrease in dose or a change in drug may be warranted. With each patient case the risks and benefits of treatment should be considered before beginning any one agent. It should be noted that all NSAIDs, including COX-2 inhibitors, can raise blood pressure in some patients. When initiating any NSAID in a patient with high cardiovascular risk, it is important to monitor blood pressure. Concurrent use of NSAIDs with antihypertensive medications has been associated with a decrease in the blood pressure lowering effects of the antihypertensive therapy.

Sat 11th October '14, 8:04pm
Pharmacist's RoleThe significance of pharmacist-patient communication is crucial in informing patients about the risks associated with use of NSAIDs. It is important for pharmacists to monitor patient profiles for NSAID usage as well as to counsel patients with existing cardiovascular disease about the use of OTC NSAIDs. Due to the wide availability of OTC NSAID products, patients may assume they are safe for all and be unaware of the increased cardiovascular risk. These situations provide an opportunity for pharmacist intervention to educate patients on the risk and inform them of preferred alternative therapies for pain management, such as acetaminophen, capsaicin, and other topical products.[1,17]

Notably, healthcare professionals should keep in mind that for patients with arthritis or other comorbid conditions who require NSAID therapy, naproxen appears to be the safest from a cardiovascular perspective. For patients at high risk of NSAID-related GI tract complications, naproxen plus a PPI is less costly, safer, and as effective as low-dose celecoxib. The cardiovascular risk with NSAIDs appears to increase as the dosage and duration of therapy increase. Patients receiving NSAID therapy should be advised to use the lowest effective dose for the shortest duration of time.[12,17]

(The End)