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Journal of the American Academy of Physician Assistants:
doi: 10.1097/01.JAA.0000444738.62411.83
Pharmacology Consult

How can NSAIDs harm cardiovascular and renal function?

McDowell, Kimberly; Clements, Jennifer N. PharmD, BCPS, CDE, BCACP

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At Presbyterian College School of Pharmacy in Clinton, S.C., Kimberly McDowell is a PharmD candidate and Jennifer N. Clements is an associate professor of pharmacy practice. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Mary Lou Brubaker, PharmD, PA-C, department editor

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ABSTRACT: Consider the potential cardiovascular and renal effects of nonsteroidal anti-inflammatory drugs when evaluating a patient for short- or long-term use of these drugs. Monitoring and extensive counseling is warranted with this particular class of medications.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most commonly used by adults to manage musculoskeletal pain. Lower doses and intermittent use of NSAIDs are often adequate for analgesia. NSAIDs' anti-inflammatory properties often make them a favorable option over acetaminophen. Prescribers typically offer higher doses with scheduled use when anti-inflammatory effects are desirable.

The determination to prescribe a particular NSAID frequently is based on safety and tolerability concerns. Of the two classes of NSAIDs (based on their selectivity to cyclooxygenase [COX] enzymes), COX-2 selective NSAIDs have an advantage over nonselective NSAIDs for gastrointestinal (GI) safety.1 NSAIDs commonly cause GI adverse events, which may even result in ulcers, but PAs also should know about potential cardiovascular and renal toxicities. With appropriate patient selection and monitoring, NSAIDs are safe and effective treatments for a wide array of acute and chronic conditions involving pain or inflammation.

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Although we do not completely understand how NSAIDs work, we know that they inhibit prostaglandin production. Cyclooxygenases serve as catalysts in the metabolism of arachidonic acid into prostaglandins. The role of NSAIDs on both COX-1 and COX-2 has been well described. COX-1-associated prostaglandins are physiologically involved in maintaining integrity of GI mucosa, gastric acid secretion, and platelet adhesion. COX-2-associated prostaglandins are inducible and predominantly mediate pain and inflammation. NSAIDs can inhibit the COX enzymes; inhibition of COX-1 prevents normal homeostasis of the GI tract, platelets, and kidneys. This is why COX-2-selective NSAIDs are preferred over nonselective agents in some patients. Disruption of both COX-1- and COX-2-associated prostaglandins is linked to renal injury. COX-1 is primarily involved in the control of renal hemodynamics and glomerular filtration; COX-2 is primarily involved in salt and water excretion.

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In general, most NSAIDs (both nonselective and COX-2 selective) have relatively similar effects on kidney function. The most common clinical features of NSAID-associated kidney injury include hypertension, salt and water retention, and hyperkalemia. Despite widespread use of these drugs, these effects are relatively uncommon. The challenge is that some patients are at increased risk for kidney injury, and may be particularly susceptible to NSAID-induced renal toxicities.

Consider the previously described roles of prostaglandins in the kidneys. In patients with normal renal function and normal renal hemodynamics, prostaglandins do not play a substantial physiologic role in maintaining renal blood flow. This is dramatically different in patients with abnormal renal hemodynamics; for example, consider a patient with a decreased circulating volume. In this patient, sympathetic nervous system activation results in vasoconstriction and increased sympathetic tone. The kidneys, in turn, produce vasodilating prostaglandins to balance the effects of vasoconstricting substances and to support renal perfusion. In this patient, prostaglandins become integral to maintaining glomerular filtration rate. Inhibition of prostaglandin production by NSAIDs can result in a myriad of adverse reactions, from hyperkalemia and acute renal failure to peripheral edema, elevated BP, and cardiac congestion.

Patients at highest risk for these NSAID-associated toxicities include those with advanced age and age-associated declines in GFR, hypovolemia, heart failure, liver cirrhosis, diabetes, hypertension, or nephrosis. The mechanisms of renal injury by NSAIDs can overlap with functional renal insufficiency associated with other drugs; combining NSAIDs with loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers can be harmful.

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NSAID-associated cardiovascular events include interference with antiplatelet therapies, worsening of heart failure, increased BP, and diminished effect of concurrent antihypertensive therapies such as ACE inhibitors or thiazide diuretics.3

The antiplatelet effects of drugs such as aspirin are mediated through binding to COX-1. When another NSAID is administered before aspirin, it can compete with and prevent aspirin binding to COX-1. Other mechanisms for how NSAIDs might interfere with the effects of antiplatelet drugs have been reported as well, but are beyond the scope of this article.

In patients with established cardiovascular disease, NSAIDs can worsen preexisting symptoms, such as symptoms of heart failure. Prostaglandin inhibition by NSAIDs can result in decreased renal perfusion and compensatory retention of sodium and water, which can reduce the effectiveness of diuretics used by patients with heart failure. Additionally, the physiologic compensatory responses (such as systemic vasoconstriction) triggered by the NSAID can worsen the patient's underlying cardiovascular condition. Consider why clinicians routinely prescribe medications that reduce sympathetic tone in patients with chronic cardiovascular disease. Medications such as ACE inhibitors or beta-blockers have demonstrated significant benefits on morbidity and mortality across numerous cardiovascular diagnoses, including heart failure. However, the incorporation of NSAID therapy can be counterproductive, if not directly harmful to these patients.

COX-2 inhibitors were developed to not only provide a selective mechanism of action, but also to prevent certain adverse reactions such as platelet aggregation due to lack of COX-1 inhibition. However, clinical evidence with rofecoxib and valdecoxib showed increased risk of cardiovascular events.4,5 COX-2 inhibitors may inhibit prostacyclin, a vasodilator that inhibits platelet aggregation and smooth-muscle proliferation. Therefore, inhibition of prostacyclin may lead to an increased risk of thrombosis.

Based on the evidence, increased thrombosis risk secondary to prostacyclin varies among COX-2 inhibitors. The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial compared rofecoxib (since withdrawn from the US market) 50 mg daily to naproxen 500 mg twice daily and ibuprofen 800 mg twice daily.4 The trial showed that rofecoxib decreased the relative risk of developing a clinical upper GI event (the study's primary endpoint) by 50%, which indicated that the number-needed-to-treat to prevent one upper GI event with rofecoxib was 62 after 9 months. However, this trial demonstrated an increased risk of cardiovascular complications, with the incidence of myocardial infarction (MI) fourfold greater in the patients on rofecoxib (0.4% versus 0.1% for those on naproxen).4

The Adenomatous Polyp Prevention on Vioxx Study was designed to investigate the role of rofecoxib in preventing polyps. However, it was terminated after 18 months due to increased risk of MI in the patients on rofecoxib (a fourfold increase in MI with rofecoxib 25 mg daily over 18 months). Other findings in the patients on rofecoxib were cardiac events (n = 46) and cerebrovascular events (n = 11). Some patients in the trial were taking 81 mg of aspirin per day for cardioprotection; the presence of aspirin did not change the results.5

Based on these two trials, it was concluded that rofecoxib 50 mg daily had the greatest cardiovascular risk.4,5 The risk of cardiovascular events from celecoxib was investigated, and no increased risk was associated with 200 mg daily.6 Valdecoxib (also since withdrawn from the US market) had contradicting results; 19 trials with more than 12,000 patients found no increased risk of cardiovascular events. However, a higher incidence of cardiovascular events was found among high-risk patients who had undergone coronary artery bypass graft surgery and were taking valdecoxib.7

Based on this evidence of the COX-2 inhibitors, the FDA and an advisory committee added a black-box warning of cardiovascular risk to COX-2 inhibitors.4–9 However, rofecoxib and valdecoxib were both subsequently withdrawn from the market, leaving celecoxib as the only available COX-2 inhibitor.

In these trials, naproxen was a comparator intervention, and was found not to increase the risk of cardiovascular events and not cardioprotective. Prescribers who decide to prescribe an NSAID in patients who have a history of or are at risk of cardiovascular events should consider limiting the NSAID dose and duration.8,9

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Counsel patients receiving NSAIDs about the cardiovascular risk and frequently monitor renal function in high-risk patients. In high-risk patients, to reduce the risk of cardiovascular events, avoid NSAIDs or use the lowest dose of an NSAID for the shortest period of time. Decreased renal function is not an absolute contraindication for NSAID use as long as the NSAID is selected carefully and the patient managed optimally. Patients who should avoid NSAIDs include those who take low-dose aspirin for cardioprotection, patients concomitantly using antihypertensives, and patients who are dehydrated. For all patients, the risk and benefit of short- or long-term NSAID use should be assessed before therapy, and if therapy is initiated and continued, monitoring and extensive counseling are warranted.

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1. American College of Rheumatology. NSAIDs: nonsteroidal anti-inflammatory drugs. Anti-inflammatory Drugs. Accessed October 19, 2013.

2. Nolin T, Himmelfarb J. Drug-induced kidney disease. In: Dipiro JT, Talbert RL, Yee GE, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw Hill; 2011:827–828.

3. Hawboldt J. Adverse events associated with NSAIDs. US Pharm. 2008;33(12):HS5-HS13.

4. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343(21):1520–1528.

5. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11):1092–1102.

6. Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med. 2005;352(11):1071–1080.

7. Nussmeier NA, Whelton AA, Brown MT, et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med. 2005;352(11):1081–1091.

9. FDA public health advisory: FDA announces important changes and additional warnings for COX-2 selective and non-selective nonsteroidal anti-inflammatory drugs. Accessed October 22, 2013.


nonsteroidal anti-inflammatory drugs; cardiovascular; renal; rofecoxib; valdecoxib; adverse drug reaction

© 2014 American Academy of Physician Assistants.


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