The safety of NSAIDs in heart failure patients
Heart failure is the most common hospital discharge diagnosis in patients older than 65 years. Typically, HF patients take four to five medications and additional medications for a myriad of other medical conditions. This puts the elderly at increased risk of drug interactions, unwanted side effects and non-compliance. CV and inflammatory diseases commonly coexist in the elderly who are the most frequent users of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors.
Although recent clinical trials have questioned the CV safety of NSAIDs, they remain the mainstay for therapy of acute and chronic pain conditions. CV risks associated with NSAIDs, particularly selective COX-2 inhibitors, have mainly focused on increased risk for thrombotic events due to relative increase in thromboxane. However, NSAIDs and selective COX-2 inhibitors exert therapeutic and adverse effects by inhibiting prostaglandin synthesis, resulting in decreased renal blood flow; compensatory retention of sodium and water; and increased vascular resistance. These antinatriuretic and vasoconstrictive properties of NSAIDs can destabilize BP control; amitigate the effectiveness of antihypertensive agents; and exacerbate HF. Additional risk factors (ie, diabetes, advanced age, hypertension and renal insufficiency) can further predispose patients with HF to the detrimental effects of NSAIDs. Hypertension is one of the most common etiologies for HF. Patients who are taking renin angiotensin system-blocking agents (ACE inhibitors, angiotensin receptor blockers, rennin inhibitors or beta-blockers) either alone or in combination with diuretics may be at particular risk of deterioration in BP control with NSAID therapy. Even small NSAID-induced rises in BP may significantly increase CV risk in these patients if sustained over time. Also, the ALLHAT trial suggested a 3.3 mm Hg increase in systolic BP may explain a 10% to 20% increase in HF. One large study looked at the safety of different NSAIDs in patients with heart disease and found that naproxen may have better CV safety compared with other drugs in this class. However, recent studies in two separate cohorts of patients with MI and HF showed a dose-related increase in the risk of death and re-hospitalizations for MI and HF with all COX-2 inhibitors and some non-selective NSAIDS, including naproxen. Interestingly, a rather small pilot study in HF patients showed that once patients were educated that NSAIDs could potentially worsen HF, they would rather avoid taking NSAIDs.
American College of Cardiology/American Heart Association practice guidelines recommend avoiding NSAIDs whenever possible in patients with HF. Guidelines also recommend exercise training in stable HF patients. Even though the HFACTION trial failed to show significant reductions in the primary endpoint of all cause mortality and morbidity between highly structured exercise program and usual care, it showed an improvement in the quality of life. However, implementation of structured exercise in the presence of chronic pain and reduced exercise tolerance can be rather challenging. Therefore, new approaches are being evaluated for treatment of chronic pain management while minimizing adverse effects of NSAIDs.
A unique class of anti-inflammatory drugs known as COX-inhibiting nitric oxide donators (CINODs) is currently under regulatory review for treatment of osteoarthritis. Naproxcinod (NicOx) is a nitric oxide derivative of naproxen and is metabolized into naproxen and a nitric oxide donator. Evidence suggests that nitric oxide plays a major role in regulating BP and improves renal and coronary blood flow. Preclinical studies of naproxcinod have shown similar analgesic activity to naproxen but with fewer gastrointestinal side effects and reduced systemic BP (2-3 mm Hg) compared with NSAIDs. Whether these results will translate into fewer CV events or reduction in HF will be determined after the drug is widely available. This drug may also be safer in renal patients due to the vasoprotective properties of nitric oxide, in whom NSAIDs are usually avoided.
Until safer alternatives are available, NSAIDs should only be prescribed after careful consideration of the balance between risk and benefits. When initiating NSAIDs in high-risk patients, diligent monitoring should be instituted (eg, BP, renal function, weight fluctuations and HF symptom assessment) within one week of initiation and monthly thereafter. Whenever possible, NSAIDs should be prescribed for short-term use and at lower doses. If stronger analgesic effects are needed, other alternatives should be considered (e.g., acetaminophen, weak opiates). Patients should be made aware that over-the-counter NSAIDs carry similar safety concerns to prescription NSAIDs.
For more information:
- Cottrell N. Clin Ther. 2007;29:717-719.
- Gislason G. Circulation. 2006;113:2906-2913.
- Gislason G. Arch Intern Med. 2009;169:141149.
- OConnor C. JAMA. 2009; 301:1439-1450.
Harleen Singh, PharmD, is a clinical associate professor of pharmacy at the Oregon Health and Science Universitys College of Pharmacy in Portland, Ore.
Joel C. Marrs, PharmD, is an assistant professor of pharmacy at the University of Colorado Anschutz Medical Campus School of Pharmacy in Denver.
The article was edited by Rhonda Cooper-DeHoff, PharmD, MS. Cooper-DeHoff is an associate professor at the University of Florida College of Pharmacy in Gainesville, Fla., and is Cardiology Todays Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board.