Pharmacology Watch

Is Naproxen the Safest NSAID for the Heart?

In this issue: NSAIDs and cardiovascular risk; new antithrombotic guidelines; warfarin during surgery; Pfizer selling Viagra online; azithromycin and cardiovascular risk; and FDA actions.

NSAIDs associated with less vascular risk

Naproxen may be the safest anti-inflammatory — at least when it comes to cardiovascular risk — according to a new study. Researchers from the United Kingdom undertook a meta-analysis of 280 trials of non-steroidal anti-inflammatory drugs (NSAIDs) vs placebo and 474 trials of one NSAID vs another. Main outcomes were major vascular events, major coronary events, stroke, mortality, heart failure, and upper gastrointestinal (GI) complications including bleeding. All NSAIDs and COX-2 inhibitors (coxibs) increased major vascular events except for naproxen (rate ratio [RR], coxibs 1.37 [95% confidence interval (CI), 1.14-1.66; P = 0.0009] and diclofenac 1.41 [95% CI, 1.12-1.78; P = 0.0036] mostly due to an increase in major coronary events). Ibuprofen also significantly increased the risk of major coronary events (RR 2.22, 95% CI, 1.10-4.48; P = 0.0253), but not major vascular events. Naproxen did not significantly increase the risk of major vascular events. Coxibs and diclofenac also significantly increased risk of vascular death, and there was a nonsignificant increase with ibuprofen, while there was no increase with naproxen. Heart failure risk was roughly doubled by all NSAIDs. The risk of upper GI complications was lowest with coxibs and highest with naproxen (coxibs 1.81, 95% CI, 1.17-2.81; P = 0.0070; diclofenac 1.89, 95% CI, 1.16-3.09; P = 0.0106; ibuprofen 3.97, 95% CI, 2.22-7.10; P < 0.0001, and naproxen 4.22, 95% CI, 2.71-6.56; P < 0.0001). The authors conclude that the vascular risks of diclofenac and possibly ibuprofen are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk (but higher GI risk) than other NSAIDs (Lancet published online May 30, 2013). The authors speculate that high-dose naproxen has fewer cardiovascular effects because it is the strongest inhibitor of COX-1, resulting in near complete suppression of platelet thromboxane biosynthesis (thus blocking platelet aggregation) throughout the 12-hour dosing interval.

New antithrombotic guidelines

A new guideline from the American Academy of Neurology gives primary care doctors guidance on periprocedural management of antithrombotic medications in patients with a history of stroke. Among the recommendations is that stroke patients undergoing dental procedures should routinely continue aspirin. Aspirin should also be considered for continuation in stroke patients undergoing invasive ocular anesthesia, cataract surgery, dermatologic procedures, transrectal ultrasound-guided prostate biopsy, spinal/epidural procedures, and carpal tunnel surgery. Aspirin should possibly be continued during other procedures such as virtroretinal surgery, EMG, transbronchial lung biopsy, colonoscopic polypectomy, upper endoscopy and biopsy/sphincterotomy, and abdominal ultrasound-guided biopsies. For stroke patients on warfarin, the guideline recommends continuation of the drug during dental procedures and probably during most dermatologic procedures. Other more invasive procedures should warrant discussion. The guideline states there is insufficient evidence to support or refute periprocedural heparin-bridging therapy to reduce thromboembolic events in chronically anticoagulated patients. Bridging therapy is probably associated with increased bleeding risk as compared with warfarin cessation, but the risk difference compared with continuing warfarin is unknown (Neurology 2013;22:2065-2069).

Continuing warfarin for surgery

In related news, a new study suggests that continuing warfarin for pacemaker or defibrillator surgery is safer than heparin bridging. Nearly 700 patients with an annual risk of thromboembolic events of 5% who required pacemaker or defibrillator surgery were randomized to continued-warfarin treatment or bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which occurred in 12 of 343 patients (3.5%) in the continued-warfarin group as compared with 54 of 338 (16.0%) in the heparin-bridging group. There was one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one TIA in the continued warfarin group. This study was stopped early after interim analysis found that the primary outcome occurred four times as often in the heparin-bridging group. These findings suggest that a strategy of continued warfarin therapy at the time of pacemaker or defibrillator surgery markedly reduced incidence of clinically significant device pocket hematoma as compared with heparin bridging (N Engl J Med 2013;368:2084-2093).

Pfizer launches own Viagra website

Pfizer is aggressively pursuing the online market for sildenafil (Viagra) by launching its own "Viagra home delivery" website. The drug will be available online directly from Pfizer but will still require a doctor's prescription. This move is also designed to counter online marketing of counterfeit Viagra, the most commonly counterfeited drug in the world. Pfizer plans to make Viagra available online at approximately $25 a pill. Meanwhile, the company has lost patent protection for its other version of sildenafil citrate marketed for pulmonary hypertension under the trade name Revatio. This version of the drug is only available in 20 mg strength, but is otherwise identical to Viagra, which is available in 25, 50, and 100 mg strengths. It is yet to be seen whether physicians will prescribe generic 20 mg sildenafil off label for erectile dysfunction.

Azithromycin and cardiovascular risk

Does azithromycin increase cardiovascular (CV) risk? A recent observational study showed that azithromycin was associated with a 2-3 times higher risk of death from CV disease in patients at high risk for CV disease (N Engl J Med 2012;366:1881-1890). A new study looks at the risk of the drug vs placebo and a comparator antibiotic (penicillin V) in Danish adults ages 18-64. As compared with no use of antibiotics, use of azithromycin was associated with a significantly increased risk of CV death (rate ratio 2.85; 95% CI, 1.13-7.24); however, when compared to penicillin V, there was no increased risk (crude rate CV death 1.1/1000 person years azithromycin vs 1.5/1000 penicillin V). With adjustment for CV risk, current azithromycin use was not associated with increased risk of CV death compared with penicillin V in a general population of young and middle-aged adults. (N Engl J Med 2013;368:1704-1712). This study is reassuring, suggesting that the increased risk of death is probably due to the illness rather than the drug, especially in low-risk populations. However, the risk of the macrolides still should be considered among patients with a high baseline risk of CV disease.

FDA actions

The FDA has approved a new once-daily combination inhaler for the treatment of chronic obstructive pulmonary disease (COPD). The product combines the long-acting beta-agonist (LABA) vilanterol with the steroid fluticasone furoate. Vilanterol is a new LABA and fluticasone furoate is reported to have longer lung retention time compared to the proprionate allowing for once-daily dosing. The product is a dry powder that is delivered via the Ellipta device. The new inhaler was evaluated in 7700 patients with COPD and showed improved lung function and reduced exacerbations compared to placebo. Vilanterol/fluticasone furoate is marketed by GlaxoSmithKline in collaboration with Theravance as Breo Ellipta.

The FDA has approved a new cholesterol combination drug, combining ezetimibe and atorvastatin. The drug is indicated for lowering cholesterol in patients with primary or mixed hyperlipidemia and in those with homozygous hypercholesterolemia. It is approved in four strengths, each containing 10 mg of ezetimibe with 10, 20, 40, or 80 mg of atorvastatin. The combination reduces LDL cholesterol levels up to 61% in clinical trials. Like the previously marketed simvastatin/ezetimibe, there is no evidence that the combination improves cardiovascular outcomes over a statin alone. The combination will be marketed by Merck as Liptruzet.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5404. E-mail: