Pharmacology Watch

ACEIs and ARBs Help Patients with Aortic Stenosis

In this issue: ACEI/ARB therapy for AS; safety alert issued for dronedarone; statins and cancer risk; nesiritide and heart failure; and FDA actions.

ACEI/ARB therapy for aortic stenosis

Drugs that block the renin-angiotensin system are not only safe, they are beneficial in patients with aortic stenosis (AS) according to a new study. This runs counter to current recommendations that suggest that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are relatively contraindicated in patients with AS. The study looked at more than 2000 patients with AS in Scotland, of which the majority had mild-to-moderate stenosis, while about one-quarter had severe AS. Of the total number, nearly 700 were on ACEI or ARB therapy. Over a mean follow-up of 4.2 years, just over half the patients died, of which 48% died from cardiovascular (CV) deaths. Those treated with ACEIs or ARBs had a significantly lower mortality rate (adjusted hazard ratio [HR] 0.76; confidence interval [CI] 0.67-0.92; P < 0.0001) and fewer CV events (adjusted HR 0.77; 95% CI: 0.65-0.92; P < 0.0001) compared to those not on ACEIs/ARBs. The authors conclude that ACEI/ARB therapy is associated with improved survival and lower risk of CV events in patients with AS. These findings were consistent in patients with nonsevere and severe AS. The rate of valve replacement also was lower in patients treated with ACEIs/ARBs (J Am Coll Cardiol 2011;58:570-576). This study was a retrospective observational study and prospective, randomized, controlled trials are warranted to confirm these findings.

Drug safety alert issued for dronedarone

The antiarrhythmic dronedarone (Multaq) is again coming under scrutiny from the FDA after review of the company-sponsored PALLAS study of more than 3000 patients, which showed that the drug is associated with an increased mortality rate in patients with atrial fibrillation (AF). Dronedarone currently is approved for treatment of paroxysmal AF and atrial flutter. The new study investigated its use in patients with permanent AF. The study was halted early when the mortality rate in the treatment group was found to be double the rate in the placebo group (32 deaths [2%] in the dronedarone arm vs 14 [0.9%] in the placebo arm). The rate of unplanned hospitalization and stroke also was double in the dronedarone group vs the placebo group. All findings were statistically significant. These findings led the FDA to issue a drug safety alert on July 21, 2011. This follows a January 2011 drug safety alert regarding rare but severe liver injury associated with use of dronedarone. Currently, the FDA is recommending that physicians should not prescribe dronedarone to patients with permanent AF while they further evaluate the data (FDA Drug Safety Communication at

Statins do not increase risk of cancer

A new retrospective cohort analysis suggests that statins are not associated with an increased risk of cancer. Researchers used the General Electric Centricity electronic medical record database of more than 11 million adult Americans to match nearly 46,000 patient pairs by propensity scores receiving and not receiving statin therapy. With an average time in the database of 8 years, the incidence of cancer in patients taking a statin was 11.37% compared with 11.11% in matched patients not taking a statin (HR 1.04; 95% CI: 0.99-1.09). The authors conclude that this analysis demonstrates no statistically significant increase in cancer risk associated with statins, although they do suggest that more research is needed (J Am Coll Cardiol 2011;58:530-537). Lingering fears about cancer risk associated with statins was strengthened by the SEAS trial published in 2008, which showed the combination drug simvastatin/ezetimibe (Vytorin) was associated with a two-fold increase in the rate of cancer in a small group of patients. The FDA has continued to study these data along with data from other studies, but this new analysis adds significant evidence of a lack of association between statins and cancer.

Nesiritide and heart failure

Nesiritide can no longer be recommended for use in congestive heart failure based on the findings of a new study. The drug is a recombinant B-type naturetic peptide (BNP) that was approved in 2001 for use in patients with acute heart failure. The approval was based on small studies showing a reduction in pulmonary capillary wedge pressure and improvement in dyspnea 3 hours after administration. However, subsequent data raised questions about the drug's safety, especially with regard to worsening renal function and even increased mortality. Based on the recommendations of an independent panel, the manufacturer performed a placebo-controlled randomized trial of more than 7000 patients hospitalized with acute heart failure to assess the drug's safety and efficacy. Patients with heart failure were randomized to receive nesiritide or placebo for 24-168 hours in addition to standard care. The drug was modestly effective at reducing symptoms of dyspnea at 6 and 24 hours. More significantly, however, the rate of rehospitalization for heart failure or death from any cause within 30 days was no different. Nesiritide was not associated with a worsening of renal function but was associated with worsening hypotension. The authors conclude that on the basis of these results, "nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure" (N Engl J Med 2011;365:32-43).

FDA actions

The highly anticipated oral factor Xa inhibitor rivaroxaban has been approved by the FDA to reduce the risk of deep venous thrombosis, blood clots, and pulmonary embolism in patients undergoing knee or hip replacement. The once-a-day medication should be taken for 12 days by patients undergoing knee replacement and 35 days for patients undergoing hip replacement. The approval was based on three studies (RECORD 1, 2, and 3) which showed that rivaroxaban is superior to subcutaneous enoxaparin in this role. Bleeding, the primary side effect of the drug, was no more common with rivaroxaban than enoxaparin. Rivaroxaban also has been looked at in phase III trials for stroke prevention in patients with nonvalvular atrial fibrillation, and treatment and secondary prevention of venous thromboembolism, although the FDA has yet to act on approval for these indications. Rivaroxaban was developed by Bayer and is marketed by Janssen Pharmaceuticals as Xarelto.

The FDA has approved ticagrelor, a new antiplatelet drug for patients with acute coronary syndrome, including unstable angina and myocardial infarction (MI). The approval was based on studies that coupled ticagrelor with low-dose aspirin. The approval recommends use with aspirin although it carries a warning that aspirin doses above 100 mg per day may decrease the effectiveness of the drug. Ticagrelor requires twice a day dosing in contrast to the other drugs in this class, clopidogrel and prasugrel, which can be dosed once daily. The approval was based on the PLATO trial, a head-to-head study with clopidogrel which showed that in combination with aspirin, ticagrelor resulted in the lower composite endpoint of cardiovascular death, stroke, or MI (9.8% vs 11.7% with clopidogrel, P < 0.001).

The FDA has approved six manufacturers for the 2011-2012 flu vaccine. The strains included this year are A/California7/09 (H1N10), A/Perth/16/2009 (H3N2), and B/Brisbane/60/2008 — the exact same components as last year's vaccine. One of the manufacturers, Sanofi Pasteur, has received permission to market Fluzone Intradermal, the first flu vaccine administered via a novel intradermal microinjection that is touted as being more comfortable than intramuscular injections. The new intradermal system in approved for adults ages 18-64 years.

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: