Pharmacology Watch

Do Perioperative Beta-Blockers Reduce Mortality?

In this issue: Beta-blockers and noncardiac surgery; prenatal medication exposure and risk of autism; reasons for statin discontinuations; and FDA actions.

Perioperative beta-blockers

The use of perioperative beta-blockers has been debated for decades. Now, a large study from the U.S. Department of Veterans Affairs (VA) suggests that the drugs may be of benefit in selected patients. In a retrospective cohort analysis, exposure to beta-blockers on the day of or the day following noncardiac surgery was evaluated among a population-based sample of nearly 137,000 patients from 104 VA medical centers. The main outcome was all-cause 30-day mortality and cardiac morbidity. Overall, 55,138 patients (40%) were exposed to beta-blockers, although the rate was nearly 68% in those undergoing vascular surgery. Exposure increased with increased cardiac risk factors. Death occurred in just over 1% of patients and cardiac morbidity occurred in just under 1%. Overall, exposure to beta-blockers was associated with a lower mortality (relative risk [RR] 0.73%; 95% confidence interval [CI], 0.65-0.83; P < 0.001; number needed to treat [NNT], 241). The effect was greater in patients with higher cardiac risk factors, which include high-risk surgery, cerebrovascular disease, ischemic heart disease, heart failure, diabetes, and renal insufficiency. When stratified by the revised Cardiac Risk Index variables, patients with two or more cardiac risk factors had a RR of 0.63 (95% CI, 0.50-0.80; P < 0.001; NNT, 105), with three risk factors the RR was 0.54 (95% CI, 0.39-0.73; P < 0.001; NNT, 41), and with four or more risk factors the RR was 0.40 (95%CI, 0.25-0.73; P < 0.001; NNT, 18). This effect was limited to patients undergoing nonvascular surgery. Beta-blocker exposure also significantly reduced the rate of nonfatal Q-wave infarction or cardiac arrest by 37%. The authors conclude that in patients undergoing noncardiac, nonvascular surgery, perioperative beta-blockers significantly reduced 30-day all-cause mortality in patients with two or more cardiac risk factors and support the use of the drugs in these patients. They also suggest a multicenter randomized trial to assess the benefit in patients with low-to-intermediate risk. The authors were unable to find a benefit in stroke risk or in patients undergoing vascular surgery. They were also unable to determine if various beta-blockers (such as metoprolol vs atenolol) were of benefit or if the benefit was from various dosing regimens. (JAMA 2013; 309:1704-1713).

Medication use and pregnancy

Two studies suggest that certain medications used during pregnancy may increase the risk of autism in offspring. In the first, which looked at antidepressants in pregnancy, researchers from Sweden reviewed the records of 4429 children with autism spectrum disorder (ASD) as well as 43,000 age- and sex-matched controls. A history of maternal, but not paternal, depression was associated with an increased risk of ASD and the association was confined to women reporting antidepressant use during pregnancy (adjusted odds ratio 3.34; 95% CI, 1.50-7.47; P = 0.003). This association was irrespective of whether serotonin reuptake inhibitors or non-selective monoamine reuptake inhibitors (tricyclic antidepressants) were used. The association was confined to autism without intellectual disability. Still, the use of antidepressants accounted for only 0.6% of cases of ASD during the study, so the drugs were "unlikely to have contributed significantly towards the dramatic increased prevalence of autism spectrum disorders" (BMJ 2013;346:f2059). In the other study, researchers from Denmark reviewed the records of children exposed in utero to valproate (used to treat seizures and other neuropsychological disorders in mothers). Of more than 655,000 children born between 1996 and 2006, 5437 identified with ASD, including 2067 with childhood autism. The overall risk of autism in all children was 1.53%, but of the 508 children exposed to valproate, the absolute risk was 4.42% (95% CI, 2.59-7.46%) for ASD and 2.50% (95%CI, 1.30-4.81%) for childhood autism (adjusted hazard ratio, 5.2). The risk was similar regardless of the indication for use of valproate in the mother. These findings suggest that maternal use of valproate significantly increases the risk for ASD and childhood autism in offspring. The authors suggest that a risk-benefit analysis should be considered for women on valproate in their childbearing years (JAMA 2013;309:1696-1703).

Discontinuation of statins

Most patients who stop statins due to side effects will tolerate the drugs if rechallenged, according to the findings of a new study. In a retrospective cohort study using data from two Boston hospitals, researchers reviewed the records of nearly 108,000 patients on statins and found statin-related events such as muscle pain documented in 18,778 (17.4%). Of those patients, 11,124 stopped the drugs at least temporarily and 6579 were restarted within the subsequent 12 months. The vast majority of patients restarted on a statin tolerated the drug (92.2%), although about half were eventually switched to a different statin. The authors conclude that statin-related side effects are common and often lead to discontinuation; however, most patients who are rechallenged can tolerate statins long-term. They suggest that "statin-related events may have other causes, are tolerable, or may be specific to individual statins rather than the entire drug class" (Ann Intern Med 2013;158:526-534).

FDA actions

The FDA has updated labeling of the new tamper-proof oxycodone (OxyContin), while at the same time denying approval of generic forms of the original formulation of oxycodone. The new labeling indicates that the product "has physical and chemical properties that are expected to make abuse via injection difficult and to reduce abuse via the intranasal route (snorting)." The agency's refusal to approve generic forms of the original formulation was based on the increased risk of abuse inherent in the non-tamper proof form leading to the risk of serious adverse events including overdose and death. Because of this, the agency has determined that the benefits of the original OxyContin and its generics no longer outweigh its risks and it has been withdrawn from sales. The new tamper-proof formulation is more difficult to crush, break, or dissolve. If tampered with, it forms a viscous hydrogel that cannot be easily injected or snorted. Oral abuse is still possible.

The FDA has approved a fixed combination of doxylamine succinate and pyridoxine for the treatment of nausea and vomiting due to pregnancy. This is a reintroduction of a product widely used between 1956 and 1983. Then marketed as Bendectin, the product was voluntarily withdrawn by the manufacturer due to lawsuits related to birth defects, although evidence of risk was not supported by scientific evidence. The reapproval was based on a study of 261 women experiencing nausea and vomiting due to pregnancy in which the drug was more effective than placebo in relieving symptoms. Since the 1980s, observational studies have shown that doxylamine and pyridoxine do not pose an increased risk of harm to the fetus. The recommended starting dose is two tablets taken at bedtime on an empty stomach. The combination is marketed by Duchesnay Inc. as Diclegis.

The FDA has approved prothrombin complex concentrate for the rapid reversal of anticoagulation by warfarin and other vitamin K antagonists. Plasma is the only other option for this use currently available, and prothrombin complex can be given at significantly lower volume than plasma. The product is made from pooled plasma of healthy donors that is processed to minimize the risk of viral and other diseases. The approval was based on a study of 216 patients who were anticoagulated and had major bleeding. Plasma complex concentrate was found to be similar to plasma in its ability to stop major bleeding. Plasma complex concentrate is marketed by CSL Behring as Kcentra.

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: