Two analyses of the safety and efficacy of serotonin (5-HT3) receptor antagonists suggest that the most effective therapies for perioperative vomiting are ondansetron plus droperidol IV and granisetron plus dexamethasone (BMC Med 2015;13:136 and 142). Granisetron plus dexamethasone was also found to be one of the most effective therapies for nausea and for postoperative nausea and vomiting (PONV).
However, the studies confirmed that granisetron plus dexamethasone is associated with a high risk for arrhythmia—the number needed to harm is between five and eight. The safest agents in terms of arrhythmia were ondansetron plus dexamethasone and dolasetron (Anzemet, Sanofi-Aventis) monotherapy.
Lead investigator Andrea Tricco, PhD, a scientist at St. Michael’s Hospital in Toronto, Ontario, Canada, and her colleagues were asked by Health Canada to compare the safety of 5-HT3 receptor antagonists in pediatric and adult patients undergoing surgery. They performed a random effects pairwise meta-analysis and network meta-analysis.
The team conducted a comprehensive literature search of multiple electronic databases for studies that examined the safety and efficacy of 5-HT3 medications. The selection method yielded 115 primary publications and five companion reports on six studies for the safety analyses, which included a total of 27,787 patients. For the efficacy analyses, the exclusion criteria yielded 450 studies involving 80,410 patients (Table).
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The vast majority of the included studies were randomized controlled trials, most had a follow-up time of 12 to 24 hours and the majority of subjects were women. The agents in the studies were ondansetron, granisetron, tropisetron, dolasetron, palonosetron (Aloxi, Eisai) and ramosetron, as well as combinations with other antiemetics, such as dexamethasone, butyrophenone and benzamide.
In the studies for the safety comparison, arrhythmia was the most frequently reported outcome (46% of studies). The team determined that the treatments least likely to cause arrhythmia are ondansetron plus dexamethasone, with an odds ratio (OR) of 0.52 versus placebo (95% CI, 0.16-1.68), and dolasetron, with an OR of 0.68 versus placebo (95% CI, 0.46-1.01). The treatment associated with the highest risk for arrhythmia was granisetron plus dexamethasone (OR, 2.96; 95% CI, 1.11-7.94); this translated into a number needed to harm of five to eight.
None of the agents significantly increased the risk for delirium or mortality, but few studies reported these outcomes.
The effectiveness comparison indicated that regardless of patient age, ondansetron plus droperidol IV and granisetron plus dexamethasone are the most effective treatments for vomiting, with ORs of 0.14 (95% CI, 0.08-0.26) and 0.15 (95% CI, 0.09-0.24), respectively, versus placebo. The most effective agents for vomiting in children were ondansetron plus dexamethasone and granisetron plus dexamethasone.
The most effective agents for nausea were granisetron plus dexamethasone and dolasetron plus droperidol IV. In children with nausea, the most effective agents were granisetron plus dexamethasone and ondansetron plus droperidol IV. For PONV, the most effective agents were granisetron plus dexamethasone and ondansetron plus droperidol IV.
Paul S. García, MD, PhD, who was not involved in the studies, told Anesthesiology News that although the studies do not take into account dosage a nd duration, their analytical quality and patient numbers are impressive. Furthermore, he said, the results support the clinical practices of many anesthesiologists.
“We use ondansetron a lot more than granisetron, so I was glad to see that ondansetron combinations are effective and also perhaps safer than granisetron combinations,” said Dr. García, who is director of the neuroanesthesia laboratory and staff physician at the Atlanta VA Medical Center, and also assistant professor of anesthesiology at Emory University, in Atlanta. “But the safety study also showed that granisetron on its own is not terribly dangerous with respect to arrhythmias. It’s really important that we don’t ‘criminalize’ one drug. It is also important to avoid an inflexible drug regimen for common clinical situations.”
Dr. Tricco told Anesthesiology News that the analyses were highly complex, and therefore adding dosage and duration would have been very challenging. She said they intend to include these parameters in their next analyses.
“I think we have some good results from what we’ve done. We can tell you which drugs are the safest and most effective with respect to nausea, PONV and vomiting,” she said. “The results also corroborate and quantify the notion that some of these drugs may increase the risk of arrhythmia.”
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