Dolasetron mesylate (Anzemet[R]; Hoechst Marion Roussel) is a new 5-hydroxytryptamine type 3 (5-HT3)antagonist currently undergoing clinical trials as an antiemetic drug [1-3]. The drug has been well tolerated and demonstrated substantial efficacy against the powerfully emetogenic effects of cisplatin chemotherapy [4-7]. Success with dolasetron against chemotherapy-induced emesis prompted evaluation of the drug in other situations that consistently produce nausea and/or vomiting in a significant percentage of patients.
Some surgical procedures commonly result in distressing side effects, such as postoperative nausea and vomiting (PONV) . Anesthetics, preanesthetic medication, surgical manipulation (e.g., suctioning, manipulation of viscera), postoperative medication, and postoperative pain may all contribute to the etiology of PONV. Patient demographic factors, such as gender, obesity, and a previous history of experiencing nausea or vomiting after surgery may increase the likelihood of emesis to some extent.
Many studies have attempted to quantify the incidence of PONV. In general, the incidence of emesis is highest in females of child-bearing age and after certain surgical procedures, including cholecystectomy, gynecological surgery, and laparoscopy . Since patients find nausea and vomiting extremely distressing, methods designed to reduce or eliminate the propensity for these effects are being evaluated. Routine prophylaxis against PONV has been generally unwarranted due to the variable efficacy and side effects of the traditional antiemetic drugs . However, the development of the newer 5-HT3 antagonists has provided more options for the prevention of nausea and vomiting without the sedative or extrapyramidal side effects that may be observed with the more traditional antiemetics .
Our study evaluated three single intravenous (IV) doses of dolasetron mesylate versus placebo in a large group of female patients undergoing outpatient laparoscopic gynecologic surgery. The study was designed to test antiemetic efficacy and safety of this compound over a 24-hour period after surgery.
This multicenter, randomized, double-blind, placebo-controlled study was a parallel-group comparison of the efficacy and safety of three different single IV doses of dolasetron mesylate salt (12.5, 25, or 50 mg) administered approximately 15 min prior to the end of anesthesia in females undergoing outpatient laparoscopic gynecologic surgery. Expressed as dolasetron base, these doses are 9.3, 18.5, and 37 mg, respectively. The antiemetic efficacy of each dolasetron mesylate dose was evaluated over a 24-h postoperative period by monitoring the number and timing of emetic episodes. The effects of dolasetron as an antinausea drug were evaluated by visual analog scales (VAS). The study was approved by the institutional review boards of the respective clinical centers.
Females scheduled for outpatient laparoscopic gynecologic surgery with general anesthesia who were >or=to18 yr of age and not pregnant were eligible for the study. All patients were required to have an ASA physical status of I or II. Any patient who experienced preoperative nausea and/or vomiting within 24 h of surgery or had taken any drug with antiemetic activity within that time was excluded from the study. Patients who had taken an investigational drug within 30 days also were excluded from the study. In addition, patients with significant cardiac conduction abnormalities or major organ dysfunction were excluded, as were those who exceeded ideal body weight by >75%. No surgical procedures other than the primary gynecologic procedure were allowed in patients who took part in the study. Each patient signed a written statement of informed consent prior to participation in the study.
A short-acting barbiturate, such as thiopental, thiamylal, or methohexital, with or without a benzodiazepine, was administered to induce anesthesia. An endotracheal tube was inserted and anesthesia was maintained by nitrous oxide (>or=to66%) and fentanyl (minimum dose: 2 micro g/kg) supplemented with isoflurane. Neuromuscular blocking and reversal drugs were administered as required. An intraoperative or postoperative gastric tube was not allowed.
The study period began when administration of dolasetron or placebo was complete and continued for at least 24 h thereafter. An electrocardiogram (ECG) was obtained 2 h after administration of study drug and clinical laboratory tests were performed prior to discharge from the outpatient surgical center. Adverse event reports were solicited throughout the 24-h post-medication period.
Dolasetron mesylate (12.5, 25, or 50 mg) or placebo was given as a single IV dose approximately 15 min before the cessation of nitrous oxide anesthesia over a minimum of 30 s. Both dolasetron and placebo solutions were provided in identical 10-mL ampules that were appropriately labeled and numbered.
Antiemetic efficacy was assessed by monitoring the timing and frequency of emetic episodes (vomiting and/or retching) after administration of study medication. An emetic episode was defined as either a single or continuous vomit/retch. A continuous vomit or retch was defined as two or more vomits/retches that occurred within 1 min of each other. If the patient experienced continuous vomiting or retching lasting for more than 1 min, each additional minute was considered a separate episode. The study coordinator reported these findings for the first 2 h after dosing; the patient recorded these data on a diary card for the remainder of the 24-h period. A complete response was defined as no emetic episodes and no escape medication within the 24-h period after administration of study medication. Escape antiemetic therapy could be given if the patient experienced continuous nausea for more than 15 min, had more than one emetic episode, or if the patient or physician requested escape therapy.
In addition, a nausea VAS (0 = no nausea; 100 mm = nausea as bad as it could be) was completed by the patient prior to surgery (at baseline) and at 30, 60, 90, and 120 min after administration of study medication. Nausea VAS measurements were also obtained at discharge, upon arrival at home, and at 24 h after administration of study medication. Patients were considered to have no nausea if the VAS was <5 mm; thus, nausea was any VAS reported >or=to5 mm. A patient satisfaction VAS, which ranged from 0 (not satisfied at all) to 100 (as satisfied as could be), also was completed at 24 h postmedication.
The safety of the three doses of dolasetron mesylate and placebo were evaluated by the type and frequency of adverse events over the 24-h study period. Vital signs were observed and recorded prior to the induction of anesthesia, at the end of the administration of study medication (Time 0), at 1, 5, 15, 30, 60, 90, and 120 min poststudy medication, and at discharge. Post-treatment ECGs were performed about 2 h after the administration of study medication. Clinical laboratory tests were performed prior to beginning the study and at discharge.
A sample size of 150 patients per treatment group was required to achieve a power of 85% (two-tailed pairwise comparison, alpha = 0.05) to detect a difference between placebo and the most effective dolasetron mesylate dose (assuming a difference in complete response rates of 20%).
Analysis of variance, logistic regression, or the Cochran-Mantel-Haenszel test were used to detect any differences among dose groups with respect to baseline and demographic characteristics. All analyses of efficacy controlled for dose, investigative site, and stratum when possible. The primary analysis of efficacy was a logistic regression of the proportion of complete responders. The placebo group was compared to each dolasetron mesylate group, beginning with the dose group showing the greatest response, until a dose group was not significantly different from placebo. A stepwise Dunnett's procedure was used to ensure an overall significance level of 0.05. Both an intent-to-treat analysis and an analysis consisting of only those patients with no major protocol deviations were performed. Nausea VAS data were analyzed by logistic regression, while patient satisfaction VAS scores were analyzed using analysis of variance.
Adverse event data were summarized by treatment group and evaluated with respect to dose-related trends using logistic regression. Posttreatment changes in vital signs, clinical laboratory test results, and ECG findings were summarized and analyzed for significant trends using a rank analysis of variance.
Data were analyzed for 635 female patients enrolled in the study at 25 clinical sites. Of these 635 patients (the intent-to-treat population), 612 (96%) had no major protocol deviations and were evaluable for efficacy. No statistically significant differences among the treatment groups were observed at baseline for any patient characteristic (Table 1). Overall, the study population was 70% Caucasian and had a mean age of 32 yr. Approximately 25% of the patients had a previous history of PONV. The anesthesia procedures, including use of muscle relaxants, induction, and reversal drugs were statistically comparable among the treatment groups (Table 2). In addition, there were no differences among the groups in concomitant medications or use of postoperative analgesics that would be expected to influence efficacy or safety data.
In the evaluation of efficacy end points, there were no interactions between dose and investigative site for any of the end points evaluated. The proportion of complete responders in each treatment group for all patients and for patients grouped by history of PONV are shown in Figure 1. Each dolasetron mesylate dose produced statistically (P <or=to 0.0003) higher complete response rates than placebo in the intent-to-treat population (635 patients). Of the 635 patients, 31% in the placebo group achieved a complete response, while complete antiemetic responses occurred in 50%, 52%, and 56% of patients who received dolasetron mesylate 12.5, 25, and 50 mg, respectively. In patients with a history of PONV, complete responses were achieved in 45%, 39%, and 44% of patients treated with dolasetron 12.5 mg, 25 mg, and 50 mg, respectively, while complete responses were achieved in 28% of placebo-treated patients. Complete response rates in patients with no history of PONV were 52%, 55%, and 59% in dolasetron 12.5-mg, 25-mg and 50-mg dose groups, respectively, and 32% in the placebo group. The Kaplan-Meier survival curves shown in Figure 2 represent the time to occurrence of the first emetic episode or use of escape medication by dose. Overall, each dolasetron group had a significantly (P <or=to 0.0003) longer time to the first emetic episode or use of escape medication than the placebo group.
The results of the nausea VAS evaluations were consistent with the efficacy evaluations described above. Patients who received any dolasetron had significantly (P < 0.0357) lower median postdose maximum nausea VAS scores (range, 16 to 20) compared with patients in the placebo group (postdose maximum nausea VAS score = 31). Results for the patient satisfaction VAS showed a statistically significant difference in favor of dolasetron (P = 0.0131).
Safety was evaluated for all 635 patients enrolled in the study. Overall, adverse events that occurred in at least 3% of patients in one or more of the four treatment groups are summarized in Table 3. None of the adverse events showed a statistically significant trend with increasing dose and no significant differences were observed between dolasetron and placebo. Minor, asymptomatic changes in ECG intervals, primarily QT interval prolongation, were observed in all treatment groups and were not considered clinically important; incidences were similar for placebo- and dolasetron-treated patients, 19% and 15%, respectively. Although 15 patients in the study had adverse events considered serious by the investigators, only one of these events was classified as possibly related to the administration of study medication; a patient who received 50 mg of dolasetron mesylate was admitted for excessive drowsiness and tiredness.
The results of this multicenter, randomized, double-blind, placebo-controlled, parallel-group study demonstrate that IV dolasetron mesylate is well tolerated and effective in preventing PONV in females undergoing outpatient laparoscopic gynecologic surgery. It is important to note that because propofol has the potential to reduce emesis [8,11], and, therefore, confound the results of the study, induction with barbiturates was used in this study. The proportion of patients with no emetic episodes within the 24-hour postoperative monitoring period was significantly greater for each of three dolasetron mesylate doses compared with placebo. These results compare favorably with those reported for oral or IV ondansetron in similar situations [12-16]; however, studies that directly compare the antiemetic efficacy of dolasetron and ondansetron are necessary. Because the differences between dolasetron mesylate doses were small, the smallest dose (12.5 mg) appears to be an appropriate choice for prevention of PONV in this patient population.
IV dolasetron was well tolerated by all patients in this study. No clinically significant safety issues were observed, and vital signs and clinical laboratory test results were unremarkable. Minor asymptomatic changes in some ECG intervals (PR, QRS, QT) were noted for patients who received dolasetron as well as for patients who received placebo, but were not considered to be clinically significant. These data are consistent with those reported in studies of other 5-HT3 antagonists [17-20] and other dolasetron studies [2,6,19,21,22]. One incidence of serious drowsiness and tiredness was possibly related to dolasetron administration. Most events were either related to the surgical procedure or to various concomitant medications used.
As nausea and/or vomiting are common postoperative conditions, patients scheduled for surgery are understandably concerned about these symptoms [8,11,23]. Both emesis and the incidence of nausea were significantly reduced by dolasetron treatment in a group of patients (females undergoing laparoscopic gynecologic surgery) that traditionally have high rates of emesis and nausea after surgery. It is important to note that the reduction in nausea observed with dolasetron treatment was demonstrated on patient evaluations rather than on subjective scales rated by the investigators. The need or request for escape antiemetic medication was similarly lower with dolasetron than with placebo. An additional benefit is the relative lack of bothersome side effects directly related to the administration of dolasetron. The incidence of adverse events with dolasetron was similar to placebo. As a consequence, patient satisfaction with dolasetron treatment was very high and was also significantly greater than with placebo.
This large, well-controlled study clearly demonstrates that IV dolasetron mesylate is effective for the prevention of PONV. A high level of efficacy was observed even at the smallest dose of dolasetron mesylate used in the trial (12.5 mg). In clinical situations in which nausea and vomiting are expected consequences, dolasetron is safe and effective for intraoperative prophylaxis.
The authors wish to thank Marc S. Eisenberg, PhD, and Neil Malone for their editorial assistance with this manuscript.
The authors wish to thank the following investigators who had a substantial role in the conduct of this study: Said Azad, Philadelphia, PA; Jared C. Barlow, Williamsville, NY; Gwendolyn Boyd, Birmingham, AL; Christina Campbell, Indianapolis, IN; Robert L. Coleman, Durham, NC; Charles B. Hantler, San Antonio, TX; Stephen Heard, Worcester, MA; W. LeRoy Heinrichs, Stanford, CA; Jonathan Jahr, New Orleans, LA; Leonard Lind, Cincinnati, OH; Donald Martin, Hershey, PA; Charles H. McLeskey, Temple, TX; Robert L. Moran, Albany, NY; Beverly Philip, Boston, MA; Julie Pollock, Seattle, WA; Benjamin M. Rigor, Sr., Louisville, KY; Phillip Scuderi, Winston-Salem, NC; Daneshvari R. Solanki, Galveston, TX; Rebecca Twersky, Brooklyn, NY; Mary Whitley, Washington, DC.
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