Evaluation of Three 5-HT 3

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1 Evaluation of Three Receptor Antagonists in the Prevention of Postoperative Nausea and Vomiting in Adults Shan Wang, PharmD, Joseph Greco, MD, Reena A. Joseph, PharmD Candidate, Martin Feuerman, MS, and Brian Malone, MS ABSTRACT Objective: Our primary goal was to determine the most cost-effective antiemetic agent among three 5-hydroxytryptamine-3 ( ) receptor antagonists (dolasetron, ondansetron, and granisetron) in preventing postoperative nausea and vomiting (PONV) in adult patients at a 600-bed teaching hospital. Methods and Study Population: We performed a retrospective chart review for 300 randomly selected men and women who underwent various abdominal, orthopedic, and gynecological surgical procedures. Eighteen patients were excluded from the study because they had received combination therapy at the outset. Therefore, 282 patients were included (65% women and 35% men). There were 89 patients in the dolasetron group, 93 in the ondansetron group, and 100 in the granisetron group. The patients received the antagonists either under anesthesia or postoperatively. Our focus was to determine the percentage of patients in each group who required additional rescue medications for PONV. We also performed a costeffectiveness analysis from the perspective of an institutional setting for this study. Results: Overall, about 20% of the patients required a rescue medication. The rescue rate for those receiving ondansetron was 11.8%; for those receiving dolasetron, it was 23%; and for those receiving granisetron, it was 24%. The combined rescue rate for dolasetron and granisetron was significantly higher than that for ondansetron alone. Ondansetron offered a statistically significant reduced median length of stay in the recovery room (2 hours), compared with dolasetron (3.3 hours) and granisetron (3 hours). These results were confirmed in a multivariate analysis in which we controlled for baseline variables. From the costeffectiveness analysis, we estimated that by using ondansetron, we could reduce the probability of a patient s needing a rescue drug by about 50% for a nominal increase in the cost per patient ($5.50). Conclusion: Compared with either granisetron or dolasetron or a combination of the two, ondansetron was associated with a lower rescue medication rate when used for the prevention of PONV, was more cost-effective in preventing PONV, and was more effective in reducing recovery-room time. Dr. Wang is a Clinical Pharmacist, Dr. Greco is Chairman of the Department of Anesthesiology, Ms. Joseph is a student, Mr. Feuerman is a Biostatistician in the Office of Academic Affairs, and Mr. Malone is Director of the Department of Pharmacy, all at Winthrop University Hospital in Mineola, New York. INTRODUCTION At Winthrop University Hospital, we set out to determine the most cost-effective agent among three 5-hydroxytryptamine-3 ( ) receptor antagonists ondansetron (Zofran, GlaxoSmithKline), granisetron (Kytril, Roche), and dolasetron (Anzemet, Aventis) in preventing postoperative nausea and vomiting (PONV). PONV is a major complication for patients undergoing surgical procedures. 1,2 Four major risk factors influence the severity of PONV: 1. Patient characteristics. Younger age, female sex, obesity, a history of migraine, and gastroparesis are some patientspecific factors. 2. Duration and type of procedure. In general, the longer the surgical procedure, the greater the likelihood and severity of PONV. 2 Gynecological, abdominal, laparoscopic, ophthalmic, and otolaryngological operations are associated with a higher incidence of PONV. 3. Type of anesthetic agent used. Anesthetics such as opioid analgesics, nitrous oxide, and inhalation agents are also known to increase the incidence of PONV. Patients who receive general anesthesia experience nausea and vomiting at rates of 37% and 20%, respectively. 4. Aspects associated with the postoperative recovery period. Postoperative risk factors include pain, dizziness, early ambulation, the use of opioids, hypotension, and premature oral intake. 1,3 Although the exact pathophysiology of PONV is not fully understood, it is believed to be the result of a compilation of several pathways in the vomiting center located in the brain. 1 These include impulses from the chemoreceptor trigger zone (CTZ), the vestibular system associated with motion sickness; the higher cortical centers; the vagus nerve, which brings signals from the gastrointestinal tract; and the spinoreticular system, which triggers nausea related to physical injury. 4 Some causes of PONV include pharyngeal stimulation, gastrointestinal distention, abdominal surgery, anesthetic agents, opioid medications, and vestibular disturbances. Antiemetic agents are considered the first-line therapy in preventing and treating PONV. Prophylaxis is recommended in patients at moderate and high risk for developing PONV, but lower-risk patients do not need prophylactic agents. 1,5 The consequences of PONV include medical complications, such as muscular contractions associated with nausea and vomiting, which can cause damage to wound stitches, thus increasing the risk of bleeding. Other complications include Vol. 30 No. 6 June 2005 P&T 341

2 esophageal tears, gastric herniation, muscular fatigue, and pulmonary aspiration of vomitus and regurgitation of stomach contents, resulting in respiratory obstruction, pulmonary inflammation, and aspiration pneumonia. Depending on the severity of PONV, patients may become dehydrated, and an electrolyte imbalance can develop. 1 Many studies have tried to quantify the costs associated with PONV. Hospitalization costs may increase by more than $400 per episode. 6 Contributing factors include personnel time in caring for patients, the expense of disposable products, extra laundry, delayed hospital discharge, unanticipated readmission, and potential reoperation. 1,2 The serotonin receptor antagonists ondansetron, dolasetron, and granisetron have been used in the prevention and treatment of PONV. 3 They inhibit the action of serotonin at the receptor peripherally in the gut, at the vagus nerve, and centrally in the CTZ, decreasing the stimulation of the medullary vomiting center. 4,6 They have also become the firstline agents for preventing and treating PONV since the U.S. Food and Drug Administration (FDA) issued a black-box warning for droperidol (Inapsine, Akorn) in 2001 because of the deaths associated with cardiac rhythm abnormalities secondary to its use. 1 Although these three agents are more expensive than other antiemetics such as metoclopramide (Reglan, Schwarz Pharma), promethazine (Phenergan, Wyeth), prochlorperazine (Compazine, GlaxoSmithKline), and scopolamine (Transderm Scop, Novartis), no other drugs have demonstrated efficacy to the extent of the serotonin antagonists while preventing the extrapyramidal side effects and sedation associated with the less expensive antiemetic agents. 3 The side-effect profile of the serotonin antagonists includes headache, constipation, and elevated liver enzyme levels. 2,3 METHODS A retrospective chart review was performed for 300 randomly selected adults undergoing inpatient and outpatient procedures from March 2003 to February Initially, 100 patients were in the dolasetron group, 99 were in the ondansetron group, and 101 were in the granisetron group. As a result of having received combination therapy at the outset, 18 patients were excluded from the study. Of the 282 patients in the study, 89 received dolasetron, 93 received ondansetron, and 100 received granisetron. Men and women who were undergoing various types of orthopedic, intra-abdominal, and gynecological surgeries were enrolled. The study focused on the percentage of patients in each group who needed further rescue medications and the antiemetic agent that was administered in the event of breakthrough nausea and vomiting. We also performed a cost-effectiveness analysis comparing different therapeutic strategies using the three agents from the perspective of an institutional setting. All continuous variables were expressed as the mean ± standard deviation. We assessed differences in rates for categorical variables among patient groups by using Fisher s exact test or the chi-square test for trend. Because of the skewness of the length of stay (LOS) data, we evaluated differences in LOS using the Wilcoxon Rank Sum test or the Kruskal Wallis test. These tests were also used for ordinal variables such as the number of anesthetic agents. If the Kruskal Wallis result was significant, Tukey s pairwise multiple comparison test (P <.05) was used to determine the source of significance. Continuous and ordinal variables were correlated with LOS via the Spearman correlation coefficient. As with many retrospective studies, there are often group imbalances with baseline variables and these variables are also predictive of the outcome variables. Multivariate analyses were used to control for baseline variables in order to confirm the univariate analyses of drug group being predictive of outcome variables. Stepwise multiple linear regression models were used to determine which variables, in addition to drug grouping, were independent predictors of LOS. We used the log of LOS to create more normally distributed data. We performed a stepwise logistic regression to determine the variables that were independent predictors of needing a rescue drug. In the stepwise procedures, P <.05 was used as a cut-off point. SAS 9.1 (Cary, North Carolina) for Windows 2000 was used to perform all statistical calculations. Results were considered statistically significant with a P value of less than.05. PHARMACOKINETICS AND PHARMACODYNAMICS Table 1 presents a summary of the pharmacokinetic and pharmacodynamic properties of ondansetron, granisetron, and dolasetron. Ondansetron Ondansetron was the first selective serotonin receptor antagonist to be marketed. It is administered both orally and parenterally. Following an oral dose, it is absorbed by the gastrointestinal (GI) tract and undergoes extensive hepatic metabolism, primarily hydroxylation, followed by glucuronide or sulfate conjugation. The drug has an oral bioavailability of 56% to 71%, a rate that is slightly enhanced by the presence of food. Its elimination half-life is three to six hours in adults and two to three hours in children under 15 years of age. About 5% to 10% of the drug is excreted unchanged in the urine. Potent inhibitors of cytochrome isozyme CYP1A2, 2D6, 2E1, and 3A4, such as cimetidine (Tagamet, GlaxoSmithKline), allopurinol (Zyloprim, Faro), ritonavir (Norvir, Abbott), and disulfiram (Antabuse, Wyeth), may alter the metabolism and clearance of the drug, resulting in an elevated serum level of ondansetron. Similarly, CYP1A2, 2D6, 2E1, and 3A4 inducers, such as rifampin, barbiturates, phenytoin (Dilantin, Pfizer), and the carbamazepines, can alter the clearance of the drug and decrease its serum level. 7 Granisetron Granisetron is also administered orally and parenterally. When given with food, the total systemic exposure is decreased and the peak concentration is increased. This drug is widely distributed in the body tissues and is approximately 65% protein-bound. It undergoes extensive hepatic metabolism, primarily by the CYP450 system, which continued on page P&T June 2005 Vol. 30 No. 6

3 continued from page 342 Table 1 Pharmacokinetic and Pharmacodynamic Properties of Ondansetron, Granisetron, and Dolasetron for Postoperative Nausea and Vomiting (PONV) Ondansetron (Zofran ) Granisetron (Kytril ) Dolasetron (Anzemet ) Drug Time to peak concentration Onset of initial response after IV Average time to peak concentration is at end of the infusion after administration is 4 10 minutes concentration is 0.6 hours levels IV administration with a duration of 24 hours after IV administration Absorption Has 56% 71% mean oral Has 60% oral bioavailability Has oral bioavailability of bioavailability; absorption 59% 80%; no effect with food increases when it is given with food Distribution Has 70% 76% protein Has 65% total protein binding Hydrodolasetron is widely binding and a V d of and is distributed widely distributed in the body with L/kg throughout the body with a a mean V d of 5.8 L/kg in adults V d of 2 4 L/kg and 69% 77% protein binding Metabolism Undergoes extensive hepatic Undergoes extensive hepatic Undergoes reduction by a metabolism via hydroxylation, metabolism via N-demethyla- ubiquitous enzyme (carbonyl followed by glucuronide or tion, oxidation, and conjugation reductase) to an active metabosulfate conjugation lite (hydrodolasetron), which undergoes subsequent hydroxylation mediated by CYP450, 2D6, and N-oxidation by CYP3A and flavin monooxygenase Excretion Renal excretion (44% 60% Renal excretion (11% 12% as Urine (as unchanged drug) as metabolites, 5% 10% as unchanged drug, 49% as unchanged drug) and fecal metabolites) and fecal excreexcretion (25%) tion (34%) Elimination half-life 3 6 hours in adults; hours in cancer patients; Less than 10 minutes hours in children younger 4 5 hours in healthy volunteers; (parent compound) 4 9 than 15 years of age 9 hours in PONV hours (hydrodolasetron) Dosage No dosing adjustment in No dosing adjustment in renal No dosing adjustment necadjustment: renal renal impairment impairment essary in renal impairment Dosage Clearance is reduced two-fold; No dosing adjustment in No dosing adjustment adjustment: mean half-life is increased hepatic impairment necessary in hepatic hepatic to 11.6 hours in patients impairment with mild-to-moderate hepatic impairment. Maximum daily dose of 8 mg in patients with severe liver disease Drug Substrate of CYP1A2 (minor), Substrate of CYP3A4 Substrate of CYP2C8/9 interactions 2C8/9 (minor), 2D6 (minor), (minor) (minor) 2E1 (minor), 3A4 (major) Inhibits CYP1A2 (weak), Inhibits CYP2D6 (weak) 2C8/9 (weak), 2D6 (weak) CYP = cytochrome isozyme; IV = intravenous; kg = kilogram; L = liters; V d = volume of distribution. 348 P&T June 2005 Vol. 30 No. 6

4 involves N-demethylation and aromatic ring oxidation, followed by conjugation. The elimination half-life varies according to the patient s condition: for cancer patients, it is 10 to 12 hours; for healthy volunteers, it is 4 to 5 hours; and for those with PONV, it is 9 hours. Almost 12% of the dose is eliminated unchanged in the urine. Granisetron is a substrate of CYP3A4. Enzyme inducers or inhibitors have the potential to affect the activity by decreasing or increasing the level of the drug. 7,8 Dolasetron Dolasetron, available orally or parenterally, is well absorbed when taken orally. The parent drug is reduced completely to hydrodolasetron by a ubiquitous enzyme, carbonyl reductase. The apparent oral bioavailability determined by hydrodolasetron is about 75% and is not affected by food. Hydrodolasetron is distributed throughout the body and is 69% to 77% protein-bound. It undergoes subsequent hydroxylation by CYP2D6 and N-oxidation by CYP3A and flavin monooxygenase. Approximately two thirds of the dose is recovered in the urine, with one third recovered in the feces. The elimination half-life is less than 10 minutes for dolasetron and eight hours for hydrodolasetron. Administration of dolasetron with CYP450 inhibitors, such as cimetidine, can increase serum levels of hydrodolasetron. The serum level may be decreased when dolasetron is administered with CYP450 inducers such as rifampin. Dolasetron has the potential to prolong the QT interval. Therefore, in patients receiving dolasetron, drugs that prolong the QT interval directly or those that alter the electrolytes should be used with caution. 7,8 DOSAGE ADJUSTMENTS No dosing adjustment is necessary for any of the three antiemetic agents in patients with renal impairment. In patients with hepatic impairment, the clearance of ondansetron is reduced and the half-life is increased significantly. In patients with mild, moderate, and severe hepatic impairment, the elimination half-life is 9.1 hours, 9.2 hours, and 20.6 hours, respectively. Therefore, the maximum daily dose of ondansetron for a patient with hepatic dysfunction is 8 mg. No dosing adjustment is necessary in patients with hepatic impairment who are using granisetron or dolasetron. 7 STUDY POPULATION Table 2 illustrates the basic characteristics of the three study groups. Most patients were female (65.3% vs. 34.7%). The majority of the procedures were abdominal (27%), orthopedic (23%), and gynecological (19%). The mean age of the patients was approximately 52.3 ± 19 years. The median duration of the procedure was 1.5 hours, and the median number of anesthetic induction agents used for the procedures was four. The median length of recovery room stay was three hours. Table 2 Characteristics of 282 Patients Evaluated for Postoperative Nausea and Vomiting Dolasetron Ondansetron Granisetron (Anzemet ) (Zofran ) (Kytril ) (n = 89) (n = 93) (n = 100) Demographics Female (%) 49 (55%) 66 (71%) 69 (69%) Male (%) 40 (45%) 27 (29%) 31 (31%) Mean age ± SD 59 ± ± ± 16 Type of Surgery Cardiovascular 13 (15%) 4 (4%) 1 (1%) Neurological 3 (3%) 0 (0%) 0 (0%) Genitourinary 10 (11%) 11 (12%) 5 (5%) Abdominal 19 (21%) 27 (29%) 30 (30%) Orthopedic 20 (22%) 21 (23%) 23 (23%) Gynecological 11 (12%) 19 (20%) 24 (24%) Other 13 (15%) 11 (12%) 17 (17%) Length of Procedure <1 hour 19 (21%) 37 (40%) 33 (33%) 1 2 hours 31 (35%) 32 (34%) 36 (36%) 2 3 hours 19 (21%) 12 (13%) 18 (18%) 3 4 hours 11 (12%) 9 (10%) 12 (12%) 4 5 hours 5 (6%) 0 (0%) 1 (1%) > 5 hours 4 (5%) 3 (3%) 0 (0%) Vol. 30 No. 6 June 2005 P&T 349

5 RESULTS Women were more likely to require a rescue drug than men (24.5% vs. 11.2%; P <.01). However, the need for a rescue agent did not depend on age. The mean age of patients receiving an antiemetic rescue drug was 50 ± 20 years vs. 53 ± 19 years for patients who did not receive a rescue drug (P =.28 by the Rank- Sum test). As the duration of the procedure increased, the likelihood of requiring a rescue medication generally increased as follows (P =.11, Trend Test): less than one hour, 12.4% of patients one to two hours, 24.2% of patients two to three hours, 24.5% of patients three to four hours, 12.5% of patients four to five hours, 33.3% of patients more than five hours, 42.9% of patients Similarly, as the number of anesthetic induction agents increased, the rescue rates increased accordingly, as follows: 9.1% with one agent, 19.4% with two agents, 10.5% with three agents, 23.1% with four agents, and 32.7% with five agents (P =.0114, Trend Test). Certain combinations of the anesthetic induction agents were used more often than others (Table 3). However, the study sample size was not large enough to predict which agent was more emetogenic than the others. Of the 282 patients, about 20% (56 patients) needed an antiemetic rescue drug. Of the 89 patients who received dolasetron 12.5 mg IV x 1 (for one dose) to prevent PONV, 23.6% (21 patients) needed a rescue medication. Of the 93 patients who received ondansetron 4 mg IV x 1 to prevent PONV, 11.8% (11 patients) needed a rescue medication. Of the 100 patients who received granisetron 0.1 mg IV x 1 to prevent PONV, 24% (24 patients) needed a rescue medication. Therefore, the need for a rescue agent was significantly reduced with ondansetron when compared with granisetron (11.8% vs. 24%; P <.04), dolasetron (11.8% vs. 23.6%, P =.05), or a combination of the two (11.8% vs. 23.8%, P <.02) (Table 4). Ondansetron 4 mg IV was used more commonly as the rescue drug and adequately resolved the symptoms of breakthrough nausea and vomiting. However, it did not make a difference, with breakthrough nausea or vomiting, whether the antiemetic was administered perioperatively or postoperatively. The rescue rate was 19.7% perioperatively and 20.8% postoperatively (P =.84). The median LOS in the recovery room was four hours for patients who received a rescue medication and three hours for patients who did not (P =.0732). The median LOS in the recovery room was 2 hours with ondansetron, 3.3 hours with dolasetron, and 3 hours with granisetron (P <.0001), according to the Kruskal Wallis test. With the Tukey test (P <.05), the ondansetron patients had a statistically significant shorter LOS than the other two groups (Table 5). The LOS was also significantly positively correlated with the patient s age (r =.30, P <.0001) and with the duration of the procedure (r =.31, P <.0001) but not with the number of anesthetic induction agents (r =.09, P =.11). MULTIVARIATE ANALYSIS As shown in Table 6, the three predictors of the increasing LOS in the recovery room, in decreasing order of importance, were: a longer duration of the procedure. older age of the patient. the antiemetic drug administered (the use of granisetron or dolasetron versus ondansetron). Therefore, the variables that were not significant predictors of LOS (both univariately and multivariately) were as follows: Table 3 Number of Patients Receiving Induction Agents Dolasetron Ondansetron Granisetron (Anzemet ) (Zofran ) (Kytril ) Induction Agent (n = 89) (n = 93) (n = 100) Propofol, sevoflurane, and fentanyl 7 (8%) 19 (20%) 15 (15%) Propofol, sevoflurane, fentanyl, and midazolam 7 (8%) 13 (14%) 13 (13%) Propofol, midazolam, and fentanyl 5 (6%) 12 (13%) 17 (17%) Propofol and fentanyl 5 (6%) 7 (8%) 4 (4%) Propofol, midazolam, fentanyl, and desflurane 19 (21%) 12 (13%) 19 (19%) Propofol, sevoflurane, and midazolam 2 (2%) 1 (1%) 0 (0%) Propofol, fentanyl, and desflurane 9 (10%) 6 (6%) 13 (13%) Midazolam and fentanyl 5 (6%) 3 (3%) 2 (2%) Midazolam, fentanyl, and desflurane 3 (3%) 0 (0%) 0 (0%) Sevoflurane and fentanyl 3 (3%) 0 (0%) 3 (3%) Midazolam, fentanyl, and sevoflurane 2 (2%) 5 (5%) 0 (0%) Propofol and midazolam 1 (1%) 3 (3%) 2 (2%) Propofol, isoflurane, midazolam, and fentanyl 4 (4%) 2 (2%) 1 (1%) Midazolam 3 (3%) 1 (1%) 0 (0%) Other combinations 17% 11% 11% 350 P&T June 2005 Vol. 30 No. 6

6 Table 4 Number of Patients Receiving Antiemetic Agents Dolasetron Ondansetron Granisetron (Anzemet ) (Zofran ) (Kytril ) 12.5 mg IV x 1 4 mg IV x mg IV x 1 (n = 89) (n = 93) (n = 100) Perioperatively 81 (91%) 56 (60%) 97 (97%) Postoperatively 8 (9%) 37 (40%) 3 (3%) Required rescue medications 21 (23.6%) 11 (11.8%) 24 (24%) Received ondansetron 4 mg IV x 1 15 (71%) 9 (82%) 22 (92%) as the rescue drug Received dolasetron 12.5 mg x 1 0 (0%) 1 (9%) 1 (4%) as the rescue drug Received ondansetron 4 mg IV x 1 5 (24%) 1 (9%) 1 (4%) and dolasetron 12.5 mg x 1 as the rescue drug Received ondansetron 4 mg IV x 1 1 (5%) 0 (0%) 0 (0%) and granisetron 0.1 mg IV x 1 as the rescue drug IV = intravenous. the need for a rescue medication the patient s sex the number of anesthetic induction agents used perioperative or postoperative administration of the antiemetic drug From the regression analysis (data not shown), the use of ondansetron, compared with dolasetron and granisetron, reduced the length of recovery by almost 19%. Table 7 summarizes the multivariate analysis of predictors of the need for a rescue drug. The variables that were most predictive of patients requiring a rescue drug, in order of decreasing importance, were: female sex. administration of dolasetron or granisetron, compared with ondansetron. the increasing number of induction agents used in the procedure. With regard to the odds ratio, women were 2.7 times more likely than men to need a rescue drug. This finding is consistent with the current literature. Patients receiving dolasetron or granisetron for the prevention of PONV were 2.5 times more likely to require a rescue agent than those receiving ondansetron. The number of anesthetic induction agents used in the procedure was also a significant factor in predicting the need for a rescue agent. As the number of induction agents increased by one agent, there was an increase of 42% in the probability of needing a rescue drug (odds ratio, 1.42). Again, the type of procedure, the age of the patient, perioperative or postoperative administration of the antiemetic drug, and the duration of the procedure were not significant predictors of the need for a rescue drug, either univariately or multivariately. Table 5 Patient Length of Stay in the Recovery Room Antiemetic Agent Dolasetron 12.5 mg IV x 1* Granisetron 0.1 mg IV x 1* Ondansetron 4 mg IV x 1 Median Length of Stay 3.3 hours 3.0 hours 2.0 hours n = 280 patients; two patients not included, missing length of stay. P <.0001, Kruskal Wallis test; P <.05,Tukey s test. IV = intravenous. * Compared with the ondansetron group of patients. Table 6 Multivariate Analysis of Predictors of Increasing Length of Stay in the Recovery Room Order of Entry Variable P Value R 2 1 Duration of procedure 2 Age of patient Antiemetic drug (ondansetron vs. granisetron and dolasetron combined) n = 280 patients; two patients not included, missing length of stay. Total R 2 = P <.0001 for this model. Vol. 30 No. 6 June 2005 P&T 351

7 Table 7 Multivariate Analysis of Predictors of the Need for a Rescue Medication Adjusted Order Odds Ratio and P of Entry Variable 95% Confidence Interval Value R 2 1 Female sex 2.7 ( ) Antiemetic drugs (dolasetron or granisetron vs. ondansetron) 2.5 ( ) Number of anesthetic induction agents 1.42 ( ) P <.0005 for this model. Total R 2 = DISCUSSION Cost Hill et al. noted that the hospital cost of each emetic episode was approximately $ Many components accounted for this expense, including: antiemetic agents, only 3% of the total expense. personnel charges, 83%. the patient s hospital admission, 10%. an extended stay in the recovery room, 4%. hospital materials, 0.2%. The cost-effectiveness of using ondansetron rather than granisetron and dolasetron for preventing (and treating, if necessary) PONV was further investigated. The costs per dosage of the three medications were as follows: granisetron, $9.25 dolasetron, $10.75 ondansetron, $ All of the patients received one of the three medications during or after the surgical procedure to prevent PONV. Rescue medications were needed as follows: granisetron: 24 of 100 patients, or 24% dolasetron: 21 of 89 patients, or 23.6% ondansetron: 11 of 93 patients, or 11.8% Even though granisetron is the least expensive drug, its rescue rate is the highest (24%). Ondansetron is the most expensive drug, but its rescue rate was the lowest (11.8%). The rescue rates for granisetron and dolasetron were similar (23.6% vs. 24%), but granisetron is 14% less expensive than dolasetron. Therefore, dolasetron was not considered in this analysis. Ondansetron appears to be a more effective antiemetic agent because it has the lowest rescue rate. Consequently, clinicians generally use it for rescue purposes in PONV to increase the chances that nausea will be resolved after the rescue drug is taken. Therefore, this cost-effectiveness analysis assumes that ondansetron is the only drug used as a rescue medication. The following two strategies were used to compute the total costs of prevention (and treatment, if necessary) of PONV: 1. Giving granisetron to prevent PONV, followed by ondansetron for rescue, if necessary): For 100 patients, it would cost 100 x $9.25, or $925, to prevent PONV with the use of granisetron. We would expect 24% (24 patients) to require ondansetron as the rescue drug. This would cost patients 24 x $16.75, or $402. The total cost of preventing PONV in 100 patients and treating it (with rescue medication) in 24 patients is $402 + $925, or $1,327. Therefore, the total cost per patient is $1, , or $ Giving ondansetron to prevent PONV and as rescue medication, if necessary): For 100 patients, it would cost 100 x $16.75, or $1,675 to prevent PONV with the use of ondansetron. We would expect 11.8% (11.8 patients) to require ondansetron as a rescue drug. This would cost 11.8 x $16.75, or $ The total cost of preventing PONV in 100 patients and treating it in 11.8 patients is $1,675 + $197.65, or $1, Therefore, the total cost per patient is $1, , or $ The difference in cost per patient for the two strategies would be $18.73 $13.27, or $5.46 ($5.50). Thus, for an additional cost of $5.50 per patient, we could reduce the chances of that patient s needing a rescue drug from 24% to 11.8% (a 50% reduction). Alternatively, the cost per 1% reduction in the percentage use of a rescue drug would be $5.46/( ), or $0.45. Considering the difference in cost per patient for the two strategies ($5.50), it is understood that even though the total cost of preventing PONV and using a rescue medication is higher for ondansetron than for granisetron ondansetron has the ability to lower the probability of a patient who would require a rescue drug by about 50% for a nominal additional amount of $5.50 per patient. As mentioned earlier, each event of breakthrough nausea and vomiting can cost the hospital up to $ The results from the LOS multivariate analysis confirm that even though the cost per dosage of ondansetron is higher than that of dolasetron and granisetron, the LOS in the recovery room is reduced by about 19%, compared with a combination of the other two agents. This reduction is significant for a hospital because this suggests a decrease in expenses on other direct and indirect medical and nonmedical costs that are associated with caring for the patient. Consequently, the potential result is more efficient utilization of resources because space is created for a new patient after a bed is vacated. Study Limitations One limitation of our study was our inability to establish a correlation between the duration and the type of procedure to 352 P&T June 2005 Vol. 30 No. 6

8 Receptor Antagonists for Postoperative Nausea and Vomiting the use of a rescue drug because the sample size was not large enough. Because this was a retrospective study, there was no control over the quality and type of data that were available. Therefore, a randomized, controlled, prospective clinical trial should be conducted with these agents to further validate our findings. Finally, the cost-effectiveness analysis considered only the cost of the antiemetic drugs for preventing and treating PONV. The analysis did not include other direct and indirect medical or nonmedical expenses, such as those for personnel, admissions, and hospital materials, all of which are associated with each emetic episode. CONCLUSION The incidence of PONV is reported to be in the range of 20% to 30%. 5 The complications of PONV can cost up to $400 per episode for a hospital. 9 After observing 282 patients who received dolasetron, ondansetron, or granisetron for the prevention of PONV, we found that significantly fewer patients receiving ondansetron needed a rescue medication, compared with patients receiving dolasetron (11.8% vs. 23.6%, P =.05), granisetron (11.8% vs. 24%, P < 0.04), or a combination of the two (11.8% vs. 23.8%, P <.02). We also noted a significant reduction in the LOS in the recovery room for patients receiving ondansetron (2 hours), compared with dolasetron (3.3 hours), or granisetron (3 hours) (P <.0001 by the Kruskal Wallis test; P <.05 by Tukey s test). On the basis of these findings, we suggest that it is more cost-effective to use ondansetron as a first-line therapy to prevent and treat PONV because it appears to be the most efficacious agent among the three, secondary to its reduced need for a rescue drug and its significant reduction of recovery-room time. Acknowledgment: We thank Shiney Thomas, PharmD, and Margaret Cottone, PharmD, for their valuable input into this research project. REFERENCES 1. Ting PH. Post-operative nausea and vomiting (PONV): An overview. Anesthesiology Info; (cited November 11, 2004). Available at: php. 2. Kazemi-Kjellberg F, Henzi I, Tramer MR. Treatment of established postoperative nausea and vomiting: A quantitative systematic review. BMC Anesthesiol 2001;1:2. 3. Post-operative nausea and vomiting. Amdipharm (serial online); April 2004 (cited November 10, 2004). Available at: andvomiting.co.uk/navres001-3-ponv.htm. 4. Rahman MH, Beattie J. Post-operative nausea and vomiting. Pharm J 2004;273: Islam S, Jain PN. Postoperative nausea and vomiting (PONV): A review article. Indian J Anaesth 2004;48(4): Flake ZA, Scalley RD, Bailey AG. Practical selection of antiemetics: Clinical pharmacology. Am Fam Physician 2004;69(5): Drug Information Handbook, 12th ed MicroMedex Healthcare Series, Hill RP, Lubarsky DA, Philips-Bute B, et al. Cost effectiveness of prophylactic antiemetic therapy with ondansetron, droperidol or placebo. Anesthesiology 2000;92(4):