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Peterson K, McDonagh M, Carson S, et al. Drug Class Review: Newer Antiemetics: Final Report Update 1 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Jan.

Introduction

Nausea and vomiting are major concerns for patients undergoing chemotherapy and radiation therapy.1, 2 Risk factors associated with chemotherapy-induced nausea and vomiting include emetogenicity of the chemotherapy regimen, dose, speed of intravenous infusion, female gender, age under 50 years, history of ethanol consumption, and history of prior chemotherapy.3 Factors predictive of radiation therapy-induced nausea and vomiting include site of irradiation (in particular, total body irradiation and radiation fields that include the abdomen), total field size, dose per fraction, age, and predisposition for emesis (history of sickness during pregnancy or motion sickness).2 Secondary risks associated with nausea and vomiting induced by chemotherapy and radiation therapy include electrolyte imbalance, aspiration pneumonia, interruption of potentially curative therapy, and reduction in quality of life.

Nausea and vomiting are also frequently associated with surgical procedures. The incidence of postoperative nausea and vomiting is estimated to be 25%–30%.4 The risk of postoperative nausea and vomiting is multifactorial and can be influenced by patient characteristics, type of surgical procedure, and anesthesia.5 Female gender, a history of motion sickness or postoperative nausea and vomiting, nonsmoking status, and use of postoperative opioids have been cited as the patient factors most predictive of postoperative nausea and vomiting.5 Surgical procedures that are associated with increased risk of postoperative nausea and vomiting include craniotomy, ear, nose, and throat procedures, open abdominal surgeries, major breast procedures, strabismus operations, laparoscopy, and laparotomy.5 Anesthesia-related factors that can affect risk of postoperative nausea and vomiting include use of opioids, nitrous oxide, and volatile inhalational agents.5 Postoperative nausea and vomiting can result in electrolyte imbalance, surgical wound bleeding, and increase in hospital stay, among other consequences.6 Numerous pharmacological and nonpharmacological interventions have been studied in an effort to prevent and manage postoperative nausea and vomiting.7, 8

Finally, nausea and vomiting are commonly associated with pregnancy. The most severe and persistent form of pregnancy-related nausea and vomiting, hyperemesis gravidarum, can lead to serious complications, including dehydration, metabolic disturbances, nutritional deficits requiring hospitalization, and even death.9

Nausea and vomiting associated with surgical procedures, chemotherapeutic agents, radiation therapy, and pregnancy are thought to be induced by stimulation of the dopamine, acetylcholine, histamine, serotonin and substance P/neurokinin 1 (NK1) neuroreceptors involved in activating areas of the brain that coordinate the act of vomiting. Earlier pharmacologic agents commonly used as antiemetics included histamine-1 blockers such as diphenhydramine, anticholinergics, and dopamine antagonists including phenothiazines (chlorpromazine, perphenazine, prochlorperazine), metoclopramide, and droperidol.10 The discovery that type 3 serotonin (5-HT3) receptor-blocking properties were contributing to the effect of one of the dopamine antagonists, metoclopramide, eventually led to the development of newer antiserotoninergic drugs.11 There are currently four 5-HT3 receptor antagonists approved for use in the United States and Canada (Table 1). The newest antiemetic drugs, aprepitant and fosaprepitant, are antagonists of the substance P/neurokinin 1 (NK1) receptors.

Table 1

Table 1

Antiemetic drug indications approved by the US Food and Drug Administration

The objective of this review was to evaluate the comparative effectiveness and harms of newer antiemetic drugs including the 5-HT3 and NK-1 antagonists. Table 1 provides an accounting of the indications approved by the US Food and Drug Administration for each of the 5-HT3 and NK-1 antagonists and Appendixes A and B provide dosage recommendations for adults and children, respectively.

Purpose and Limitations of Systematic Reviews

Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. A systematic review focuses on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with a careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix C and are defined as they apply to reports produced by the Drug Effectiveness Review Project.

Systematic reviews emphasize the importance of the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are emphasized over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each groups, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than the absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat.

Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well-executed randomized controlled trials are considered better evidence than results of cohort, case-control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, cohort designs are preferred, when conducted well, for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted.

Systematic reviews pay particular attention to whether results of efficacy studies performed in controlled or academic settings can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbiddiseases, meaning diseases other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that may be impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

Systematic reviews highlight studies that reflect actual clinical effectiveness in unselected patients and community practice settings. Effectiveness studies conducted in primary care or office-based settings use less stringent eligibility criteria, more often assess health outcomes, and have longer follow-up periods than most efficacy studies. The results of effectiveness studies are more applicable to the “average” patient than results from the highly selected populations in efficacy studies. Examples of effectiveness outcomes include quality of life, frequency or duration of hospitalizations, social function, and the ability to work. These outcomes are more important to patients, family, and care providers than surrogate or intermediate measures such as scores based on psychometric scales.

Efficacy and effectiveness studies overlap. For example, a study might use very narrow inclusion criteria like an efficacy study, but, like an effectiveness study, might examine flexible dosing regimens, have a long follow-up period, and measure quality of life and functional outcomes. For this report we sought evidence about outcomes that are important to patients and would normally be considered appropriate for an effectiveness study. However, many of the studies that reported these outcomes were short-term and used strict inclusion criteria to select eligible patients. For these reasons, it was neither possible nor desirable to exclude evidence based on these characteristics. Labeling each study as either an efficacy or an effectiveness study, while convenient, is of limited value; it is more useful to consider whether the patient population, interventions, time frame, and outcomes are relevant to one’s practice or to a particular patient.

Studies anywhere on the continuum from efficacy to effectiveness can be useful in comparing the clinical value of different drugs. Effectiveness studies are more applicable to practice, but efficacy studies are a useful scientific standard for determining whether characteristics of different drugs are related to their effects on disease. Systematic reviews thoroughly cover the efficacy data in order to ensure that decision makers can assess the scope, quality, and relevance of the available data. This thoroughness is not intended to obscure the fact that efficacy data, no matter how large the quantity, may have limited applicability to practice. Clinicians can judge the relevance of studies’ results to their practice and should note where there are gaps in the available scientific information.

Unfortunately, for many drugs there exist few or no effectiveness studies and many efficacy studies. Yet clinicians must decide on treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of the different drugs are uncertain. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment.

In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. By themselves, they do not say what to do. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice.

Scope and Key Questions

The purpose of this review is to compare the benefits and harms of different pharmacologic treatments for nausea and vomiting. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

  1. What is the comparative effectiveness of newer antiemetics in treating or preventing nausea and/or vomiting?
  2. What are the comparative tolerability and safety of newer antiemetics when used to treat or prevent nausea and/or vomiting?
  3. Are there subgroups of patients based on demographics (age, race, gender), pregnancy, other medications, or comorbidities for which 1 newer antiemetic is more effective or associated with fewer adverse events?

Inclusion Criteria

Populations

Adults or children at risk for or with nausea, vomiting (including retching), or both related to the following therapies and conditions:

In this report, we use the emetogenicity classification scale that Hesketh defined in 1997 and modified in 199912, 13 to clarify the level of emetogenicity of the chemotherapeutic regimen with which the cancer population of the study is being treated. This scale rates the emetic potential of the chemotherapeutic agent (or combination of agents) given to a cancer patient as if the patient would not be receiving any antiemetic drugs; that is, it classifies the chemotherapeutic agents by the likelihood that the patient will experience emesis. Chemotherapeutic agents rated as “1” on this scale have a low emetic potential, while agents rated as “5” are considered to be severely emetic (a >90% chance of emesis in patients).

Interventions

Included interventions are listed in Table 2.

Table 2

Table 2

Included interventions

Effectiveness outcomes

Treatment of established postoperative nausea and/or vomiting

  • Success: Absence of vomiting and/or retching in a nauseated or vomiting and/or retching patient
  • Success: Absence of any emetic event (nausea, vomiting, retching)
  • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, delay until first emetic episode, number of emesis-free days

Prevention of postoperative nausea and/or vomiting

  • Success: Absence of vomiting and/or retching in the postoperative period
  • Success: Absence of any emetic event (nausea, vomiting and/or retching, or nausea and vomiting and/or retching) in the postoperative period
  • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, delay until first emetic episode, number of emesis-free days

Prevention of nausea and/or vomiting related to chemotherapy

Prevention of radiation-induced nausea and/or vomiting

  • Success: Absence of vomiting and/or retching
    • Acute: During the first 24 hours of onset of radiation therapy
    • Delayed: After the first 24 hours of onset of radiation therapy or after consecutive radiation therapy doses given during several days
  • Success: Absence of any emetic event (nausea, vomiting, retching)
    • Acute: During the first 24 hours of onset of radiation therapy
    • Delayed: After the first 24 hours of onset of radiation therapy or after consecutive radiation therapy doses given during several days
  • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, or need for rescue medications, serious emetic sequelae, worst day nausea/vomiting and/or retching, delay until first emetic episode, number of emesis-free days

Treatment of nausea and/or vomiting associated with pregnancy (including hyperemesis gravidarum)

  • Success: Absence of vomiting and/or retching in a nauseated or vomiting and/or retching pregnant woman
  • Success: Absence of any emetic event (nausea, vomiting, retching)
  • Change in Rhodes index or visual analog scale assessments of symptom severity
  • Fetal outcome
  • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes per period of time, need for rescue medications, serious emetic sequelae, number of emesis-free days, number of episodes and duration of hospitalization

Wherever possible, data on effective dose range, dose response, and duration of therapy (time to success) will be evaluated within the context of comparative effectiveness.

Harms

  • Overall adverse events
  • Specific adverse events (headache, constipation, dizziness, sedation, etc)
  • Withdrawals due to adverse events
  • Serious adverse events reported

Study designs

The benefit of the randomized controlled trial design is the ability to obtain a reliably unbiased estimate of treatment effects in a controlled setting. This is accomplished by using randomization to produce groups that are comparable based on both known and unknown prognostic factors.14, 15 However, randomized controlled trials can vary in quality, and their generalizability to a broader patient population often is limited. Observational studies are thought to have greater risk of introducing bias, although they typically reflect effects in a broader section of the overall patient population. While some observational studies and randomized controlled trials of the same treatments have similar findings, there are also multiple examples of situations where this has not been true; the question of what type of evidence is best has not been resolved.16, 17 While randomized controlled trials also provide good evidence on short-term adverse events, observational designs are useful in identifying rare, serious adverse events, which often require large numbers of patients exposed to a treatment over longer periods of time to be identified.

Copyright © 2008, Oregon Health & Science University, Portland, Oregon.
Cover of Drug Class Review: Newer Antiemetics
Drug Class Review: Newer Antiemetics: Final Report Update 1 [Internet].
Peterson K, McDonagh M, Carson S, et al.
Portland (OR): Oregon Health & Science University; 2009 Jan.

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