An abundance of information about existing and emerging health care interventions is readily available, posing challenges for clinicians, patients and researchers to determine the best available treatment at a given time.1
Among methods for assessing the comparative effectiveness of health care interventions, systematic reviews are an important tool for enhancing the ability of health care professionals to interpret and apply research evidence in a timely manner.2, 3
Meta-analysis – the statistical analysis of the results from multiple independent studies – is a useful method for increasing statistical power and the precision of the estimate of treatment effect.4
Systematic review and meta-analysis have been widely used in comparing different pharmaceutical treatments, as exemplified by the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and the Drug Effectiveness Review Project.
Although systematic review and meta-analysis are valuable for comparing effects of different medications, conclusions are often limited by available evidence. One problem unique to pharmaceutical comparisons is the issue of drug dose. When comparing the benefits or harms of one treatment to another, comparable doses rarely are defined. Clinicians generally have a sense of how the dose of one drug compares to the dose of an alternative drug, although these distinctions usually are not evidence-based. This often leads to concerns as to whether differences – or lack of differences – in comparative effectiveness are related to drug dose.
Considering second-generation antidepressants, for example, a general rule of thumb may be that fluoxetine 20mg is roughly equivalent to sertraline 100mg or escitalopram 10mg. If this rule of thumb is true and we compare these drugs at equivalent doses, we assume that any differences in comparative effectiveness are attributed to the drug rather than the drug dose. However, how do you interpret the results of a study that compares non-equivalent doses such as fluoxetine 20mg, sertraline 200mg, and escitalopram 20mg? In the same regard, looking across studies or combining data from differently designed studies, can anything be said about the effect size of fluoxetine compared to the effect sizes of sertraline or escitalopram if relative drug doses differed?
This example presents several problems. First, we assume that increases in drug dose are related to an increased effectiveness, indicating a positive dose-response relationship. A clear dose-response relationship is well established for some drug classes (e.g., inhaled corticosteroids follow a logarithmic dose-response curve),5,6
but is less clear for other drug classes such as the antidepressants. Second, there is a general lack of standardized dosing guidelines for assessing the comparative effectiveness of different drugs within the same therapeutic class. Clinicians generally have a sense of how doses of different drugs within the same class compare, but universally accepted comparative dosing evidence is not available for most drugs. Mechanisms such as the World Health Organization’s Defined Daily Dose exist, but this establishes an average therapeutic dose rather than a range of comparable doses. Third, methods to handle drug dose in comparative effectiveness studies are not well developed. Most systematic reviews and meta-analyses handle the issue of drug dose qualitatively – narratively describing differences. Quantitative methods for dealing with dose differences include stratification7,8
Stratification allows for comparison of the relative risk or odds ratio across dosing levels while meta-regression explores the influence of dose on the effect size across trials. Still, these methods assume that some form of comparative dose equivalence guideline exists and require that a sufficient number of eligible studies exist for analysis. Unfortunately for researchers and health care professionals, studies using such methods are the exception rather than the norm.
The purpose of this paper is to illustrate a dose classification method for quantitatively addressing if drug dose is an important factor to consider in a meta-analysis. We base our discussion on the analysis of studies previously identified by a systematic review of the comparative effectiveness of second-generation antidepressants. Our specific objectives are:
- to describe a simple method for detecting inequalities in dose when comparing across different drugs in the same therapeutic class,
- to describe the relationship between dose and effect size for second-generation antidepressants, and
- to determine whether the comparative effectiveness of second-generation antidepressants is related to differences in drug dose.