Therapeutic substitution: guilty until proven innocent.

The “evidence” is evidence-based medicine, which defines therapeutic efficacy and safety for specific pharmacological interventions. The “weight” or power of evidence in support of treatment is maximum when determined by large, placebo-controlled, randomized trials (Level A), less definite when based on smaller randomized trials and/or clinical registries (Level B), and least reliable when dependent on expert panel consensus (Level C). Clinical practice guidelines (CPGs), such as those jointly sponsored by the American College of Cardiology and American Heart Association, provide an algorithm by which evidencedbased medicine may be applied to clinical practice. Considerable public and private industry resources are routinely expended to devise and execute randomized controlled trials that demonstrate the efficacy and safety of a specific therapeutic agent or strategy. Pharmacotherapeutic agents have traditionally been grouped into classes on the basis of a demonstrated affinity for a single biological target. However, individual members of a therapeutic class may be widely disparate in pharmacokinetic and pharmacodynamic response, side effect profile, and propensity for drug–drug interactions. For example, in the class of low-molecularweight heparins, the US Food and Drug Administration has determined that individual agents are structurally and biochemically distinct. Unfortunately, randomized controlled comparisons of specific agents within a therapeutic class rarely are performed, and the clinician is forced to rely on much less definitive (and at times misleading) sources of information, such as indirect trial comparisons, meta-analyses of multiple trials, or statistical pooling of agents in a class. Regrettably, the complexity of clinical science is compounded by economic considerations. Economic considerations provide the impetus to make both generic and therapeutic substitutions for agents that have established clinical efficacy according to definitive, placebocontrolled, randomized trials. Economic factors have made the choice of specific pharmacotherapeutic agents the purview of hospital pharmacies and health benefit plans, not physicians. This unfortunate situation has understandably spawned “the most savage controversies” as described by Bertrand Russell, from which the “evidence either way” is presented in the current issue of Circulation by Drs Ferguson and Antman1 and Furberg and Psaty.2 Each of these thought leaders has been intimately involved in constructing and executing multiple clinical trials that have contributed to the evidence base from which current guidelines are derived. The consistency of their expert opinions on this topic allows for potential consensus to be drawn.