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 THE SCIENCE OF DRUG THERAPY - John A. Oates

THE SCIENCE OF DRUG THERAPY: INTRODUCTION

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Drug therapy affords an expanding opportunity for preventing and treating disease and for alleviating symptoms. Pharmacologic agents also expose patients to risk. Basic principles of drug therapy provide a conceptual framework for deploying drugs with maximal efficacy while minimizing the risk of adverse effects.

Optimal therapeutic decisions are based on an evaluation of the individual patient in concert with assessment of the evidence for efficacy and safety of the treatment under consideration. An understanding of the pharmacokinetics and pharmacodynamics of the drug should be integrated with this patient-focused information to guide implementation of therapy.

EVALUATION OF THE EVIDENCE

Introduction

Initial determination of the effectiveness and safety of drugs is based predominantly on evaluation of experimental interventions in clinical trials. Well-designed and effectively executed clinical trials provide the scientific evidence that informs most therapeutic decisions. Evidence from clinical trials may be supplemented by observational studies, particularly in assessing adverse effects that elude detection in clinical trials designed to determine efficacy and that do not occur frequently or rapidly enough.

Clinical Trials

Similarity of the control group with the group receiving the intervention is key to obtaining valid information in all experimental science. In clinical trials, this similarity is best achieved by random assignment of patients or volunteers to the control group or the group receiving the experimental therapy. Such randomization is the optimal method for distributing between the treatment and control groups the known and unknown variables that could affect outcome. Recognizing that a randomized clinical trial is the "gold standard" of clinical trials, it nonetheless may be impossible to use this design to study all disorders; for patients who cannot¾by regulation, ethics, or both¾be studied with this design (e.g., children, fetuses, or some patients with psychiatric disease) or for disorders with a typically fatal outcome (e.g., rabies), it may be necessary to resort to historical controls.

A second important element of study design is concealment of the outcome of randomization from the study participants and investigators. Concealing whether participants are assigned to the control or the treatment group is referred to as blinding or masking the study. In therapeutic investigations, participants in the control group will receive an inactive replica of the drug, e.g., a tablet or capsule containing inert ingredients that is identical in appearance to the active agent. This inert replica of the drug is designated as a placebo. When only the study participants are blinded to treatment assignment but investigators know whether the active agent is being given, this is designated as a single-blind study. In a double-blind study, neither the study participants nor the investigators knows whether the active agent is being given. Blinding the investigators not only removes bias in interpreting the outcomes and in decisions regarding management of the patient but also eliminates selectivity in the enthusiasm for therapy typically conveyed by clinicians. By eliminating participant and observer bias, the randomized, double-blind, placebo-controlled trial provides the highest likelihood of revealing the truth about the effects of a drug (Temple, 1997). The double-blind, placebo-controlled design permits evaluation of subjective end points, such as pain, that are powerfully influenced by the administration of placebo. Striking instances in which placebo effects are observed include pain in labor, where a placebo produces approximately 40% of the relief provided by the opioid analgesic meperidine with a remarkably similar time course, and angina pectoris, where as much as a 60% improvement in symptoms is achieved with placebo. The response to placebo in patients with depression is often 60% to 70% as great as that of an active antidepressant drug; as described below, this complicates clinical trials of efficacy.

Benjamin Franklin pioneered the blinded study design. The king of France appointed him to a commission to evaluate the claims of the flamboyant healer Friedrich Anton Mesmer, who employed magnetized iron rods to heal illnesses. Franklin and the commission conducted an experiment in which patients were blindfolded to conceal whether or not they received Mesmer's treatment and found that the healing effects were independent of exposure to the magnetized rods.

The existence of a therapy already known to improve disease outcome may provide an ethical basis for comparing a new drug with the established treatment rather than placebo (Passamani, 1991). If the aim is to show that the new drug is as effective as the comparator, then the size of the trial must be sufficiently large to have the statistical power to demonstrate a meaningful difference between the two groups if such a difference were to exist. Trials conducted against comparators as controls can be misleading if they claim equal effectiveness based on the lack of a statistical difference between the drugs in a trial that was too small to demonstrate such a difference. When trials against comparator drugs examine the relative incidence of side effects, it also is important that the doses of the drugs are equally effective.

A clear hypothesis for the trial should guide the selection of a primary end point, which should be specified before the trial is initiated. Ideally, this primary end point should measure a clinical outcome, either a disease-related outcome, such as improvement of survival or reduction of myocardial infarction, or a symptomatic outcome, such as pain relief or quality of life. Examination of a single, prospectively selected end point is most likely to yield a valid result from the study. A few additional (secondary) end points also may be designated in advance; the greater the number of end points that are examined, the greater is the likelihood that apparently significant changes in one of them will occur by chance. The least rigorous examination of trial results comes from retrospective selection of end points after viewing the data. Because this introduces a selection bias and increases the probability of a chance result, retrospective selection should be used only as the basis to generate hypotheses that then can be tested prospectively.

In some instances, therapeutic decisions must be based on trials evaluating surrogate end points¾measures such as clinical signs or laboratory findings that are correlated with but do not directly measure clinical outcome. Such surrogate end points include measurements of blood pressure (for antihypertensive drugs), plasma glucose (for diabetic drugs), and levels of viral RNA in plasma (for antiretroviral drugs). The extent to which surrogate end points predict clinical outcomes varies, and two drugs with the same effect on a surrogate end point may have different effects on clinical outcome. Of greater concern, the effect of a drug on a surrogate end point may lead to erroneous conclusions about the clinical consequences of drug administration. One compelling example of the danger of reliance on surrogate end points emerged from the Cardiac Arrhythmia Suppression Trial (CAST). Based on their ability to suppress the surrogate markers of ventricular premature contractions and nonsustained ventricular tachycardia, antiarrhythmic drugs such as encainide, flecanide, and moricizine frequently were used in patients with ventricular ectopy after myocardial infarction (see Chapter 33). The CAST study showed that despite their ability to suppress ventricular ectopy, the drugs actually increased the frequency of sudden cardiac death (Echt et al., 1991). Thus, the ultimate test of a drug's efficacy must arise from actual clinical outcomes rather than surrogate markers (Bucher et al., 1999).

The sample of patients selected for a clinical trial may not be representative of the entire population of patients with that disease who may receive the drug. The patients entered into a trial usually are selected according to the severity of their disease and other characteristics (inclusion criteria) or are excluded because of coexisting disease, concurrent therapy, or specific features of the disease itself (exclusion criteria). It always is important to ascertain that the clinical characteristics of an individual patient correspond with those of patients in the trial (Feinstein, 1994). For example, the Randomized Aldactone Evaluation Study (RALES) showed that treatment with the mineralocorticoid-receptor antagonist spironolactone was associated with a 30% reduction in death in patients with severe congestive heart failure (Pitt et al., 1999). The potential adverse effect of hyperkalemia was seen only rarely in this study, which excluded patients with serum creatinine levels of greater than 2.5 mg/dl. With the expanded use of spironolactone after the RALES results were published, numerous patients, many of whom did not meet the criteria for inclusion that minimized the risk in the RALES trial, have developed severe hyperkalemia on spironolactone (Jurlink et al., 2004). Knowledge of the criteria for selecting the patients in a trial must inform the application of study results to an individual patient.

Determination of efficacy and safety is an ongoing process that usually is based on the results of more than one randomized, double-blind, controlled trial. Because the trials may not all provide the same results, and some may show an apparent effect that does not achieve statistical significance, it may be useful to aggregate the results of several similarly designed drug trials that examined the same clinical end point into an overview termed a meta-analysis. The larger numbers of patients and controls in such a meta-analysis can yield narrower confidence limits and strengthen the likelihood that an apparent effect is (or is not) due to the drug rather than chance. In one example, a meta-analysis of 65 randomized trials involving nearly 60,000 patients strongly supported the current use of low-dose aspirin to prevent death, myocardial infarction, and stroke in high-risk patients (Antiplatelet Trialists' Collaboration, 2002).

Observational Studies

Important but infrequent adverse drug effects may escape detection in the randomized, controlled trials that demonstrate efficacy. In controlled trials that form the basis for approval of drugs for marketing, the number of patient-years of exposure to a drug is small relative to exposure after it is marketed. Also, some adverse effects may have a long latency or may affect patients excluded from the controlled trials. Therefore, nonexperimental or observational studies are used to examine those adverse effects that only become apparent with widespread, prolonged use of the drug in the practice of medicine. For example, such observational studies identified peptic ulcers and gastritis as serious adverse effects of nonsteroidal antiinflammatory drugs and aspirin.

The quality of information derived from observational studies varies with the design and depends highly on the selection of controls and the accuracy of the information on medication use (Ray, 2004; Sackett, 1991). Automated prescription databases provide a relatively reliable measure of drug exposure for such studies. Cohort studies compare the occurrence of events in users and nonusers of a drug; this is the more powerful of the observational study designs. Case-control studies compare drug exposure among patients with an adverse outcome with that in control patients. Because the control and treatment groups in an observational study are not selected randomly, there may be unknown differences between the groups that determine outcome independent of drug use. Because of the limitations of observational studies, their validity cannot be equated with that of randomized, controlled trials (Table 5-1). Rather, the role of observational studies is to raise questions and pose hypotheses about adverse reactions. However, if it is not feasible to test these hypotheses in controlled clinical trials, then replicated findings from observational studies may form the basis for clinical decisions.

PATIENT-CENTERED THERAPEUTICS

Introduction

Optimal treatment decisions are based on an understanding of the characteristics of the individual patient that will determine the response to the drug. Interindividual differences in drug delivery to its site(s) of action can profoundly influence therapeutic effectiveness and adverse effects. Pharmacodynamic differences in the response to a drug may result from alterations in the effect on the target organ or from differences in the body's adaptation to the target-organ response owing to disease or other drugs. Moreover, precision in diagnosis and prognosis governs the type of therapy and the therapeutic regimen, as well as the urgency and intensity of treatment. Some of the determinants of interindividual variation are indicated in Figure 5-1. Thus, therapeutic success and safety are determined by integration of evidence of efficacy and safety with knowledge of the individual factors that determine response in a particular patient.

Drug History

A thorough drug history is a key element in individualizing therapy, and information on concurrent therapy must be accessible at each encounter to guide safe and effective treatment. Documentation of current prescription drug use is a starting point in the drug history. Despite increasing use of computerized drug lists, it often is very helpful for patients to bring all current medications with them to the clinical encounter. Specific prompting is required to elicit the use of over-the-counter drugs and herbal medications, both of which may affect therapeutic decisions. Information about medications that are used only sporadically (e.g.,  sildenafil for erectile dysfunction) may not be volunteered without a specific query. With cognitively impaired patients, it may be necessary to go beyond the interview to include caregivers and pharmacy records; as noted earlier, requests to examine the actual medications also can be invaluable.

Adverse reactions to drugs, allergic or otherwise, should be documented with specifics regarding severity. Full elucidation of adverse effects is aided by asking whether patients or their physicians have discontinued any medications in the past.

An accessible current drug profile and list of adverse effects are required for each patient encounter. Review of the medication list on hospital rounds and during outpatient visits is essential to maximize effectiveness and safety of treatment. With electronic medical records, the medication list can be printed for the patient to optimize communication about therapy and adherence to the regimen.

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