To assess medication compliance over time, we prospectively performed pill counts among 121 ambulatory hypertensive subjects for less than or equal to 12 months. Prescribed regimens consisted of pinacidil or hydralazine administered four times a day and of secondary drugs administered up to twice daily. Surreptitious pill counts occurred every 1 to 12 weeks. Among a middle-aged subject group that had been selected for high rates of compliance, we observed mean compliance rates that approximated 100%. We noted marked intrasubject and intersubject variability for any one medication, between medications, and over time. From baseline blood pressures (+/- SE) of 155.5 +/- 1.9/97.3 +/- 1.0 mm Hg, subsequent mean blood pressures varied by compliance subgroup: "hypocompliers" (less than 80%), 151.3/91.0 mm Hg; "hypercompliers" (greater than or equal to 120%), 147.6/91.4 mm Hg; and "eucompliers" (80% to 119%), 143.3/88.5 mm Hg (systolic blood pressure: F1,52 = -220.9, NS; diastolic blood pressure: F1,52 = -121.4, NS). We concluded that weekly pill counts indicated marked intersubject and intrasubject variability, obscured by long-term averages; that compliance lapses appeared to be random; and that excessive medication-taking was the most consistent with "pill dumping."
To assess the value of improved monitoring of medication-taking behavior in a drug trial, we employed a modified pill vial with microcircuitry to record the precise times when the vials were opened. After a 3-week placebo washout period, 21 ambulatory subjects with mild hypertension (mean age, 57 years; 67% men; 76% white) randomly received isradipine or enalapril twice daily in a double-blind titration during 10 weeks. Both drugs achieved a 13% reduction in sitting diastolic blood pressure (p less than 0.01) with minimal symptomatic or laboratory toxicity. Although pill counts indicated near-perfect compliance (92% to 99% for both groups), the electronic monitor showed that fewer than half of all openings occurred at the prescribed interval of 12 +/- 2 hours. Modest overdispensing was documented in the 3 days before scheduled visits. The monitor confirmed that pill count misclassified compliance sufficiency in 22% of visits and permitted more discrete attribution for drug-associated adverse reactions and secondary resistance to treatment. We conclude that the electronic monitor reduces ambiguity about medication compliance and helps interpret both the biology and pharmacology of the trial.
To evaluate pill counts as a compliance measure for drug trials, we followed 121 ambulatory hypertensives selected for good compliance over less than or equal to 12 months. The medication regimens consisted of either pinacidil or hydralazine as monotherapy or with propranolol and/or hydrochlorothiazide. Pill counts for the two primary drugs were obtained at each of the 20 return visits. The population was characterized by chronic uncomplicated hypertension and sociodemographic diversity; mean age was 53 years. Despite excellent average weekly pill counts (overall mean compliance rate [+/- SD] = 96.0 +/- 13.2%), we observed large intersubject and intrasubject variance in weekly pill count assessment: individuals' mean standard deviation = 13.7% (range = 0%-86%) and mean coefficient of variation = 0.138 (range = 0.001-0.410). By pill count, 35% of individuals exhibited greater than 110% compliance on at least 1 visit. We conclude that (a) pill count variability is large, even among highly selected subjects, (b) traditional reports of overall pill counts are suboptimal, and (c) pill counts may unreliably measure medication-taking behavior because "supranormal" compliance by this method is improbable but common.
Distinguishing among biological, pharmacological, and behavioural variability is essential for proper interpretation of the therapeutic experiment at each return visit. Within the behavioural component, partial compliance refers to all sub-optimal levels of concordance between the patient’s behaviour and the clinical prescription. However, the assessment of compliance is limited largely by imperfect measures of medication taking which are frequently distant in time and space from the medication-taking event itself. Most studies indicate compliance levels of only 50-70% with antihypertensive regimens as well as considerable variance from day to day and person to person. Therapeutic outcome may be a misleading method to assess the sufficiency of a regimen because of the high prevalence of suboptimal medication-taking behaviour. In selected situations, prolongation of pharmacological effect may compensate for imperfect medication-taking behaviour, confirmed by electronic medication monitors. Such pharmacodynamic prolongation exemplifies therapeutic sufficiency, a new paradigm for therapeutics in the 1990s.
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