Durability of Improvement Achieved in a Clinical Trial: Is Compliance an Issue?
METHODS: Nineteen previously untreated middle-aged men with hypertension had their office and ambulatory blood pressure recorded after 4 weeks of placebo treatment, 4 weeks of active treatment in a clinical trial, and 31 months of treatment in clinical practice. All recording was done by the same physician (IE).
RESULTS: Mean 24-hour blood pressure was 138/92 mm Hg after 4 weeks of placebo treatment, 128/85 mm Hg after 4 weeks of active treatment in the clinical trial, and 136/87 mm Hg after a mean of 31 months of treatment in clinical practice. The corresponding blood pressure values Ž140/90 mm Hg during the daytime were 47%, 24%, and 39%, and office blood pressures were 155/101, 145/93, and 150/91 mm Hg. Individual comparison revealed that 6 of the 19 patients had higher mean 24-hour blood pressure after several months of treatment in clinical practice than after 4 weeks of active treatment in the clinical trial.
CONCLUSIONS: In our study, the significantly reduced blood pressure in the clinical trial did not persist when followed up in clinical practice. At follow-up, one third of the patients had blood pressure values similar to those before active treatment. The reason for this is unclear, but inconsistent compliance may play a part in the lack of durability of the improvements. Our results indicate that effects seen in short-term clinical trials may not translate to long-term benefits in clinical practice.
Poor compliance with prescribed drug regimens attenuates the benefits of treatment, making compliance a key link between process and outcome in ambulatory care.1 In clinical trials, noncompliance, also called nonadherence, is one of the most important sources of the variance in drug response.2 Inconsistent compliance has the largest impact on statistical power, since it lowers the mean drug response and adds variance.3 Deficient compliance can also lead to overestimates of dosage requirements. The rate of compliance differs in clinical trials4,5 and in clinical practice.4,6,7 It has been calculated that depending on the method used to monitor compliance, only 20% to 80% of patients treated for hypertension can be considered good compliers.7
In our pilot study we examined the persistence of blood pressure effects 31 months after a clinical trial of 4 weeks of treatment with hypotensive agents.
Methods
Our study included 19 previously untreated middle-aged men with hypertension (mean age=52.1 years; range=40-64 years) recruited from a blood pressure screening project in a municipality in southern Sweden.8 They were followed up in 1991-1992 in clinical practice after having completed a trial comparing 50 mg atenolol with 20 mg enalapril, which were found to be equally effective in lowering blood pressure.9 Office and ambulatory blood pressures recorded after 4 weeks of placebo treatment and after 4 weeks of active treatment in the clinical trial were compared with office and ambulatory blood pressures recorded after several months of treatment in a clinical practice at the same health center. The same physician (IE) involved in the clinical trial followed up and treated the patients in her practice at the health center. Although some patients were treated with the same drugs as in the clinical trial, most had a different treatment ([Table 1]). Side effects were the most common reason for a patient to change treatment. In the clinical trial, ambulatory blood pressure was recorded every 15 minutes between 6 AM and 6 PM and every 30 min between 6 PM and 6 AM with the SpaceLabs 5200 equipment (Chatsworth, Calif). At the follow-up in clinical practice, ambulatory blood pressure was recorded every 20 minutes with SpaceLabs 90207 equipment (Redmond, Wash). Both these equipments have been validated and found to be accurate.10-12 The equipment was attached to the patient between 8 AM and 10 AM in the clinical trial and at other various times of the day, but mostly between 2 PM and 5 PM when followed up in clinical practice. Office blood pressure was recorded as the mean of 4 measurements obtained by the same physician in the same way (supine position after 5-10 minutes of rest with appropriate cuffs), twice when the ambulatory blood pressure equipment was attached and twice when it was removed from the patient. All patients worked full time during the clinical trial; in the follw-up in clinical practice 7 were retired and 1 had part-time work.
Statistical Analysis
Standard statistics such as mean, standard deviation, minimum, and maximum were used to summarize the data. Mean blood pressure values are presented together with 95% confidence intervals, which were calculated using normal approximation. Daytime was defined as the time between waking and going to bed.
