Durability of Improvement Achieved in a Clinical Trial: Is Compliance an Issue?

Results

Mean (standard deviation [SD]) 24-hour blood pressure was 138/92 (14/5) mm Hg after 4 weeks of placebo treatment, 128/85 (14/7) mm Hg after 4 weeks of active treatment, and 136/87 (18/9) mm Hg after 31(19) months of treatment in clinical practice. Confidence intervals are given in [Table 2]. The corresponding blood pressure values Ž140/90 (SD) mm Hg during the daytime were 47% (25%), 24% (22%), and 39% (29%), and office blood pressures were 155/101 (16/4), 145/93 (17/6), and 150/91 (23/9) mm Hg. Individual comparison revealed that 6 patients had a 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. Of these 6 patients, 3 had the same treatment (atenolol 50 mg) as in the clinical trial, 1 had changed from enalapril to atenolol, 1 from enalapril to nifedipine, and 1 from atenolol to diltiazem.

Discussion

We examined the persistence of blood pressure effects 31 months after a clinical trial of hypotensive agents. The results showed that mean ambulatory blood pressure was lower after 4 weeks of treatment in the clinical trial than after several months of treatment in clinical practice. Although 4 weeks of treatment with either 50 mg atenolol or 20 mg enalapril in the clinical trial reduced ambulatory blood pressure significantly, these lower blood pressure values did not persist after a longer period of treatment. Individual analysis revealed that 6 patients had higher blood pressure values at follow-up in clinical practice than in the clinical trial. In our clinical trial, all patients except 1 (95%) had reduced their ambulatory blood pressure during active treatment.

In any case of poor response to therapy, it is important to suspect defective compliance. It has been estimated that 16% to 50% of patients with newly diagnosed hypertension discontinue their antihypertensive medications within the first year.⁶ Electronic monitoring methods have revealed that many patients omit prescribed doses irrespective of disease, prognosis, or symptoms.¹ Subjects at particular risk of poor compliance with antihypertensive drugs seem to be middle-aged men still active in work and without previous cardiovascular disease.⁶ In our study, however, blood pressure was lower during the clinical trial, when all patients were still active in work, than at the follow-up when some patients were retired. In fact, 2 of the patients whose blood pressure was not controlled at the follow-up were retired at that time.

It might be argued that changed antihypertensive treatment could be the reason for the higher blood pressure at follow-up in our study. This, however, seems unlikely, since 3 of the 6 nonresponders at follow-up had the same treatment (50 mg atenolol). Progression of the disease cannot be excluded, but it seems unlikely in 2 of the 6 nonresponders who were followed up after 3 and 10 months. The reason for the almost 100% response rate in the clinical trial did not appear be caused by an extraordinarily enthusiastic physician, since the same physician treated the patients in her clinical practice. Perhaps a patient taking part in a clinical trial feels better cared for and attended to than a patient in clinical practice, when the time between visits has been prolonged. It is known that many people have difficulty following self-administered medical treatment. There are many trials for individual drug efficacies, but only a handful of rigorous trials of adherence interventions.¹⁴ And many of the interventions for long-term medications are exceedingly complex and labor intensive, including care provided at the work site, special pill containers, counseling, reminders, self-monitoring, support groups, feedback, and reinforcement.^15,16 Most studies also lack follow-up after the intervention had been discontinued.¹⁴

Being aware of the importance of noncompliance, manufacturers have tried to make things easier for the patient by producing, for example, sustained-release preparations and blister packages that indicate each day of the week. However, the reason for noncompliance may not always be forgetfulness, and lately a change in the terminology from compliance to concordance has been proposed in the hope that this might lead to a new view of the patient’s role.¹⁷ The price of compliance is said to be dependency and thus belongs to an older world.¹⁸ However, since there have been great advances in medical therapeutics during the past 2 decades, adherence to medication today may be more important for the outcome than it used to be. People today are more exposed to various kinds of information that may influence them. Information technology not only makes people more informed but sometimes also more irresolute. Alarm reports, more or less true, about adverse effect of medicines are not rare and can make patients discontinue their medication without consulting their physicians.