Flaws in Dose-Finding of Antihypertensive Drugs

The random variation of BP and the intraindividual variation in the BP response to treatment cause considerable difficulties in the evaluation of the dose-response relationship of antihypertensive drugs. Thus, failures in finding the optimal dose of antihypertensive drugs have not been uncommon. The notion that angiotensin receptor antagonists (angiotensin receptor blockers) have a relatively flat dose-response relationship also appears to be due to limitations of dose-finding studies. The conventional method of office BP measurement that is typically used in dose-finding studies is poorly reproducible and is subject to the white coat effect, placebo effect, and observer bias. These problems can be overcome by using ambulatory or home BP monitoring, which are known to improve the accuracy of studies aiming to detect BP changes. A crossover design study allows all participants to receive all treatments (doses) and paired comparisons are performed. Thus, this design significantly enhances the power to detect differences between doses, compared with the typical parallel-group dose-finding study. A separate analysis of the dose-response relationship exclusively in subjects with a good BP response to the drug (responders) can provide clear insight about the drug effect when it actually works. These measures improve the accuracy of drug trials investigating the dose-response relationship and might prevent misleading information at an early stage of clinical development.