Methodological considerations in calculation of the trough: peak ratio.

AIM

The Food and Drug Administration in the United States has published guidelines which indicate that a minimum trough: peak ratio of 50-66% is required for the efficacy of an antihypertensive drug to be considered satisfactory in relation to its proposed dosage interval. However, these guidelines do not give any definition of the most appropriate methodology, and published data contain widely disparate values which often reflect methodological inconsistencies. This article attempts to define the principal methodological requirements for the accurate and reproducible measurement of trough and peak antihypertensive effects and for calculation of the trough: peak ratio. PROBLEMS IN CALCULATING THE TROUGH:PEAK RATIO: It is essential to take account of the antihypertensive effect of placebo, otherwise the results may be spurious. Similarly, account must be taken of the closely related circadian variability in blood pressure, which is particularly likely to compromise the interpretation of the peak effect. While the incorporation of placebo in a randomly allocated, crossover design is ideal, there are practical (and ethical) difficulties with this approach.

CONCLUSIONS

Provided there is an adequate placebo run-in period (of not less than 4 weeks) and individual patients are studied under carefully standardized conditions, with multiple blood pressure recordings throughout the dose interval, it is possible by means of a sequential, placebo-active treatment design to calculate the trough: peak ratio with acceptable accuracy and reproducibility.