The Trough-to-Peak Ratio as an Instrument to Evaluate Antihypertensive Drugs

Abstract

The U.S. Food and Drug Administration designed the trough-to-peak ratio as an instrument for the evaluation of long-acting antihypertensive drugs, but the ratios are usually reported without accounting for interindividual variability. This study investigated how the trough-to-peak ratio would be affected by interindividual and intraindividual variability and by smoothing of the diurnal blood pressure profiles. The ambulatory blood pressure was recorded on placebo in 143 hypertensive patients (diastolic pressure on conventional measurement > 95 mm Hg). After 2 months, the recordings were repeated on 10 mg (n = 66) or 20 mg (n = 77) lisinopril given once daily between 7 and 11 PM. The baseline-adjusted trough-to-peak ratios were determined from diurnal blood pressure profiles with 1-hour precision. Lisinopril reduced (+/- SD) the 24-hour pressure by 16 +/- 17 mm Hg for systolic and 10 +/- 10 mm Hg for diastolic (P < .001). According to the usual approach, disregarding interindividual variability, the trough-to-peak ratio was 0.72 for systolic pressure and 0.67 for diastolic pressure. In the 143 patients the ratios were not normally distributed. They were the same on both lisinopril doses. When interindividual variability was accounted for, the median trough-to-peak ratio was 0.34 (P5 to P95 interval, -0.46 to 0.87) for systolic pressure and 0.26 (-0.44 to 0.84) for diastolic pressure. In 66 patients examined twice on 10 mg lisinopril at a median interval of 32 days, the trough-to-peak ratios were characterized by large intraindividual variability.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of Fourier analysis in the calculation of trough to peak ratio from ambulatory blood pressure measurements

“…3,22,23 A small decrease in BP, however, may be observed during the first 2-6 h of ambulatory monitoring in placebo-treated groups. 21,23,24 This effect seems inconsistent and, in contrast to the treatment-induced effect, is not normally distributed. 21 In our patients, the peak effect occurred on average 11 h after drug intake.…”

“…Some authors claim that placebo correction reduces the peak effect and consequently, increases the T:P ratio of a single antihypertensive drug. 6,21,24,26 According to Omboni et al 21 this effect is small and placebo correction may even worsen the scatter in the T:P ratio. In view of this, and taken into account that the BP values used for the actual calculation of T:P ratio are obtained at time points when the placebo effect has no great impact, we feel that placebo treatment is not required when T:P ratios are calculated from ABPM data.…”

“…3,17,21,24 As in our method of analysis the peak effect is defined as the greatest difference in BP between the treated and untreated condition which can be found at any point of the 24-h curves, a fall in BP will always be detected and the trough effect can never be greater than peak, and the T:P ratio cannot exceed unity. In case of little effect of the drug, the trough effect, which is determined at a fixed time interval at the end of the dosing interval, may well be greater without treatment due to random variations, resulting in a positive trough value.…”

Trough to peak ratio as a guide to BP control: measurement and calculation

“…Thus spurious responses are very easy to obtain. An example of the magnitude of this effect is provided in a report of the APTH study 32 which is discussed below.…”

“…How should T:P be measured if the drug is taken at night? The problems associated with this are well illustrated in the APTH study, 32 in which medication was taken between 7.00 and 11.00 pm. The peak effects were at 9.5 (systolic) and 13 h (diastolic) after dosing and were large (41/31 mm Hg).…”