Untersuchungen zur antihypertensiven Langzeitwirkung von Candesartan-cilexetil in verschiedenen Dosierungen unter dem Einfluß therapiefreier Intervalle

Abstract

In a randomized, phase IV clinical study with 4 parallel treatment arms, the long-lasting treatment effect of candesartan cilexetil (CAS 145040-37-5, CC, Blopress) was to be demonstrated for a repeated therapy-free interval of 48 h in the dosages 8 and 16 mg with or without hydrochlorothiazide 12.5 mg (CAS 58-93-5, HCT; 4 groups totally). The reason for this design was the known possibility of missed tablet doses in the patients' daily practice leading to a not always sufficient lowering of blood pressure in essential hypertension. Therefore, the intake of the daily tablet dose was intentionally omitted twice (after 6 and 8 weeks) during the 8-week study treatment period. Primary efficacy variable was the comparison of blood pressure lowering before and after the first 48-hour therapy-free interval following a 6-week treatment period. The confirmatory analysis was done on the basis of paired t-tests and the Bonferroni-Holm "step-down procedure" for the systolic and diastolic results in each of the four treatment groups. Secondary variables were the efficacy 24 and 48 h after the last tablet intake following a 6- and 8-week treatment period, the blood pressure normalization rate and the tolerability. 312 out-patients from 46 study centers in Germany with mild or moderate essential hypertension strictly treated according to the protocol requirements were evaluated in terms of all primary and secondary study parameters. The patient allocation to the 4 treatment arms as well as the conditions at study start concerning demographic data, physical investigation, patient history, ECG, concomitant diseases/therapy and baseline values of blood pressure were well comparable between the four groups. The antihypertensive therapy with CC showed the expected clear effect on blood pressure lowering in 312 per-protocol treated patients with in addition an increase for the higher dosages and for the combination with HCT. The mean rate of lowering (systolic/diastolic) after 24 h for all treatment groups together was 14.5/8.1 mmHg after 6 weeks and 17.3/9.5 mmHg after 8 weeks of therapy. The described antihypertensive blood lowering effect could be maintained in nearly 100% diastolic and 100% systolic values for the first 48-hour therapy-free interval after 6 weeks and in about 100% diastolic and 80% systolic values for the second interval after 8 weeks. These results could be reproduced without relevant differences for the respective single outcome in the four treatment groups. Regarding the primary study efficacy criterion the achieved lowering of blood pressure was highly statistically significant with p-values < 0.0001 in all 4 groups both for systolic and diastolic results. In addition, the long-term action over 48 h could be confirmed by the specific analysis according to Bonferroni-Holm showing that the p-values of all eight hypotheses were below the adjusted significance levels, i.e. in terms of the systolic and diastolic endpoints within the 4 treatment groups. Furthermore, statistically significant differences between the four treatment arms could not be detected regarding the long-lasting blood pressure lowering effect over As for tolerability the entire study provides no evidence on new or unknown pathologic drug reactions as well as on a frequent occurrence of specific adverse events or relevant laboratory changes. The objectives of the present study were completely met by confirming statistically and clinically the assumption of a clear, long-lasting, safe and metabolically neutral action of CC both for low and high dosages with or without HCT. The intended lowering of blood pressure is effective and well tolerable also repeatedly during the 48-h, therapy-free interval (missed dose trial) which corresponds to a frequent omission of the daily tablet dose and thus well reflects the daily practice in antihypertensive therapeutic regimens.