| Methods |
Randomized, double‐blind, placebo‐controlled trial (parallel arms). 4 x 3 factorial design. Wash‐out period = 2 to 4 weeks. Multicenter, conducted in Germany |
| Participants |
DBP 100 to 115 mmHg. Median age 48.2 years (range 21 to 68). Males 56.6%. Baseline BP range was 157.4 to 163.9/105.9 to 108.1 mmHg across the 12 treatment groups |
| Interventions |
Ramipril 2.5 mg, 5 mg or 10 mg/d, ramipril 2.5 mg, 5 mg or 10 mg/d + HCTZ 12.5 mg or 25 mg/d, HCTZ 12.5 mg or 25 mg/d, or placebo. N = 534 randomized (42 to 48 patients per treatment group)
Trial duration = 6 weeks |
| Outcomes |
Change from the baseline in trough mean standing and supine SBP and DBP (at weeks 1, 2, 4 and 6); pulse rate; biochemical data including serum potassium and uric acid; hematology and urinalysis (values not shown) |
| Notes |
A sample size calculation of 40 patients per treatment group was required to detect a difference ranging from 3 to 6 mmHg between groups depending on monotherapy versus placebo or combination therapy versus monotherapy comparisons at a power of 37% to 99%. The study authors stated that "overall, the treatment groups were balanced" with respect to baseline patient demographics and characteristics and baseline BP. Baseline data were incomplete, therefore we could not calculate P values. Body weight, hematology, urinalysis and serum biochemistry (except for potassium levels) were measured but actual values were not reported on. Mortalities, SAEs and total AEs were not reported |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
"This study was a randomised placebo‐controlled, parallel‐group, Multicenter trial with a 4 x 3 factorial design (2.5, 5 and 10 mg ramipril; 12.5 and 25 mg HCT; all combinations of ramipril and HCT; placebo)." (line 1 under "Methods‐Design" p.218). "Randomization was stratified by centre." (line 9 under "Methods‐Design" p.218). No further information was given |
| Allocation concealment (selection bias) |
Unclear risk |
Not stated by the study authors |
| Blinding (performance bias and detection bias)
All outcomes |
Unclear risk |
"A 2‐ or 4‐week, single‐blind, placebo run‐in phase was followed by a 6‐week, double‐blind, active treatment phase." (line 5 under "Methods‐Design" p.218). No further information was given |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Efficacy analysis was based on an intention‐to‐treat (ITT) technique
Exclusions: 47/581 (8%) of patients were excluded from the study before randomization i.e. during or after the run‐in period
Attrition: a total of 17/534 (3.2%) of patients withdrew from the study early due to the following reasons: 5 ‐ adverse events alone, 6 ‐ adverse events + elevated BP, 2 ‐ adverse events + low BP, 3 ‐ persistent elevation of BP and 1 ‐ alcohol abuse. Four of the 17 patients were receiving combination therapy; it is not known which treatment groups the remaining 13 patients were from
WDAEs: 13/534 (2.4%) patients withdrew due to adverse events: 5 ‐ adverse events alone, 6 ‐ adverse events + elevated BP, 2 ‐ adverse events + low BP. Of these 13 patients, 1 (0.19%) was receiving HCTZ and 1 placebo, however it is not known what the adverse event was that caused them to withdraw |
| Selective reporting (reporting bias) |
Unclear risk |
Body weight, hematology, urinalysis and serum biochemistry (except for potassium levels) were measured at baseline and endpoint but actual values were not reported on. BP was measured but not reported at weeks 1, 2 and 4. Variability was not given for serum potassium levels or baseline patient demographics and characteristics. Mortalities, SAEs and total AEs were not reported. Treatment‐related (possibly or probably related) AEs: 6.8% of patients, all HCTZ groups combined; and 9.1% in the placebo group |
| Industry sponsorship |
High risk |
Supported by Hoechst AG |
