Schmieder 2009.
| Methods | Randomized, double‐blind, placebo‐controlled trial (parallel arms). Wash‐out period = 2 weeks followed by a single‐blind placebo run‐in of 2 to 5 weeks. Multicenter; Belgium, Finland, Germany, Italy, the Netherlands and Spain | |
| Participants | DBP 90 to < 110 mmHg. Mean age in HCTZ group: 56 years. Males 56%, white 99%, obese 34% in HCTZ group Baseline BP in HCTZ group was 154.3/99.0 mmHg (PLB arm demographics/characteristics not mentioned) | |
| Interventions | Aliskiren 150 mg/d forced titrated at week 3 to 300 mg/d (N = 459), HCTZ 12.5 mg/d forced titrated at week 3 to 25 mg/d (N = 444) or placebo (N = 221) Duration 12 weeks (full trial duration including extension phase was 52 weeks). After the first 6 weeks patients in the placebo arm were re‐assigned to aliskiren or HCTZ and after 12 weeks, combination therapy was introduced with aliskiren 300 mg/d + amlodipine 5 mg or 10 mg/d, or HCTZ 25 mg/d + amlodipine 5 mg or 10 mg/d | |
| Outcomes | Change from the baseline to endpoint in mean trough sitting DBP and SBP; response rate; ECG, hematology, urinalysis and serum biochemistry. Subgroup analysis was performed (based on age) | |
| Notes | A sample size calculation was provided based on approximately 440 patients in each active treatment group to detect a non‐inferiority margin of 2 mmHg between aliskiren and HCTZ regimens (SD ± 8 mmHg) at a power of 95%. The study authors stated that there were no statistically significant differences in the baseline patient demographics and characteristics between the HCTZ and aliskiren (not classified as a thiazide) treatment groups. The study did not make comparisons between HCTZ and placebo groups. Baseline patient demographics and characteristics were not reported in the placebo group. Patients randomized to receive the placebo were on it for 6 weeks before being switched to active treatment, therefore only BP data of up to 6 weeks can be used in this review, including that from the HCTZ group. Another important note: after 3 weeks on HCTZ 12.5 mg, patients were given a forced titration to 25 mg |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "...[a] randomised, double‐blind, parallel‐group, active‐controlled, dose‐titration study was performed..." (line 1 under "Study Design" p.418). "Randomization by centre was performed by the interactive system that automates the random assignment of patients to randomisation numbers." (line 19 from top of p.418, right column) |
| Allocation concealment (selection bias) | Unclear risk | "Randomization data were kept strictly confidential until the time of unblinding." (line 22 from top of p.418, right column). No further information was given |
| Blinding (performance bias and detection bias) All outcomes | Unclear risk | "...[a] randomised, double‐blind, parallel‐group, active‐controlled, dose‐titration study was performed..." (line 1 under "Study Design" p.418). No further information was given |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | The primary efficacy analysis was based on an intention‐to‐treat (ITT) technique with the LOCF (last observation carried forward) Exclusions: 151/1275 (12%) of patients were excluded from the study during the placebo run‐in period prior to randomization (specific reasons were given) Attrition: 67/1124 (6%) of patients withdrew from the study after 6 weeks of DB therapy; 26/444 (5.9%) and 21/221 (9.5%) of patients from the HCTZ and placebo groups, respectively. The main reasons for withdrawing: AEs (see below) and withdrawal of consent (HCTZ: 11 patients; placebo: 6 patients) WDAEs: 5/444 (1%) of patients in the HCTZ group and 6/221 (2.7%) of patients from the placebo group withdrew due to adverse events |
| Selective reporting (reporting bias) | High risk | Baseline demographics and characteristics were not reported in patients on the placebo. Results from physical exams, hematology, biochemistry and urine samples were not reported at baseline and only BUN and serum potassium and creatinine levels (patients were grouped according to certain threshold levels; actual mean values were not given) were reported at the study's endpoint. Mortalities: none. SAEs: Only those considered by the investigator to be related to the study medications were counted; they included 1 from the HCTZ group (moderate hypokalemia) and 1 from the placebo group (myocardial infarction). Total AEs: 24.5% of patients in HCTZ group and 28.5% in the placebo group experienced AEs. A listing of other AEs and laboratory results from patients in the placebo group were not reported |
| Industry sponsorship | High risk | Supported by Novartis Pharmaceuticals |