| Methods |
Randomized, double‐blind, placebo‐controlled trial. Wash‐out period = 4 to 6 weeks. Multicenter, USA |
| Participants |
Mean age 53 years. Males 67%. Supine DBP 95 to 110 mmHg. Supine SBP 153.4 + 2.2 (SEM) mmHg and supine DBP 100.2 + 0.5 (SEM) mmHg |
| Interventions |
Diltiazem SR 120 mg q12h (N = 73), diltiazem SR 120 mg q12h + HCTZ 12.5 mg q12h (N = 77), HCTZ 12.5 mg q12h (N = 74), or placebo (N = 74)
Trial duration = 6 weeks |
| Outcomes |
Change from the baseline in mean trough supine and standing DBP and SBP; 12‐hour BP monitoring; heart rate; ECG; hematology and serum biochemistry. Subgroup analyses were performed (based on age, race, weight, sex and smoking status) |
| Notes |
A sample size calculation was not provided. Both male and female patients were, on average overweight or obese which has several implications including a higher incidence of concomitant illnesses compared to other studies reviewed here. 114 of the study's patients selected from certain clinics underwent BP monitoring while in clinic both at baseline and at endpoint to determine residual drug effects every 2 hours for up to 12 hours post‐dose. Study authors stated that the baseline patient demographics and characteristics were not significantly different across treatment groups. WDAEs, mortalities and SAEs were not reported |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
"Eligible patients were allocated to one of four treatment groups, as noted above, using a blinded, blocked randomisation schedule." (line 1 under "Randomization and Dose Selection" p.489) |
| Allocation concealment (selection bias) |
Low risk |
"Eligible patients were allocated to one of four treatment groups, as noted above, using a blinded, blocked randomisation schedule. (line 1 under "Randomization and Dose Selection" p.489) |
| Blinding (performance bias and detection bias)
All outcomes |
Low risk |
"In this multicenter, randomised, double‐blind, placebo‐controlled, parallel group trial, DTZ SR‐HCTZ 120 mg‐12.5 mg (Cardizide), DTZ SR 120 mg (Cardizem SR), HCTZ 12.5 mg, or placebo was administered every 12 hours." (line 1 under "Methods‐design" p.488). "All drugs and placebo were identical in appearance." (line 3 under "Randomization and Dose Selection" p.489) |
| Incomplete outcome data (attrition bias)
All outcomes |
Unclear risk |
Primary efficacy analysis was based on an intention‐to‐treat (ITT) technique
Exclusions: 206/504 (41%) of patients were excluded from the study during the single‐blind, placebo run‐in period prior to randomization
Attrition: 44/298 (15%) of patients withdrew from the study. 10 patients withdrew for "protocol violations", but the specific reasons were not given for the other 34 patients. Data were pooled from all treatment groups, therefore it could not be determined from which groups the withdrawing patients originated
WDAEs: not given |
| Selective reporting (reporting bias) |
High risk |
Medical history was not included in the baseline patient demographics and characteristics. Heart rate and ECG were measured, but not reported on at the study's endpoint. Multivariate analyses comparing BP effects based on age, sex, weight, ethnicity and smoking status were conducted without any details included in the methods section of the study. Variability in residual BP and HR effects (i.e. 0 to 12 hours post‐dose) was not reported. Mortalities and SAEs were not documented. All adverse events were not reported. Treatment‐related adverse events: 40.5% (30/74) of patients in the HCTZ group and 27% (20/74) of patients in the placebo group. Only the 8 most commonly reported AEs "possibly" related to the study drug were listed |
| Industry sponsorship |
High risk |
Funded by a research grant from Marion Merrell Dow Inc. |
