| Methods |
Randomization was conducted by an independent advisor by resampling without replacement after the placebo run‐in period. The study was not double‐blind because one outcome was the difference in compliance between once‐daily and twice‐daily regimens. However, the investigator responsible for analyzing the results was blinded as to the treatment phase |
| Participants |
27 patients with a history of mild hypertension (well controlled on monotherapy), with a diastolic BP between 90 to 110 mm Hg were included. Patients were excluded if they had secondary hypertension or significant end organ damage, were pregnant or lactating mothers, had cardiovascular complications in addition to hypertension (e.g. MI within the past 6 months), stroke, congestive heart failure, angina pectoris, had poor renal function, a history of renal artery stenosis, were obese (weighing over 125% of ideal body weight), had hyperkalemia, had a history of angioneurotic edema, had any contraindication or hypersensitivity to ACE inhibitors, or if they were taking non‐steroidal anti‐inflammatory drugs, corticosteroids or any other medication that would significantly alter blood pressure |
| Interventions |
Patients were randomly assigned to a sequence of enalapril 20 mg once daily or 10 mg twice daily in 3 4‐week periods following a 4‐week run‐in period. Treatment A comprised enalapril 20 mg once daily, and treatment B comprised enalapril 10 mg twice daily. The first 2 periods in each group constituted a conventional 2‐period cross‐over design. The third treatment period was included to detect any carryover effects between the periods without having to incorporate a washout phase between treatments. The 4 study arms were organized as follows (each period lasted 4 weeks): ABB BAA ABA BAB |
| Outcomes |
Measurement of compliance: patient compliance was measured via pill counts and electronic monitoring using medication electronic monitoring system (MEMS), which record the exact date and time of each opening and closing of the drug container. Measurement of clinical health outcomes: blood pressure reduction was measured at each visit. Patients were asked not to take their blood pressure tablet on the morning of the clinical visit until after the investigator had measured their blood pressure so that the blood pressure (BP) readings were trough values. 2 readings were taken after 10 minutes rest in the seated position. The arm was supported at heart level and the diastolic blood pressure taken as the disappearance of the Korotkoff sounds (phase V). Ambulatory blood pressure was measured at the end of the placebo run‐in period and at the end of periods 1 and 2 |
| Notes |
― |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Unclear risk |
No mention of method of randomization. (pg 1628) "Randomization was conducted by an independent advisor (by resampling without replacement) after the placebo run‐in period." |
| Allocation concealment (selection bias) |
Unclear risk |
No mention of allocation concealment, though reference to an "independent advisor" may have meant allocation was concealed from study staff. (pg 1628) "Randomization was conducted by an independent advisor (by resampling without replacement) after the placebo run‐in period." |
| Selective reporting (reporting bias) |
Unclear risk |
No protocol available |
| Other bias |
Unclear risk |
No biases noted in discussion, no other obvious risks of bias in study |
| Blinding of outcome assessment (detection bias)
Adherence measure |
High risk |
(PRIMARY) PILL COUNT ‐ (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase." |
| Blinding of outcome assessment (detection bias)
Adherence measure |
High risk |
(PRIMARY) MEMS ‐ No mention of blinding outcomes assessors, but (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase." |
| Blinding of outcome assessment (detection bias)
Patient outcome |
Low risk |
(PRIMARY) BLOOD PRESSURE ‐ (pg 1628‐9) "Blood pressure was measured at each visit using the Hawksley Random‐Zero Sphygmomanometer (Lancing, UK)" |
| Blinding of participants (performance bias)
Adherence measure |
High risk |
(PRIMARY) MEMS ‐ Patients would have been aware that their pills were being tracked |
| Blinding of participants (performance bias)
Adherence measure |
High risk |
(PRIMARY) PILL COUNT ‐ Patients would have been aware that their pills were being counted |
| Blinding of participants (performance bias)
Patient outcome |
Low risk |
(PRIMARY) BLOOD PRESSURE ‐ (pg 1628‐9) "Blood pressure was measured at each visit using the Hawksley Random‐Zero Sphygmomanometer (Lancing, UK)" |
| Blinding of personnel (performance bias)
Adherence measure |
High risk |
(PRIMARY) MEMS ‐ (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase." |
| Blinding of personnel (performance bias)
Adherence measure |
High risk |
(PRIMARY) PILL COUNT ‐ (pg 1628) "The study could not be double‐blind since an important outcome was the difference in compliance between the once daily and twice daily regimens. However, the investigator responsible for analysing the results was blinded as to the treatment phase." |
| Blinding of personnel (performance bias)
Patient outcome |
Low risk |
(PRIMARY) BLOOD PRESSURE ‐ (pg 1628) "Blood pressure was measured at each visit using the Hawksley Random‐Zero Sphygmomanometer (Lancing, UK)." |
| Incomplete outcome data (attrition bias)
Adherence measure |
Unclear risk |
(PRIMARY) MEMS ‐ No mention of groups missing data were from. (pg 1629) "Twenty‐seven patients were recruited into the study, two of whom had to be withdrawn after experiencing headache, nausea and dizziness upon commencing enalapril therapy. The remaining 25 patients completed". |
| Incomplete outcome data (attrition bias)
Adherence measure |
Unclear risk |
(PRIMARY) PILL COUNT ‐ No mention of groups missing data were from. (pg 1629) "Twenty‐seven patients were recruited into the study, two of whom had to be withdrawn after experiencing headache, nausea and dizziness upon commencing enalapril therapy. The remaining 25 patients completed." |
| Incomplete outcome data (attrition bias)
Patient outcome |
Unclear risk |
(PRIMARY) BLOOD PRESSURE ‐ No mention of groups missing data were from. (pg 1629) "Twenty‐seven patients were recruited into the study, two of whom had to be withdrawn after experiencing headache, nausea and dizziness upon commencing enalapril therapy. The remaining 25 patients completed." |
