Abstract: Thirteen randomized double-blinded placebo-controlled trials that examined the blood pressure lowering efficacy of six partial agonists in 605 hypertensive patients were included in this review. Five of the included studies were parallel studies and the other eight were cross-over studies. The overall risk of bias is high in this review due to the small sample size and high risk of detection bias. Pindolol, celiprolol and alprenolol lowered SBP and DBP compared to placebo. Acebutolol lowered SBP but there was no clear evidence that it lowered DBP. There was no clear evidence that pindolol and oxprenolol lowered SBP or DBP. Other than for celiprolol, sample sizes were generally small increasing the uncertainty in findings for individual agents versus placebo. In patients with moderate to severe hypertension, partial agonists (considered as a subclass) lowered peak BP by an average of 8 mmHg systolic (95% CI, -10 to -6, very low quality evidence), 4 mmHg diastolic (95%CI, -5 to -3, very low quality evidence) and reduced heart rate by five beats per minute (95%CI, -6 to -4, very low quality evidence). Higher dose partial agonists did not appear to provide additional BP lowering effects compared to lower dose. The maximum BP lowering effect of the overall subclass occurred at the starting dose. Partial agonists reduced pulse pressure by 4 mmHg (95% CI, -5 to -2, very low evidence). Only one study reported withdrawal due to adverse effects, the risk ratio (95% confidence interval) was 0.72 (0.07, 7.67). There was very low quality evidence that in patients with moderate to severe hypertension, partial agonists lowered peak BP by an average of 8/4 mmHg and reduced heart rate by five beats per minute. There was no evidence of a greater effect at doses higher than the initial doses. This estimate was probably exaggerated as it was subject to a high risk of bias. Based on the indirect comparison of the results in this review and two Cochrane reviews on angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which also used similar inclusion criteria as this review, the BP lowering effect appeared to be less than the effect in patients with mild to moderate elevated BP who were taking ACE inhibitors and ARBs based on an indirect comparison. Withdrawals due to adverse effects were only reported in one trial so it is impossible to assess the harm of these drugs.

Plain-language summary: We developed a comprehensive search strategy to search relevant scientific databases for clinical trials and found 13 trials that randomly assigned 605 high blood pressure patients to either fixed-dose partial agonist treatment or placebo for up to 12 weeks. On average, partial agonists lowered blood pressure by eight points in systolic and four points in diastolic pressure in patient with moderate to severe high blood pressure. We did not find any evidence showing that doses higher than the recommended starting doses would further lower blood pressure. On average, partial agonists lowered pulse pressure by 4 mmHg. The included studies generally did not report side effects serious enough that lead to termination of treatment. It was not clear whether partial agonists provide more side effects serious enough that lead to withdrawal compared to placebo. The quality of evidence is very low due to small sample size and high risk of bias.