Blood pressure lowering efficacy of partial agonist beta blocker monotherapy for primary hypertension

Gavin W K Wong, Heidi N Boyda, James M Wright
Cochrane Database of Systematic Reviews 2014 November 27, (11): CD007450

BACKGROUND: Partial agonists are a subclass of beta blockers used to treat hypertension in many countries. Partial agonist act by stimulating beta receptors when they are quiescent and blocking beta receptors when they are active. The blood pressure (BP) lowering effect of partial agonist beta blockers has not been quantified.

OBJECTIVES: To quantify the dose-related effects of various partial agonists beta blockers on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate versus placebo in patients with primary hypertension.

SEARCH METHODS: We searched the Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE In-Process, EMBASE and for randomized controlled trials up to October 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Group's Specialised Register.

SELECTION CRITERIA: Randomized double-blinded placebo-controlled parallel or cross-over trials. Studies must contain a partial agonist monotherapy arm with fixed dose. Patients enrolled into the studies must have primary hypertension at baseline (defined as SBP/DBP > 140/90 mmHg). Duration of studies must be between three to 12 weeks.

DATA COLLECTION AND ANALYSIS: Two authors (GW and HB) confirmed the inclusion of studies and extracted the data independently.

MAIN RESULTS: 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).

AUTHORS' CONCLUSIONS: 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.

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