Results of the search

In order to save time and effort, our trial search coordinator developed a comprehensive search strategy so that all four subclasses of beta blockers were searched simultaneously (Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5) and three additional beta blocker reviews (Wong 2008; Wong 2014a; Wong 2014b) used the same study inclusion criteria. Citations were sorted according to their respective subclasses afterward. Please refer to Figure 1 for the flow of study selection. The search was first run in May 2010; subsequent searches were performed up to October 2014. We identified a total of 22,195 citations, 8353 of which were confirmed to be duplicates. The review authors then screened 13,842 titles and abstracts, 13,229 citations of which were excluded. Based on titles and abstracts, they judged that 613potentially met the inclusion criteria; these were retrieved for detailed review. Four hundred and ninty‐seven full‐text articles did not meet our inclusion criteria and were excluded. One hundred and fifteen studies met our inclusion criteria. Twelve studies, among the 115 studies, studied dual receptor blockers. Four studies were excluded with reasons listed in the Characteristics of excluded studies table. Eight studies were included in this review.

Figure 1

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Study flow diagram

Included studies

Please refer to the Characteristics of included studies table for detailed descriptions of each included study. We included eight RCTs, that examined the blood pressure lowering efficacy of dual receptor blockers in 1493 hypertensive patients for 3 to 12 weeks. Five of the eight included studies were parallel studies; the other three were cross‐over studies. Four RCTs studied 12.5 mg/day to 50 mg/day doses of carvedilol in 1381 patients; the other four RCTs studied 300 mg/day to 800 mg/day doses of labetalol in 112 patients. Weighted mean baseline DBP was 101 millimetres of mercury (mm Hg) in carvedilol studies and 105 mm Hg in labetalol studies. Baseline SBP was not given in most included studies.

Excluded studies

Four studies that met the inclusion criteria were excluded after detailed reading. The reasons for exclusion were lack of useful data for outcomes listed in the review and misleading information on methods. Please refer to the Characteristics of excluded studies table for the reasons of exclusion.

Allocation

Kane 1976 and Lechi 1982 described the details of methods of randomization and allocation concealment. The other six included studies did not report any information on this matter, therefore, it was difficult to assess the risk of bias in this category. The baseline characteristics of parallel groups were similar, thus we did not find any evidence that suggested randomization was not properly done. It was impossible to assess the integrity of randomization in cross‐over studies without additional information. Five out of 8 of the included studies in this review were parallel studies therefore the risk of selection bias was low in this review. Even though we did not find any evidence to suspect any bias in randomization and allocation concealment, more precise reporting would allow us to better assess the risk of bias and quality of the evidence.

Blinding

Beta blockers generally present a high risk of detection bias as they lower heart rate. It was likely possible for assessors to detect the treatment group based on the change in heart rate. This risk could be mitigated by using an automated BP machine. However, none of the studies in this review reported using automated BP machines. Therefore, the risk for detection and performance bias was high in this review (Jadad 1996).

Incomplete outcome data

All but one included study, Frick 1976, reported the information on dropouts. The dropout rate was low in the included studies. Therefore the risk of attrition bias was low in this review.

Selective reporting

McPhillips 1988 did not report the data for heart rate according to intervention groups and Frick 1976 did not report withdrawal due to adverse effects (WDAE). Other than that, blood pressure and heart rate were reported in all studies. In addition, five of the eight studies reported useful WDAE. We judged that the risk of selective reporting bias was low in this review.

Carvedilol

Carvedilol is indicated for the treatment of hypertension, left ventricular dysfunction following MI and heart failure in the U.S. (FDA). It is indicated only for heart failure in Canada (eCPS). However, it can be used off label for hypertension. The recommended doses for hypertension in the U.S. are 6.25 mg twice daily to 25 mg twice daily for the immediate release form and 20 to 80 mg daily for the controlled release form.

We included four studies that examined the blood pressure lowering efficacy of 6.25 to 50 mg/day carvedilol in 1381 mild to moderate hypertensive patients (Carvedilol GSK B100; Carvedilol GSK B101; McPhillips 1988; Weber 2006). Carvedilol GSK B100 and Carvedilol GSK B101 were two unpublished RCTs obtained from the manufacturer's web‐site. The unpublished data contributed 72% of the data (1000 of 1381 subjects). Patients enrolled in these studies were on average 52 to 56 years old, with no co‐morbidities that could affect their blood pressure. The weighted mean baseline DBP of the four included studies was 100.9 mm Hg. Three of the four studies measured blood pressure at trough hours (Carvedilol GSK B100; Carvedilol GSK B101; Weber 2006).

Carvedilol 6.25 mg/day did not significantly lower SBP or DBP compared to placebo (SBP = ‐1 mmHg [‐5, 3]; DBP= ‐1 mmHg [‐3, 2];Analysis 1.1 & Analysis 1.2). Starting from 12.5 mg/day (the recommended starting dose), carvedilol significantly lowered SBP and DBP compared to placebo (Analysis 1.1 & Analysis 1.2). Heterogeneity was not significant in any of the subgroups (I²=0%). All 4 studies had multiple dose subgroups, allowing direct comparison between doses. Tests for subgroup differences by direct comparison were not significant for SBP and DBP within the product monograph range of recommended doses. (12.5 mg/day, 25 mg/day and 50 mg/day). The 1x and 2x starting dose (12.5 mg/day and 25 mg/day) subgroups contained the largest patient sample in carvedilol. The estimate for combining the average trough BP lowering effect combining the 1x and 2x starting dose (12.5 mg/day and 25 mg/day) carvedilol was ‐4/‐3 mmHg.

Carvedilol 6.25 mg/day did not significantly lower heart rate compared to placebo (‐1 BPM [‐4, 1]; Analysis 1.3). Tests for subgroup differences between carvedilol 12.5 mg/day and higher doses were significant for heart rate (P < 0.0005; Analysis 1.3). Carvedilol did not significantly change pulse pressure compared to placebo in any of the dose subgroups (Analysis 1.4).

Blood pressure variability was assessed by comparing the end treatment SD of carvedilol and placebo groups with a t‐test. Twelve SDs from carvedilol subgroups and four SDs from placebo subgroups were included. Carvedilol did not significantly change blood pressure variability in SBP (P = 0.37) or DBP (P = 0.65). The weighted mean SD for carvedilol group (SBP/DBP) was 15.9/9.0 and for placebo group was 16.4/9.2.

Labetalol

Labetalol is indicated for the treatment of hypertension in both Canada and the U.S. (eCPS; FDA). The recommended doses for hypertension in U.S. and Canada are 100 mg twice a day to 400 mg twice a day.

Four studies examined the BP lowering efficacy of 400 to 800 mg/day labetalol in 112 hypertensive patients were included in the analysis (Frick 1976; Kane 1976; Lechi 1982; Rouffy 1986). The baseline characteristics of patients were not well described in the articles. The mean baseline BP of patients enrolled in the studies was 165/105 mm Hg. Sixty per cent of the patients were middle age men with no co‐morbidities.

We did not find any data for the recommended starting dose (200 mg/day) of labetalol. Both labetalol 400 and 800 mg/day subgroups significantly lowered SBP and DBP (Analysis 2.1; Analysis 2.2). Tests for subgroup differences were significant by direct comparison for SBP (p= 0.09) and DBP (p= 0.0006). Heterogeneity was not significant in any of the subgroups (both I²=0%). Both 400 and 800 mg/day labetalol significantly lowered heart rate (400 mg/day :‐7 BPM [‐9, ‐5]; 800 mg/day ‐8 [‐10, ‐5]; Analysis 2.3). The effect on heart rate was not significantly different between 400 and 800 mg/day labetalol (p=0.6).

Labetalol 400 mg/day significantly reduced pulse pressure (‐4 mmHg [‐7, ‐0], p=0.02; Analysis 2.4), but 800 mg/day subgroup did not significantly change pulse pressure (‐5 [‐10, 0], p=0.07; Analysis 2.4).

Pooled hemodynamic effects of dual blockers

Our analyses showed that the BP lowering effect of carvedilol was much smaller than labetalol. If the difference in effect size was true, it would not be appropriate to pool the data. However, the difference of effect size might be the result of small sample size or bias. The possible reasons for the differences between the drugs are explained in the discussion. Since only carvedilol provided data for the recommended starting dose (12.5 mg/day), the pooled effect size at the recommended starting does was the same as carvedilol. Dual blocker lowered BP (SBP/DBP) by ‐6 mmHg [‐8, ‐4]/‐4 mmHg [‐5, ‐3] at twice the recommended starting dose (25 mg/day carvedilol and 400 mg/day labetalol). The BP lowering effect was ‐9 mmHg [‐12, ‐7]/‐7 mmHg [‐8, ‐5] at four times the recommended starting dose (50 mg/day carvedilol and 800 mg/day labetalol). Please refer to Analysis 3.1; Analysis 3.2; Analysis 3.3; Analysis 3.4; Analysis 3.5 for the pooled effect of dual alpha and beta blockers.

summary of findings Table for the main comparison also summarizes the results for combining the starting dose and twice the starting dose (Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4).

Withdrawal due to adverse effects (WDAE)

We pooled the WDAE data of carvedilol and labetalol together in order to include all valuable data. Five studies provided data for WDAE in 1412 patients (Carvedilol GSK B100; Carvedilol GSK B101; McPhillips 1988; Rouffy 1986; Weber 2006). Four of the studies used carvedilol as the active treatment (Carvedilol GSK B100; Carvedilol GSK B101; McPhillips 1988; Weber 2006).There was no significant difference in relative risk (RR) of WDAE between dual blocker treatment and placebo (RR 0.88;95% CI 0.54 to 1.42;P = 0.6).

Subgroup and sensitivity analyses

With the exception of baseline BP, the baseline characteristics of patients were similar in all studies. None of the studies reported data separated by subgroups. Therefore, the subgroup analyses for sex, co‐morbid conditions, race, age or severity of disease was not possible.

Difference between published and unpublished data

We performed a sensitivity analysis in order to examine the differences between estimated mean effect size of published and unpublished studies. The estimated means (SBP/DBP) for the 2x starting dose subgroup (25 mg/day carvedilol and 400 mg/day labetalol) from the published data were ‐3/‐4 mm Hg as compared to ‐5/‐2 mm Hg from the unpublished data. The estimate of SBP/DBP in 4x starting dose (50 mg/day carvedilol and 800 mg/day labetalol) subgroup from published data was ‐8/‐7 mm Hg as compared to ‐5/‐4 mm Hg from the unpublished data. For the 50 mg/day carvedilol and 800 mg/day labetalol, the published estimate exceeded the unpublished estimate by ‐3/‐3 mm Hg.