Table 6 Summary of study findings

Prescription of selective or non-selective beta blockers did not affect mortality other than no treatment. Prescription of non-selective beta blockers was associated with lower mortality in sex-adjusted models

Full regression model of the whole study sample adjusted for sex and all other covariates:

non-selective beta blockers vs. beta 1-selective beta blockers HR 0.62 (95% CI: 0.41–0.95).

men aged ≥80 y (HR (95 %CI)):

beta 1-selective vs. no treatment:

Model A: 1.01 (0.60–1.70) Model B: 1.09 (0.64–1.85)

non-selective vs. no treatment:

Model A: 0.47 (0.14–1.64) Model B: 0.53 (0.15–1.88)

non-selective vs. beta 1-selective

Model A: 0.42 (0.13–1.37) Model B: 0.39 (0.12–1.25)

men all ages (HR (95%CI)):

beta 1-selective vs. no treatment:

Model A: 0.99 (0.69–1.40) Model B: 1.12 (0.77–1.59)

non-selective vs. no treatment:

Model A: 0.55 (0.28–1.08) Model B: 0.68 (0.34–1.36)

non-selective vs. beta 1-selective

Model A. 0.57 (0.32–1.05) Model B: 0.54 (0.29–1.01)

women aged ≥80 y(HR (95%CI)):

beta 1-selective vs. no treatment:

Model A: 0.87 (0.58–1.31) Model B: 0.90 (0.59–1.38)

non-selective vs. no treatment:

Model A: 0.77 (0.36–1.64) Model B: 0.76 (0.35–1.64)

non-selective vs. beta 1-selective

Model A:0.88 (0.44–1.76) Model B: 0.86 (0.41–1.75)

women all ages(HR (95%CI)):

beta 1-selective vs. no treatment

Model A: 0.85 (0.60–1.20) Model B: 0.88 (0.62–1.25)

non-selective vs. no treatment

Model A: 0.62 (0.33–1.17) Model B. 0.66 (0.34–1.25)

non-selective vs. beta 1-selective

Model A: 0.76 (0.43–1.35) Model B: 0.73 (0.41–1.31)

Model A (prospensity score age group, cardiovascular comorbidity (diabetes, CHD, CHF and CVDs), educational level and marital status)

Model B (propensity score including all variables in Model A and all the antihypertensive drugs, antithrombotics and statins (except the studied drug class).

Compared with the atenolol-based regimen, the amlodipine-based regimen reduced:

- the relative risk of cardiovascular events more effectively in both age groups: by 17% in patients ≥65 years (hazard ratio: 0.83; 95% CI 0.75, 0.91; P < 0.01) and 15% in patients <65 years (hazard ratio 0.85; 95% CI 0.78, 0.95; P < 0.01)

- cardiovascular mortality by 23% in the older group (hazard ratio 0.77; 95% CI 0.63, 0.94; P < 0.01) and by 24% in the younger group (hazard ratio 0.76; 95% CI 0.58, 1.00; P = 0.05)

- fatal and nonfatal stroke by 30% in the older group (hazard ratio 0.70; 95% CI 0.59, 0.84; P < 0.01) and by nonsignificant 9% in the younger group (hazard ratio 0.91; 95% CI 0.71, 1.15; P = 0.42)

- - significant in total of coronary endpoints, nonfatal MI (excluding silent MI) and fatal CHD in the younger, but not in the older group

Overall no significant difference in the total mortality was found neither in treatment nor in the control group. The rate of all deaths in the intervention group was 0.97 of that in the control group (95% CI 0.70–1.42).The rate of fatal stroke in the intervention group was 0.30 of that in the control group (95% CI 0.11–0.84) p < 0.025. Rate of all stroke in the intervention group was 0.58 of that in the control group (95% CI 0.35–0.96) p < 0.03.

The subgroup analysis of patients by age (70–79 years) showed a similar reduction in total stroke in both groups, but the study was not large enough for these differences to be significant.

Beta blocker use as the sole antihypertensive medication was associated with a lower risk of developing cognitive impairment (defined as a CASI [Cognitive Abilities Screening Instrument]) score < 74) compared with untreated men (IRR 0,69; 95% CI 0,50–0,94). Non- beta blocker drug combinations were also associated with a reduced risk (IRR 0,78; 95% CI 0,62–0,98).

Cognitive decline (defined as a ≥ 9 point decrease in CASI score) occurred in 1167 men (53.1%). Beta blocker use was also associated with a trend toward a decreased risk of cognitive decline: model 2 IRR 0.78 (95% CI 0.61–1.00) for beta blocker use alone; 0.81 (95% CI 0.64–1.03) for beta blocker in combination with other drugs. None of the other drug categories was significantly associated with cognitive decline.

No significant differences in primary outcome (first occurrence of all-cause death, nonfatal MI or nonfatal stroke) were seen between the calcium antagonist group and the non-calcium antagonist group (RR 0.98 CI 0.90–1.06). No significant differences were seen in these outcomes analysed individually.

In the subgroup analysis of patients >70 years the primary outcome occurred in 596 of the 3694 patients of the calcium antagonist group (16.3%) and in 664 of the 3829 patients of the non- calcium antagonist group (17.34%). RR 0.93 (95% CI 0.84–1.03) [p-values missing]

In this post-hoc analysis of the LIFE study, patients were divided in subgroups of aged 66 or younger and aged 67 or older. In the older subgroup, losartan significantly reduced the risk of the composite primary endpoint of cardiovascular death, nonfatal stroke or nonfatal MI compared to atenolol (HR 0.79, 95% CI 0.69–0.91). In the younger subgroup the effect was not significant (HR 1.03, 95% CI 0.82–1.28). Further subdividing suggested a “cut-off age” of 71 years, above which losartan based treatment is better than atenolol based treatment.

Older adults taking atenolol showed a greater mortality and higher pulse arterial pressure values than those not taking atenolol (73.9% vs 55.0%; p = 0.047 and 74.7 ± 14.1 vs 63.0 ± 14.2 mmHg, P < 0.001, respectively). Cox regression analysis showed that atenolol use (HR 1.91; 95% CI 1.04–4.31; p = 0.04) and pulse arterial pressure (HR 1.02; 95% CI 1.01–1.03; p = 0.032) were predictive of long-term mortality.

For the subgroup ≥70 years: There are no statistical significant differences for the primary cardiovascular endpoint in people over 70 years regarding the three intervention arms.

Primary cardiovascular composite endpoint:

Hazard ratio (95%CI)

P-value

beta blocker/ARB:

<70 years: 1.24 (0.72–2.12)

≥70 years: 1.21 (0.63–2.33)

Overall population: 1.22 (0.80–1.85)

beta blocker/ARB:

subgroup: 0.9671

overall: 0.3372

ARB/TD:

<70 years: 1.59 (0.83–3.02)

≥70 years: 0.97 (0.50–1.91)

Overall population: 1.26 (0.80–2.01)

ARB/TD:

subgroup: 0.3017

overall: 0.3505

beta blocker/TD:

<70 years: 1.96 (1.05–3.66)

≥70 years:1.18 (0.61–2.27)

Overall population: 1.54 (0.98–2.41)

beta blocker/TD:

subgroup: 0.2698

overall: 0.0567

The number of patients who discontinued the trial because of serious adverse events was 12 (1.1%), 11 (1.0%), and 11 (1.0%) in the benidipine-ARB, benidipine-beta blocker, and benidipine-thiazide groups, respectively. The percentage of adverse events was similar among the treatment groups: 505 (45.5%), 495 (45.5%), and 522 (47.7%) patients reported adverse events. The following adverse events occurred more frequently in another group or in two groups: bradycardia (benidipine-beta blocker,P < 0.0001), hyperkalemia (benidipine-ARB, P = 0.0395), vertigo (benidipine-b-blocker and benidipine-thiazide, P = 0.0188).

In this analysis of the COPE trial with 3293 patients in the subgroup of patients aged 65 years or older, benididpe + beta blocker reduced less fatal and non-fatal strokes than benidipine + TD (HR 2.74 (1.08–6-96) and benidipine +beta blocker was associated with more new onset diabetes than benidipine +ARB (HR 2.47 (1.03–5.91). There was no significant difference regarding the composite primary endpoint, cardiovascular endpoints, and all-cause mortality (benidipine plus beta blocker vs. benidipine plus angiotensine receptor blocker HR 0.99 (0.54–1.82); benidipine plus beta blocker vs. benidipine plus thiazide diuretic HR 1.34 (0.69–2.60).

Overall, the beta blocker group had significantly more withdrawals than the diuretic group for both suspected major side effects (beta blocker 30.2% (n = 333); diuretic 14.8% (n = 160); placebo 3.7% (n = 82), and inadequate blood pressure control (beta blocker n = 12; diuretic n = 1; placebo n = 175). After adjusting for baseline characteristics the diuretic group had significantly reduced risk of stroke (31% 95 CI 3% to 51%, p = 0.04), coronary events (44% 95 CI 21% to 60%, p = 0.0009), and all cardiovascular events (35% 95 CI 17% to 49%, p = 0.0005) compared with the placebo groups. The beta blocker group showed no significant reductions in these end points.

Depression Questionnaire (% of participants with depressed mood)

Paired Associate Learning Test (% of participants with a score ≤ 15)

The Trial-Making Test (seconds)

Antihypertensive treatment with either 25 mg hydrochlorothiazide and 2.5 mg amiloride or atenolol 50 mg for 9 months in a population aged between 65 and 74 years old with moderate raised blood pressure did not impair cognitive function, depression, or behavioural changes which would cause concern in confidants. The study did not find a linear relationship between blood pressure levels in their moderately elevated range and psychometric test scores, nor showed that lowering of blood pressure levels is associated with any impairment of performance on these tests

This secondary analysis of the MRC trial found evidence that atenolol does not perform as well as the hydrochlorothiazide plus amiloride (Moduretic ©) in terms of stroke prevention: Moduretic 41.6 number of events /1000 patient years, beta blocker 50.8% and placebo 60.5% (statistical tests missing). For stroke, we found that after adjusting for current systolic blood pressure variability in systolic blood pressure over time, as measured by the standard residual or root successive variance, contained significant prognostic capability:

the rate ratio associated with an increase of 1 standard deviation in the standard residual was 1.25 95% CI 0.86–1.81 and 1.16 95% CI 0.85–1.59 for the root successive variance.

In this article reporting on the MRC trial, the beta blocker group showed no significant differences to placebo regarding the outcomes stroke, coronary events, all cardiovascular events and all-cause mortality.

In this article reporting on the MRC trial, a RCT with 4396 patients (mean age 70.3 years) randomized to beta blocker, diuretic or placebo, the beta blocker group showed no significant differences to placebo regarding the outcomes stroke, coronary events, all cardiovascular events and all-cause mortality.