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Table 3 Summary of characteristics of the included studies

From: Effectiveness and safety of beta blockers in the management of hypertension in older adults: a systematic review to help reduce inappropriate prescribing

Author year Type of study Aim Intervention/control Sample size Follow-up Outcomes and measurement tools if applicable
Carlsson 2014 [43] Cohort study To study mortality rates in men and woman with hypertension and AF prescribes different cardiovascular pharmacotherapies
(time to death between registration of AF diagnosis and 31.12.2007)
Antithrombotic drugs alone:
- antiplatelet agents vs. no treatment
- anticoagulants vs. no treatment
- anticoagulants vs. antiplatelets
Beta blocker:
- Selective vs. no treatment
- non-elective vs. no treatment
- non-selective vs. selective
RAS-blocking agents:
- vs. no treatment
- ARBs vs. ACE inhibitors
- RAS blocking agents + other vs. no treatment
- ARB + thiazide vs. ACE inhibitor + thiazide
Calcium receptor- blocking agents:
- Vessel selective vs. no treatment
- Heart active vs. no treatment
- Vessel selective vs. heart active
- - Statins
n = 5602
4748 aged ≥65 y
854 aged <65 y
Mean follow-up 3.4 years Mortality
Collier 2011 [42] Multicentre, international randomized trial To evaluate the efficacy and safety of an amlodipine versus an atenolol-based antihypertensive regimen among older (≥ 65 years) and younger (<65 years) patients. Atenolol-based (atenolol ± thiazide diuretic)
Amlodipine-based (amlodipine ± perindopril)
n = 19,257
8137 aged ≥65 and 11,020 aged <65
Median follow up 5.5 years Nonfatal myocardial infarction and fatal coronary heart disease and cardiovascular events
Coope 1986 [34] RCT To explore, if the treatment of hypertension in patients between the ages of 60 and 79 years old reduces the incidence of stroke or coronary disease or affects cardiovascular or overall mortality Intervention group:
Step 1: atenolol 100 mg
If blood pressure control was insufficient the further treatment steps were applied:
Step 2: bendrofluazide 5 mg
Step 3: alphamethyldopa 500 mg (and eventually nifedipine retard 20 mg or other antihypertensive medication)
Control group: usual care
n = 884,
intervention group n = 419
control group n = 465
Mean follow up 4.4 years
(range 1–10, SD not reported)
Primary outcomes:
myocardial infarction, major strokes, minor strokes, transient ischaemic attacks,
death
Secondary outcomes:
Congestive heart failure
Heart failure
Atrial fibrillation
Clinical gout
Diabetes
Non- fatal cancer
Vertigo
Dizzy spells
Subgroup analysis in Coope 1986 [34] See above To analyse whether the treatment of hypertension in patients between the ages of 70 and 79 years old reduces the incidence of all strokes See above Not stated Not stated Incidence of all strokes including major strokes, minor strokes, transient ischaemic attacks
Gelber 2013 [45] Prospective, community- based cohort study To determine the associations between classes of antihypertensive medication use and the risk of cognitive impairment among elderly hypertensive men. No drug, BB alone, ACE alone, Diuretic alone, CCB alone, vasodilators alone, BB & 1 other, Other drug combinations n = 2197 Median follow up 5.8 years (SD 5.1) Development of cognitive impairment
CASI Score, a combination of the
Hasegawa Dementia Screening Scale, the Folstein Mini-Mental
State Examination, and the Modified Mini-Mental State Examination
Pepine 2003 [32] RCT To test the hypothesis, that the risk for adverse outcomes in older people with hypertension and coronary artery disease treated with a calcium antagonist based strategy or a non-calcium antagonist (atenolol) based strategy is equivalent. Step 1: either
calcium antagonist group:
240 mg/d of verapamil sustained release
or non-calcium antagonist: 50 mg/d of atenolol
If target blood pressure was not achieved, further steps:
Step 2:
calcium antagonist group additional trandolapril
non-calcium antagonist group additional hydrochlorothiazide
Step 3:
dosage increase
Step 4:
calcium antagonist group additional hydrochlorothiazide
non-calcium antagonist group additional trandolapril.
n = 22,576
Calcium antagonist group, n = 11,267 Non-calcium antagonist group, n = 11,309
Mean follow up 2.7 years (range 1 day to 5.4 years, SD not reported) Primary outcome:
first occurrence of
-death (all cause)
-non-fatal myocardial infarction
-non-fatal stroke
Secondary outcomes:
death (all cause), non-fatal myocardial infarction, non-fatal stroke, time to most serious event (ranked from death as most serious, to myocardial infarction, to stroke as last serious), cardiovascular death, angina, cardiovascular hospitalizations, cancer, Alzheimer disease, Parkinson, gastrointestinal bleeding, blood pressure control, new diagnosis of diabetes, adverse experiences.
Subgroup analysis in Pepine 2003 [32] See above See above See above Subgroup >70 years old: calcium antagonist group: n = 3694 non- calcium antagonist group: n = 3829 See above See above
Ruwald 2012 [41] Post hoc analysis of a double-blind, double-dummy randomized trial To investigate the influence of age on the effects of losartan versus atenolol-based antihypertensive treatment Intervention:
losartan 50 mg
(step 2: + HCT 12.5 mg HCT
step 3: losartan 100 mg + HCT 12.5 mg
step 4: losartan 100 mg + HCT 12.5-25 mg HCT + another antihypertensive treatment)
Control:
atenolol 50 mg
(step 2: + HCT 12.5 mg
step 3: atenolol 100 mg + HCT 12.5 mg
step 4: atenolol 100 mg + HCT 12.5-25 mg + another antihypertensive treatment)
n = 9193
n = 4304 < 67 years (46.8%)
n = 4889 ≥ 67 years (53.2%)
Mean follow up 4.8 years Primary outcome:
Composite of cardiovascular death, nonfatal stroke, nonfatal MI
Testa 2014 [44] Cross sectional study To evaluate long-term mortality in hypertensive older adults taking atenolol No atenolol (Intervention)/atenolol (control) 972 patients aged ≥65 with isolated hypertension
mean age 74.4 ± 6.4
Follow up of 12 years from 1992 to 2003 (not stated if median or mean follow up) Taking atenolol showed a greater mortality (73.9% vs 55.0%; p = 0.047) and higher pulse arterial pressure values (74.7 vs 63.02 mmHg, p < 0.001) than those not taking atenolol. Atenolol use (HR 1.91; 95% CI: 1.04–4.31; p = 0.04) was predictive of long-term mortality. Pulse
arterial pressure (HR 1.02; 95% CI 1.01–1.03; p = 0.032) was weakly predictive of long-term mortality.
Studies based on the COPE (Combination Therapy of Hypertension to Prevent Cardiovascular Events) trial
Matsuzaki 2011 [35] Main trial multicentre, prospective, randomized, open-label, blinded-endpoint trial To determine the optimal CCB benidipine-based combination therapy (angiotensin-receptor blocker (ARB), beta-blocker or a thiazide) in terms of lowering BP and preventing
cardiovascular events
3 intervention arms:
1. ARB (benidipine 4 mg + angiotensin receptor blocker usual dose)
2. BB (benidipine 4 mg + beta-blocker usual dose)
3. TD (benidipine 4 mg + half daily dose of thiazid diuretic
step 2: benidipine 8 mg (plus ARB/BB/TD)
step 3:benidipine 8 mg plus dose increase of ARB/BB/TD
n = 3293
1. ARB n = 1110 (analysed)
2. BB n = 1089 (analysed)
3. TD n = 1094 (analysed)
n = 1533 ≥ 65 years (46.6%)
n = 1760 < 65 years (53.4%)
Median follow up 3.61 years Primary outcome:
composite of cardiovascular morbidity
and mortality (sudden death, fatal or non-fatal stroke, fatal or non-fatal
myocardial infarction, hospitalization due to unstable angina, new onset of
heart failure new onset or worsening
of peripheral arterial disease, new onset or worsening of renal failure)
Secondary outcomes:
(1) All-cause mortality
(2) Death from cardiovascular events
(3) Fatal and non-fatal cardiovascular events
(4) New onset of diabetes mellitus
(5) Safety (adverse events and adverse drug reaction)
(6) Nonfatal stroke
Hospitalization due to heart failure (results on outcome not reported)
Ogihara 2012 [40]
COPE trial
post hoc analysis of the COPE trial To evaluate the efficacy and safety in older (≥65 years) and younger (<65 years) hypertensive patients
Studies based on the Medical Research Council (MRC) trial
MRC 1992 [33]
Main trial
RCT To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death. Patients were randomized to atenolol 50 mg daily; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg (Moduretic©) daily; or placebo. n = 4396
Three groups
(a) potassium sparing diuretic regimen (hydrochlorothiazide +amiloride) n = 1081
(b) beta blocker atenolol n = 1102
(c, d) matching placebo tablets
n = 2213
Mean follow up 5.8 years
25,355 patients years of observation (SD not reported)
Strokes, coronary events, and deaths from all causes.
Bird 1990 [36] RCT, secondary analysis To explore if cognitive dysfunction, manifested as an increased incidence of confusional states or impaired concentration and attention are associated either with a particular antihypertensive regime or with the reduction in blood pressure level that it induces. To explore if a continuous reduction in mildly elevated blood pressure levels affect the rate of change in cognitive function. Patients were randomly assigned to hydrochlorothiazide 25 mg and 2.5 mg amiloride, (Moduretic©) daily, atenolol 50 mg daily, or placebo. n = 2401
hydrochlorothiazide amiloride 24%
atenolol 24%
Placebo 52%
Results reported at month 1 and 9 (median or mean follow up and SD not reported) Cognitive tests:
Verbal intelligence measured with the Nelson Adult Reading Test (NART),
Non verbal intelligence (performance ability) measured with the Ravens Matrice, part a & b,
Capacity to learn and remember new material measured with the Paired Associate Learning Test (PALT),
Alertness and speed of reaction measured with the Trail-Making Test (TMT),
Depression with the self-rating Depression Questionnaire (DQ) Blood Pressure
Carr 2012
[37]
RCT, secondary analysis To assess the impact of the blood pressure profile on cardiovascular risk in the Medical Research
Council (UK) elderly trial and to investigate whether the effects of
hypertensive drugs in reducing event rates are solely a
product of systolic pressure reduction.
Intervention:1. atenolol 50 mg daily or
2. hydrochlorothiazide 25 mg (50 mg) + amiloride 2,5 mg (5 mg)
Control:
Placebo
n = 4396
atenolol: n = 1102
hydrochlorothiazide + amiloride: n = 1081 hydrochlorothiazide + Placebo n = 2213
Mean follow up 5.8 years Primary outcomes:
stroke
CHD
secondary outcomes:
association between BP and outcomes
Lever 1992 [48] RCT, secondary analysis To study the effect of two treatments for hypertension on all-cause mortality and morbidity from cardiovascular disease see above see above see above Stroke
coronary events
all cardiovascular events
all-cause mortality
withdrawal/loss to FU from treatment
Lever 1993
[38]
RCT, secondary analysis To determine whether hypotensive drug treatment in men and women aged 65–74 reduces stroke, CHD and mortality see above see above see above Stroke
coronary events
all cardiovascular events
all-cause mortality
change in blood pressure
  1. Legend: RCT randomized controlled trial, ACE angiotensin-converting enzyme, ARB angiotensin-receptor blockers, BB Beta-blockers, CCB calcium channel blockers, FU Follow up, TD Thiazide diuretic