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Bangalore et al. (1) state that unlike results from post-myocardial infarction and congestive heart failure studies, a beta-blocker–induced low heart rate (HR) in hypertension is associated with an increase in death rate and cardiovascular (CV) events. This conclusion is highly misleading.
In post-myocardial infarction and congestive heart failure studies, the benefit from beta-1 blockade arises from decreased work of the heart (via reduced HR and blood pressure), reduced ventricular fibrillation risk, and a reduction in catecholamine-induced (beta-1) cardiac necrosis and apoptosis (2); thus, intrinsic sympathomimetic activity reduces efficacy (2). The situation with hypertension is complex, as diastolic hypertension in the young/middle-aged arises from a link with obesity (3) and high sympathetic nerve activity plus raised cardiac output (2). In contrast, isolated systolic hypertension arises in the elderly via a decrease in vascular compliance (3).
The 3 main contributor trials in the Bangalore et al. (1) study were the ASCOT (Anglo-Scandinavian Cardiac Outcomes), LIFE (Losartan Intervention for Endpoint Reduction in Hypertension), and INVEST (International Verapamil SR Trandolapril Study) studies in elderly patients with hypertension, which involved moderately beta-1 selective atenolol as the first-line choice. Atenolol does not improve vascular compliance (2), so it does not lower central systolic pressure; indeed first-line atenolol slightly increases central pressure (4), possibly linked to partial beta-2 blockade (2) and a fall in HR (1). Thus, a low HR would be linked to a high central pressure.
In contrast, second-line beta-blockade alongside a first-line agent that improves vascular compliance and lowers central pressures in the elderly (e.g., a low-dose diuretic or calcium antagonist ), is linked to highly significant falls in CV end points as in the SHEP (Systolic Hypertension in the Elderly Program), ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), and MRC (Medical Research Council)-Elderly (2) studies.
The next 2 main contributor trials (1) were the IPPPSH (International Prospective Primary Prevention Study in Hypertension) and HAPPHY (Heart Attack Primary Prevention in Hypertension) trials involving young/middle-aged hypertensive patients. The first-line beta-blockers were nonselective oxprenolol and partially beta-1 selective atenolol/metoprolol—beta-blockers that lower blood pressure in different ways (5). Metoprolol and atenolol act via a fall in HR and cardiac output; oxprenolol acts via a modest fall in HR and cardiac output plus a modest fall in peripheral resistance via beta-2 intrinsic sympathomimetic activity. Thus, linking a final HR or HR difference with CV events is unhelpful. For atenolol/metoprolol, quoting intra-trial (rather that end-trial) changes in HR (if known) would be useful, enabling HR/CV-event relationships to be studied.
Cigarette smoking is another relevant, vital issue for younger and middle-aged hypertensive patients, as significant benefit with oxprenolol (IPPPSH), propranolol (MRC-1), and metoprolol (MAPHY [Metoprolol Atherosclerosis Prevention in Hypertensives]) occurred only in nonsmokers (2). Nonsmokers (70% of the whole) in MRC-1 experienced a significant 38% reduction in CV events on propranolol, similar to the results of atenolol versus less-tight blood pressure control in overweight middle-aged hypertensive patients with type-2 diabetes in the UKPDS (United Kingdom Prospective Diabetes Study) (6,7), in which all 7 hard end point trends (including myocardial infarction and stroke) favoring the beta-blockers over the angiotensin-converting enzyme inhibitor at 9-year follow-up (7), strengthened over 20-year follow-up, achieving significance in the case of all-cause death (8). Smoking induces epinephrine release (9) and in the presence of beta-1/beta-2 blockade, unopposed alpha stimulation occurs; the resultant increase in blood pressure induces reflex falls in HR (10). In such a scenario, a low HR would be linked to an increase in CV events. Such a worrisome beta-blocker-epinephrine interaction is not observed with high beta-1 selectivity (e.g., bisoprolol) (11).
- American College of Cardiology Foundation
- Bangalore S.,
- Sawhney S.,
- Messerli F.H.
- Franklin S.S.,
- Pio J.R.,
- Wong N.D.,
- Larson M.G.,
- Leip E.P.,
- Vasan R.S.
- Morgan T.,
- Lauri J.,
- Bertram D.,
- Anderson A.
- Man in't Veld A.J.,
- Schalekamp A.D.
- UK Prospective Diabetes Study Group
- ↵(1998) Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713–720.