(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Beta-Blockers Are not a Good Initial Choice for Hypertension: True or False?
A meta-analysis (Lindholm et al. 2005) concluded that beta-blockers should not remain the first choice in the treatment of primary hypertension. This analysis included randomized controlled trials (RCTs) with poor methodology.
In most of the RCTs analyzed by these investigators, atenolol was the beta-blocker used for comparison. Worldwide, atenolol is one of the most prescribed beta-blockers.
Their analysis indeed suggests that atenolol does not give hypertensive patients adequate protection against cardiovascular disease (CVD). These investigators failed to recognize that beta-blockers possess important and subtle clinical properties. Their analysis does not indicate that other beta-blockers provide the same poor CVD protection as atenolol.
In the second edition of Cardiac Drug Therapy (1988), this author emphasized that beta-blockers are not all alike:
Those with ISA activity (oxprenolol, pindolol) are not cardioprotective; see discussion of ISA activity in Chap. 1.
Propranolol proved cardioprotective in BHAT (1982), and in the Medical Research Council (MRC 1985) trial of treatment of mild hypertension, but only in nonsmokers (see the last section of Chap. 1, Which Beta-Blocker Is Best for Your Patients?)
Bucindolol, a vasodilatory beta-blocker, surprisingly proved to be of no value for the treatment of heart failure (HF) (Beta-Blocker Evaluation of Survival Trial Investigators 2001) whereas carvedilol (in COPERNICUS (Packer et al. 2002) and CAPRICORN (The CAPRICORN Investigators 2001) significantly decreased coronary heart disease (CHD) outcomes.
Bisoprolol (in CIBIS [CIBIS-II Investigators and Committees 1999]) and metoprolol succinate (in MERIT/HF [MERIT-HF Study Group 1999]) significantly reduced fatal and nonfatal myocardial infarction (MI) and recurrence of HF.
In CAPRICORN, carvedilol achieved a 50 % reduction in nonfatal MI patients aged mainly >55 years. There was a 30 % reduction in total mortality and nonfatal MI. Carvedilol decreased CHD events in elderly normotensive and hypertensive patients.
The causation of a fatal or nonfatal MI in patients with CHD is the same in a hypertensive and nonhypertensive individual. Thus calcium antagonist or diuretic therapy used for management of hypertension cannot give more cardioprotection (decrease in fatal and nonfatal MI) than treatment with beta-blockers that are proven in RCTs to prevent outcomes.
Newer beta-blockers have other possible benefits. Carvedilol and nebivolol are beta-blockers with direct vasodilating and antioxidant properties. Nebivolol stimulates the endothelial l-arginine/nitric oxide pathway and produces vasodilation; the drug increases nitric oxide (NO) by decreasing its oxidative inactivation (Cominacini et al. 2003).
These two beta-blockers should be subjected to long-term outcome trials in the treatment of primary hypertension.
Atenolol is a hydrophilic beta-blocker that attains low brain concentration. Most important, increased brain concentration and elevation of central vagal tone confers cardiovascular protection (Pitt 1992). Lipid-soluble beta-blockers (bisoprolol, carvedilol, metoprolol, propranolol, and timolol) have all been proven in large RCTs to significantly decrease cardiac deaths; they all attain high brain concentration block sympathetic discharge in the hypothalamus better than water-soluble agents (atenolol and sotalol) (Pitt 1992) Timolol in the Norwegian trial (1981) caused an astounding 67 % reduction in sudden cardiac deaths.
Äblad et al. (1991), in a rabbit model, showed that although metoprolol (lipophilic) and atenolol (hydrophilic) caused equal beta-blockade, only metoprolol caused a reduction in sudden cardiac death. Metoprolol, but not atenolol, caused a significant increase, which indicates an increase in sympathetic tone.
Importantly, only the lipophilic beta-blockers (carvedilol, bisoprolol, propranolol, and timolol) have been shown in large RCTs to prevent fatal and nonfatal MI and sudden cardiac death. In the timolol infarction RT, the drug caused a 67 % reduction in sudden deaths. These agents have been shown to quell early morning catecholamine surge and control early morning and exercise-induced excessive rise in blood pressure better compared with atenolol (Neutel et al. 1993; Kokkinos et al. 2006).
It is surprising that the experts who constructed the recent hypertensive guidelines (JNC8 et al. 2014) fail to understand the subtle but important differences that exist between the available beta-blocking agents. These experts do not recommend a beta-blocking drug for the management of hypertension based on an unsound study in which the poorly effective atenolol was administered.
“The panel did not recommend beta-blockers for the initial treatment of hypertension because in one study use of beta-blockers “atenolol” resulted in a higher rate of the primary composite outcome of cardiovascular death, MI, or stroke compared to use of an ARB”, (JNC8 2014). These experts state “a finding that was driven largely by an increase in stroke (Dahlöf et al. 2002).
The study by Dahlöf et al. did not reveal a significant change in cardiovascular deaths or occurrence of fatal and nonfatal MI as claimed by this expert panel. 204 losartan and 234 atenolol patients died from cardiovascular disease (0 · 89, 0 · 73—1 · 07, p = 0 · 206); 232 and 309, respectively, had fatal or nonfatal stroke (0 · 75, 0 · 63—0 · 89, p = 0 · 001); and myocardial infarction (nonfatal and fatal) occurred in 198 and 188, respectively (1 · 07, 0 · 88—1 · 31, p = 0 · 491).(Dahlöf et al. 2002) the poorly effective atenolol (see chapter 1) was not a failure.
To deny the use of a more effective beta-blocking drug [bisoprolol, carvedilol, nebivolol, Toprol Xl] as first line or second line in some patients is illogical thinking.
Importantly, the duration of action of atenolol varies from 18 to 24 h and fails in some individuals to provide 24 h of CVD protection. The drug leaves an early morning gap, a period crucial for the prevention of fatal MI and sudden cardiac death, information that escapes panel members.
The observation that atenolol is less effective than other antihypertensives including vasodilatory beta-blockers at lowering aortic pressure despite an equivalent effect on brachial pressure may partly explain the poor cardioprotection. In the Conduit Artery Function Evaluation (CAFÉ 2006) study, brachial and aortic pressures were measured in a subset of 2,199 patients from ASCOT (PBLA 2005). Despite virtually identical reductions in brachial pressure, the aortic systolic pressure was 4.3 mmHg lower in the amlodipine/perindopril arm versus those on atenolol/bendroflumethiazide.
It is clear that beta-blockers are not all alike with regard to their salutary effects, and older beta-blocking drugs including atenolol should become obsolete (Khan 2003). Beta-blockers are CVD protective provided that bisoprolol, carvedilol, metoprolol, propranolol, or timolol are chosen and not atenolol (Khan 2005). Chockalingam et al. (2012), based on a multicenter study “recommend treatment of symptomatic long QT (LQT1) and LQT2 patients with either propranolol or nadolol, as clearly not all beta-blockers are equal in their antiarrhythmic efficacy in LQTS. Propranolol was superior to both nadolol and metoprolol in terms of shortening the cardiac repolarization time, particularly in high-risk patients with markedly prolonger QTc. A New York–based LQTS Registry indicated that nadolol was the only beta-blocker associated with a significant risk reduction in patients with LQT2 (Abu-Zeitone 2014).
It is poor logic to accept the conclusions drawn from the Lindholm et al. (2005) meta-analysis and the JNC 8 recommendations. In the majority of clinical trials analyzed, atenolol was the beta-blocker administered.
Nebivolol, bisoprolol carvedilol, or metoprolol succinate extended release [ToprolXL] are recommended for the initial management of mild primary hypertension depending on the age and ethnicity of the individual (see treatment tables and algorithms in Chap. 9, Hypertension Controversies).
Beta-Blockers Are not Recommended for Treatment of Elderly Hypertensives: True or False?
Messerli et al. (1998) concluded that this statement is truely based on their meta-analysis, which included the poorly run MRC trial in the elderly (1992).
The MRC Working Party ( 1992 ) confirmed that 25 % of patients were lost to follow-up and more than half the patients were not taking the therapy assigned by the end of the study.
How can a learned expert use this unsound study result? But nonetheless it has convinced the world not to use beta-blockers in the elderly hypertensive. This statement is in major textbooks and editorials are taught to students and interns.
There was no difference in total mortality between atenolol and diuretic therapy, but, surprisingly, diuretics reduced coronary heart disease (CHD) events, and atenolol did not. This is a spurious finding; to this date we do not use diuretics to effectively treat patients with CHD, but we do use beta-blockers. Atenolol, the beta-blocker used, is a poorly effective beta-blocker as outlined earlier in this chapter, and its use should be curtailed (Khan 2003).
The spurious and misleading finding nevertheless led Messerli et al. ( 1998 ) to publish an article in the Journal of the American Medical Association entitled “Are β-Blockers Efficacious as First-Line Therapy for Hypertension in the Elderly?”
These analysts concluded that beta-blockers should not be first-line therapy for elderly hypertensives. Unfortunately, this faulty expert opinion of Messerli and colleagues (1998) has gained access to notable textbooks and journals. It appears that virtually all internists and guideline providers (UK and USA) share this faulty opinion, which has been spread worldwide.
The beta-blocker hypertension controversy, including appropriate use in elderly hypertensive patients, is discussed fully in Chaps. 8 and 9, and algorithms are provided indicating which initial drug is best depending on the age and ethnicity of the hypertensive patient.
Beta-Blockers Cause Genuine Diabetes Mellitus: True or False?
A small presumed increased risk for the development of type 2 diabetes caused by beta-blocker therapy in hypertensive individuals has become a concern. Many national guidelines have been changed based on this notion. Thus, worldwide, many hypertensive patients and diabetics are denied treatment with a beta-blocking drug.
Insulin secretion is probably partly beta2 mediated. Glucose-sulfonylurea–stimulated insulin secretion is partially inhibited by beta-blockers (Loubatiere et al. 1971).
Clinically, however, no significant worsening of glycemic control is seen when beta-blockers are combined with these agents.
Long-term beta-blocker therapy may increase blood glucose concentration by approximately 0.2–0.5 mmol/L (~3–9 mg/dL), as observed in RCTs with follow-up beyond 5 years, but this mild increase in fasting glucose levels does not prove a diagnosis of type 2 diabetes.
The increase in blood glucose observed in some subjects may be due to benign reversible glucose intolerance or genuine diabetes in prediabetics.
In ASCOT-BPLA (2005), baseline glucose concentration for amlodipine and the atenolol-based regimen was 6.24 versus 6.4 mmol/L.
At follow-up 5 years later, levels for the atenolol regimen were only 0.2 mol/L higher than in the amlodipine group.< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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