(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
Beta-Blockers Should Not Remain First Choice in the Treatment of Primary Hypertension: True or False?
A meta-analysis by Lindholm et al. (2005) concluded that beta-blockers should not remain as the first choice in the treatment of primary hypertension and should not be used as reference drugs in future randomized controlled trials (RCTs) of hypertension. Unfortunately, many experts in the field have endorsed the conclusions of this faulty meta-analysis produced by Lindholm et al. (2005).
Beta-blockers have been used for more than 40 years for the treatment of hypertension. The controversy regarding their continued use is of paramount importance, particularly because there are more than one billion hypertensive individuals who require treatment, and only four classes of antihypertensive agents are available: beta-blockers, diuretics, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). The two other drug classes [alpha-blockers (doxazosin) and centrally acting agents (methyldopa, clonidine)] have been rendered relatively obsolete for the management of primary hypertension (see discussion and alpha-blocker section in Chap. 8). Methyldopa remains useful mainly for some patients with hypertension in pregnancy.
Unfortunately, Lindholm and colleagues (2005), trialists, and physicians fail to realize that beta-blocking agents are not all alike and that the most prescribed beta-blocker, atenolol, has poor efficacy. Beta-blockers have subtle and important differences among them (Khan 2005) that have not been recognized by senior researchers and clinicians worldwide:
In 14 studies analyzed by Lindholm et al., atenolol was the beta-blocker used; in four trials, mixtures of atenolol, metoprolol, and pindolol were used (see Table 9-1).
Table 9-1
Clinical trials assessed in the meta-analysis by Lindholm et al. (2005) and relevant effects
Trial
No. of patients (year of follow-up)
Total mortality
Stroke
Myocardial infarction
MRC 1985
8,700
Propranolola
vs. placebo
120 vs. 253
42 vs. 109
103 vs. 234
RR 0.93
RR 0.76
RR 0.87
vs. diuretic
120 vs. 128
42 vs. 18
103 vs. 119
RR 0.91
RR 2.28
RR 0.84
MRCb 1992
4,396
Atenolol vs. diuretic
(5.8)
–c
–c
–c
IPPSH (1985)
6,357
108 vs. 114
45 vs. 46
96 vs. 104
Oxprenolold vs. placebo
(4)
RR 0.94
RR 0.97
RR 0.92
Berglund (1986)
106
5 vs. 4
–
–
Propranolol vs. diuretic
(10)
NS
Yurenev (1992)
304
1 vs. 7
6 vs. 11
7 vs. 6
Propranolol vs. non-beta-blocker
(4)
RR 0.15
RR 0.56
RR 1.2
Dutch TIA (1993)
1,473
64 vs. 58
52 vs. 62
45 vs. 40
Atenolol vs. placebo
(2.6)
RR 1.12
RR 0.85
RR 1.14
UKPDS (1998)
758
59 vs. 75
17 vs. 21
46 vs. 61
Atenolol vs. captopril
(9)d
RR 0.88
RR 0.90
RR 0.84e
LIFE (2002)
9,193
431 vs. 383
309 vs. 232
188 vs. 198
Atenolol vs. losartan
(4.8)
RR 1.13
RR 1.34
RR 0.95
ASCOT-BPLA (2005)
19,257
820 vs. 738
422 vs. 327
444 vs. 390
Atenolol + diuretic Amlodipine + perindopril
(5.7)
RR 1.11
RR 1.29
RR 1.1f
STOP-2 (Hansson et al. 1999a)
6,614
369 vs. 742
237 vs. 422
154 vs. 318
Atenolol
RR 0.99
RR 1.12
RR 0.96
Pindolold
Metoprolol
2,213
vs. ACE inhibitor
(5)
or
2,205
calcium antagonist
2,196
NORDIL (Hansson et al. 1999a)
10,881
228 vs. 221
196 vs. 159
157 vs. 183
Any beta-blocker vs. diltiazem
(4.5)
RR 0.98
RR 1.22
RR 0.85e
CONVINCE (2003)
16,476
319 vs. 337
118 vs. 133
166 vs. 133
Atenolol vs. verapamil
(3)
RR 0.93
NS
RR 1.23g
Not assessed by Lindholm et al. CAPP (Hansson et al. 1999b)
10,985
82 vs. 95
193 vs. 149
163 vs. 164
Captopril vs. atenolol or metoprolol
(6)
NS
RR 1.25h
NS
In a Lancet letter, Cruickshank (2006) stated that by lumping together all randomized hypertension trials involving beta-blockers, Lars Lindholm and colleagues have arrived at misleading conclusions, but letters in journals are perused by few readers.
Atenolol should not be used in hypertensive drug trials that compare it with other antihypertensive agents (khan 2003 ). This widely prescribed beta-blocker should become obsolete (Khan 2011). The author used atenolol from 1974 to 1984 and agrees that the drug probably causes less side effects than propranolol and metoprolol.
But less adverse effects equates with lower salutary effects because of poor brain concentration.
Unfortunately the majority of hypertensive RCTs done from 1985 to 2007 used atenolol. There are no sound RCTs in which propranolol, metoprolol or bisoprolol were used.
This discussion reviews trials selected by Lindholm and colleagues and emphasizes that the meta-analysis suggests that atenolol is not an effective choice for the management of hypertension but does not indicate that other beta-blockers are ineffective in decreasing cardiovascular disease (CVD) morbidity and mortality associated with hypertension.
The reasons for the ineffectiveness of atenolol and the subtle differences that prevail among the available beta-blocking drugs are discussed.
Trials selected for meta-analysis by Lindholm et al. include the following:
The International Prospective Primary Prevention Study in Hypertension (IPPSH): Oxprenolol was used (IPPPSH collaborative group 1985). The drug has intrinsic sympathomimetic activity (ISA), which renders it noncardioprotective; thus, all beta-blockers cannot be blamed for a poor choice of oxprenolol.
Berglund et al. (1986), Yurenev et al. (1992), and a Dutch trial (1993): These investigators studied only 106, 304, and 720 patients, respectively. Should clinicians accept this type of meta-analysis of apples and oranges?
The Swedish Trial of Old Patients-2 (STOP-2) (Hansson et al. 1999a, b: 7): In 6,614 elderly hypertensive patients, a diuretic or beta-blocker (atenolol, metoprolol, and pindolol, an ISA beta-blocker) or both were compared with newer drugs – ACE inhibitors (enalapril, lisinopril) or calcium antagonists (felodipine or isradipine). The findings at 6 years were as follows: old and newer antihypertensive drugs were similar in the prevention of cardiovascular mortality or events. At the final visit, only 61–66 % of patients were still taking the agents allocated to them, and this was not a comparative beta-blocker trial. An unsound trial.
Medical Research Council (MRC 1985) trial: For mild hypertension, propranolol was the beta-blocker used compared with diuretic therapy. Propranolol, but not diuretics, reduced the risk of myocardial infarction by 13 %, which increased to a significant 18 % when silent infarctions were included. In a subsequent subanalysis compared with placebo, the reduction in nonsmokers was 33 %. Nonsmokers given propranolol showed a trend toward reduction in coronary events and significant decrease in strokes; the diuretic bendrofluazide showed a reduction in strokes but not in coronary events. Another unsound trial. Methodology was poor.
A Lancet editorial (1985) considered the possibility that beta-blockers were preferable in nonsmoking men. The expert author of the editorial did not know that the cardioprotective effects of beta-blockers other than propranolol are not decreased by cigarette smoking.
Cigarette smoke increases the rate of metabolic degradation of propranolol, and a decrease in plasma propranolol levels has been shown in smokers. Timolol, a partially metabolized drug, was shown to be effective in significantly reducing total and cardiac deaths in smokers and nonsmokers (Norwegian trial 1981).
MRC trial in the elderly (1992): The beta-blocker used was atenolol.
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. A pathetic study used by Messerli et al. (1989) in an editorial condemning beta-blockers.
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.
This obscure 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 opinion has gained access to notable textbooks and journals and the brains of medical teachers. It appears that virtually all internists and guideline providers (UK and USA) share this faulty opinion, which has been spread worldwide.< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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