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The Beta-Blockers

Dr. Hernßn Doval
Hospital Italiano
Buenos Aires, Argentina

Introduction
Beta-blockers have been known for years as myocardial depressants and a cause of worsening heart failure, thus their use was proscribed. In the last two decades it has been recognized that the paradigm that the sympathetic activation was necessary to maintain the cardiac output was false; in fact the increased adrenergic activity was found deleterious for cardiac function and survival in the long term.
In 1974, Waagstein (1) published for the first time that practolol, a selective ▀1 blocker, was well tolerated by patients with acute myocardial infarction in spite of having signs of heart failure. To exclude that the mechanism of the beneficial effect was due to a decrease of the ischemic burden, studies in patients with dilated cardiomyopathy were performed, that also demonstrated improvement that could not be attributed
to a decrease in myocardial ischemia (2).

Possible mechanisms of the beta-blocker effect.
Protection of cardiac myocytes from the direct cardiotoxic effects of cathecholamines, improvement of baroreflex function, and also reduction of renin secretion. Reducing the heart rate they reduce metabolic demands, prolong the filling phase and in this way time for perfusion, increase
coronary blood flow, and also improve myocardial strength-rate relationship. In clinical trials they contribute to a decrease in myocardial infarction.The reduction of ventricular and supraventricular arrhythmias due to the diminished sympathetic activity and myocardial ischemia, the improvement of baroreflex function and the prevention of hypokalemia, may all contribute to the reduction of sudden death in chronic heart failure (3).

Effect on left ventricular ejection fraction
It is important to recognize that there may be an acute drop of the ejection fraction up to one month after initiation of treatment with beta-blockers. Reduction of ventricular volumes and improvement of ejection fraction is only apparent after 3 months, and it is known that ventricular function may continue to improve until 18 months from initial therapy.In a review of 13 randomized, double-blind, clinical trials of
beta-blockers against placebo (excluding trials of less than 3-month duration or less than 40 patients)(4-16), all showed statistically significant improvement of the ejection fraction from 5 to 9%, absolute values; much more significant than those achieved by angiotensin converting enzyme inhibitors, that was only of 2%.
It could be that the improved ejection fraction was due to the reduced heart rate and increased left ventricular end-diastolic volumes, through the Frank-Starling mechanism, rather than to an improved left ventricular function. However, contrary to this hypothesis is the fact that it has been shown in clinical trials, that ventricular size does not change or diminish during chronic therapy with beta-blockers.

Effect on exercise tolerance
The effects of long-term beta-blockers on exercise tolerance have been discordant.
Most of the former studies with metoprolol, a (1 selective agent, showed improved exercise tolerance over a period longer than 3-4 months. At the same time the non-selective beta-blockers such as bucindolol, mebivolol and most of the studies with carvedilol, did not show improvement in maximal or sub-maximal exercise tolerance (3).
It is possible that selective blockade of (1 receptors, leaving untouched (2 receptors, allow an increase of the heart rate during exercise. The exercise-induced vasodilation is mediated via (2 receptors, and this fact perhaps is also important in the beneficial effect seen with selective (1 beta-blockers.
A selection bias can not be excluded. It is possible that mortality among patients with severe disease in the placebo groups was higher than in the beta-blocker groups, that resulted in a better exercise tolerance in the survivors of the placebo group, thus masking an improved exercise capacity effect of beta-blockers.

Effect on hospitalization
In this evaluation we will only consider the 6 randomized, placebo-controlled clinical trials with more than 200 patients.
The first trial with a significant number of patients, the Metoprolol in Dilated Cardiomyopathy (MDC)(4), showed a decrease in hospitalizations.
The number of hospitalizations for cardiovascular causes was also reduced by 32% with bisoprolol, in the Cardiac Insufficiency Bisoprolol Study (CIBIS)(6). In the studies with carvedilol, such as the US Multicenter Program (US Trial)(17) hospitalizations were reduced by 38%, and in the Australia-New Zeland Trial by 29% (18).
In CIBIS-II (19), hospitalizations for heart failure were reduced by 36%. The primary endpoint, all cause mortality, was published from the recent Metoprolol Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)(20), but the secondary endpoint, total mortality plus hospitalizations, has not yet been published.
Thus, all the large trials, including those that did not show mortality benefits, have shown a significant reduction in hospitalizations between 29 to 36%.

Effect on total mortality
Metoprolol in Dilated Cardiomyopathy (MCD)(4).
It randomized 383 patients with idiopathic dilated cardiomyopathy, mean age of 49 years, and an ejection fraction of 22%, functional class II-III, followed for an average of 15 months (range 12-18 months).
In this study there was a non-significant reduction of the combined endpoint of mortality and cardiac transplantation from 20.1 to 12.9% (p=0.058).
But in reality the reduction of this combined endpoint was entirely due to the reduced rate of cardiac transplantation, since in fact mortality was non-significantly higher by 19% in the metoprolol treated group (11.9 vs 10.1%).

The Cardiac Insufficiency Bisoprolol Study (CIBIS) (6)
It included 641 patients with heart failure class III-IV, of various etiologies (coronary disease in 45%), randomized to bisoprolol or placebo. The mean age was 60 years, a mean ejection fraction of 25%, with an average follow up period of 21 months.
Total mortality was decreased by bisoprolol from 20.9 to 16.6%, with a risk reduction of 20% that was not statistically significant.
Although mortality in a subgroup of patients without previous history of myocardial infarction was reduced significantly by 47%, this information should be regarded with caution since no stratification by etiology was carried out at randomization and this was not a pre specified endpoint.

US Multicenter Trial Program (US Trial) (17)
Included 1094 patients with a mean age of 59 years, and an ejection fraction of 23%, with 47% of them having ischemic cardiomyopathy, functional class II-IV. They were randomized to carvedilol or placebo and followed for a mean of 6.5 months.
This study is in reality the publication of four clinical trials in different patient groups, stratified according to the distance they covered during a six-minute walk test, and was planned as a study of "efficacy and safety" of carvedilol (17).
This combined analysis found a 65% reduction of total mortality (p=0.0001).Analyzing each of the 4 clinical trials, the study of "chronic
mild heart failure" randomized 366 patients (2:1 randomization in favor of carvedilol), follow up of 12 months, found a mortality reduction of 78%. The studies in patients with "moderate" heart failure included 278 patients (133 carvedilol), and the one in patients with "severe" heart failure, 105 patients (70 carvedilol), followed for 6 months, found a mortality reduction of 43 and 47%, respectively. The last was a "dose-response study" in  364 patients (262 on carvedilol), with 6-month follow up, and it found a reduction in mortality of 73% (p=0.0008). The best effect was obtained with a dose of 25 mg twice/day.
This is an important study, with the drawbacks noted by the authors: "This limited experience limit our ability to reach conclusions about the real magnitude or persistence of any effect of carvedilol on survival" (17).

Australia-New Zeland Trial (18)
An average of 18 months was the follow up 415 patients, with a mean ejection fraction of 29%, and an average age of 67 years.
All participants had ischemic cardiomyopathy. They found a non significant reduction of mortality of 23%.

Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) (19)
This multicenter clinical trial carried out in Europe, randomized 2,647 patients with class III-IV heart failure, ejection fraction of <35%, treated with diuretics and an ACE inhibitor (19). They were randomized to 1.25 mg/day of bisoprolol (n=1327) or placebo (n=1320). The initial dose was gradually increased to 10 mg/day. Follow up was 1.3 years.
The CIBIS-II was terminated prematurely because bisoprolol showed significant benefit in mortality. There were 228 (17.3%) deaths for any reason in the group assigned to placebo and 156 (11.8%) in those treated with bisoprolol, a risk reduction of 34% (CI 19-46, p<0.0001). There were less sudden deaths in bisoprolol treated patients than in those treated with placebo, with a risk reduction of 44% (p=0.0011).
The effects of treatment were independent from etiology (ischemic or non-ischemic), or the severity of heart failure. Hospitalizations for heart failure were reduced by 36% (p=0.0001).

Metoprolol Randomized Intervention Trial in Congestive Heart failure (MERIT-HF) (20)
This recently published study included 3991 patients with heart failure class II-IV, ejection fraction equal or less than 40%, who were randomized to metoprolol (n=1990) or placebo (2001).
After 12 months this study was stopped prematurely after a significant reduction of mortality was noted, from 11.0% in the placebo group to 7.2% in the metoprolol group, a risk reduction of 34% (CI 19-47, p=0.00009).
In patients treated with metoprolol, there were less sudden deaths (79 vs 132, RR 31%, CI 22-55), and less deaths for progression of heart failure (30 vs 58, RR 49%, CI 21-67).

Summarizing the results of the three largest controlled clinical trial with beta-blockers, the US Trial with carvedilol (17), the CIBIS-II with bisoprolol (19) and the MERIT-HF with metoprolol (20), all of which showed a decrese in mortality, we can conclude that the improved mortality and morbidity achieved with beta blockers is a class effect. These effects are observed with drugs that are ▀1 selectives, such as bisoprolol and metoprolol, and with non-selective drugs such as carvedilol that blocks both ▀1 and ▀2 adrenoreceptors; but this drug also have other effects
such as blocking the ▀1 receptors, and a potent antioxidant effect.

Summary of Mortality Clinical trials with Beta-Blockers
Combining the results of the 6 controlled clinical trials of more than 200 patients each, there are more than 9,000 patients with ischemic and non-ischemic etiology, and varied degree of heart failure severity.

Clinical
Trials

F-U (months)

Placebo
Deaths/total (%)

Beta-blockers
Deaths/Total (%)

RR% (95% CI)

P Value

MDC

15

19/189 (10.1%)

23/193 (11.9%)

21%(-36a+129)

0.56

CIBIS-I

21

67/321 (20.9%)

53/320 (16.6%)

-25% (-49a+12)

0.16

ANZ

18

26/208 (12.5%)

20/207 (9.7%)

-25% (-61a+38)

0.36

US trials

6.5

31/398 (7.8%)

22/696 (3.2%)

-63% (-35a-79)

0.0006

CIBIS-II

15.6

228/1320(17.3%)

156/1327(11.8%)

-36% (-20a-48)

0.0001

MERIT

12

217/2001(10.8%)

145/1990(7.3%)

-35% (-19a-48)

0.0001

TOTAL

13.4

588/4437(13.3%)

419/4733(8.9%)

-34% (-25a-43)

0.0001

Table I- Metaanalysis using the method of Mantel-Haenszel, modified by Peto
MDC: Metoprolol in Dilated Cardiomyophathy; CIBIS I & II: Cardiac Insufficiency Bisoprolol Study I & II; US trials: US Multicenter Trial Program; ANZ: Australia-New Zealand Heart Failure Research Collaborative Group; MERIT-HF: Metoprolol Randomised Intervention Trial in Heart Failure; F-U : mean follow up period.

In the metanalysis, we find that approximately two thirds of the total number of patients came from the CIBIS-II and the MERIT-HF trials, versus one-third of the 4 previous trials. Mortality decreased from 13.3% in the placebo groups to 8.9% in the beta-blocker groups, during a follow up period of 13.4 months, with a mortality risk reduction of 34% (p=0.00001). From these data, the number needed to treat to prevent one death, are 25 patients per year.

Who, how, and when to use beta-blockers?
Initiation and titration of the doses of beta-blockers in a patients with heart failure, produce a general uneasiness to the physician who has not used these drugs. In this situation it is convenient that those that make the decision to use them follow these general instructions.
Avoid administration of beta-blockers in patients with asthma, or chronic obstructive reversible lung disease, and with heart rates of < 60 beats/minute, or A-V block greater than 1st degree, without a permanent pacemaker. Also in patients with severe heart failure, class IV, or decompensated, until this becomes stable with standard therapy, since a significant number of patients do not tolerate these medications, they may get worse or even die in the initial phase of treatment.

Beta-blocker should be started at low doses increasing the dose slowly. The initial dose in the large clinical trials were:
metoprolol XL 12.5 mg to 25 mg/day (20), carvedilol 3.125-6.25 mg twice/day (17,18), bisoprolol 1.25 mg/day (19); doubling the dose each week or even better each two weeks according to the clinical response, until maximal doses used in clinical trials are achieved.
According to the evidence available to date, we should aim for metoprolol XL 200 mg/day, carvedilol 50 mg twice/day, and bisoprolol 10 mg/day.

It is possible that in clinical practice, beta-blockers may not be tolerated as well as in the clinical trials, where strict inclusion and exclusion criteria were followed, and careful follow up existed. In clinical trials about 5% of patients did not tolerate the initial doses of beta-blockers due to hypotension or worsening of cardiac failure; this proportion is greater in patients with severe heart failure. In patients who present symptomatic hypotension or bradicardia while increasing the dose (monitoring these every 2-3 hours is thus important), it is necessary to go back to the previous dose and decrease stepwise, first the dose of diuretics and then the dose of the ACE inhibitor in those with hypotension, or digoxin and other drugs with bradycardic effects in those with critical drop of the heart rate, in order to attempt an increase again 2 weeks later.If heart failure gets worse, on the contrary, these drugs should be increased in the same sequence.
It must be noted that those patients in whom the dose of diuretics need to be increased to control worsening of heart failure during titration, also appear to benefit from beta-blockers over the long-term. In those patients who tolerate the starting doses and get clearly better clinically, occasionally deteriorate later on, which could be due to the natural evolution of the cardiac disease, it is not known whether stopping beta-blockers is associated with improvement or worsening of an already critical patient.

Tope


Bibliography

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Update
10/04/99