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Beta-blockers

In heart failure, the nervous system is overstimulated. This raises levels of a hormone called norepinephrine. The increased level of circulating norepinephrine can cause heart remodeling. High levels of norepinephrine are directly toxic to heart cells and increase risk of death.
     Blocking beta receptors with drugs reduces these effects, so beta-blockers have recently been added to the standard of care for CHF. Four trials recently ended that tested beta-blocker therapy for CHF.
     Overall mortality was reduced 65% by Coreg, 34% by Toprol, and 33% by bisoprolol. Bucindolol did not have much impact on mortality.

Some History

In 1993, The Metoprolol in Dilated Cardiomyopathy Trial studied 383 patients with class 2-3 CHF for 18 months. The target dose of immediate-release metoprolol was 100 to 150mg per day. The metoprolol group showed reduced all-cause mortality compared to the placebo group, but the difference was small. The major benefit was in need for heart transplant. Two metoprolol patients needed a heart transplant but 19 in the placebo group did. Metoprolol improved EF, quality of life, and exercise capacity compared to placebo. There was no difference in hospitalization.

In 1994, the Cardiac Insufficiency Bisoprolol Study started a 3 year study of class 3 to class 4 CHF patients. The target dose was 5mg per day. Bisoprolol significantly improved heart class and reduced hospitalizations for heart failure. However, it did not reduce mortality.

In 1997, the New Zealand Carvedilol Trial studied 415 patients with class 2-4 heart failure over 19 months. The target Coreg dose was 25mg BID. Average EF was 5% higher in the Coreg group than in the placebo group. Combined endpoint of death and hospital admission was 21% lower. However, when death only was examined, there was no significant difference between groups. There were also no significant differences in treadmill exercise time, distance walked in 6 minutes, or heart class.

More Recent Trials

Recently 4 randomized, double-blind, placebo-controlled trials concluded:

  1. the U.S. Carvedilol Heart Failure Study
  2. the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)
  3. the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)
  4. the Beta-blocker Evaluation Survival Trial (BEST)
U.S. Carvedilol Heart Failure Study 
1,094 patients were studied. The primary endpoint was all-cause mortality and the secondary endpoint was hospitalization. Patients were 77% male with class 2 to 3 CHF. Their average age was 58 and average EF was 22%. About half were ischemic and half idiopathic. The target dose was 25-50mg Coreg BID, based on patient weight.
     The trial was stopped early. Coreg patients had a 65% lower risk of death than placebo patients. Coreg also reduced risk of hospitalization for heart causes. The most common reason for withdrawing from the trial was worsening heart failure, which was more frequent in the placebo group.
MERIT-HF 
Extended-release metoprolol was tested for treating CHF. The two primary endpoints were all-cause mortality and all-cause mortality plus all-cause hospitalization. There were 3,991 patients with class 2 to 3 CHF, averaging 64 years old with an average EF of 28%. The target dose was 190mg per day.
     The study was stopped early. Metoprolol patients had a 34% lower risk of death than placebo patients. Metoprolol reduced mortality and all-cause hospitalization by 19%. All-cause mortality plus hospitalization for heart failure went down 31%. All-cause hospitalization alone was lowered by 13%, hospitalization for all heart-related causes by 20%, and hospitalization for worsening CHF by 32%. The most common reason for withdrawing from the trial was worsening heart failure, which was more frequent in the placebo group.
CIBIS-II 
The primary endpoint was all-cause mortality. Secondary endpoints included all-cause hospitalization and heart-related mortality. All 2,647 patients were class 3-4. They were 80% male, averaging 61 years old, with an average EF of 27%. Half had ischemic CHF and half idiopathic. The target dose of bisoprolol was 10mg per day.
     The study was stopped early. Risk of death in the bisoprolol group was 33% lower than in the placebo group. Bisoprolol patients had fewer heart-related deaths and were hospitalized less.
BEST 
The primary endpoint was all-cause mortality. Secondary endpoints were heart-related death, hospitalization, all-cause death, heart transplant, and changes in EF and quality of life. The 2,708 patients were class 3-4, 78% male, averaging 60 years old, with an average EF of 23%. Most had ischemic CHF. The target dose of bucindolol was 50-100mg BID, based on patient weight.
     The study was stopped early. There was no difference in all-cause mortality between bucindolol and placebo groups. However, there were fewer heart-related deaths with bucindolol. EF increased in bucindolol patients compared to placebo. Fewer bucindolol patients were hospitalized for CHF. Black patients did not have any survival benefit with bucindolol.

Comparisons

Differences in metoprolol trial results suggests that only extended-release metoprolol (Toprol XL) works for CHF. This was studied in a small 12-week trial comparing regular metoprolol to extended-release metoprolol. Twenty-seven patients took one form of metoprolol or the the other at equivalent doses. Patients were mainly class 3 with an average EF of 11%. Most had idiopathic cardiomyopathy. Six-minute walk distance, heart class, and EF all improved about the same in each group.

A 12-week trial published in 1999 directly compared Coreg to metoprolol.. The 51 patients were mostly men, averaged 60 years old, and had class 2 to 3 CHF with an average EF of 26%. Primary endpoints were change in symptoms, change in 6-minute walk distance, and change in EF. The target doses were 25mg Coreg BID and 50mg metoprolol BID. Both drugs caused nearly equal patient improvement. 

The Carvedilol or Metoprolol European Trial (COMET) is now comparing Coreg to metoprolol in over 3,000 patients. It is designed to test whether blocking beta-1 receptors or some other drug property improves CHF. The primary endpoint is all-cause mortality. Enrollment was completed in January of 2000 and follow-up is for 2-4 years.

Considerations

When beta-blocker therapy is started in CHF patients, some drug properties must be considered. Target doses should be the same doses used in trials. Beta-blockers are processed by the liver so patients with liver problems must be carefully monitored.
     Decompensation can occur when starting beta-blockers. Only stable patients should start them, meaning patients with no dose changes in ACE inhibitors for one month, in diuretics for 2 weeks, and no IV inotropes for one month.
     It is very important to raise dose slowly. For Coreg, a patient should be closely watched after the first dose for one hour, looking for lightheadedness or dizziness. The dose can be doubled every 2 weeks as long as the patient's systolic blood pressure is over 85mm Hg, the heart rate is over 55 beats per minute, and the patient is not suffering CHF symptoms. If the heart rate drops below 55 beats per minute, dose should be cut by 50%.
     All current beta-blockers seem to have similar side effects. Most common are fatigue, slow heart rate, low blood pressure, dizziness, and diarrhea. Different beta-blockers do show different actions though. Differences include which beta receptors are blocked (beta-1 or beta-2 or both), vasodilation, and other properties.
     Metoprolol and bisoprolol "like" beta-1 receptors best, while Coreg and bucindolol like both beta-1 and beta-2 receptors equally. Coreg and bucindolol are direct vasodilators - enlarging arteries - which increases blood flow and lowers "afterload." Coreg also has some alpha-blocking ability, and is an antioxidant.

Discussion

Beta-blockers often reduce heart failure symptoms. They lower risk of all-cause mortality, heart-related mortality, sudden death, and death from progressive heart failure. Beta-blockers also reduce hospitalizations. This class of drugs may save more patient lives than ACE inhibitors. The most recent treatment guidelines list beta-blockers as standard therapy for CHF patients. Trial results strongly support this idea. A recent meta-analysis showed that beta-blockers reduce all-cause mortality in CHF patients by 29%.
     Beta-blockers are not all the same but most are effective for treating heart failure. It is very, very important to raise the dose gradually to prevent decompensation. Symptoms that may overwhelm patients if the dose is raised too fast include fatigue, low heart rate, low blood pressure, dizziness, and diarrhea. Beta-blockers should only be given to patients with stable CHF.
     When each different beta-blocker is viewed independently, there seems to be quite a bit of difference. Metoprolol and bisoprolol reduced all-cause mortality by about the same amount - 34%. Coreg gave a 65% risk reduction. Bucindolol only lowered all-cause mortality by 9%. Coreg has many actions besides beta-receptor blocking. It is a vasodilator, anti-oxidant, and has some anti-endothelin effect. It is unclear why bucindolol did not give benefits as great as the other tested beta-blockers.
     Caution is called for. Not all these drugs have been compared to each other in a clinical trial. That is the purpose of COMET. At this time, the only comparison we are sure of is that bucindolol should not be chosen for CHF treatment.

Another concern has been the safety of using beta-blockers in patients with severe - class 4 - CHF. Several trials have addressed this. You can see results on Jon's Coreg page. COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Trial) was a trial of 2,200 patients studying this group of CHF patients. The study was stopped early because a substantial survival benefit was seen with Coreg use.
     A patient group not much studied is class one CHF patients. The CARMEN study is testing the benefits of both ACE inhibitors and beta-blockers in 450 class one CHF patients without symptoms.

Large Beta-blocker Trials in CHF
Trial patients in heart class Relative risk reduction with beta-blocker use
  2 3 4 all-cause mortality heart-related mortality all-cause hospitalization heart-related hospitalization
US Carvedilol HF Study 582
53%
480
44%
32
3%
65% 63% n/a 27%
MERIT-HF 1636
41%
2210
55%
145
4%
34% 38% 12.6% 19.8%
CIBIS-II 0
0%
2202
83%
445
17%
33% 29% 20% 36%
BEST 0
0%
2491
92%
217
8%
8.5% 12.5% n/a 16.7%
Total 2218
21%
7383
71%
839
8%
25% 27% 14% 25%
Dose For CHF Beta-blockers
Drug Starting dose Target dose in milligrams
  Patient groups
Coreg
carvedilol
3.125mg BID raise to 25mg BID under 188 pounds raise to 50mg BID over 187 pounds
Toprol XL
metoprolol extended release
12.5mg daily for class 3-4 patients
25mg daily for class 1-2 patients
190mg regardless of body weight
Zebeta
bisoprolol
start at 2.5mg daily 10mg regardless of body weight
Not available
bucindolol
start at 6.25mg BID raise to 50mg BID under 175 pounds raise to 100mg BID over 174 pounds

Reprint requests to Dr. Manley at the University of Missouri at Kansas City
M3-C19 Medical School
2411 Holmes Street
Kansas City, Mo
64108-2792
E-mail: manleyh@umkc.edu

All information on this site is opinion only. All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor. Use the reference information at the end of each article to search MedLine for more complete and accurate information. All original copyrights apply. No information on this page should be used by any person to affect their medical, legal, educational, social, or psychological treatment in any way. I am not a doctor. This web site and all its pages, graphics, and content copyright © 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004 Jon C.

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