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More beta-blocker info here  Updated June 6, 2004

 Atenolol For Severe CHF

1999 - Fifteen consecutive Taiwanese patients with advanced heart failure were in this study. Nine of the 15 patients were class 3 and six were class 4. All 15 patients had been hospitalized 2 to 5 times in the past 6 months because for CHF despite digoxin, diuretics, ACE inhibitor or vasodilators.
     We added 6.25mg atenolol daily to their meds. The dose was doubled every 2 to 4 weeks. Holter monitor and echo were done at study start and 1, 3, and 9 months. All echos were done by the same cardiologist.
     Two patients died from heart attack or sudden cardiac death. The 13 survivors were an average age of 57 years. Ten patients had idiopathic dilated cardiomyopathy and 3 had ischemic cardiomyopathy, as shown by cath. All 13 surviving patients improved in heart class, with reduced heart size and increased EF after at least 3 months of atenolol use. A rise in heart rate variability was also a good sign.
     This study showed that adding beta-blockers to heart failure treatment can improve heart function and nervous system activity. Beta-blocker use may increase 24-hour heart rate variability. Potentially dangerous very low frequency (Cheyne-Stokes) heart rate changes were reduced by beta-blocker use.
     The study had a few drawbacks - don't they all? It was not placebo-controlled. The patient group was small and restricted to those with advanced heart failure. The final atenolol dose used was low.
 
Title: Long-Term Beta-Blocker Therapy Improves Autonomic Nervous Regulation in Advanced Congestive Heart Failure: A Longitudinal Heart Rate Variability Study
Authors: Jiunn-Lee Lin, Chao-Chen Du, Yung-Zu Tseng, Wen-Pin Lien, I-Nan Lin, Chuan-Wei Lai, Ko-Teh Lin, Hsiao-Lung Chan, Chien-Ping Wu
Source: Am Heart J 137(4):658-665, 1999

 Coreg Overview

July, 1997 - Coreg blocks beta-1, beta-2 and alpha-1 receptors. The drug vasodilates through its alpha-1 blocking. Coreg may provide protection from heart cell death, arrhythmia, and free radical cell damage. Coreg also improves symptoms in stable angina patients.
     Data from over 1,000 patients with mild to severe heart failure in the US Coreg Heart Failure Study Program (4 trials) sparked interest in the drug. After an average follow-up of 6-1/2 months, a lower death rate (3%) was seen in Coreg patients versus placebo patients(8%). Over-all mortality went down 65%, hospitalization for heart-related events went down 28%, and hospitalization costs went down 62% for Coreg patients in these 4 trials.
     The Australia and New Zealand Heart Failure Research Group also did a study that followed 415 Coreg-treated CHFers. That study showed a 26% reduction in death or hospitalization after 19 months. Coreg's side effects are usually seen early in therapy. The most often reported side effects were low blood pressure, dizziness, and headaches. Also seen were shortness of breath, asthma attacks, too-slow heart rate, lack of energy, and weakness.
     Coreg has a strong role in heart failure management but further studies are needed to show the place of beta-blockers in general for CHF, and how Coreg compares to other beta-blockers.
 
Title: Coreg. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders
Author: Dunn CJ, Lea AP, Wagstaff AJ
Source: Drugs 1997 Jul;54(1):161-185
PMID: 9211087, UI: 97354892

 Coreg Helps Severe CHF

September 15, 1995 - The effectiveness and safety of beta-blockers in patients with advanced heart failure have not been tested. We enrolled 56 patients with severe chronic heart failure in a double-blind, placebo-controlled Coreg trial. Patients had an average EF of 16% despite digoxin, diuretics, and an ACE inhibitor.
     After a 3 week period of increasing Coreg dose, 49 patients were randomly assigned to take either 25mg Coreg twice a day or placebo for 14 weeks. Previous therapy was continued unchanged. Patients were tested at the start and at the end of the study.
     Compared to the placebo group, Coreg patients showed improved heart function. They also showed increased exercise ability and improved heart class. Combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the Coreg group than in the placebo group, but Coreg patients had more dizziness and advanced heart block.
 
Title: Double-blind, placebo-controlled study of the long-term efficacy of Carvedilol in patients with severe chronic heart failure
Authors: Krum H, Sackner-Bernstein JD, Goldsmith RL, Kukin ML, Schwartz B, Penn J, Medina N, Yushak M, Horn E, Katz SD, et al
Source: Circulation 1995 Sep 15;92(6):1499-1506
PMID: 7664433, UI: 95393567

 Coreg For Mortality And Exercise

December, 1996 - Does Coreg slow worsening of heart failure in CHF patients? There were 366 patients with mild heart failure, an EF of 35% or less, and mild disability in this study.
     All patients were taking best standard therapy. They added either Coreg (232 patients) or placebo (134 patients) and were followed for one year. Disease progression was defined as death due to heart failure, hospitalization for heart failure, or an increase in heart failure meds.
     Heart failure worsened in 21% of placebo patients but only 11% of Coreg patients. This effect was not influenced by sex, age, race, cause of heart failure, or beginning EF. Coreg also improved EF and heart class. Coreg reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale (a quality of life test) or the distance walked in 9 minutes on a self-powered treadmill.
     Coreg, when added to standard therapy including an ACE inhibitor, reduces worsening of heart failure patients with mild symptoms.
 
Title:Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure
Authors: US Carvedilol Heart Failure Study Group. Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA
Source: Circulation 1996 Dec 1;94(11):2800-2806
PMID: 8941105, UI: 97096081

 Long Term Benefits and Exercise Capacity

February 8, 1997 - Beta-blockers improve heart function in CHFers at 3 to 6 months, but benefits beyond a year are unclear. Effects on exercise or symptoms are not clear either. (see N Engl J Med 1996 May 23; 334:1349)
     This double-blind trial randomized 415 patients with ischemic, stable CHF to either Coreg or placebo. The patients were tested for heart function, exercise ability, and symptoms at 6 and 12 months. They were checked for worsening heart failure, hospital admissions and death at 19 months. Almost all were on CHF meds: 85% were on ACE inhibitors, 75% were on diuretics and 38% were on digoxin.
     At 6 months, EF increased in the beta-blocker group compared to placebo patients. Heart rates at rest and during activity were reduced in the Coreg group.
     However, activity, exercise, and symptoms were similar at the one year follow-up, though the Coreg group had slightly worse symptoms at 6 months. At 19 months, there was a 26% reduction in death or hospital admission with Coreg.
     Coreg gives long-term benefits for ischemic CHF through improved heart function and reduced death or hospital admission, but does not improve exercise ability.
 
Title: Randomised, placebo-controlled trial of Carvedilol in patients with congestive heart failure due to ischemic heart disease
Authors: Australia/New Zealand Heart Failure Research Collaborative Group
Source: Lancet 1997 Feb 8; 349:375-380

 Coreg and Left Ventricle Change

April, 1997 - Data from the U.S. Coreg Multicenter Program were used in this study. An increase in ejection fraction of at least 5% was seen in 57% of Coreg patients compared to 26% of placebo patients. A decrease in ejection fraction of at least 5% was seen in 4% of the Coreg patients compared to 11% of placebo patients. The study showed that improvement in left ventricle function lowered death rates and improved patients' sense of well-being.
     However, the authors rightly cautioned that ejection fraction should not be used routinely in place of clinical assessment.
 
From: The American College of Cardiology 46th Annual Scientific Session, March 16-19, 1997, Anaheim, CA
Presenter: Milton Packer, MD, New York, NY
Source: Journal Watch: Cardiology 28 April 1997

 Coreg Patients Should Still Exercise

April, 1997 - We wondered if CHF patients taking Coreg benefit from exercise or not. We studied 23 CHFers taking Coreg or Inderal in addition to ACE inhibitors, Lasix and digoxin. Of the Coreg patients, 8 did exercise training and 8 were couch potatos. Peak oxygen consumption (Vo2max) was measured in all patients. Blood flow was tested in the calf and forearm at study start and after 12 weeks of training.
     Vo2max of exercising patients increased 25% but did not change in the non-exercising patients. Exercise-caused blood flow increased significantly in the calves but not in the forearms of exercising patients. Patients taking long-term beta-blockers still benefit from exercise training.
 
Title: Nonselective beta-adrenergic blockade with Carvedilol does not hinder the benefits of exercise training in patients with congestive heart failure
Author: Demopoulos L, Yeh M, Gentilucci M, Testa M, Bijou R, Katz SD, Mancini D, Jones M, LeJemtel TH
Source: Circulation. 1997 Apr 1;95(7):1764-7.
PMID: 9107160

 Coreg Benefits Severe CHF Patients

April 28, 1997 - This randomized, placebo-controlled trial studied Coreg use in patients with severe CHF. The trial included 278 patients with an average ejection fraction of 22%. We studied death due to heart failure, hospitalization for heart failure, or an increased need for heart failure meds. Coreg reduced all the above from 33% to 20% over 250 days.
 
From: The American College of Cardiology 46th Annual Scientific Session, March 16-19, 1997, Anaheim, CA
Presenter: Wilson Colucci, MD
Source: Journal Watch: Cardiology 28 April 1997

 Long Term Coreg Use

May, 1997 - We report results from 3 to 4 years of Coreg use in 40 patients with idiopathic DCM. In the first 4-month trial, 20 patients got placebo and 20 took Coreg. All patients took digoxin, Lasix and ACE inhibitors.
     Coreg or placebo doses went up once a week, up to 25mg BID. After the 4-month double-blind period, all patients were followed-up for an average of 4 years and 8 months.
     Of the 20 Coreg patients, 3 died from heart-related causes, one died from other causes and 2 had heart transplants. Among the 20 placebo patients, 5 died from heart-related causes, 3 had heart transplants and 4 were started on Coreg because their CHF got worse during the 4-month study. The remaining 8 patients were controls.
     Each patient was tested by questionnaire, MUGA and bicycle exercise testing (Vo2max). Exams were done before treatment, at 4, 12, and 48 months.
     Coreg patients' EF increased from 22% to 34% at 4 months, to 37% at one year, and stayed at 37% at 4 years. Their heart size went down 40% and their heart class improved from 2.6 to 2.0 after four months and stayed there. Vo2max went up slightly at one year, then stayed level. The benefits of Coreg on EF remains throughout long-term treatment.
 
Title: The effects of mid- and long-term administration (3-4 years) of Carvedilol in patients with idiopathic dilated cardiomyopathy
Author: Metra M, Nodari S, Garbellini M, Boldi E, Rosselli F, Milan E, Giubbini R, Dei Cas L
Source: Cardiologia 1997 May;42(5):503-512
PMID: 9289367, UI: 97368891

 Auto-Immune Response and Beta-Blockers

February 8, 1999 - A new study links an abnormality in the immune system to CHF. German researchers say their study shows that the immune system in CHFers produces antibodies programmed to attack the heart.
     In a study of 104 patients, the researchers found that 26% of those with dilated cardiomyopathy - heart failure not caused by coronary disease - had auto-antibodies attacking a specific part of the heart called the beta-andrenergic receptors. These auto-antibodies stimulated the heart to beat too fast. Only 10% of people with CHF caused by coronary disease had auto-antibodies. Only 1% of 108 healthy people had them.
     Dr. Fritz Boege says this research might explain why beta-blockers help heart failure patients. Beta-blockers act directly on the beta-andrenergic receptors. These receptors are places on the surface of cells that act as gatekeepers, receiving other molecules, allowing interaction.
     Dr. Roland Jahns says, "Individuals with heart failure make extra adrenaline that makes the heart pump faster. The binding of adrenaline to the beta-receptors makes the heart beat even faster yet. Auto-antibodies seem to stimulate the receptor, which enhances adrenaline's effect."
     Researchers found that in dilated cardiomyopathy, the hearts of those who had the auto-antibodies pumped less blood compared to those who did not. "The constant beta-receptor activity leads to a vicious cycle of overdrive wearing out the heart muscle," says Jahns.
     They say it is too soon to conclude that there is a cause and effect relationship between auto-antibodies and heart failure. Researchers do not understand yet why the autoantibodies are produced.
 
Title: Autoimmune Response May Be Linked to Congestive Heart Failure
Source: Circulation: Journal of the American Heart Association

 Coreg Versus Metoprolol

May 25, 1999 - Coreg is a non-selective beta-blocker with alpha-blockade. Another beta-blocker named metoprolol is a selective beta-blocker (it blocks only beta-1 receptors). A limited comparison of these 2 drugs for treating heart failure is the subject of this very small study.
     Sixty-seven patients with symptomatic CHF were given either Coreg or metoprolol in addition to standard CHF meds. We studied symptoms, exercise, ejection fraction, and thiobarbituric acid-reactive substances (TBARS) as an indicator of free radicals.
     Both groups showed benefit in every area, with no between-group differences. Average ejection fraction increased over 6 months from 18% to 23% with metoprolol and from 19% to 25% with Coreg. TBARS values went down about the same amount in both groups.
     Coreg and metoprolol gave the same benefits in measured areas over a 6-month period.
 
Title: Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure
Authors: Marrick Kukin, Jill Kalman, Robert Charney, Daniel Levy, Cathleen Buchholz-Varley, Ofelia Ocampo, Calvin Eng
Source: Circulation

 Coreg Versus Metoprolol For CHF

November 3, 1999 - In Hong Kong, Dr. John Sanderson gave either 25mg Coreg or 50mg metoprolol twice daily to 51 CHF patients for 12 weeks. Both beta-blockers improved quality of life, exercise capacity, and ejection fraction. There was no difference between the 2 drugs except that Coreg lowered sitting and standing diastolic blood pressures more than metoprolol.
 
Source: J Am Coll Cardiol 1999;34:1522-1528

 Does Coreg Improve Exercise Capacity?

1999 - Chronic heart failure reduces lung function, which limits peak exercise oxygen use (Vo2max). Coreg improves heart function, but not Vo2max. We studied the pulmonary (lung) response to this heart improvement in 21 CHFers. Twenty-one patients in class 2 to 3 heart failure took either 25mg Coreg BID (14 patients) or placebo (7 patients) for 6 months.
     At-rest ability to breathe out, vital capacity, total lung capacity, carbon monoxide diffusing capacity, heart size, stroke volume, ejection fraction and other measurements were taken at study start and at 3 and 6 months. Vo2max, Vo2 at anaerobic threshold (Vo2at) and other lung function measurements were also taken.
     Placebo caused no changes. Most pulmonary measures did not change with Coreg treatment. Coreg reduced heart size and increased ejection fraction and stroke volume but did not improve Vo2max, Vo2at or other lung function measures at 3 and 6 months.
     In chronic heart failure, Coreg improves heart function at rest but does not affect breathing or functional capacity. These results suggest that improvement in heart function with Coreg does not reverse loss of lung function.
 
Title: Pulmonary Function, Cardiac Function, and Exercise Capacity in a Follow-Up of Patients with Congestive Heart Failure Treated with Carvedilol
Authors: Marco Guazzi, Piergiuseppe Agostoni, Marco Matturri, Gianluca Pontone, Maurizio Guazzi
Source: Am Heart J 138(3):460-467, 1999

 CIBIS II - Beta-blockers Reduce Death In CHF

January 2, 1999 - CHFers with mild to moderate heart failure taking standard CHF meds, who also took a beta-blocker, were less likely to die than those not taking a beta-blocker.
     The CIBIS-II trial included 2,647 people with stable, symptomatic heart failure in heart classes 2 to 4. All patients had an ejection fraction less than 35%. They were treated with standard CHF meds including diuretics and ACE inhibitors. Half the patients also took the beta-blocker bisoprolol at a starting dose of 1.25mg per day, increasing to a maximum dose of 10mg per day during the following 6 months.
     The trial was stopped early because of obvious benefit. During a 16-month follow-up, 12% of bisoprolol patients died compared to 17% of placebo patients. In the beta-blocker group, there were 34% fewer deaths from all causes and 44% fewer sudden deaths; hospital admissions were 20% less.
 
Title: American Heart Association Comment: Results of Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)
Source: The Lancet

 BEST Trial Results

November 10, 1999 - The BEST trial added the beta-blocker bucindolol to standard CHF meds in class 3 to 4 CHFers. BEST was stopped after 2 years in July of 1999 because a positive result was no longer expected in the trial. A total of 2,708 patients were enrolled. This was a randomized, placebo-controlled trial of bucindolol versus placebo.
     Bucindolol dose was raised from 3mg to 50mg twice a day for patients weighing less than 165 pounds, and to 100mg twice a day for those weighing more than 165 pounds. A MUGA, blood tests, chest x-ray, and EKG were done at study start, and at 3 and 12 months. Follow-up was done at 3, 6, and 12 months; then every 6 months. The primary endpoint was all-cause mortality.
     In BEST, 78% were men, 92% were heart class 3 and 8% were class 4. Average age was 60 years. Cause of heart failure was ischemic in about 60% in each group. Thirty-five percent of patients were diabetic. Average EF was 23% in each group. Almost all patients were taking ACE inhibitors, digoxin, and diuretics.
     All-cause mortality was the same in the drug (30%) and placebo (33%) groups. There was a 13% reduction in heart-related deaths with bucindolol. There was no difference between the 2 groups in deaths from other causes. All-cause hospitalizations were the same but hospitalizations for CHF were 17% lower in the bucindolol group. Progression to death or transplant was also reduced 10% by bucindolol.
     Non-black patients had a benefit from bucindolol, but black patients did not. The lack of benefit in BEST is different from other beta-blocker trials, such as MERIT-HF and CIBIS II. The question is whether these differences are because BEST had patients with more severe heart failure or if they are from a difference in the drug bucindolol.
 
Source: 72nd Scientific Sessions of the American Heart Association, Plenary Session XII: Late-Breaking Clinical Trials
Presenter: Dr. Michael Domanski

 MERIT-HF Metoprolol Trial

November 8, 1999 - MERIT-HF was the largest-ever heart failure trial of a beta-blocker. Results show that adding Toprol-XL to standard heart failure treatment reduced the overall death rate by 34%, the SCD rate by 41%, and heart failure deaths by 49%.
     This study is the first trial of beta-blockers to include lots of patients across a wide range of heart classes, including those with slight symptoms to those with severe symptoms. Adding Toprol-XL improved patients regardless of how severe their CHF was. Response to the beta-blocker was similar for class 2, 3 and 4 patients.
     Almost 4,000 CHF patients in 14 countries were given a daily dose of placebo or Toprol-XL, titrating from 12.5mg to anywhere from 25 to 200mg per day over 6 weeks. More than 1,000 Americans participated.
     MERIT-HF was stopped early, in 1998, because of the significant reduction in risk of death in Toprol-XL patients. Like most beta-blockers, Toprol-XL should not be used in people with slow heart rate, heart block greater than first degree, or acute heart failure. Patients with ischemic heart disease taking the medication should not stop taking it suddenly.
 
Source: American College of Cardiology (ACC) 48th annual scientific session

 ACE Inhibitors Plus Beta-blockers Better

September 3, 2002 - The CARMEN trial shows that early treatment with Coreg plus an ACE inhibitor improves patients with mild chronic heart failure. Heart remodeling worsens heart failure, so treatment must begin early in mild cases to prevent or reverse it, said Professor Willem J. Remme said at the Congress of the European Society of Cardiology.
     CARMEN included 572 patients in 65 European medical centers. The trial compared enalapril plus Coreg to each of the drugs given independently over 18 months of treatment.
     The drugs taken together reduced heart size compared to enalapril alone. Also, compared to study start, patients taking Coreg alone had improved left ventricular remodeling and reduced heart size; results not seen with the ACE inhibitor alone. Professor Remme said, "You can safely start with Coreg and then add an ACE inhibitor."
 
Source: Reuters Health

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