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|More beta-blocker info here||Updated September 3, 2006|
Beta-blockers approved by the US FDA for heart failure include Toprol-XL and Coreg. Toprol-XL blocks beta-1 receptors. Coreg blocks beta-1, beta-2, and alpha-receptors. They are both good for heart failure. Coreg lowers blood pressure more, so if you already have low blood pressure, you might want to use Toprol-XL. Toprol-XL costs less, and may improve exercise ability more.
Target dose for Toprol-XL is usually 190mg once a day. Coreg target dose depends on your weight - if you weigh 187 pounds or less, it will probably be 25mg twice a day. If you weigh more then 187 pounds, it will probably be 50mg twice a day. With either drug, you should start at low dose and work your way up slowly, raising dose about every 2 weeks.
Coreg's generic name is carvedilol with brand names in different countries like Dilitrend, Dimitone, and Kredex. Toprol-XL is the controlled release version of metoprolol, but is not the same thing as "metoprolol."
Your weakened heart is wearing itself out, trying to make up for its weak pumping action by pumping more times per minute. Beta-blockers slow your heart rate, which lessens this wearing-out process. Coreg also blocks alpha receptors in artery walls. This relaxes (expands) your arteries, lowering the resistance your heart pumps against - your blood pressure.
Beta-blockers can also reduce some heart arrhythmias, including PVCs. Coreg is also an antioxidant, but how much this helps CHF is hotly debated. Which beta-blocker should you take? Read the articles below and then talk to your doctor.
Do beta-blockers help CHFers live longer? Yes. Beta-blockers reduce the number of times we end up in the hospital to have fluid drained, and also reduce our risk of death. Beta-blockers are right behind ACE inhibitors as a CHFer's best drug friend.
A word of caution - our "numbers" get better on Coreg but many CHFers do not feel any better on Coreg. Other CHFers feel great after starting Coreg. Go figure. I have personally noticed since starting Coreg that when I get really stressed, adrenaline seems to stay in my system a lot longer, making me feel sort of sick and nasty for an hour or two. Other than that, it doesn't mess with me much.
Beta-blockers may raise blood sugar so they can change your insulin requirements if you are diabetic. Monitor your blood sugar carefully. Taking a beta-blocker also raises your risk for developing diabetes.
People with asthma should not take a beta-blocker. If you do, you should be monitored continuously for several hours after your first dose and whenever your dose is changed. Asthmatics should never start or raise the dose of any beta-blocker without a doctor present.
Digoxin (Lanoxin) levels in your blood go up about 15% when you take Coreg. This may not matter but your blood should be tested during beta-blocker start-up if you are taking digoxin. Always take Coreg with food. This affects how your body absorbs the drug. If you don't take food with it, you may suffer more serious side effects.
You may not have any side effects at all, but most CHFers do have some increased side effects when starting or raising their beta-blocker dose. A lot of people in Coreg trials got upper respiratory infections but no one knows exactly why. Some other potential side effects include:
More about Coreg and its side effects here, here, here, here, here, and here
May 30, 2002 - Metoprolol (Lopressor) is not the same as Toprol-XL for treating heart failure! Metoprolol is not a generic form of Toprol-XL. Metoprolol is not time-released like Toprol-XL. Your blood level of the drug spikes up and down with metoprolol. With Toprol-XL, you get a nice steady blood level of the drug. Which do you think your heart likes better?! You can read the technical information on this from the manufacturer at chfpatients.com/text/toprol-xl_is_not_metoprolol.txt. For more about this, see chfpatients.com/text/toprol-xl_versus_metoprolol.txt. AstraZeneca's patent on Toprol-XL lasts until 2004, so there won't be a generic form of Toprol-XL until then.
December 18, 2005 - We know that different beta-blockers have different effects in CHFers. For instance see (let it load) chfpatients.com/archives/archive2-2006a.htm#Jon2-1 for many differences between Toprol-XL and Coreg. These differences really matter to us CHFers.
Nebivolol is a new beta-blocker that blocks mainly beta-1 receptors like Toprol-XL and also relaxes (vasodilates) arteries like Coreg. However, nebivolol does this by stimulating endothelial nitric oxide production, which reduces side effects a lot while reducing the heart's work load. Strict trials show that once-daily treatment reduces both systolic and diastolic blood pressure, has very few side effects, and does not cause adverse events.
Nebivolol significantly reduces symptoms and risk of death in elderly patients with chronic heart failure, regardless of EF. Nebivolol is already available in Europe for high blood pressure and is expected to be available soon in the United States.
Source: Am J Hypertens. 2005 Dec;18(12 Pt 2):169S-176S.
Title: The role of the new beta-blockers in treating cardiovascular disease.
Author: Weber MA
March 27, 2006 - A "third generation" (new) beta-blocker called Nebivolol is on the way. Nebivolol has the main good benefit of Toprol-XL (beta-1 blocking without beta-2 blocking) plus one of the good benefits of Coreg (relaxing the arteries, called vasodilation). It also helps endothelial function and is a powerful anti-oxidant. Nebivolol does this without all of Coreg's side effects.
Researchers studied how nebivolol affects systolic versus diastolic left heart function in patients. This substudy included 104 patients; 43 had an EF less than 36%. Echo was done on each patient to take quite a few heart measures at study start and again one year later.
In the group with EF less than 36%, nebivolol reduced heart size and improved EF 5%. Other measures remained the same. In patients with EF higher than 36%, no changes in the heart muscle were seen.
So in patients with weakly pumping hearts (low EF), nebivolol reduces heart size and improves EF. In patients with near-normal or normal EF (diastolic heart failure) no changes in the heart muscle were seen. None the less, risk of death or heart-related hospitalization improved in both groups in SENIORS.
The SENIORS trial showed that nebivolol reduces risk of death and heart-related hospitalizations in senior CHFers regardless of EF. What does this mean? It suggests that CHFers with diastolic heart failure may now have a drug proven to help them.
Jon's note : The average age in the SENIORS trial was 76 years.
Source: Eur Heart J. 2006 Mar;27(5):562-8. Epub 2006 Jan 27.
Title: Effects of nebivolol in elderly heart failure patients with or without systolic left ventricular dysfunction: results of the SENIORS echocardiographic substudy.
Authors: Ghio S , Magrini G , Serio A, Klersy C, Fucilli A, Ronaszeki A, Karpati P, Mordenti G, Capriati A, Poole-Wilson PA, Tavazzi L; SENIORS investigators. PMID: 16443607
February 2, 2006 - While some CHFers suffer serious "wasting" or cachexia, most of us actually get fatter than before we had CHF. European researchers now find that beta-blockers may be partly responsible.
Researchers studied changes in body make-up in 41 CHFers taking beta-blockers. Sixteen of the 41 CHFers were already on beta-blockers at study start; by the study's end all were taking beta-blockers. Average age was 67 years and average EF was 37%. Average follow-up was 263 days.
No changes were seen in body weight, body mass index, or total body water. However, in beta-blocker patients, total body fat increased in 28 of 41 patients. The average increase was from 27.4 to 28.3 kg - over 2 pounds. Total body fat percentage increased in 33 patients, from 32.3% to 33.4%. Taking beta-blockers causes body fat increase. Note that heart class did improve and so did quality of life survey scores.
Source: Reuters News
Title: Body composition changes in patients with systolic heart failure treated with beta blockers: a pilot study.
Authors: Lainscak M, Keber I, Anker SD.
Source: Int J Cardiol. 2006 Jan 26;106(3):319-22.
1999 - Very few studies address whether beta-blockers can be safely stopped. We studied 13 Japanese DCM patients on beta-blockers. There were 9 men and 4 women, with an average age of 62 years. They had been taking metoprolol at doses between 20 and 120mg per day for 3 to 5 years. The patients ranged from class one to class 3.
Metoprolol dose was reduced every 4 to 8 weeks until the drug was finally stopped. Measurements were taken before reducing dose and after stopping the drug. We measured heart class, blood pressure, and heart rate; we did a chest x-ray, echocardiogram, EKG, and Holter monitor.
|Number of patients||Before reducing β-blocker dose||After stopping β-blocker|
|10||class one||6 unchanged|
2 worsened to class two
2 deaths at 6 to 10 weeks (one from CHF, one SCD
|2||class two||1 worsened to class three|
1 death (SCD at 17 weeks)
|1||class three||1 death (from CHF at 8 weeks)|
|After stopping the drug, bad things happened a lot|
|Heart rate went up from 66 bpm to 92 bpm|
|Cardiothoracic ratio went up from 55% to 57%|
|Heart size increased from 60mm to 62mm|
|Ejection fraction went down from 38% to 34%|
|PVCs went up from 1,871 per day to 2,923 per day|
Forty-six percent of patients who stopped metoprolol were unchanged, while 54% got worse. Fifteen percent of the worsening patients died.
Side effects do sometimes require that a beta-blocker be stopped. When beta-blockers are suddenly stopped, a rebound effect occurs. Heart rate greatly speeds up and CHF gets worse. For this reason, we lowered the dose very slowly. Despite this precaution, heart rate in our patients shot up from 66 beats per minute to 92 beats per minute. This may have been the cause of worsening heart failure.
In our study, 4 of 13 patients died within 4 months after stopping the beta-blocker. We conclude that patients with DCM in whom a beta-blocker is useful should keep taking it because stopping it could prove fatal. Beta-blockers should not be stopped in this patient group.
Title: Can Beta-Blocker Therapy Be Withdrawn from Patients with Dilated Cardiomyopathy?
Authors: Shin-ichiro Morimoto, MD; Keisuke Shimizu, MD; Kenji Yamada, MD; Shinya Hiramitsu, MD; Hitoshi Hishida, MD
Source: Am Heart J 138(3):456-459, 1999
May, 1997 - Coreg is a multiple-action drug. It reduces blood pressure, mainly by blocking the heart's beta receptors and by vasodilation (expanding the arteries). Blocking beta-receptors fools the heart into thinking it is not receiving orders to speed up, so heart rate slows down. Vasodilation happens because Coreg blocks alpha-1 receptors in arteries, preventing them from getting the orders to tighten, thus keeping them relaxed.
Coreg lowers the heart's work load by reducing all 3 parts of your heart's oxygen demand: heart rate, ability to contract, and wall tension. Vasodilation reduces afterload: lowering resistance to the heart's pumping. This offsets the common beta-blocker problem of reducing the heart's pumping strength.
Coreg is also a powerful antioxidant. In theory, this could protect the heart from damage caused by oxidative stress. Coreg also inhibits certain molecules which invade heart tissue and cause further damage.
In theory, Coreg slows bad cholesterol accumulation in and around the heart. At the same time, it protects the layer of cells lining the blood vessels (endothelium).
Title: Pharmacology of Coreg: rationale for use in hypertension, coronary artery disease and congestive heart failure
Author: Ruffolo RR Jr, Feuerstein GZ
SmithKline Beecham Pharmaceuticals
Source: Cardiovasc Drugs Ther 1997 May;11 Suppl 1:247-256
PMID: 9211017, UI: 97354822
1992 - We studied Coreg's effects on PVCs in 65 patients treated with Coreg for 4 to 8 weeks. Twelve patients had high blood pressure, 41 had stable angina, and 12 had CHF. Holter monitoring was done for 24 hours before and after Coreg therapy.
Continued Coreg use reduces PVC activity in a wide range of patients.
Title: Effects of carvedilol on ventricular arrhythmias
Authors: Senior R, Muller-Beckmann B, DasGupta P, van der Does R, Lahiri A
Source: J Cardiovasc Pharmacol 1992;19 Suppl 1:S117-S121
PMID: 1378137, UI: 92326380
March 4, 2003 - Long-term beta-blocker use often improves heart function in CHFers, but may not improve exercise capacity. Previous studies showed that beta-blockers do not always improve exercise in CHFers. We studied patients on beta-blockers long-term.
Dr. Mathew Maurer compared the exercise ability of 9 CHFers who had improved EF after long-term beta-blocker use with the exercise ability of 11 CHFers without EF improvement after long-term beta-blocker use.
Ability to exercise in the two groups was very similar. Peak oxygen consumption, perceived exertion, and levels of lactate in the veins (a sure sign of muscle fatigue) were the same in each group. This suggest that maximum exercise performance is limited by how muscles get and use oxygen in heart failure patients - not just by heart function alone.
Source: Am J Cardiol 2003;91:356-360
March 8, 2000 - Dr. Ake Hjalmarson studied 3,991 CHFers taking either Toprol-XL or placebo in addition to their standard heart failure meds. The researchers estimated how much Toprol-XL reduced risk compared to placebo (not compared to Coreg). Toprol-XL reduced the risk of:
Toprol-XL patients had improved symptoms and ability to function. The researchers write, "Toprol-XL improved survival, reduced hospitalizations due to worsening heart failure, improved functional heart class and improved patients' quality of life.".
Source: JAMA. 2000;283:1295-1302,1335-1337
February 6, 2001 - The FDA has approved using Toprol-XL (metoprolol extended release) for heart failure. The drug was already approved to treat high blood pressure and angina. The FDA's decision was based on trials showing that Toprol-XL reduces mortality rates by 34% in CHF patients.
Source: Reuters Health
February 18, 2002 - We studied data from the first 90 days of the MERIT-HF trial. During drug start-up and while raising the dose, placebo patients and Toprol-XL patients had the same mortality and hospitalization rates, regardless of heart class or EF.
After 60 days, Toprol-XL patients started to do better than placebo patients. Slow heart rate was the main reason that drug dose was raised more slowly. In class 3 to class 4 patients, 6% of placebo patients stopped taking their "drug" versus 8% of Toprol-XL patients (in the first 90 days). After 90 days, more placebo patients stopped taking their "drug" than Toprol-XL patients. Most patients reported no change in SOB or fatigue while raising drug dose.
The researchers believe that Toprol-XL can be started and the dose raised in the overwhelming majority of patients with stable mild to moderate heart failure - with few side effects.
Title: Tolerability of Beta-Blocker Initiation and Titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
Authors: Stephen Gottlieb, Michael Fisher, John Kjekshus, Prakash Deedwania, Lars Gullestad, Jiri Vitovec, John Wikstrand
Source: Circulation. 2002;105:1182
September 21, 2005 - The REVERT trial studied people with an EF under 40% but with no heart failure symptoms. Almost everyone in the trial was on an ACE inhibitor, and many took diuretics and digoxin. All had enlarged hearts. Two doses were tested: 50 mg (low dose) and 200 mg (high dose), added to their other meds for one year. Average age was 66 years and 21% were black.
Fifty-four patients were low dose, 53 were high dose and 57 took placebo. At 6 and 12 months, there were no consistent changes in systolic blood pressure (the first number) but heart rate was reduced in Toprol-XL patients. Jon's Note - This is important since it suggests that people with low blood pressure may tolerate Toprol-XL better than Coreg.
The primary endpoint of the trial was change in LVESVI, meaning Left Ventricular End-Systolic Volume Index. In plain English, that means how big the heart's main pumping chamber is when it has just pumped out as much blood as it can. At 12 months, low dose Toprol-XL patients had their heart size go down more than twice as much as placebo. High dose Toprol-XL patients' heart size went down 4 times as much as placebo patients.
EF improved in both Toprol-XL groups but not in placebo patients. All other heart measurements also improved in Toprol-XL patients. There were more total adverse events in the placebo group than in either Toprol-XL group.
Toprol-XL may be an important addition to meds for CHFers who don't have symptoms, as well as for those who do.
Source: Program from 9th Annual Scientific Meeting of the Heart Failure Society of America.
Authors:Colucci WAS, Kolias TJ, Adams KR, et al.
Title: Metoprolol reverses LV remodeling in patients with asymptomatic systolic dysfunction: The REVERT trial.
March 22, 2000 - The COPERNICUS trial was halted March 21, 2000, because its Data and Safety Monitoring Board decided that survival in the Coreg group was much better than in placebo patients. The trial included 2,200 patients with advanced CHF. The target Coreg dose was 25mg twice a day for patients in the active treatment group.
"The effect of Coreg is compelling," Dr. Milton Packer said. "Treatment effects appear to be larger than those seen in other beta-blocker trials, which show about a 34% risk reduction in mortality. Most other trials have been in patients with mild-to-moderate heart failure." Whether Coreg is more effective than other beta-blockers is being tested now. The COMET trial is comparing Coreg to metoprolol in CHFers," Dr. Packer said.
Source: Reuters Health
March 30, 2000 - Beta-blockers may increase risk for diabetes. Dr. Frederick Brancati studied data on 12,550 non-diabetic patients from 45 to 64 years of age. At 3 and 6 years, patients were screened for diabetes.
Overall, patients with high blood pressure were 2-1/2 times more likely than others to develop type 2 diabetes. After adjusting for other factors, patients taking a thiazide diuretic, an ACE inhibitor, or calcium channel blocker did not have higher risk for diabetes. However, the risk for diabetes was 1-1/4 times higher for beta-blocker patients.
The authors note that "this adverse effect must be weighed against the proven benefits of beta-blockers in reducing risk of cardiovascular events."
Source: N Engl J Med 2000;342:905-912,969-970
September 4, 2000 - Results from 3-year long trials show that Coreg reduced risk of death in CHFers already taking other standard meds. Coreg trials running from October of 1997 till March of 2000 were stopped when the safety committee decided all patients should get Coreg.
"The results tell us that Coreg can reduce the risk of death in a much broader range of patients than we previously thought," Dr. Milton Packer said. Coreg studies were done at 334 medical centers and enrolled 2,200 patients with advanced heart failure.
Patients with severe heart failure taking Coreg had an 11% risk of death versus 19% for placebo patients. Coreg's manufacturerer will use this data to seek approval to use the drug in patients with advanced CHF. Until now, the drug has only been okayed for patients with mild to moderate CHF.
Source: Reuters Health
March 27, 2001 - Some people with heart failure do better than others when taking beta-blockers. Perhaps now we have one clue why - genetics.
ACE activates a hormone to increase blood flow. This system over reacts in heart failure, wearing out the heart. Everyone has two copies of an ACE gene, which has 2 forms called alleles. The forms are the I (insertion) and the D (deletion) alleles, based on whether one small section of the gene is missing or not. You may have two I (II), two D (DD), or a D and an I (DI). The D form of the gene is affected by beta-blockers.
Having this D allele makes you more likely to do poorly overall - but if you take a beta-blocker, that tendency to do poorly is corrected, says Dr. Dennis McNamara, the study leader. "CHFers with 2 copies of the D allele (DD) clearly got the most benefit from taking a beta-blocker."
Of the 328 CHFers in this study, 32% were DD, 21% were II, and 47% were DI. Eighty-seven percent were taking an ACE inhibitor and 37% also took a beta-blocker. Patients were followed for 2 years.
In patients who not on beta-blockers, only 48% in the DD group survived for 2 years without a transplant. That compares to 81% in II patients. However, in patients taking a beta-blocker, 77% in the DD group were alive and transplant-free after 2 years - about the same as the 70% in the II group.
"We may see therapy based on genetics in the next 5 to 10 years," McNamara says. "We've got to find a way to get the right drugs to the right people. I believe genetics will be part of that."
Source: American Heart Association news release
March 11, 2002 - An analysis of the MERIT-HF trial shows that Toprol-XL benefits women as much as men.
Dr. Jalal Ghali studied the outcomes of 898 women from the MERIT-HF trial. All the women were class 2 or worse with EF less than 40%. A subgroup of 183 women with class 3 and class 4 CHF and an EF less than 26% were included.
Compared with untreated women, women taking Toprol-XL had a "21% reduction in the primary endpoint of all-cause mortality plus all-cause hospitalizations (164 Toprol-XL women versus 137 placebo women)," the authors write. Toprol-XL patients were hospitalized less often. These results applied even to women with severe heart failure.
Data from MERIT-HF and 2 other large trials shows that women taking beta-blockers for heart failure get the same benefits men get.
Source: Reuters Health; Circulation 2002;105:00-00
July, 2002 - The trial included 408 CHFers with EF under 45%. Fifteen percent were class one, 41% were class 2, 42% were class 3, and 2% were class 4. The groups were very similar in age, sex, heart class, blood pressure, and Vo2max. Beta-blocker patients had lower resting heart rate, higher EF, and lower NE blood levels.
Patients were divided into 2 groups: one taking beta-blockers (165 patients or 40%) and one group not taking beta-blockers (243 patients or 60%).
|Patient group||Vo2max under 10||EF under 20%||NE over 2.24 nmol/L||NT-proBNP over 364 pmol/L|
|This despite the fact that those taking beta-blockers were only getting about 40% of target dose|
Only 6% beta-blocker patients died of heart-related causes within one year compared to 17% of patients not taking beta-blockers. Twelve percent of beta-blocker patients were hospitalized from worsening CHF compared to 24% of non-beta-blocker CHFers.
The reduced risk in beta-blocker patients applied to all heart classes, and regardless of CHF cause. Overall, beta-blocker patients had a much better outcome. Beta-blocker patients at high risk - with peakVo2 less than 14 - only had heart events at a rate similar to lower-risk non-beta-blocker patients.
DISCUSSION Although beta-blocker patients received only 40% of recommended target doses, they had a 65% lower one-year mortality (6%) than non-beta-blocker patients (17%).Annual hospital admission for worsening CHF was 50% lower (12%) in beta-blocker patients than in those not on beta-blockers (24%).
Vo2max is the gold standard for selecting heart transplant candidates. A score less than 14 is considered ready for transplant. Average Vo2max scores in our trial were about the same in both groups, but outcomes were better in beta-blocker patients. For any range of Vo2max scores, beta-blocker patients in that range had a better outcome than non-beta-blocker patients in the same range.
Even in patients with the highest risk - Vo2max under 10 - one-year mortality was only 17% in beta-blocker patients compared to 38% mortality in those non-beta-blocker patients. The Vo2max cut-off point of 14 for heart transplant may need to be changed now that most CHFers are be taking beta-blockers.
This study shows that beta-blocker use greatly influences the measures used as end points in trials. Since these measures are used to predict patient outcome, we need to rethink the way we figure risk for CHF patients.
Title: Impact of Beta-Blocker Treatment on the Prognostic Value of Currently Used Risk Predictors in Congestive Heart Failure
Authors: Christian Zugck, Armin Haunstetter, Carsten Kruger, Robert Kell, Dieter Schellberg, Wolfgang Kubler, Markus Haass
Source: J Am Coll Cardiol 2002;39:1615-22
November, 1998 - The question is, "Which beta-blocker should be used for CHF?" We compared metoprolol to Coreg in CHFers with moderate to severe symptoms. Coreg does several things metoprolol does not - it is also an alpha-receptor blocker, so it relaxes arteries (vasodilation).
It is also an antioxidant. This may help because CHFers have less ability to cope with oxygen-free radicals compared to healthy people. We measured blood level of TBARS - a marker of high antioxidant activity - in CHFers to see if Coreg had a positive antioxidant effect.
The study included 67 CHFers with an average age of 57 years and average EF of 19%. There were 46 men and 21 women. Thirteen were class two, 48 were class three, and 6 were class four. All patients were taking digoxin and diuretics, with 96% taking ACE inhibitors. Thirty patients took metoprolol and 37 took Coreg.
Patients had a baseline exam including blood pressure, 6-minute walk, Vo2max, and quality of life questionnaire. Blood was drawn for TBARS at baseline and months 4, 6, and 12 of therapy. Patients took either metoprolol or Coreg. Starting dose was 6.25mg metoprolol once a day or 3.125mg Coreg twice a day. Doses were then raised weekly.
Twenty patients did not complete the study because of death, heart transplant, worsening CHF, or relocation from the area. Withdrawals were equally divided between the 2 groups. There were 3 deaths in the metoprolol group and 4 deaths in the Coreg group during this 12-month study.
The 47 patients completing the study showed improved in each area measured. Heart rate slowed in both groups. The decline in heart rate with Coreg was slightly greater than with metoprolol. Metoprolol patients went from 46 to 31 points on the Minnesota Living With Heart Failure Questionnaire, while Coreg patients went from 52 to 41 (lower is better).
Maximum exercise capacity improved only slightly in both groups with no difference between groups. Ejection fraction improved by 5% in both groups with no difference between groups. Both drugs improved markers of oxidative stress equally.
Coreg and metoprolol showed the same benefits over 12 months. There was no difference between the two beta-blockers in the measured areas. Oxidative stress declined in both groups. There was no selective benefit to either drug. The number of adverse events was about the same with each drug.
Title: One-Year Comparison of Metoprolol and Carvedilol in CHF
Speaker: Marrick L. Kukin, Cardiovascular Institute, Mount Sinai School of Medicine
Source: AHA 71st Scientific Sessions, November 1998
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: Kukin ML, Kalman J, Charney RH, Levy DK, Buchholz-Varley C, Ocampo ON, Eng C.
Source: Circulation. 1999 May 25;99(20):2645-51.
August 8, 2000 - Dr. Marco Metra randomized 150 CHFers to take either 49mg Coreg per day or 124mg metoprolol per day. Coreg patients had "larger increases in ejection fraction at rest (+11% versus +7% for metoprolol), and in left ventricular stroke volume after 13 months of treatment," according to their report.
Both at rest and during exercise, Coreg lowered pulmonary artery pressure and PCWP more than metoprolol. However, metoprolol patients had more improvement in maximum exercise capacity.
Source: Circulation 2000;102:484-486,546-551
November 2, 2001 - Non-selective (like Coreg) and selective (like metoprolol) beta-blockers may have different effects on hormone release. Thirty-six patients with chronic CHF took either Coreg (non-selective) or metoprolol (selective). Heart function and norepinephrine were measured before and after 4 months of drug therapy.
Coreg patients (17 patients) had reduced total and heart norepinephrine. Metoprolol patients (14 patients) had no changes in either. Both drugs reduced heart rate and increased pulse pressure, but arterial pressure did not change. Sympathetic nerve traffic to skeletal muscle did not change in either group.
Coreg lowered systemic and heart norepinephrine but metoprolol did not. This suggests that Coreg blocks more, or different beta receptors.
Title: Nonselective Versus Selective B-Adrenergic Receptor Blockade in Congestive Heart Failure Differential Effects on Sympathetic Activity
Authors: Eduardo Azevedo, Toshihiko Kubo, Susanna Mak, Abdul Al-Hesayen, Anne Schofield, Rebecca Allan, Susan Kelly, Gary Newton, John Floras, John Parker
July 5, 2003 - COMET was a double-blind, randomized trial comparing Coreg to metoprolol (not Toprol-XL) in CHFers. COMET was sponsored by the maker and distributor of Coreg.
Both Coreg and metoprolol are beta-blockers. Metoprolol blocks mostly beta-1 receptors. Coreg blocks both beta-1 and beta-2 receptors and also blocks alpha-1 receptors, which causes vasodilation and lowers blood pressure. The beta receptors most involved in heart failure are beta-1 receptors.
The Trial - COMET enrolled 3,029 patients in 15 European countries. Most patients were class 2 or class 3; all had an EF less than 36%. All had been hospitalized for a heart "event" at least once in the last 2 years. All patients were taking diuretics and ACE inhibitors but none required IV drugs or amiodarone.
Patients took either metoprolol (1,518 patients) or Coreg (1,511 patients). Metoprolol was started at 5mg BID and Coreg was started at 3.125mg BID. Dose was raised to 50mg BID for metoprolol and 25mg BID for Coreg or less if a patient did not tolerate that dose.
When follow-up ended in November of 2002, 1112 patients had died. Average doses during the study were 21mg Coreg BID and 43mg metoprolol BID. The study showed 5.7% better absolute survival in Coreg patients over 5 years. The researchers do not know why Coreg patients did better in this trial.
The Controversy - Doctors argue that:
Jon's Comments - A patient's perspective:
|If you can't afford to buy it, does it matter if one drug is a little better?|
|Coreg - 25mg taken twice a day costs about 270 US dollars for a 90-day supply|
|Toprol-XL - 200mg taken once a day costs about 163 US dollars for a 90-day supply|
|Metoprolol - 50mg taken twice a day costs about 16 US dollars for a 90-day supply|
Meeting of the Working Groups on Heart Failure of the European Society of Cardiology, June 21-24, 2003
Poole-Wilson PA, Swedberg K, Cleland JGF, et al for the COMET Investigators: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): a randomised controlled trial. Lancet. 2003;362:7-13
Poole-Wilson PA, Cleland JGF, Di Lenarda A, et al: Rationale and design of the carvedilol or metoprolol European trial in patients with chronic heart failure: COMET. Eur J Heart Fail. 2002;4:321-329
July 5 issue of The Lancet
And much other reading. ;-)
2002 - Doctors question whether heart failure patients need to reach target beta-blocker dose to benefit, so researchers analyzed a previous trial of 4,000 patients with chronic heart failure.
They compared 2 patient groups who took Toprol-XL to a group of patients who took placebo. Patients in the high-dose group reached an average daily dose of 192mg after 3 months, while patients in the low-dose group reached an average daily dose of 76mg.
Compared to placebo, total mortality was reduced 38% in both groups. Both groups had the same survival benefit and the same reduction in hospitalizations for worsening heart failure. However, Dr. John Wikstrand said, "The maximum target dose of 200mg Toprol-XL was well tolerated by most patients, and should be strived for."
Dr. Wikstrand said, "Doctors should be strongly encouraged to consider beta-blocker treatment in all patients with stable chronic systolic heart failure" and "results support the idea of an individualized dose-raising schedule, guided by patient tolerability and heart rate response.".
Source: J Am Coll Cardiol 2002;40:491-498
July 3, 2003 - Some of Coreg's benefit may be from "resuscitation" of hibernating heart muscle. "Hibernating" cells are not functioning but are not really dead either. Sometimes they start working again and sometimes they die instead.
In this study, 387 patients with stable, chronic CHF from ischemia took either placebo or Coreg for 6 months. Patients were called hibernators (181 patients) or non-hibernators (124 patients) based on how much of their heart muscle was hibernating.
Coreg patients had increased EF by the study's end. Placebo patients had no EF change. The more heart muscle that was hibernating, the more EF improved over time with Coreg use.
Study author Dr. John Cleland said that Coreg seems to slow worsening of hibernating cells and to revive some areas close to death. No one knows yet if other beta-blockers will also do this. Heart muscle hibernation is common, affecting about half of all CHF patients with CAD.
Source: Lancet 2003;362:2-3,14-21.
October, 2004 - Trials of Coreg, bisoprolol, and Toprol-XL show that these beta-blockers reduce hospitalizations and risk of death, and improve symptoms and heart size in CHFers. However, most trials ended early because the drugs' benefits were so clear. That means long-term results have been hard to find. For example:
|Beta-blocker Trial||Length of Trial|
|US Carvedilol Trial||6 to 12 months|
|CIBIS II||16 months|
Long-term Coreg use in 60 SHF patients was studied in the early 1990s in a 4-month, placebo-controlled, phase 2 trial. Fifty-seven patients finished the trial. Average patient age was 53 years.
|At Study Start||Number of Patients|
|Heart Failure Cause||Number of Patients|
|Heart Class||Number of Patients|
|Drug Therapy||% of Patients|
|ACE Inhibitors||93 %|
|Digoxin (Lanoxin)||82 %|
|Coumadin (warfarin)||75 %|
|Anti-arrhythmic Drugs||19 %|
All patients kept taking Coreg after the trial ended. Heart size, EF (at rest and during exercise), and quality of life were measured at 4, 6, 12, and 24 months after starting Coreg. Survival was recorded again January 1, 2004.
Average follow-up in these patients was about 13 years. Average Coreg dose was 42mg twice a day. Five patients had died at 2 years and 29 by January of 2004. Eight patients had received heart transplants by that time. Risk of death was reduced the most with Coreg use in people with non-ischemic heart failure.
|Heart Failure Causes and Outcomes|
|Still living 13 years after study start||27 %||57 %|
|Dead 13 years after study start||73 %||43 %|
Coreg use increased resting EF by 11%, reduced heart size by 8mm, and improved quality of life scores by 1.2 points at 4 and 24 month follow-ups compared to study start. Ability to exercise more or better did not improve. The only things that predicted risk of death were low EF and poor heart class at study start, and less strongly, ischemic cause of heart failure.
EF usually improved as much as it was going to improve in the first 4 months of Coreg use. Heart size continued to improve for about 2 years after starting the drug. There was no specific year after starting Coreg that marked an increased risk for death. This suggests that Coreg's benefits stick with you for the long term!
Title: Carvedilol Produces Sustained Benefits Over 12 Years of Follow-Up.
Presenters: Dr. John MacGregor and colleagues.
Source: HFSA conference, 2004.
December 24, 2003 - In a randomized, double blind trial, researchers studied the effects of digoxin plus Coreg, Coreg alone, and digoxin alone, in 47 CHFers with persistent a-fib. Average EF was 24%.
Phase One - Digoxin alone was compared to digoxin plus Coreg for 4 months. Digoxin-only patients showed no changes. Digoxin plus Coreg improved EF and symptoms. There was also some improvement in heart class and heart rate both at rest and during exercise. There were no changes in BNP levels.
Phase Two - Digoxin was stopped in patients taking Coreg. Digoxin alone was compared to Coreg alone for 6 months. There were few differences between digoxin alone and Coreg alone. However, BNP levels were higher in patients taking Coreg alone than in patients taking only digoxin. Both drugs equally reduced average heart rate and exercise heart rate.
Conclusions - None of the therapies influenced 6-minute walk distance. Stopping digoxin in patients taking Coreg increased heart rate and reduced EF. The researchers concluded that in heart failure patients with a-fib, standard care should include both digoxin and Coreg.
Title: Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure?
Authors: Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JGF.
Source: J Am Coll Cardiol. 2003;42:1944-1951.
July 31, 2006 - Toprol-XL is now available as a generic per the FDA. It's generic name is metoprolol succinate. It is only currently available at 25mg strengths but next year, other dosages will also be available as generic.
Source: FDA, See www.fda.gov/cder/foi/appletter/2006/076969s000LTR.pdf
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, 2005, 2006 Jon C.