Coreg in heart failure trial

This syndrome is manifested by symptoms of fatigue, dyspnea and congestion. Physicians treating patients with heart failure have traditionally selected agents with positive inotropic or peripheral vasodilatory effects and have avoided agents such as beta blockers, which exert negative inotropic effects. It has become increasingly apparent that the view of heart failure as primarily a hemodynamic disorder is incomplete.

Although drugs with positive inotropic effects can produce short-term symptomatic improvements in patients with heart failure, 10 , 11 their long-term use does not prolong life. In fact, some positive inotropic agents, such as beta agonists e.

In addition to the familiar hemodynamic changes, heart failure also results in widespread neurohumoral activation. Aortic and ventricular baroreceptors are reset to permit less sympathetic inhibition, ultimately resulting in increased adrenergic tone. Decreased glomerular flow also activates the renin-angiotensin system. Both of these systems—adrenergic and renin-angiotensin—activate each other.

Initially, these neurohumoral changes are compensatory, functioning to retain fluid and maintain cardiac output. Unfortunately, with prolonged activation, such neurohumoral changes have detrimental effects on the heart.

Patients with the highest levels of norepinephrine have the least favorable prognosis. Moreover, because the sympathetic nervous system is the principal neurohumoral system activated in patients with mild symptoms of heart failure, the use of medications such as beta blockers, which inhibit sympathetic activity, might reduce the risk of disease progression in patients with mildly symptomatic heart failure.

Recent controlled studies of patients with heart failure who received beta blockers have indeed shown that, with long-term use, these agents can improve left ventricular function 20 — 22 and symptoms of CHF. The benefits of using carvedilol in patients with CHF have been demonstrated in both single-center 24 — 26 and multicenter 2 , 16 , 17 , 27 trials.

The Australia—New Zealand Research Collaborative Group 28 studied patients with stable heart failure of ischemic origin and found that treatment with carvedilol improved left ventricular function and decreased the risk of the combined end points of death or hospitalization over a month period. However, the use of carvedilol was not shown to significantly reduce either mortality or hospitalization. The U. Carvedilol Study Group 16 enrolled 1, patients with chronic heart failure who were stratified into one of four groups on the basis of their performance on a six-minute walking test.

This study was terminated early after researchers concluded that treatment with carvedilol resulted in a 65 percent relative reduction in the mortality rate among patients with heart failure. Carvedilol is a nonselective beta-adreno-receptor antagonist and an alpha 1 -adreno-receptor antagonist. It has no intrinsic sympathomimetic activity. The first group consists of nonselective beta blockers without ancillary properties and includes such drugs as propranolol Inderal and timolol maleate Blocadren.

The second group consists of selective blockers of beta receptor subtypes without ancillary properties. This group includes metoprolol Lopressor and atenolol Tenormin. The third group consists of nonselective beta blockers that have the ancillary property of vasodilation. Included in this group are labetalol Normodyne , carvedilol and bucindolol currently in phase 3 trials. Inverse agonism is the ability of a beta blocker to inactivate active state receptors.

The beta blockers with the most inverse agonism, like propranolol, produce the greatest negative chronotropic and inotropic effects. Thus, bucindolol and carvedilol produce relatively fewer negative chronotropic and inotropic effects when compared with beta blockers like propranolol. The beta-blocking actions of carvedilol are generally evident in humans within one hour of administration, and the alpha-mediated vasodilatory effects, manifested by decreased peripheral resistance and decreased blood pressure, are evident within about 30 minutes of administration.

The clinical significance of alpha blockade in conjunction with beta blockade in the treatment of CHF is not known. The use of alpha blockers alone, however, does not appear to reduce mortality in patients with symptomatic CHF.

At high dosages, carvedilol exerts calcium channel blocking activity. This antioxidant activity may contribute to carvedilol's cardioprotective effects. Carvedilol is rapidly absorbed following oral administration, achieving peak plasma concentrations within one to two hours.

The apparent mean terminal elimination half-life of carvedilol generally ranges from seven to 10 hours. The rate of absorption is delayed by taking carvedilol with food. Carvedilol is metabolized by the liver and undergoes extensive first-pass metabolism. Three active metabolites of carvedilol have been identified, but none of these compounds appears to contribute to carvedilol's beta-blocking activity.

Carvedilol is primarily metabolized by the liver, with less than 2 percent of a given dose excreted unchanged in the urine. Plasma concentrations of carvedilol are nevertheless increased in patients with renal failure. Carvedilol is highly bound to plasma proteins and is, therefore, not cleared significantly by hemodialysis. Carvedilol is contraindicated in patients with bronchial asthma or related bronchospastic conditions, decompensated NYHA functional class IV heart failure requiring intravenous inotropic therapy, severe liver impairment, second- or third-degree atrioventricular block, sick sinus syndrome unless a permanent pacemaker is in place , cardiogenic shock, severe bradycardia or known hypersensitivity to the drug.

Although carvedilol has not been demonstrated to have adverse effects on lipids, beta blockers without intrinsic sympathomimetic activity can worsen lipid profiles. Family physicians should, therefore, pay careful attention to lipid levels in patients with hyperlipidemia who are treated with carvedilol. Parameters of glycemic control should also be monitored.

Patients with diabetes or thyroid disease should be warned that carvedilol, like other beta blockers, can mask the signs and symptoms of hypoglycemia and hyperthyroidism, including tachycardia. Moreover, nonselective beta blockers, like carvedilol, can potentiate insulin-induced hypoglycemia. Carvedilol should be used with caution in patients with peripheral vascular disease because beta blockers can precipitate or aggravate symptoms of arterial insufficiency.

Finally, carvedilol therapy should be avoided in patients with known hepatic impairment, since mild hepatocellular injury has occurred, although rarely, among patients treated with the drug. Carvedilol is generally well-tolerated. In clinical trials comparing carvedilol monotherapy with placebo, 4. Discontinuation of therapy because of postural hypotension was more common among patients treated with carvedilol 1 percent versus zero percent.

Rare cases of thrombocytopenia have also been reported. Much of the initial study of carvedilol's tolerability did not include patients with heart failure. Nevertheless, the U. Carvedilol Heart Failure Study Group 16 also found that dizziness and fatigue were the most common adverse reactions reported by patients treated with carvedilol.

They also noted increased reports of dyspnea 25 percent with carvedilol versus 22 percent with placebo , heart failure 21 percent versus 16 percent and cough 10 percent versus 8 percent. Because of carvedilol's extensive oxidative liver metabolism, its pharmacokinetics can be profoundly affected by certain drugs that significantly induce or inhibit oxidation.

Rifampin Rifadin , an inducer of hepatic metabolism, can reduce plasma concentrations of carvedilol by 70 percent when these drugs are coadministered. In contrast, cimetidine Tagamet , an inhibitor of the cytochrome P 2D6 isoenzyme the same isoenzyme involved in the metabolism of carvedilol , can increase carvedilol's plasma concentration by 30 percent.

Other inhibitors of the cytochrome P 2D6 isoenzyme, such as quinidine, fluoxetine Prozac , paroxetine Paxil and propafenone Rythmol , could be expected to have similar effects on carvedilol's plasma concentrations. Digoxin Lanoxin concentrations increase by approximately 15 percent in patients also taking carvedilol.

Consequently, digoxin levels should be closely monitored when initiating, adjusting or discontinuing carvedilol therapy. As with other beta blockers, combining carvedilol with verapamil Calan or diltiazem Cardizem should be done with caution. When these agents are combined, it is recommended that blood pressure and electrocardiographic changes be closely monitored.

Coadministration of beta blockers and catecholamine-depleting drugs, such as reserpine Serpasil or monoamine oxidase MAO inhibitors can result in severe hypotension. These agents should be combined with great caution, and patients taking these drugs should be closely monitored. Similarly, coadministration of carvedilol and clonidine Catapres should be undertaken carefully because beta blockers can potentiate blood pressure and heart rate reductions in such patients.

When clonidine therapy is discontinued, it is recommended that the beta blocker be discontinued first. Then, after several days, clonidine can be gradually tapered and discontinued in the hope of avoiding reflex tachycardia and hypertensive crisis.

The combination of carvedilol Coreg and calcium channel blockers verapamil [Calan] or diltiazem [Cardizem] has resulted in rare conduction disturbances. Cimetidine may increase plasma concentration by 30 percent in patients receiving carvedilol.

Clonidine potentiates the blood pressure and heart-rate lowering effects of beta blockers. If combination therapy with clonidine and a beta blocker is terminated, the beta blocker should be discontinued first.

The concentration of digoxin is increased by 15 percent when used in combination with beta blockers. Rifampin causes a reduction in the plasma concentration by 70 percent in patients receiving carvedilol. Other inhibitors of cytochrome P 2D6 isoenzyme fluoxetine [Prozac], paroxetine [Paxil], propafenone [Rythmol], quinidine [Quinaglute].

Adapted with permission from Carvedilol. In: Drug facts and comparisons. Louis: Facts and Comparisons, Patients taking diuretics, digitalis or ACE inhibitors should be taking stable dosages of these medications before carvedilol therapy is initiated. Carvedilol may also be used in patients unable to tolerate an ACE inhibitor and in those not taking digoxin, hydralazine Apresoline or nitrate therapy.

In most cases, however, ACE inhibitor therapy should be initiated and stabilized before the introduction of carvedilol therapy. Consequently, alpha 1-blockade results in vasodilation of the peripheral arteries, decreasing SVR Packer ; Fonarow In addition, preclinical evidence suggests that carvedilol can also produce nitric oxide-mediated vasodilation Kozlovski et al Carvedilol does not possess intrinsic sympathomimetic activity Toda Intrinsic sympathomimetic activity induces weak stimulation of the beta-adrenergic receptors that may dampen the positive effects of beta 1-adrenergic receptor blockade Egan et al ; Frishman a.

Of note, beta-blockers with intrinsic sympathomimetic activity have failed to demonstrate reductions in morbidity and mortality in patients with heart failure Maack et al Carvedilol has also demonstrated antioxidant effects possibly attributable to stimulation of endothelial nitric oxide production or reduced nitric oxide inactivation Toda Furthermore, carvedilol may protect against reactive oxygen species ROS through scavenging of free radicals, suppression of free radical generation, and prevention of ferric ion-induced oxidation Toda ; Dandona et al The ability of carvedilol to scavenge free radicals has been correlated with improved outcomes in patients with heart failure and a recent MI Goldhammer et al In a study involving 39 patients with heart failure and a recent MI, carvedilol IR was shown to decrease oxygen free radical measurements using thiobarbituric acid reactive substances assay, thermochemoluminescence, and conjugated dienes methodologies in 29 patients irrespective of dosage after 6 months of treatment Goldhammer et al Antioxidant activities decrease elevated oxidative stress, which, in turn, reduces lipid peroxidation.

Reduced lipid peroxidation may contribute to protection from myocardial and brain cell ischemic death in patients with hypertension, heart failure, ischemic heart disease, diabetes, and renal dysfunction Maggi et al ; Giugliano et al ; Moreno et al ; Nakamura et al ; Padi et al Anti-oxidant activities of carvedilol may also inhibit low-density lipoprotein LDL oxidation, which could decrease accumulation of oxidized LDL in vessel walls Maggi et al In patients with heart failure, free fatty acid levels become elevated possibly from SNS hyperactivity and the myocardial rate of fatty oxidation may increase; however, during disease progression, myocardial energy efficiency is increased through a compensatory shift from the free fatty acid substrate to glucose Stanley et al Preliminary clinical evidence suggests that pharmacologic treatments facilitating the compensatory metabolic switch at an earlier stage of disease may provide mortality benefits Stanley et al Indeed, carvedilol has demonstrated decreased myocardial use of free fatty acids and either increased or neutral effects on myocardial glucose use in patients with heart failure Wallhaus et al ; Podbregar et al ; Al-Hesayen et al Carvedilol is also known to have anti-inflammatory properties.

Inflammation has been linked to the pathogenesis of heart failure and atherosclerosis Yang et al ; Tatli et al In a clinical trial in patients with hypertension and diabetes, carvedilol IR In addition, carvedilol has been shown to stimulate beta-arrestin signaling Wisler et al Recent results in animal models suggest that beta-arrestin G protein-independent signaling may also occur and provide cardioprotective effects Patel et al Carvedilol CR was developed to achieve sustained concentrations over a hour period, allowing once-daily dosing.

The pharmacokinetic and pharmacodynamic bioequivalence of carvedilol CR and IR was established through 2 clinical studies Henderson et al ; Packer et al In a double-blind, parallel-group, crossover study, patients with essential hypertension were randomized to receive either low-dose carvedilol CR 20 mg daily or carvedilol IR 6. After 22 days of treatment, patients were crossed over to the equivalent alternate carvedilol formulation for 8 days of treatment. Patients in the placebo treatment group continued to receive placebo throughout the study.

Pharmacokinetic parameters were assessed at the end of each treatment session. The pharmacodynamic endpoint was the percentage change from baseline in exercise-induced heart rate.

The pharmacokinetic profiles of both enantiomers were equivalent between carvedilol CR and IR Figure 1 Henderson et al In addition, both formulations maintained a reduced exercise-induced heart rate over a hour period Henderson et al Pharmacokinetic and pharmacodynamic comparison of controlled-release carvedilol and immediate-release carvedilol at steady state in patients with hypertension.

Am J Cardiol , L—26L. In a separate 4-week study, patients with either mild to severe heart failure or with asymptomatic post-MI LVD were treated with the carvedilol IR 3. However, the median time to maximum observed plasma concentration for carvedilol CR lagged 3 hours behind that of carvedilol IR, in accordance with the prolonged-release characteristics expected in a once-daily formulation.

The pharmacodynamics of carvedilol CR were dose proportional over the dose range tested 10 mg to 80 mg Packer et al Carvedilol CR is based on carvedilol phosphate, which has a higher molecular weight than carvedilol free base and contains additional carvedilol free base compared with carvedilol IR to adjust for bioavailability. A model of carvedilol pharmacokinetics that takes into consideration both the IR and CR formulations has been developed and performed robustly in leverage analyses Othman et al Similar to carvedilol IR, the bioavailability and pharmacokinetics of carvedilol CR are influenced by food, and both formulations are recommended to be taken with food Tenero et al However, the pharmacokinetics of carvedilol CR 40 mg were not affected by ethanol 38 g intake from 2 hours before to 2 hours after dosing in 39 healthy volunteers Henderson et al Poor glycemic control predicts cardiovascular events; in particular, glycosylated hemoglobin levels linearly correlate with the risk of cardiovascular complications in patients with type 2 diabetes Colagiuri et al ; Manley Moreover, dyslipidemia is a common comorbid condition in patients with hypertension Johnson et al Traditional, nonvasodilating beta-blockers have been associated with worsening of glycemic control and impaired lipid metabolism Bakris et al a.

In contrast, because of its vasodilatory mechanism of action, which facilitates muscle uptake of glucose and increases the availability of lipoprotein lipase, carvedilol does not negatively affect glycemic control or lipid profile compared with metoprolol Messerli et al Carvedilol CR is currently being studied in a randomized, double-blind clinical trial comparing lipid effects of metoprolol succinate extended release with carvedilol CR in patients with hypertension and either normal lipids or mild dyslipidemia Bakris et al b.

The primary endpoints are the change from baseline in HDL-C and in triglycerides after 6 months of treatment. Several other trials have reported on glucose and lipid metabolism parameters using carvedilol IR and results have generally demonstrated improved profiles compared with metoprolol Bakris et al ; Basat et al ; Torp-Pedersen et al After 5 months of treatment in this randomized, double-blind, parallel-group trial, carvedilol IR did not increase HbA 1c 0.

Moreover, a greater number of patients withdrew because of worsening glycemic control in the metoprolol group 2. These data support the results of an earlier comparison study of metoprolol and carvedilol, which found that insulin sensitivity increased with carvedilol and decreased with metoprolol treatment Jacob et al Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial.

JAMA , — All Rights Reserved. In contrast with metoprolol, carvedilol did not significantly increase mean triglyceride levels. The neutral effects of carvedilol on glycemic control and lipid metabolism have also been established in patients post-MI. Fifty-nine patients post-MI were randomized to add either metoprolol mg twice daily or carvedilol IR 25 mg twice daily to their currently prescribed regimen for 12 weeks Basat et al Treatment with carvedilol IR has been shown to reduce the incidence of diabetic events and new-onset diabetes among patients with heart failure.

In a cohort of patients without diabetes at trial initiation, diabetic events adverse events of diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance, or hyperglycemia and new-onset diabetes clinical diagnosis, repeated high random glucose level, or glucose-lowering drugs were assessed.

Over a 5-year period, fewer diabetic events were reported with carvedilol IR of patients; New-onset diabetes investigator reported was also significantly less prevalent in the carvedilol IR treatment group patients; The majority of clinical data for carvedilol come from studies with the IR formulation.

However, several studies, both of bioequivalence and efficacy, have been conducted with carvedilol CR Tenero et al ; Weber et al b. Data presented in this section are a mixture of carvedilol IR and CR studies. Change from baseline in DBP measured by hour ambulatory blood pressure monitoring after 6 weeks of treatment was the primary endpoint Weber et al a. Carvedilol CR treatment resulted in significant, dose-dependent reductions in peak and trough blood pressure measurements Figure 3.

Controlled-release carvedilol in hypertension. Am J Cardiol , L—38L. Note: Data are change from baseline in model-adjusted peak 3 to 7 hours diastolic blood pressure and systolic blood pressure measured by ambulatory blood pressure monitoring. These data build on the established safety and efficacy of carvedilol IR in the treatment of hypertension demonstrated in several US and international placebo-controlled trials.

In patients with hypertension, carvedilol IR has been shown to reduce blood pressure and exercise and resting heart rates Pedersen et al Blood pressure reductions are likely linked to reductions in SVR in addition to the other BP-lowering properties of all beta-blockers, which have been demonstrated in healthy volunteers treated with carvedilol IR Sundberg et al The antihypertensive efficacy of carvedilol has been reported in patients with hypertension and comorbid conditions, such as diabetes, which make hypertension more difficult to treat Bakris et al ; Wright et al It should be noted that patients enrolled in this study were already receiving a stable regimen of antihypertensive therapy with an angiotensin-converting enzyme ACE inhibitor or an angiotensin-receptor blocker.

Additionally, based on the results of trials conducted with carvedilol IR, carvedilol CR may provide an equivalent extent of efficacy in more difficult to treat patients such as those patients with hypertension and diabetes.

Along the cardiovascular continuum, heart failure is a natural progression of uncontrolled hypertension.

A recently completed trial in patients with heart failure compared the effects of carvedilol CR with those of carvedilol IR. The primary efficacy endpoint was the change from baseline in left ventricular end-systolic volume index at 6 months. Secondary endpoints included change from baseline in left ventricular remodeling and serum B-type natriuretic peptide, hospitalization for heart failure and all other causes, death from all causes, compliance, and safety and tolerability of carvedilol CR.

Full results are not yet published. The beneficial effects of carvedilol IR have been demonstrated along the spectrum of severity from mild to severe heart failure Frishman Carvedilol IR increased left ventricular ejection fraction from baseline by 5.

The US Carvedilol Heart Failure Study Group enrolled patients with mild to severe heart failure in a double-blind, stratified program, assigning patients to 1 of 4 treatment protocols on the basis of their exercise capacity Packer et al The mortality and hospitalization data from these 4 trials were analyzed together and considered together by the Data and Safety Monitoring Board for the trial. Patients were randomized to receive carvedilol IR from 6. Compared with placebo, carvedilol IR significantly reduced mortality rates 3.

The program was stopped early based on the significant improvements in survival with carvedilol IR compared with placebo. This finding is notable as the patients were only followed for an average of 6. It should be noted that metoprolol tartrate at 50 mg twice daily has not been shown in clinical trials to provide a mortality benefit. However, of note in the metoprolol succinate heart failure trial MERIT-HF , the mean daily dose was mg daily, which is equivalent to mg daily of metoprolol tartrate Poole-Wilson et al Lancet , — These findings are of note because attenuation of exercise-induced heart rate is used as a surrogate for the extent of beta 1-adrenergic blockade and possibly to evaluate dosing equivalency.

Many reasons may contribute to the results of these trials, including nonequivalent doses or different formulations or durations of treatment. The only clinical data available in this patient population is with carvedilol IR.

The mean follow-up duration was 1. However, there was no significant difference between groups in the composite endpoint of all-cause mortality or cardiovascular hospital admission. The authors speculate that the influence on ventricular remodeling may be a substantial contributing factor to the clinical efficacy observed in patients with post-MI LVD.

Reductions with carvedilol IR versus placebo were observed in mortality, fatal or nonfatal MI; the composite endpoint of death, nonfatal MI, or cardiac arrest; and the composite endpoint of all-cause mortality or nonfatal MI Fonarow et al This compares favorably with data from the atenolol Beta-Blocker Heart Attack Trial BHAT showing that 80 patients would need treatment for 1 year to prevent 1 death Otterstad et al In contrast, the Norwegian Timolol Trial reported that 25 patients needed treatment for 1 year to prevent 1 death Otterstad et al The clinical utility of traditional beta-blockers has been limited by concerns regarding negative effects on glucose and lipid metabolism Bakris et al a ; Bangalore et al b and a high incidence of side effects, including fatigue, erectile dysfunction, and weight gain Bangalore et al b.

Unlike traditional beta-blockers, the alpha 1-blocking vasodilatory activity with carvedilol does not interfere with glucose and lipid metabolism discussed previously and has a positive influence on its tolerability profile. Carvedilol CR is generally well tolerated across its therapeutic indications Henderson et al ; Packer et al ; Weber et al a.

Adverse events reported in clinical trials were consistent with the mechanism of action of carvedilol and the health status of the patient population under evaluation. Moreover, headache, orthostatic hypotension, diarrhea, and dizziness occurred more frequently with carvedilol IR than with carvedilol CR Table 1 Henderson et al Therefore, it is likely that other effects of carvedilol compared with metoprolol are important for the treatment of heart failure.

Further research is necessary to clarify whether beta-2 inhibition, alpha-1 inhibition, antioxidative properties of, inhibition of endothelin-1biosynthesis, or yet another effect is beneficial Table 1. The possible effect of the adrenoreceptors in the progression of heart failure. Beta-blockers in heart failure: are pharmacological differences clinically important?

Heart Fail Rev, — As for the clinical consequence at this time what remains is a continuing debate. National Center for Biotechnology Information , U. Vasc Health Risk Manag. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC. Abstract Beta-blockers have been shown to improve survival in patients with chronic heart failure. Keywords: beta-blockers, chronic heart failure, carvedilol.

Introduction Heart failure is a growing problem with an increasing number of affected people and with an increasing burden on society Greenberg Beta-blocker treatment in heart failure Beta-blockers have been shown to be of clinical benefit in patients with chronic heart failure Greenberg Open in a separate window.

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