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01.09.2000 | Adis Drug Evaluation
Metoprolol
A Review of its Use in Chronic Heart Failure
Erschienen in: Drugs | Ausgabe 3/2000
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Abstract
Metoprolol, a relatively selective β1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. The drug has an established role in the management of essential hypertension and angina pectoris, and more recently, in patients with chronic heart failure.
The effects of metoprolol controlled-release/extended-release (CR/XL) in patients with stable, predominantly mild to moderate (NYHA functional class II to III) chronic heart failure have been evaluated in the large Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial and the much smaller Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Treatment with metoprolol CR/XL was initiated at a low dosage of 12.5 to 25mg once daily and gradually increased at 2-weekly intervals until the target dosage (200mg once daily) or maximal tolerated dosage had been attained in patients receiving standard therapy for heart failure.
At 12 months, metoprolol CR/XL was associated with a 34% reduction in relative risk of all-cause mortality in patients with chronic heart failure due to ischaemic or dilated cardiomyopathy in the MERIT-HF trial. The incidence of sudden death and death due to progressive heart failure were both significantly decreased with metoprolol CR/XL. Similarly, a trend towards decreased mortality in the metoprolol CR/XL group compared with placebo was observed in the RESOLVD trial. Data from small numbers of patients with severe (NYHA functional class IV) heart failure indicate that metoprolol CR/XL is effective in this subset of patients. However, no firm conclusions can yet be drawn. Improvement from baseline values in NYHA functional class, exercise capacity and some measures of quality of life with metoprolol CR/XL or immediate-release metoprolol were significantly greater than those with placebo.
The drug is well tolerated when treatment is initiated in low dosages and gradually increased at intervals of 1 to 2 weeks.
Conclusions: Metoprolol CR/XL effectively decreases mortality and improves clinical status in patients with stable mild to moderate (NYHA functional class II or III) chronic heart failure due to left ventricular systolic dysfunction, and the drug is effective in patients with ischaemic or dilated cardiomyopathy. Although limited data indicate that metoprolol CR/XL is effective in patients with severe (NYHA functional class IV) chronic heart failure, more data are needed to confirm these findings. Treatment with metoprolol CR/XL significantly reduced the incidence of sudden death and death due to progressive heart failure.
Pharmacodynamic Properfies
Metoprolol is a relatively selective β1-blocker which is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity.
Initiation of metoprolol treatment in patients with chronic heart failure may be associated with a decline in haemodynamic function in some patients but coadministration of a vasodilator has not been shown to provide any sustained benefit versus monotherapy with metoprolol. Treatment for ≥3 months with metoprolol 100 to 150 mg/day decreased heart rate and improved systolic function, as evidenced by increased left ventricular ejection fraction, increased stroke volume index and increased stroke work index, in patients with moderate to severe chronic heart failure receiving standard therapy. Despite the improvement in systolic function, the myocardial oxygen consumption at rest and during submaximal exercise either decreased or remained unchanged from pretreatment values after metoprolol, indicating that treatment with the drug increased myocardial efficiency. Improvement in systolic function with metoprolol was similar to that with captopril, celiprolol or carvedilol. Diastolic function, as assessed by peak filling rate, isovolumic relaxation, and myocardial and chamber stiffness, remained unchanged after treatment with metoprolol. Long term treatment (3 to 18 months) with metoprolol was associated with reduction in left ventricular mass and an improvement in left ventricular geometry.
Metoprolol controlled-release/extended-release (CR/XL) 200 mg/day improved haemodynamic parameters more than placebo. This formulation significantly reduced total episodes of nonsustained ventricular tachycardia, ventricular couplets and dispersion of the rate-corrected QT interval after 26 weeks in patients with chronic heart failure.
The haemodynamic effects with metoprolol CR/XL 100 to 200mg once daily were similar to those with immediate-release metoprolol 50mg twice or 3 times daily in clinically stable patients with mild to severe chronic heart failure.
Treatment with metoprolol, but not carvedilol, is reported to normalise cardiac β-adrenoceptor density in patients with chronic heart failure. Although 6 to 12 months’ treatment with metoprolol has been reported to normalise immune function (increases in total T cells, T-suppressor cells, natural killer cells, mitogen-stimulated lymphocyte proliferation and interleukin-2 receptor expression) in patients with chronic heart failure, it is unclear whether these effects are secondary to improved cardiac function.
Pharmacokinetic Properties
Immediate-release metoprolol incorporates the tartarate salt of the drug and is almost completely absorbed after oral administration. The drug has a bioavailability of 50% because of hepatic first pass metabolism. Because of its lipophilic nature and low plasma protein binding (12%), the drug has a large volume of distribution of 5.6 L/kg. Metoprolol is primarily metabolised by the hepatic cytochrome P4502D6 enzyme system and has an elimination half-life of 3 to 4 hours. Two metabolites, α-hydroxymetoprolol and O-demethylmetoprolol, are reported to contribute 5% of the β1-blocking activity of the parent drug. Age and renal dysfunction do not alter the pharmacokinetics of metoprolol. The pharmacokinetics of the drug are affected in a predictable manner in patients with hepatic cirrhosis (bioavailability and elimination half-life are increased and total body clearance is decreased) and in those with hyperthyroidism (decreased time to peak plasma concentration and decreased area under the plasma concentration-time curve).
Metoprolol CR/XL utilises the succinate salt of the drug which is less water soluble than the tartarate salt. Each metoprolol CR/XL tablet comprises individual spherical pellets of the active drug coated with a non-proteolytic polymeric membrane (mainly ethylcellulose) compressed together with tablet-forming excipients. A 100mg CR/XL tablet contains 95mg of metoprolol succinate and is considered to have equivalent activity to lOOmg metoprolol tartarate. After ingestion the tablet disintegrates into individual pellets, and each pellet acts as a diffusion cell releasing the drug at a relatively constant rate over a period of approximately 20 hours. Results from in vitro tests indicate that the release of the drug from the CR/XL formulation is unlikely to be affected by pH or peristalsis. Ingestion of metoprolol CR/XL with food led to a small increase in bioavailability (mean 5%) compared with ingestion in fasting state, but ingestion of immediaterelease metoprolol with food is reported to increase bioavailability by 40% compared with ingestion in the fasting state.
Because of a relatively constant rate of drug release, the CR/XL formulation provides more sustained and stable 24-hour plasma metoprolol concentrations compared with the immediate-release formulation. Peak plasma metoprolol concentrations after once daily metoprolol CR/XL 200 mg/day were similar to those after immediate-release metoprolol 50mg administered 3 times daily in patients with chronic heart failure, but the trough/peak plasma metoprolol concentration ratio was more favourable after metoprolol CR/XL than after immediate-release metoprolol.
Therapeutic Use
Immediate-Release Metoprolol: The effects of immediate-release metoprolol on clinical status [New York Heart Association (NYHA) functional class and exercise capacity] have been compared with those of celiprolol, carvedilol or placebo in randomised double-blind trials of 3 to 12 months duration conducted in relatively small numbers of patients (n = 10 to 194 per treatment group) with stable chronic heart failure. Patients included in these trials continued to receive standard therapy for heart failure (most commonly comprising digitalis, diuretics and angiotensin converting enzyme inhibitors).
Improvement in clinical status from pretreatment values after 3 to 12 months’ treatment was greater with immediate-release metoprolol 12.5 to 150 mg/day than with placebo and similar to that seen with celiprolol 200 mg/day or carvedilol 6.25 to 50 mg/day.
12 to 18 months’ treatment with immediate-release metoprolol significantly improved quality of life in patients with chronic heart failure. Improvements in quality-of-life indices such as physical activity, emotions, life satisfaction and total score, were significantly greater with immediate-release metoprolol than with placebo. The effects of immediate-release metoprolol on quality of life at 3 months were similar to those of carvedilol as assessed by a similar decrease from pretreatment values in the Minnesota Living with Heart Failure questionnaire total score (4.8 vs 13.1 and 8.1 vs 17.2, respectively).
Although limited data indicate that treatment with metoprolol improves the clinical status in patients with severe (NYHA class IV) chronic heart failure, these findings need to be assessed in greater numbers of patients.
14 months’ treatment with immediate-release metoprolol was associated with a 34% reduction in the relative risk of death or need for cardiac transplantation compared with placebo in the randomised, double-blind Metoprolol in Dilated Cardiomyopathy trial, and there was a trend towards better prognosis in immediate-release metoprolol recipients than in placebo recipients at 18 and 36 months after initial randomisation.
Metoprolol CR/XL: The Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial in 3991 patients is the largest trial reported so far to evaluate the effect of a β-blocker in patients with chronic heart failure. Although it was intended to last for 36 months, the trial was stopped after a mean duration of 12 months on the recommendations of the independent safety committee, because of the superiority of metoprolol CR/XL.
Improvement in NYHA functional class with metoprolol CR/XL 200mg once daily (target dose) was significantly greater than that with placebo after 12 months in the MERIT-HF trial. Whereas significantly greater improvement in quality of life with metoprolol CR/XL than with placebo was evident using the McMaster Overall Treatment Evaluation total score, the difference between the 2 groups was not significant on the Minnesota Living with Heart Failure questionnaire total score. Compared with baseline values, no change in the NYHA functional class and quality of life were observed after 24 weeks’ treatment with metoprolol CR/XL once daily in the much smaller Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study.
Treatment with metoprolol CR/XL slowed disease progression in patients with predominantly mild to moderate chronic heart failure of ischaemic or nonischaemic origin. Relative risk reductions in metoprolol CR/XL recipients compared with placebo recipients at trial end-point were as follows: 34% for total mortality, 38% for cardiovascular death, 41% for sudden death and 49% for death due to progressive heart failure. Disease severity at inclusion did not affect reduction in mortality with metoprolol CR/XL; however, only 3.6% of the randomised patients had severe (NYHA functional class IV) chronic heart failure in this trial. The effects of metoprolol on mortality need to be further assessed in this subset of patients.
Compared with placebo, treatment with metoprolol CR/XL was also associated with significant reductions in all combined end-points including total mortality or all cause hospitalisation, total mortality or hospitalisation due to worsening heart failure, death or heart transplantation; cardiac death or nonfatal acute myocardial infarction and total mortality or hospitalisation due to worsening heart failure or emergency department visit due to worsening heart failure. Finally, metoprolol CR/XL significantly reduced the number of patients that required hospitalisation, the total number of hospitalisations and the total number of days spent in the hospital compared with placebo.
Tolerability
Limited data from clinical trials in small numbers of patients indicate that oral metoprolol at dosages of up to 200 mg/day is well tolerated in selected patients with stable mild to moderate (NYHA functional class II to III) chronic heart failure. Most published data on metoprolol pertain to the use of the immediate-release formulation in patients with hypertension and the drug has been associated with the following adverse events: fatigue/weakness/lethargy/malaise (6.2%), dizziness/vertigo (3.8%), headache (3.6%), diarrhoea (2.6%), nausea/vomiting (2.4%), bradycardia (1.7%), depression (1.7%), insomnia (1.7%), pruritus/dermatitis (1.5%), visual disturbance (1.3%) and dyspnoea (1.3%).
In patients with chronic heart failure, treatment with immediate-release metoprolol was initiated at low dosages and recipients were closely monitored for the most common cardiovascular adverse events, such as bradycardia, hypotension, intensification of atrioventricular block, complete heart block and shortness of breath, during dose titration. The dosage of the drug was carefully titrated to minimise initial adverse haemodynamic events. The majority of patients (75 to 100%) receiving immediate-release metoprolol were able to tolerate the predetermined target dosage (100 to 200 mg/day) of the drug.
The total number of withdrawals from treatment was similar in the immediate-release metoprolol and placebo treatment groups in a 12-month randomised, double-blind trial (23 vs 31). Adverse events thought to be related to β-blockade led to treatment withdrawal in 1 immediate-release metoprolol and 3 placebo recipients. No trials have specifically addressed the tolerability of metoprolol in patients with chronic heart failure and data from highly selected patients in clinical trials can not necessarily be generalised to clinical practice.
Metoprolol CR/XL was well tolerated in patients with chronic heart failure and 64 and 81% of patients received the target dose of 200mg once daily in the MERIT-HF trial and RESOLVD pilot study, respectively. Cause-specific adverse events (experienced by >0.5% of patients) that led to withdrawal from treatment were not different between the metoprolol CR/XL and placebo treatment groups in the MERIT-HF trial. Withdrawals from treatment due to adverse events were similar between metoprolol CR/XL and placebo recipients (24 vs 22) in the RESOLVD pilot study.
Dosage and Administration
In 11 clinical trials, the dosage of immediate-release metoprolol was commonly initiated at 6.25 to 12.5 mg/day in divided doses and increased at weekly intervals to a target dosage range of 100 to 200mg in 2 daily doses. Metoprolol CR/XL was initiated at a dosage of 12.5 or 25mg once daily and increased at 2-weekly intervals up to a target dosage of 200mg once daily.
Clinical trials with metoprolol have restricted enrolments of patients to those with heart rate at rest ≥50 beats/min and systolic blood pressure ≥80mm Hg. However, metoprolol dosage was not increased or decreased if the following adverse events were observed with drug treatment: symptomatic bradycardia or heart rate at rest <50 beats/min, orthostasis or systolic blood pressure <80mm Hg or signs and symptoms suggestive of worsening chronic heart failure. If treatment with metoprolol has to be discontinued, it is advised to taper the dose gradually over a 2-week period to reduce the potential for worsening of cardiac symptoms.
The dose of metoprolol may have to be reduced in patients with hepatic impairment and the drug should be used with caution in patients with diabetes mellitus, thyrotoxicosis, bronchospastic disease and in those undergoing major surgery involving general anaesthesia.
The use of metoprolol is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure and in those with right ventricular failure secondary to pulmonary hypertension.