Author + information
- Received February 25, 1999
- Revision received July 9, 1999
- Accepted September 21, 1999
- Published online January 1, 2000.
- Marrick L Kukin, MD, FACCa,* (, )
- Michael M Mannino, MD, FACCa,
- Ronald S Freudenberger, MD, FACCa,
- Jill Kalman, MDa,
- Cathleen Buchholz-Varley, NPa and
- Ofelia Ocampo, NPa
- ↵*Reprint requests and correspondence: Marrick Kukin, Cardiovascular Institute, Department of Medicine, Box 1030, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029
To compare the hemodynamic effects of twice daily metoprolol tartrate (MT) and once daily metoprolol succinate (MS) in congestive heart failure patients.
Adverse hemodynamic effects with MT demonstrated during initiation persist with drug readministration during chronic therapy.
Patients were randomly assigned to 6.25 mg MT or 25 mg MS orally and the dose was gradually increased to a target of 50 mg twice a day or 100 mg once a day, respectively. Hemodynamic measurements were obtained at baseline and after three months of therapy—both before and after drug readministration.
Long term metoprolol therapy produced significant functional, exercise and hemodynamic benefits with no difference in response between either metoprolol preparation in the 27 patients (MT , MS ). When full dose metoprolol was readministered during chronic therapy, there were parallel adverse hemodynamic effects in both drug groups. Cardiac index decreased by 0.6 liters/min/m2(p < 0.0001) with MT and by 0.5 liters/min/m2(p < 0.0001) with MS. Systematic vascular resistance increased by 253 dyne-sec-cm−5(p < 0.001) with MT and by 267 dyne-sec-cm−5(p < 0.0005) with MS. Stroke volume index decreased by 7.0 ml/m2(p < 0.0005) with MT and by 6.5 ml/m2(p < 0.0001) with MS, while SWI decreased by 6.2 g-m/m2(p < 0.0005) with MT and by 6.0 g-m/m2(p < 0.001) with MS.
Metoprolol tartrate and MS produce similar hemodynamic and clinical effects acutely and chronically despite the fourfold greater starting dose of MS used in this study. A more rapid initiation with readily available starting doses of MS may offer distinct advantages compared with MT in treating chronic heart failure patients with beta-adrenergic blocking agents.
Mortality benefits with both beta-1 selective and beta nonselective adrenergic blockers in congestive heart failure have now been shown in three recent survival trials (1–3). However, despite these impressive mortality results, the use of beta-adrenergic blocking agents to treat heart failure requires careful medical management. Initiation of therapy with low dose beta-blockers can cause adverse hemodynamic effects by decreasing cardiac output and increasing systemic vascular resistance. These adverse hemodynamic effects generally do not cause significant clinical deterioration but may require dose adjustments of concomitant medications. Gradual up-titration of any beta-blocker is achieved over several weeks (with adjustments of diuretics and angiotensin-converting enzyme inhibitors as clinically indicated) to achieve eventual target doses.
We have previously shown that the acute adverse hemodynamic effects with initial low dose metoprolol tartrate (MT) therapy persist in patients with heart failure during long term treatment when “full” target doses are readministered (4). Metoprolol succinate (MS), the drug that was used in Metoprolol Randomized Intervention Trial (MERIT-HF) (3), is a longer acting formulation of metoprolol that is dosed once daily (q.d.). We hypothesized that the adverse hemodynamic effects seen with MT may have been due to variations in peak and trough drug levels with a twice a day (b.i.d.) dosed drug and that a longer acting formulation would have less variation of drug levels and consequently not demonstrate any hemodynamic compromise with subsequent dosing.
Therefore, the objective of this study was to compare the acute and chronic hemodynamic response of MT with that of MS in patients with chronic heart failure being initiated on beta-blocker therapy. Additionally, we studied the safety of a more rapid initiation and dose up-titration with MS compared with the conventional dosing and up-titration of MT.
Eligible patients had chronic heart failure with symptoms of persistent dyspnea or fatigue at rest or on exertion (New York Heart Association [NYHA] class II to IV) despite intensive therapy with digoxin, diuretics and a converting enzyme inhibitor. All patients were enrolled while clinically stable without evidence of peripheral edema, having not received IV diuretics for at least two weeks before baseline evaluation. Patients were excluded from the study if they had experienced an acute myocardial infarction within six weeks, an acute exacerbation of heart failure within two weeks, history of obstructive lung disease, claudication, a systolic blood pressure less then 85 mm Hg or a resting heart rate less than 64 beats/min. The study was approved by the institutional review board and patients signed informed consent prior to enrollment into the study.
Following this stabilization period, each patient’s clinical status was assessed by a review of symptoms and by determination of the NYHA functional class. Each patient underwent a 6-min walk test to assess submaximal exercise endurance (5)and bicycle ergometry with gas exchange to assess peak maximal oxygen consumption (6). A right heart catheterization was performed for measurement of intracardiac pressures via an internal jugular approach using local anesthetic and fluoroscopic guidance with a triple lumen flow directed thermodilution catheter.
The next morning baseline hemodynamic measurements were determined in the fasting state (7). Complete details of the hemodynamics protocol have been published previously (4). In brief, three complete sets of hemodynamic measurements [right atrial, pulmonary artery and pulmonary capillary wedge pressures (PCW)] with four determinations of thermodilution cardiac output with iced injectate were obtained 5 to 10 min apart for baseline values. A baseline left ventricular filling pressure of ≥14 mm Hg was required for continuation in the study. All cardiac medications (digoxin, diuretics and angiotensin converting enzyme inhibitor) were held either for 12 hours (for three times a day or b.i.d. medications) or 24 h (for q.d. medications) before the hemodynamic evaluations for that day except for the test drug (metoprolol) as indicated. Blood was collected from the indwelling catheter side port for the measurement of plasma norepinephrine after the patients had rested in the supine position for at least 30 min.
Patients were randomly assigned to receive open-label MT or MS. The initial dose of MT was 6.25 mg and the initial dose of MS was 25 mg. Hemodynamic measurements were then repeated 2 hours after the initial dose of assigned metoprolol. Patients were discharged home on their assigned medication: either MT 6.25 mg po b.i.d. (Lopressor: Novartis, East Hanover, New Jersey; recompounded by hospital research pharmacist for doses through 12.5 b.i.d.; subsequent doses given via prescription) or 25 mg MS (Toprol XL: Astra Zeneca, Wayne, Pennsylvania). Patients were seen once a week for the subsequent 4 week period. Metoprolol tartrate was increased to 12.5 po b.i.d., 25 mg po b.i.d. and 50 mg po b.i.d. sequentially each week if the prior dose was clinically tolerated. Metoprolol tartrate was increased to 50 mg q.d. and then 100 mg q.d. each week. The target dose of MT was 50 mg b.i.d. and MS was 100 mg q.d., but for patients weighing more than 85 kg, the target was doubled. A fallback dose of 25 mg b.i.d. of MT and 50 mg of MS was allowed based on patient response. Thus, by protocol design the time to reach target dose with MS was one half that of MT. If there were significant signs or symptoms of bradycardia, orthostasis or worsening congestive heart failure, the metoprolol dose was held constant or reduced and reevaluated for increase the following visit. Diuretics were adjusted when there was evidence of fluid retention.
After three months of continuous therapy, all clinical and exercise assessments were repeated. A repeat right heart catheterization was performed for measurement of intracardiac pressures in an identical manner to the initial hemodynamic evaluation. The following morning, long term baseline hemodynamic measurements were determined in the fasting state prior to the metoprolol dose (trough). Blood was again collected from the indwelling catheter for the measurement of plasma norepinephrine after the patients had rested in the supine position for at least 30 min. After the next scheduled full dose of MT or MS was given, hemodynamic variables were redetermined 2 h later. All other cardiac medications were held until the completion of hemodynamic readings for that day.
A two-way repeated measures analysis of variance was used to assess the significance of the between group differences of the completers for each hemodynamic parameter with respect to changes from baseline to the following three time points: 1) 2 h after the first dose, 2) long term trough, and 3) long term peak. For clinical responses, a paired ttest was used with respect to changes from baseline.
Following these overall tests, within group hemodynamics were compared for MT and MS, respectively, using the Student ttest for paired data. Group data are expressed as means ± SD. All hemodynamic parameters measuring peak effect of drug are reported as the readings from 2 h after the drug was given (to avoid a bias in evaluating drug effect). Two hours was chosen as a pharmacologic approximation of full absorbance of MT. A p value of ≤0.05 was considered significant.
Twenty-seven patients entered the study. Four patients were NYHA class II, 19 were class III and 4 were class IV. All patients had a left ventricular ejection fraction less than 25% as assessed by radionuclide ventriculography, ranging from 6% to 18% with a mean of 11%. There were 24 men and 3 women with a mean age of 50 (range 29 to 72). The cause of heart failure was ischemic heart disease in 8 patients, primary cardiomyopathy in 18 patients and valvular cardiomyopathy in one. There were 15 whites, 6 blacks and 6 hispanic patients, equally divided between drug groups.
Of the 27 patients, 26 were on ACEI as background therapy—captopril (9), enalapril (12) or lisinopril (5), equally divided between MT and MS. Converting to enalapril equivalence doses, both groups were taking an average daily dose of 16 mg. Of the 27 patients, 26 were taking furosemide and one was taking bumetanide. By furosemide equivalents, the mean dose for the MT patients was 133 mg and for the MS patients was 108 mg with no between group difference. Additionally, six patients were taking supplemental metolazone (four in the MT group, two in the MS group). All patients were taking digoxin with an equal mean dose of 0.22 mg.
Fourteen patients were randomly assigned to MT and 13 patients were randomly assigned to MS. The groups were evenly matched at baseline following randomization (Table 1). Twenty-four patients (89%) completed the protocol and the long term hemodynamic evaluation. One patient did not tolerate low dose MT and withdrew from the study. One patient died suddenly on MT 25 mg b.i.d. One MS patient returned to his home in St. Lucia and did not complete the repeat hemodynamic evaluation. Eleven completers reached the target dose of MT 50 mg po b.i.d.; two patients (one of whom died) received 25 mg po b.i.d. due to intolerance at the higher dose. All 13 patients assigned to MS reached target dose (11 patients at 100 mg and for two patients the target was 200 mg based on weight).
Overall, long term therapy with metoprolol was associated with significant functional and exercise improvements in those patients who completed the protocol. New York Heart Association class improved by one functional class (chi-square p < 0.0001) with no between group differences. Metoprolol tartrate patients who completed the study improved their NYHA class from 0/2/8/2 to 3/6/3/0, while MS patients who completed the study improved from 0/1/10/1 to 0/9/3/0. Measurements of both submaximal and maximal exercise capacity showed improvements. Distance on the 6 min walk increased from 1,117 ± 299 to 1,237 ± 367 feet with MT and from 927 ± 221 to 1,212 ± 301 feet with MS with no between group difference. Similarly maximal oxygen consumption increased from 12.8 ± 3.5 to 14.9 ± 4.9 ml/kg/min with MT and from 11.3 ± 3.7 to 14.4 ± 4.5 ml/kg/min with no between group difference.
Ejection fraction increased from 11.5% ± 3.6% to 17.0% ± 5.7% with MT and from 10.4% ± 2.8% to 14.1% ± 4.1% with MS, with no between group difference. Measurements of norepinephrine levels showed parallel declines: 539 ± 172 to 455 ± 295 pg/ml with MT and 607 ± 223 to 484 ± 233 pg/ml with MS, p = NS between groups.
For all hemodynamic variables, there were statistically significant time effects (p < 0.005) with no overall separate drug effects (p > 0.2). There was no interaction (p > 0.5) between groups. The changes within drug groups was consistent over time for the two treatments.
The acute adverse hemodynamic effects of 6.25 mg MT were similar to those seen with 25 mg of MS despite the fourfold difference in dose. Cardiac index (CI) decreased by 0.2 l/min/m2(p < 0.001) with MT and by 0.3 l/min/m2(p < 0.01) with MS. Systemic vascular resistance (SVR) increased by 176 dyn-sec-cm(−5)(p < 0.0025) with MT and by 128 dyn-sec-cm(−5)(p < 0.05) with MS. Consequently, stroke volume index (SVI) declined by 2.8 ml/m2(p < 0.0025) with MT and by 3.0 ml/m2(p < 0.025) with MS. Furthermore, stroke work index (SWI) acutely decreased by 1.4 g-m/m2(p < 0.025) with MT and by 2.7 g-m/m2(p < 0.025) with MS.
Continuous therapy with metoprolol demonstrated significant long term parallel hemodynamic benefits when measured before the next scheduled dose of metoprolol (trough) in addition to the clinical benefits described above. For those completing the study, resting heart rate decreased from 93 ± 11.2 to 73 ± 13.7 (p < 0.005) beats/min with MT and a similar 93 ± 15.8 to 73 ± 16.9 (p < 0.001) beats/min with MS. Pulmonary capillary wedge pressure (PCW) decreased from 29.1 ± 5.5 to 22.5 ± 9.8 mm Hg (p = NS) with MT and from 28.8 ± 8.0 to 22.3 ± 6.8 mm Hg (p < 0.05) with MS. Cardiac index increased from 2.1 ± 0.4 to 2.7 ± 0.5 liters/min/m2(p < 0.01) with MT and from 2.4 ± 0.6 to 2.7 ± 0.6 liters/min/m2(p = NS) with MS. Systematic vascular resistance decreased from 1,287 ± 297 to 1,002 ± 246 dyne-sec-cm−5(p < 0.05) with MT and from 1,300 ± 468 to 1,083 ± 257 dyne-sec-cm−5(p = NS) with MS. Importantly, SVI increased from 23.2 ± 5.8 to 39.0 ± 12.8 ml/m2(p < 0.005) with MT and from 27.0 ± 10.8 to 37.9 ± 9.6 ml/m2(p < 0.0005) with MS. Stroke work index increased from 16.3 ± 5.8 to 30.5 ± 13.7 g-m/m2(p < 0.01) with MT and from 21.0 ± 8.4 to 30.3 ± 9.4 g-m/m2(p < 0.0001) with MS.
In order to determine the subsequent hemodynamic effects of full dose metoprolol after three months of continuous therapy, measurements were compared between long term baseline and 2 h after the next scheduled full dose of metoprolol. The p values represent the differences between long term baseline and long term peak within group. When the next full dose of metoprolol was administered, CI decreased by 0.6 liters/min/m2(p < 0.0001) with MT and by 0.5 liters/min/m2(p < 0.0001) with MS. This occurred while SVR increased by 253 dyne-sec-cm−5(p < 0.001) with MT and by 267 dyne-sec-cm−5(p < 0.0005) with MS. Furthermore, SVI decreased by 7.0 ml/m2(p < 0.0005) with MT and by 6.5 ml/m2(p < 0.0001) with MS. Finally, SWI decreased by 6.2 g-m/m2(p < 0.0005) with MT and by 6.0 g-m/m2(p < 0.001) with MS.
The changes with PCW, SVR, SVI and SWI are shown graphically for four time points (baseline, 2 h after first dose, long term trough after three months of metoprolol therapy and 2 hours after drug readministration) in Figure 1for the 24 patients who completed the protocol.
Despite the known adverse acute hemodynamic effects of beta-blockade, there is compelling evidence that chronic beta-blockade provides long term hemodynamic, symptomatic, exercise (8–16)and survival benefits (1–3)in patients with congestive heart failure. Due to the negative hemodynamic effects of beta-blockers in heart failure, therapy is initiated with minute doses of beta-blockers and only gradually increased over the course of several weeks.
In this study, patients treated with the shorter acting MT or the longer acting MS exhibited significant parallel long term hemodynamic improvements before the next dose of drug (trough period) following a minimum of 3 months of therapy. As was seen with MT previously (4), each subsequent full dose of either metoprolol preparation, upon readministration, produced significant similar declines in CI, SVI and SWI, with an increase in SVR.
A probable mechanism of this phenomenon of adverse hemodynamics with beta-blockers is a disruption of the delicate balance between the negative hemodynamic (presumably as a negative inotrope) properties of metoprolol due to adrenergic withdrawal and the beneficial effects of blocking norepinephrine (thereby chronically improving left ventricular function). Even after three months of continuous metoprolol therapy, the negative hemodynamic effects are still measurable with the next dose (peak), albeit with an overall net of hemodynamic and clinical benefit of chronic metoprolol therapy.
The persistent adverse hemodynamic effects of MT did not differ when compared with the longer acting MS. Although we do not have drug levels to correlate with hemodynamics, the adverse hemodynamics are temporally related to drug readministration. It is important to note that the chronic adverse hemodynamic effects with subsequent dosing are not associated with any clinical deterioration. In fact, over the long term, patients demonstrate substantial clinical and hemodynamic benefits. Of perhaps even greater significance, in this study, we were able to demonstrate the safety of a more rapid initiation with a dose of 25 mg and a subsequent uptitration of MS over a two to three week period compared with the conventional initiation of the cumbersome 6.25 mg MT (which requires recompounding) and gradual uptitration of MT over a four to six week time frame. This schedule of MS would allow for a faster initiation and easier uptitration of metoprolol in clinical practice if safety is demonstrated in a larger trial. The MS dosing utilized here was more rapid than that used in MERIT-HF (3). We increased the dosing weekly, and our target was 100 mg q.d. rather than the dosing schedule in MERIT of doubling every other week to a target of 200 mg q.d. Additionally, all of our patients started at 25 mg q.d., whereas in MERIT, only NYHA II patients started at 25 mg; NYHA III patients were started at 12.5 mg.
We did not measure inotropy of the ventricle; our results are based on hemodynamic indexes that reflect loading conditions as well as contractility. This is an open label study. This may bias the subjective clinical results to show overall improvement but probably does not affect the more objective hemodynamic results.
This study reconfirms the beneficial hemodynamic, clinical and exercise benefits of beta-blocker therapy in a moderate to severely symptomatic heart failure population. Parallel results were seen with MT and MS. Most importantly, we have demonstrated that initiation of therapy with MS can be achieved more rapidly yet with the same safety profile as that with MT. Ease of administration may allow for wider use of beta-blocker therapy in clinical practice which is essential given the newly demonstrated mortality benefits and the recently revised heart failure clinical guidelines promulgating beta-blocker use in heart failure (17).
We thank Marilyn Steinmetz, MA for conducting the exercise portion of this study and we thank Sylvan Wallenstein, PhD, of the Department of Biomathematical Sciences for invaluable assistance in the statistical design and analysis.
- twice a day
- cardiac index
- Metoprocol Randomized Intervention Trial
- metoprolol succinate
- metoprolol tartrate
- New York Heart Association
- pulmonary capillary wedge pressure
- every day
- stroke volume index
- systemic vascular resistance
- stroke work index
- Received February 25, 1999.
- Revision received July 9, 1999.
- Accepted September 21, 1999.
- American College of Cardiology
- Kukin M.L.,
- Kalman J.,
- Mannino M.M.,
- Buchholz C.,
- Ocampo O.
- Guyatt G.H.,
- Sullivan M.J.,
- Thompson P.J.,
- et al.
- Packer M.,
- Medina N.,
- Yushak M.
- Waagstein F.,
- Hjalmarson A.,
- Varnauskas E.,
- Wallen I.
- Krum H.,
- Sackner-Bernstein J.D.,
- Goldsmith R.L.,
- et al.
- Englemeier R.S.,
- O’Connell J.B.,
- Walsh R.,
- Rad N.,
- Scanlon P.J.,
- Gunnar R.M.
- Anderson B.,
- Blomstrom-Lundqvist C.,
- Hedner T.,
- Waagstein F.
- Currie P.J.,
- Kelly M.J.,
- McKenzie A.,
- et al.
- Metra M.,
- Nardi M.,
- Giubbini R.,
- Dei Cas L.
- ↵Packer M, Cohn JN, on behalf of the steering committee and membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure. Consensus recommendations for the management of heart failure. Am J Cardiol 1999;83 Suppl 2A:17A–22A.