All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- Title: Metoprolol CR/XL in the Treatment of Chronic Heart Failure Author: Wendy A. Gattis, Pharm.D. Source: Pharmacotherapy 21(5):604-613, 2001 Toprol-XL is different than standard metoprolol in ways that are important to heart failure patients. The MERIT-HF trial studied Toprol-XL. It showed lower all-cause mortality in Toprol-XL patients. Toprol-XL is selective, meaning it 'prefers' beta 1 receptors. The drug comes in 4 strengths : 25, 50, 100, and 200 mg. The 100mg tablet is made of hundreds of individually coated metoprolol pellets, each of which is actually a separate delivery system. Fluid penetrates the membrane of each pellet and dissolves the drug. The drug is released at a constant rate over a 20 hour period, giving consistent blood levels over the once a day dosing period. Unlike most pills, the proper dose is delivered over 24 hours even when the scored tablet is divided, as long as the half tablet is swallowed whole and not chewed. Toprol-XL is more consistent at targeting beta 1 receptors, while metoprolol affects more beta 2 receptors. The slow-release property keep drug level more constant. Peak blood level is lower and the time to reach it is longer. Toprol-XL and metoprolol are NOT bioequivalent and should not be considered interchangeable. Differences may or may not be significant in any given person and should be evaluated patient by patient. Metoprolol is absorbed mainly through the small intestine and colon, not through the stomach. About 10% of patients will have problems metabolizing the drug, causing a higher drug level in their blood. Patients who have side effects such as slow heart rate, difficulty breathing, or low blood pressure even on low doses of Toprol-XL, may be in this patient group. Such patients may require quickly lowering the starting dose. Especially in patients with coronary artery disease, the consistency of drug level with Toprol-XL is a big plus over metoprolol. MERIT-HF MERIT-HF included 3,991 class 2 to class 4 heart failure patients. Patients were already taking diuretics and ACE inhibitors, with or without digoxin. 1,990 patients took Toprol-XL and 2,001 took placebo. Starting dose was 25mg once a day for class 2 patients and 12.5mg once a day for class 3 to class 4 patients. Target dose was 200mg once a day. 65% of MERIT-HF patients had ischemic heart failure and 96% were class 2 or class 3. Average age was 64 years, 77% were men, and 25% had diabetes. Average dose of Toprol-XL achieved at the end of the study was 159mg once a day. This trial was stopped early because all-cause patient mortality was greatly reduced. Toprol-XL patients had a 34% risk reduction for all-cause mortality. Heart-related mortality was reduced 38%, sudden death by 41%, and heart failure death by 49%. The drug reduced mortality in patients regardless of heart class. The drug was safe and well tolerated. About 14% of Toprol-XL patients stopped the drug for some reason versus 15% of placebo patients. More placebo patients (12%) than Toprol-XL patients (10%) stopped the drug because of adverse effects, which included CHF, a-fib, angina, dizziness, slow heart rate, and low blood pressure. Based on the results of MERIT-HF and other trials, the Heart Failure Society of America, ACC, and AHA recommend the following for patients with class 2 or class 3 heart failure : 1) take a beta-blocker if clinically stable with systolic heart failure and taking ACE inhibitors, diuretics, and digoxin, whether or not you have CHF symptoms 2) Begin beta-blockers at low dose and raise dose slowly, no sooner than 2-week intervals. Patient should be evaluated before each dose raise. If symptoms get worse, other meds may have to be adjusted, or beta-blocker dose reduced. In some cases, beta-blocker may need to be stopped SPECIAL PATIENT GROUPS - ASTHMA, COPD, DIABETES, ELDERLY These patients may require more monitoring after starting a beta-blocker to avoid worsening their other diseases. People with heart failure who also have COPD or diabetes usually CAN take a beta-blocker. In MERIT-HF, diabetics showed no signs of extra risk from beta-blocker use. They got about the same benefit in mortality as other CHFers. Toprol-XL was well tolerated by these patients. In COPD patients, a beta-blocker selective for the beta 1 receptor is probably best. Toprol-XL is such a drug, while Coreg is not. However, people with true asthma may not be able to tolerate a beta-blocker. Heart failure patients with COPD not requiring beta agonist therapy and who do not show worsening lung function should try a beta-blocker. As with diabetes, the mere presence of COPD is not an absolute contraindication to beta-blocker use. Beta-blockers should be used cautiously and with close monitoring to detect wheezing or worsening COPD. It is known that at higher doses, selective beta-blockers get less selective, so high doses may not be possible. Toprol-XL should be used instead of metoprolol in COPD patients to avoid high peak blood levels. TOLERABILITY Adverse events that may be associated with beta-blockers include low blood pressure, fluid retention, worsening heart failure, slow heart rate, and heart block. Non-selective beta-blockers like Coreg and bucindolol are more likely to cause low blood pressure than selective beta-blockers like Toprol-XL and bisoprolol. This is because non-selective beta-blockers also relax arteries, making blood flow more easily. Thus may be a very good thing in patients without low blood pressure to start with. However, in patients with low blood pressure to start with, Toprol-XL may be a better choice. Regardless of drug choice, low blood pressure problems can often be managed by avoiding too much diuretic and by not taking all heart meds together at one time. Staggering meds stops peak drug levels from happening all at once. Because trough to peak differences with Toprol-XL are very low, some adverse effects may be greatly reduced with this drug. We don't know if the elderly CHF patient gets extra benefit from Toprol-XL over other beta-blockers. CONCLUSIONS As noted, Toprol-XL was well tolerated by patients in the MERIT-HF trial. Class 3 to class 4 CHFers went from 12.5mg to 200mg once a day. Class 2 CHFers went from 25mg to 200mg once a day, as tolerated. The average dose reached was 159mg once a day. 64% reached the target dose of 200mg. Roughly the same number of patients stopped taking placebo as stopped taking Toprol-XL due to adverse effects. Less than 1 in 100 patients receiving Toprol-XL for a year withdrew because of slow heart rate, low blood pressure, or dizziness. Treating heart failure patients with any beta-blocker requires very low starting doses, and raising dose slowly. In a patient with worsening symptoms or other ill effects after beginning a beta-blocker, it may be necessary to adjust the dose of other meds or postpone dose increases. In patients with dizziness, consider the possibility of too much diuretic. Adjusting diuretics to the lowest working dose can greatly improve dizziness. SUMMARY Beta-blockers are important therapy for heart failure and should be given to all patients with mild to moderate CHF who are otherwise without contra-indications. Patients should be taking ACE inhibitors and diuretics as needed before beginning a beta-blocker. The beta-blocker must be started at low doses and raised slowly to the highest dose the patient can tolerate. Toprol-XL offers convenient once a day dosing. Toprol-XL is different in many ways from regular metoprolol. Its formulation, action, and adverse effects are different. The Toprol-XL drug is more effective than metoprolol for maintaining smooth, uniform drug blood levels and heart rate. Toprol-XL is the only metoprolol formula that has been properly studied through well-designed clinical trials in heart failure patients. Successful beta-blocker treatment in heart failure patients requires education of doctors and nurses, pharmacists, patients, and caregivers. Comparison of metoprolol to Toprol-XL ---------------------------------------------------------- Parameter metoprolol Toprol-XL 100mg 100mg Absorption 95% 95% Systemic bioavailability 50% 30 to 35% Excretion through liver Liver Liver Peak blood level 786 nmol/L 168 nmol/L Time to peak blood level 1 to 2 hours 3 to 7 hours Length of action 8 to 12 hours 24 hours ----------------------------------------------------------- Mortality Trials of Beta-Blockers in CHF Patients ----------------------------------------------------------- Trial Comparators Mortality Relative Risk Reduction US Carvedilol Coreg (696) 3.2% 65% Placebo (398) 7.8% MERIT-HF Toprol-XL 7.2% 34% (1,990) Placebo 11% (2,001) CIBIS II Bisoprolol 11.8% 34% (1,327) Placebo 17.3% (1,320) BEST Bucindolol 30.2% Placebo 33% COPERNICUS Coreg 11.4% 35% (1,156) Placebo 18.5% (1,133) ----------------------------------------------------------- MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure Title: Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure Authors: MERIT-HFStudy Group Source: Lancet 1999;353:2001-7 Title: Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the metoprolol CR/XL randomized intervention trial in congestive heart failure Authors: Hjalmarson A, Goldstein S, Fagerberg B, et al Source: JAMA 2000;283: 1295-1302 See: http://www.chfpatients.com/coreg.htm ------------------------------------------------------------ CIBIS II = second Cardiac Insufficiency Bisoprolol Study BEST = Beta-Blocker Evaluation of Survival Trial COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival trial. See: http://www.chfpatients.com/beta_overview.htm ----------------------------------------------------------- This report was funded by a grant from AstraZeneca - the manufacturer of Toprol-XL and metoprolol