Switching to Once-Daily Evidence-Based β-Blockers in Patients With Systolic Heart Failure or Left Ventricular Dysfunction After Myocardial Infarction

Reducing dosing frequency for patients with heart failure simplifies the medication plan and may improve adherence to prescribed medications. The author discusses the practical considerations of the use of evidence-based β-blockers.Polypharmacy, the use of multiple medications resulting in complex drug regimens, is increasing among patients with heart failure.1 Ideally, at discharge from the hospital, each patient should be prescribed evidence-based medications (ie, medications that published evidence indicates are effective for the patient’s condition). The list of such medications is becoming long. According to the National Heart Care Project for 2000–2001, the mean numbers of heart failure medications and doses per day were 7.5 and 11.1, respectively.2 National guidelines rarely address the problem of polypharmacy for high-risk patients, and they do not consider patients’ adherence, the risk of adverse effects, or pharmacoeconomic considerations. Patients who have had a myocardial infarction, especially those who have concomitant heart failure, are prescribed an equal, if not higher, number of medications than are patients with just heart failure.3Perhaps the easiest way to improve clinical and health outcomes is to improve adherence to the drug treatment plan by simplifying the medication regimen4 (Figure 1). Among patients with heart failure and other cardiovascular conditions, such as hypertension, changing regimens from doses taken 2 or 3 times a day to a dose taken once a day increased adherence.5–8 In a large meta-analysis,4 increased treatment adherence improved health outcomes, including survival, readmission rates, blood pressure, cholesterol level, and hemoglobin A1c level. Fewer pills per day may be particularly beneficial for patients after myocardial infarction or for patients with heart failure.9Medication adherence was previously thought to be in the domain of the patient, but a recent shift in philosophy advocates forming a partnership between healthcare provider and patient, who enter into a contractual agreement to support self-care by the patient once the patient is discharged from the hospital.10 This approach has been evaluated in several studies,11–16 which showed successful health outcomes in patients who were better educated about drug regimens in nurse-directed intervention programs. By using education and communication facilitated by a heart failure or a cardiac nurse and reducing the numbers of pills required by choosing once-daily regimens over twice-daily or more frequent treatments, adherence to therapy can be improved. Cardiac nurses, especially advanced practice nurses, are well positioned to discuss drug adherence issues with patients and determine whether a once-daily agent would increase patients’ ability to take heart failure medications as prescribed.In this article, I discuss the practical considerations of the use of evidence-based β-blockers. Specifically, I propose changing from twice-daily to once-daily β-blockers and changing from commonly used non–evidence-based agents to evidence-based, once-daily β-blockers in patients with heart failure and patients with left ventricular systolic dysfunction (LVSD) after myocardial infarction. In patients with chronic systolic heart failure and LVSD and heart failure after myocardial infarction, β-blockade is considered a key pharmaceutical therapy.17,18 Simplifying the β-blocker regimen with once-daily dosing offers an opportunity to improve patients’ outcomes by boosting the probability of adherence to treatment. Availability of once-daily formulations of evidence-based β-blockers should prompt nurses to consider a new treatment model to help overcome the barrier to adherence created by high dosing frequency.Simplifying a patient’s medical regimen by reducing dosing frequency to once a day is likely to be associated with improved adherence to therapy, greater satisfaction among patients, and possibly more favorable outcomes. In a recent study,19 researchers compared patients’ compliance (measured electronically) and treatment effectiveness in patients with stable angina pectoris treated with oral nitrates administered once daily versus twice daily. Patients receiving once-daily therapy had significantly greater overall medication adherence than did patients receiving twice-daily therapy (88.9% vs 73.8%; P<.001), a higher percentage of days with the correct number of doses taken (85.5% vs 59.5%; P<.001), and a greater reduction in mean number of episodes of weekly chest pain (94% less vs 30% less; P<.001).19Many researchers20–27 have studied the effects of daily doses on drug adherence in both observational studies and randomized clinical trials. Simply put, once-daily agents were taken more regularly than were twice-daily agents,20–27 supporting better adherence to drug regimens; however, whether the use of once-daily β-blockers improves adherence has not yet been assessed in a clinical trial.Specific to β-blocker therapy, improved adherence has been associated with improved outcomes in 2 studies.28,29 In patients with heart failure, lower adherence to metoprolol tartrate was associated with a higher rate of emergency room visits (P<.001) and hospital admissions (P<.001).28 After surviving a myocardial infarction, patients in the Beta Blocker Heart Attack Trial who took 75% or less of prescribed β-blockers were 2.6 times more likely to die in the first year of follow-up than were patients who were adherent to therapy.29The American College of Cardiology/American Heart Association management guidelines include recommendations that long-term therapy with β-blockers be started and continued indefinitely in all survivors of acute myocardial infarction who do not have absolute contraindications17 and in patients with mild to severe heart failure.18 β-Blockers significantly reduced mortality in patients with heart failure and acute myocardial infarction in several large-scale randomized clinical trials17,30–35 and in a national registry of patients hospitalized for acute decompensated heart failure.36Only carvedilol and metoprolol succinate are approved in the United States for the treatment of heart failure (Table 1).18 Carvedilol (both formulations, see following) is the only β-blocker approved by the US Food and Drug Administration for patients with LVSD after myocardial infarction; approval was based on mortality benefits of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRI-CORN) trial.35 Carvedilol is also the only β-blocker approved for use in patients with severe advanced, chronic heart failure.37A once-daily controlled-release formulation of carvedilol (carvedilol phosphate extended-release, or carvedilol CR) was approved by the Food and Drug Administration with the same indications as the original twice-daily formulation of carvedilol: mild to severe heart failure, LVSD after myocardial infarction with or without signs and symptoms of heart failure, and hypertension.38 An ongoing trial of adherence to once-daily carvedilol CR versus twice-daily carvedilol will provide more information about adherence to β-blocker use in patients with heart failure.39The 2 formulations of carvedilol (twice-daily dosing with the original formulation and once-daily dosing with carvedilol CR) have equivalent steady-state pharmacokinetic characteristics and pharmacodynamic properties.40,41 The pharmacokinetic profile of the 2 formulations was compared in patients with mild to severe heart failure and in patients with asymptomatic LVSD after myocardial infarction.42 The mean steady-state concentration-time profile of the β-blocking enantiomer, S(−)-carvedilol, was equivalent between the 2 formulations in a crossover pharmacokinetic study of 188 patients with mild to severe heart failure or asymptomatic LVSD after myocardial infarction, reflecting no discernible difference between carvedilol and carvedilol CR.42 Additionally, medication adherence was better in the carvedilol CR group (93% vs 85%); however, this open-label clinical trial did not have sufficient power to allow statistical evaluation of differences in adherence between the groups.42Less-frequent dosing regimens combined with a favorable tolerability profile result in better medication-taking behavior.20,43,44 Surveys45–47 have repeatedly indicated that the occurrence of adverse effects is an important predictor of nonadherence by patients. The original twice-daily carvedilol formulation had a favorable tolerability profile; common adverse effects reported by patients with heart failure that were deemed likely to be related to the drug were dizziness, fatigue, hypotension, and bradycardia.48Data from the US Carvedilol Heart Failure trial33 and the Carvedilol Prospective Randomized Cumulative Survival study34 revealed that fewer patients receiving carvedilol than patients receiving placebo discontinued therapy because of adverse events. In elderly patients with heart failure who were receiving carvedilol, overall tolerability at 6 months was between 77% and 84%.49 In a study of carvedilol CR in patients with LVSD, the once-daily formulation had similar tolerability to the twice-daily carvedilol formulation,40 indicating equivalence in safety when patients are switched from twice-daily carvedilol to once-daily carvedilol CR.Switching patients from twice-daily carvedilol to once-daily carvedilol CR is straightforward; the once-daily doses of 10, 20, 40, and 80 mg of carvedilol CR are equivalent to the 4 twice-daily dose levels of carvedilol, respectively (Table 2).40 Patients currently taking twice-daily carvedilol should start the equivalent dose of carvedilol CR the following morning after their last evening dose of carvedilol.Carvedilol may be preferable to metoprolol succinate in some clinical situations. Carvedilol has neutral metabolic effects in patients with hypertension for example, it causes no increases in insulin resistance or level of hemoglobin A1c, a property not shared by β1-specific blocking agents, including metoprolol succinate.50–52 In single-center studies, carvedilol had no negative metabolic effects in patients after a myocardial infarction, whereas insulin resistance was increased in similar patients receiving metoprolol tartrate.53 Carvedilol may also be warranted in heart failure patients with diabetes because of its neutral metabolic profile, which was shown in hypertensive patients.51In a substudy54 of adverse events from the Carvedilol or Metoprolol European Trial, more events related to new onset of diabetes (diabetic coma, peripheral gangrene [diabetic foot], decreased glucose tolerance, hyperglycemia) occurred in patients with heart failure who were taking metoprolol tartrate than in patients taking carvedilol (13.0% vs 10.6%; hazard ratio = 0.78; 95% confidence interval [CI], 0.61–0.99; P=.04).54 Additionally, patients with LVSD after myocardial infarction should be preferentially switched to carvedilol CR, because other β-blockers are not indicated in such patients.Some clinical situations may warrant choosing metoprolol succinate over carvedilol. Patients with reactive airway disease could have an exacerbation of their underlying disease by the β2-receptor–blocking property of carvedilol.48 Because of its relative β1-selectivity, metoprolol succinate can be used with caution in patients with bronchospastic disease. However, because β1-selectivity is not absolute, a β2-stimulating agent should be administered concomitantly and the lowest possible dose of metoprolol succinate should be used.55Dosing requirement is an important factor in medication nonadherence and may adversely affect elderly patients. Reductions in mortality have been observed for patients with heart failure who were consistently treated with low doses of carvedilol (6.25 twice daily),30 yet a similar mortality benefit was observed only in patients who had their doses of metoprolol succinate adjusted to a higher equivalent.31 Thus, when the dose of metoprolol succinate cannot be titrated up to the level of target doses used in large, randomized, controlled trials, switching from metoprolol succinate to carvedilol may be beneficial, especially in elderly patients.Switching from a non–evidence-based β-blocker to an evidence-based agent was safe in the Carvedilol or Metoprolol European Trial.56 The recommended starting dose was half the equivalent of the last study medication dose; for example, if the current metoprolol dose was 100 mg/day (50 mg twice daily), then the starting dose of carvedilol would be the equivalent of 50 mg/day metoprolol (6.25 mg twice daily). Among patients taking carvedilol who were switched to metoprolol tartrate, 9.4% experienced a serious adverse event (discontinuation of therapy due to dizziness, bradycardia, headache, or presyncope), and 4.7% experienced worsening heart failure (worsening New York Heart Association functional class).In patients switched from metoprolol tartrate to carvedilol, 3.1% experienced a serious adverse event, and 1.5% experienced worsening heart failure.56 In a single-center study57 of 30 patients with baseline mean left ventricular ejection fractions of 29%, compared with patients maintained on metoprolol therapy, patients who switched treatment from metoprolol to carvedilol had an improvement in left ventricular ejection fraction (+7%, standard error of the mean [SEM] ±3% vs −1%, SEM ±2%; P=.04). In a comparison58 of the effects of metoprolol tartrate and carvedilol in 150 patients, patients receiving carvedilol had a significantly greater improvement in ejection fraction after 12 months of treatment (carvedilol: from 20.4% [SEM ±7.6%] to 31.2% [SEM ±11.9%] vs metoprolol: 21.6% [SEM ±7.2%] to 28.8.2% [SEM ±11.3%], P=.03).Ultimately, nurses with prescriptive privileges should consider switching patients with heart failure from a non–evidenced-based β-blocker (eg, atenolol or metoprolol tartrate) to an evidence-based agent (carvedilol, carvedilol CR, metoprolol succinate, or bisoprolol). Cardiac nurses without prescriptive privileges are key team members in ensuring implementation of processes that optimize ordering and administration of drug therapy and should ensure that patients are on an evidence-based β-blocker therapy before discharge from the hospital.Table 3 shows a strategy for switching patients with heart failure from 2 common non–evidence-based β-blockers to carvedilol CR, metoprolol succinate, or bisoprolol, once-daily agents.56,59–61 The strategy is based on suggestions from previous publications as well as the dose equivalency observed in the carvedilol and carvedilol CR profiles.40–42 Figure 2 shows a strategy for switching from non–evidence-based β-blockers to carvedilol CR in patients with LVSD after myocardial infarction.62The suggested equivalent dose conversions from a non–evidence-based β-blocker to the original twice-daily carvedilol formulation in patients with heart failure and LVSD after myocardial infarction were used as the starting point in Figure 2 and Table 3.59,62 The dose equivalencies used were derived from clinical experience59,62 and the degree of β1-blockade (heart rate lowering) and blood pressure lowering that can be expected with each dose.Failure Patients with heart failure who are currently being treated with a non–evidence-based agent such as metoprolol tartrate or atenolol should be switched to metoprolol succinate, carvedilol CR, or bisoprolol. When patients with hypertension are treated with β-blockers such as atenolol or metoprolol tartrate and then LVSD or heart failure develops, the patients’ treatment should be switched to a β-blocker that has proved effective in reducing poor outcomes in heart failure (Table 3). When β-blockers are being switched, especially to a nonselective agent with α-blocking effects, patients should be started at a low dose to ensure tolerance. Once the β-blocker has been tolerated for 2 weeks, the dose can be titrated up to the maximal dose as tolerated over time by doubling the dose stepwise every 2 weeks.63 Although a change from one β-blocker to another is generally safe and well tolerated, monitoring for adverse effects should be routine whenever medications are switched.The switch to a once-daily evidence-based β-blocker can be done 12 hours after the last dose of a twice-daily agent by beginning the first dose of the new agent the next morning after the last dose of the old agent was taken the previous evening. Likewise, treatment with a once-daily evidence-based β-blocker can be started 24 hours after a once-daily non–evidence-based agent is discontinued. In patients at high risk for precipitating or worsening ischemia, an option rather than direct switching is maintaining full β1-blockade and gradually increasing β1-mediated vasodilatation in a stepwise fashion by overlapping decreasing doses of metoprolol tartrate or atenolol with increasing doses of carvedilol every 2 weeks. It is crucial not to add agents with vasodilatory properties, such as calcium antagonists, nitrates, or other antihypertensives, directly before carvedilol. The details on how to switch β-blockers with this overlapping protocol were developed by W. T. Abraham.59If switching to another β-blocker is being considered because of a lack of clinical response, the patient’s condition should first be stabilized by modulating his or her diuretic or angiotensin-converting enzyme inhibitor. Switching β-blockers as a form of rescue therapy while a patient’s clinical condition is deteriorating is not recommended. For patients experiencing severe decompensation of heart failure, destabilization of clinical condition, marked hypotension, or continuing requirements for intravenous inotropes or diuretics, switching β-blockers is not recommended.59 On the other hand, a switch in β-blocker might be considered in patients whose disease is either not improving or is progressing despite treatment with another β-blocking agent (Table 4). Before a switch in β-blocker therapy, all other medication dosing should be stable (steady state), and patients should be free of volume overload.Treatment of patients with LVSD after myocardial infarction should start with carvedilol CR, because it is the only once-daily β-blocker indicated in this setting. Before the CAPRICORN trial, which specifically enrolled patients with LVSD after myocardial infarction, large-scale trials65–67 provided evidence that atenolol, metoprolol tartrate, and timolol were beneficial in patients without overt heart failure or uncontrolled cardiac failure after myocardial infarction; therefore, nurses may encounter patients receiving these agents who should be switched to an evidence-based agent. In patients with acute myocardial infarction without evidence of intravenous administration of metoprolol tartrate or atenolol should be started then patients should be switched to oral carvedilol CR because the oral of metoprolol tartrate or atenolol have not been studied in patients with LVSD after myocardial infarction. After treatment with carvedilol CR is of the dose should be every 3 to days the target dose is severe or up to the recommended a lower dose can be from non–evidence-based oral agents to carvedilol CR is shown in Figure In patients with LVSD after myocardial infarction and recent heart failure, carvedilol CR may be started at mg rather than mg and titrated to the dose In hospitalized patients with LVSD after myocardial infarction, twice-daily carvedilol may be because of its and can be the in ensuring that patients are switched to a once-daily dose formulation before discharge to increase the probability of better adherence to the medication switch of β-blocking agents, nurses should each patient’s and medication and may be Additionally, before a patient is discharged from the hospital, nurses should provide about signs and symptoms of worsening heart failure and should the patient’s of or has been may increase of an adverse event before the event serious or and advanced practice nurses are with the of hospitalized patients with heart failure and LVSD after myocardial infarction. the use of therapy recommended in guidelines and nurses can improve patients’ clinical outcomes and improved of however, of on patients’ overall in to once-daily vs twice-daily dosing of drug are not In the Carvedilol or Metoprolol European Trial, of was associated with New York Heart Association functional but not with the patient’s or or with the β-blocker once-daily β-blocker therapy a large change in dose regularly functional possibly could improve to a greater improving include patients and treatment with and doses of and following a plan of to adherence to drug and and for patients. agents to mortality and improve functional are patients are more likely to have fewer emergency room visits and greater satisfaction with and improved of of patients’ treatment is by and also by the level of of nurse who are the of evidence-based practice and are for ongoing and communication with other members of the healthcare For example, may be to a switch in β-blocker treatment because switching monitoring and of the a may a patient the patient is being treated with a β-blocker but not the related to starting treatment with that Thus, if patients more or develops, they may the drug is not for and taking between the evidence that used in heart failure and patients who have had a myocardial infarction and practice in patient Because multiple have shown that the of is not yet and studies have shown that patients’ adherence to is practice improvement clinical and are to the of a team of healthcare nurses can use clinical and study to processes that of patients’ and effective a randomized controlled clinical of patients with heart failure, ejection fraction of or and no to use of were to of 3 education education on the use of β-blockers in heart failure, including and of and with guidelines for β-blocker and of the provider and patient were when they a patient’s for the first 2 visits after and patients were that they might be for β-blocker therapy and that they should discuss this treatment with their and use of a nurse nurse by 2 for treatment with the and a patient’s clinical condition in patients with heart the of patients who started treatment with β-blockers or had the dose titrated and were maintained on was in of of patients in the nurse group compared with of of patients in the group and of of patients in the education group for the between the nurse group and both other The of patients receiving target doses of β-blockers at the of the study follow-up 12 was also higher in the nurse group than in the education group and the group The frequency of adverse events did not among nurses are well to in and for in therapy when in the just advanced practice nurses with privileges can treatment with an evidence-based β-blocker in indicated patients. The switching provided can be in nurses improve to in cardiovascular disease is to worsening disease and to medication adherence are including complex medication regimens, adverse effects, and poor education of patients. can increase the use of by treatment at discharge and using once-daily agents that will result in regimens in may improve patients’ adherence and to better outcomes. After a patient’s current medical and and his or her ability to to nurses may that switching β-blockers is management have shown that nurses can patients’ outcomes by patients about medication of once-daily formulations of β-blocker with favorable tolerability may adherence to therapy with evidence-based once-daily β-blocker are for treatment of patients with heart carvedilol CR, metoprolol succinate, and bisoprolol. Carvedilol CR is also indicated for the treatment of patients with LVSD after myocardial infarction. formulations can use of evidence-based β-blocker therapy that nurses in and ensuring patients’