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Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure

Background: Angiotensin-converting enzyme inhibitors (ACEI) and beta-blockers (BB) have been found beneficial for heart failure patients. There is some evidence that sympathetic activation precedes the activation of the renin-angiotensin system in heart failure. The majority of heart failure patients are stabilized on an ACEI and then put on a BB; however the impact of which medication to initiate first has not been determined.

Objective: The purpose of this study was to evaluate the therapeutic value of initiating a beta-blocker before an ACEI in the treatment of heart failure.

Methods: This was a single-center, prospective, randomized, open label study. It was a one-year study that included 78 patients from one center in South Africa. Newly diagnosed heart failure patients were enrolled if they were between the ages of 18 and 70, they had a New York Heart Association Functional Class (NYHA FC) of 2 or 3, a left ventricular ejection fraction (LVEF) of less than 40 when measured by radionuclide ventriculography and had sinus rhythm. Patients were excluded on the basis of having COPD, significant valvular heart disease, history or evidence of ischemic heart disease, SBP greater than 160 mmHg or DBP >95 mmHg. Digoxin 0.25 mg daily was given throughout the study along with furosemide at varying doses. Newly diagnosed heart failure patients were given digoxin and furosemide for one week prior to initiation of the study medications. After that one week the patients were randomized to either receive a beta-blocker (carvedilol; n=38) or an ACEI (perindopril; n=40) for 6 months. During this 6 months the dosage would be adjusted to the highest tolerable dose, which was defined as having a SBP greater than 85 mmHg, no dizziness, and no orthostatic hypotension. After the 6 months, the opposite medication was added to their current regimen and titrated up. Patients came in for check-ups monthly and were evaluated for compliance and clinical assessment. The primary outcome of LVEF and secondary outcomes of NYHA FC, BP, HR, and plasma NT-pro BNP concentration were measured at baseline and at 6 and 12 months. The study had an 80 percent power and followed a per protocol approach.

Results: A total of fifty-seven patients completed this study. A total of twenty-one patients having dropped out due to either death or a lack of follow-up. Eleven of the dropouts were from the perindopril treatment group compared to ten from the carvedilol group. The LVEF endpoint showed an improvement 6 and 12 months (p<0.001)in the group that started the carvedilol first compared to baseline. The only statistically significant difference for the perindopril group was at 12 months (p<0.05). Heart rate was reduced at 6 months (p<0.05) and at 12 months (p<0.005) in the carvedilol first group but only reduced at 12 months for the perindopril first group (p<0.05). Systolic blood pressure actually increased at 6 months and 12 months (p<0.05) for the carvedilol first group and remained unchanged in the perindopril group. The plasma NT-pro BNP concentration was markedly reduced at 6 and 12 months (p<0.0005) in the patients started on carvedilol compared to only a trend towards reduction at 12 months for the patients started on perindopril. The LV end systolic diameter (LVESD) decreased at 6 and 12 months in the carvedilol first group (p<0.05) with a trend for decrease of the LV end diastolic diameter (LVEDD). The perindopril group only saw a trend towards decrease in the LVESD and LVEDD but it was not statistically significant. Adverse events were not studied in this study except for when determining the dosing adjustments of the medications. The authors conclude from this study that initiation of carvedilol before perindopril allowed a higher maximum dose of the carvedilol to be achieved. They also discussed how it had better improvement of the NYHA FC and more marked changes in LV systolic and diastolic function. This allows them to suggest a possible alternative therapy option for newly diagnosed heart failure patients even though they mention a need for larger studies that also look at mortality data.

Strengths: Strengths of this study include the use of pertinent medications for heart failure. Another strength was that the study length was adequate to see results. All of the measurements were taken by the same person, allowing for less variability between the tests. The study also included a discussion about the weaknesses.

Weaknesses: This study did not enroll a large number of patients. A larger study group could have allowed the observers see a more discernable difference in outcomes between the groups. This study also was open-labeled instead of blinded which could have influenced the investigators and the results. Confidence intervals were not included in the analysis to see how the results would translate into the population of patients with similar characteristics. Patient demographic information was not given besides the inclusion criteria. Dosing was not clearly defined to see how adjustments were made and on what basis. The concurrent use of digoxin in this study is also not recognized as initial treatment for heart failure patients and dosing was not adjusted for this medication throughout the study. Mortality data was also not evaluated in this study.

Conclusion: This study showed some increased benefit with starting therapy with a beta-blocker compared to an ACE inhibitor; however; a larger trial needs to be undertaken to look at mortality data as well as the efficacy in a controlled environment. The higher dose of tolerated carvedilol that was found in this study may lead clinicians to start using a beta-blocker before the ACEI once these results are verified from a large, controlled study.

Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-converting enzyme therapy on cardiac function in newly diagnosed heart failure. Journal of the American College of Cardiology. 2004; 44(9), 1825-30.

Doug Donovall, Pharm.D. Candidate