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Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy
Petra Nijst, Pieter Martens, Jeroen Dauw, W.H. Wilson Tang, Philippe B. Bertrand, Joris Penders, Liesbeth Bruckers, Gabor Voros, Rik Willems, Pieter M. Vandervoort, Matthias Dupont and Wilfried Mullens
Summary By: Adriana C. Mares - Founder & President, The Institute of Cardiology at El Paso
Overall Study Question:
Is the withdrawal of neurohumoral blockade therapy (ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade) appropriate in patients with heart failure (HF) but with recovered left ventricular (LV) ejection fraction (HFrecEF) after implantation of cardiac resynchronization therapy (CRT)?
Background:
Millions of people worldwide suffer from congestive heart failure (CHF), a serious and common problem that is often due to weak pumping of the heart muscle (4). Knowing that neurohormonal activation induces development and progression of CHF, a solid base of clinical and scientific evidence now supports the inhibition of neurohormonal activation for CHF therapy (5). Specifically, according to the CONSENSUS trial and SOLVD study group, angiotensin-converting enzyme (ACE) inhibitors are known to reduce neurohormonal activation which can significantly reduce morbidity and mortality in severe CHF (6,7) and moderate CHF (8-11), respectively. On the other hand, patients often aren’t recipients of these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers) (5).
Study Summary:
This open label randomized control multicenter pilot trial, after inclusion, involved 80 patients with HF, left bundle branch block (LBBB), normalized ejection fraction (EF) and dimensions after implantation of cardiac resynchronization therapy (CRT). Patients were followed for two years and were randomized to four groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular (LV) end-systolic volume index of more than 15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure–caused hospitalizations, and incidence of sustained left ventricular arrhythmias at 24 months. As a result, of the 80 subjects, 6 (7.5%) met the primary endpoint and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 (28 %) subjects because of hypertension or supraventricular arrhythmias. Overall, these low incidence values of the primary and secondary endpoints could possibly indicate that heart failure could have been more related to an abnormal electrical activity than a myocardial problem (1, 2). Thus, neurohumoral blocker withdrawal should be avoided unless there are specific reasons that discontinuation would limit benefit relative to risk for a particular patient (1-3).
My insights:
It is important to note that in the study’s editorial comment by Drs. Lynne Warner Stevenson and Allen J. Naftilan read by Dr. Valentin Fuster mentioned, “this approach tell us very little on left ventricular function and structure, so today is more appropriate to discuss the four different stages of HF: A, B, C, and D”. In my view, despite literature citing the benefits of neurohumoral blockade therapy for CHF therapy, this study reported interestingly low incidences of primary and secondary endpoints in the four randomized groups. Perhaps in this study, HF was associated with an electrical problem independently from recovered left ventricular (LV) ejection fraction (HFrecEF) and withdrawal of medication known to cause disease relapse.
Back to other Article Summaries
Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy
Petra Nijst, Pieter Martens, Jeroen Dauw, W.H. Wilson Tang, Philippe B. Bertrand, Joris Penders, Liesbeth Bruckers, Gabor Voros, Rik Willems, Pieter M. Vandervoort, Matthias Dupont and Wilfried Mullens
Summary By: Adriana C. Mares - Founder & President, The Institute of Cardiology at El Paso
Overall Study Question:
Is the withdrawal of neurohumoral blockade therapy (ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade) appropriate in patients with heart failure (HF) but with recovered left ventricular (LV) ejection fraction (HFrecEF) after implantation of cardiac resynchronization therapy (CRT)?
Background:
Millions of people worldwide suffer from congestive heart failure (CHF), a serious and common problem that is often due to weak pumping of the heart muscle (4). Knowing that neurohormonal activation induces development and progression of CHF, a solid base of clinical and scientific evidence now supports the inhibition of neurohormonal activation for CHF therapy (5). Specifically, according to the CONSENSUS trial and SOLVD study group, angiotensin-converting enzyme (ACE) inhibitors are known to reduce neurohormonal activation which can significantly reduce morbidity and mortality in severe CHF (6,7) and moderate CHF (8-11), respectively. On the other hand, patients often aren’t recipients of these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers) (5).
Study Summary:
This open label randomized control multicenter pilot trial, after inclusion, involved 80 patients with HF, left bundle branch block (LBBB), normalized ejection fraction (EF) and dimensions after implantation of cardiac resynchronization therapy (CRT). Patients were followed for two years and were randomized to four groups (continuation of neurohumoral blocker therapy, n = 20; withdrawal of renin-angiotensin-aldosterone system inhibitors, n = 20; withdrawal of beta-blockers, n = 20; and withdrawal of renin-angiotensin-aldosterone system inhibitors and beta-blockers, n = 20). The primary endpoint was a recurrence of negative remodeling, defined as an increase in left ventricular (LV) end-systolic volume index of more than 15% at 24 months. The secondary endpoint was a composite safety endpoint of all-cause mortality, heart failure–caused hospitalizations, and incidence of sustained left ventricular arrhythmias at 24 months. As a result, of the 80 subjects, 6 (7.5%) met the primary endpoint and 4 (5%) the secondary endpoint. However, re-initiation of neurohumoral blockers occurred in 17 (28 %) subjects because of hypertension or supraventricular arrhythmias. Overall, these low incidence values of the primary and secondary endpoints could possibly indicate that heart failure could have been more related to an abnormal electrical activity than a myocardial problem (1, 2). Thus, neurohumoral blocker withdrawal should be avoided unless there are specific reasons that discontinuation would limit benefit relative to risk for a particular patient (1-3).
My insights:
It is important to note that in the study’s editorial comment by Drs. Lynne Warner Stevenson and Allen J. Naftilan read by Dr. Valentin Fuster mentioned, “this approach tell us very little on left ventricular function and structure, so today is more appropriate to discuss the four different stages of HF: A, B, C, and D”. In my view, despite literature citing the benefits of neurohumoral blockade therapy for CHF therapy, this study reported interestingly low incidences of primary and secondary endpoints in the four randomized groups. Perhaps in this study, HF was associated with an electrical problem independently from recovered left ventricular (LV) ejection fraction (HFrecEF) and withdrawal of medication known to cause disease relapse.
Back to other Article Summaries
References
1. Mukherjee DP. Withdrawal of Neurohumoral Blockade After CRT. American College of Cardiology. https://www.acc.org/latest-in-cardiology/journal-scans/2020/03/23/15/50/withdrawal-of-neurohumoral-blockade. Published March 23, 2020. Accessed March 25, 2020.
2. Fuster V. Apple Podcasts Preview. Apple Podcasts Preview. March 2020. https://podcasts.apple.com/us/podcast/withdrawal-neurohormonal-blockade-after-cardiac-resynchronization/id932118437?i=1000469265119.
3. Nijst P, Martens P, Dauw J, et al. Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy. Journal of the American College of Cardiology. 2020;75(12):1426-1438. doi:10.1016/j.jacc.2020.01.040.
4. Inamdar AA, Inamdar AC. Heart Failure: Diagnosis, Management and Utilization. J Clin Med. 2016;5(7):62. Published 2016 Jun 29. doi:10.3390/jcm5070062
5. Willenbrock R, Philipp S, Mitrovic V, Dietz R. Neurohumoral Blockade in CHF Management. Journal of the Renin-Angiotensin-Aldosterone System. 2000;1(1_suppl):24-30. doi:10.3317/jraas.2000.030.
6. The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).N Engl J Med 1987;316:1429-35.
7. Rucinska EJ. Enalapril in the treatment of congestive heart failure: effects on signs, symptoms and mortality. Acta Cardiol 1991;46:231-46.
8. Greenberg B, Quinones MA, Koilpillai C et al., for the SOLVD Investigators. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD Echocardiography Substudy. Circulation 1995;91:2573-81.
9. Konstam MA, Rousseau MF, Kronenberg MW et al., for the SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation 1992;86:431-8.
10. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med 1991;325:293-302.
11. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.
1. Mukherjee DP. Withdrawal of Neurohumoral Blockade After CRT. American College of Cardiology. https://www.acc.org/latest-in-cardiology/journal-scans/2020/03/23/15/50/withdrawal-of-neurohumoral-blockade. Published March 23, 2020. Accessed March 25, 2020.
2. Fuster V. Apple Podcasts Preview. Apple Podcasts Preview. March 2020. https://podcasts.apple.com/us/podcast/withdrawal-neurohormonal-blockade-after-cardiac-resynchronization/id932118437?i=1000469265119.
3. Nijst P, Martens P, Dauw J, et al. Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy. Journal of the American College of Cardiology. 2020;75(12):1426-1438. doi:10.1016/j.jacc.2020.01.040.
4. Inamdar AA, Inamdar AC. Heart Failure: Diagnosis, Management and Utilization. J Clin Med. 2016;5(7):62. Published 2016 Jun 29. doi:10.3390/jcm5070062
5. Willenbrock R, Philipp S, Mitrovic V, Dietz R. Neurohumoral Blockade in CHF Management. Journal of the Renin-Angiotensin-Aldosterone System. 2000;1(1_suppl):24-30. doi:10.3317/jraas.2000.030.
6. The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).N Engl J Med 1987;316:1429-35.
7. Rucinska EJ. Enalapril in the treatment of congestive heart failure: effects on signs, symptoms and mortality. Acta Cardiol 1991;46:231-46.
8. Greenberg B, Quinones MA, Koilpillai C et al., for the SOLVD Investigators. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD Echocardiography Substudy. Circulation 1995;91:2573-81.
9. Konstam MA, Rousseau MF, Kronenberg MW et al., for the SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation 1992;86:431-8.
10. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med 1991;325:293-302.
11. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-91.