Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial
BackgroundChronic heart failure has high morbidity and mortality, with approximately half of the patients dying within 5 years of diagnosis. Recent additions to the armamentarium of anti–heart failure therapies include angiotensin receptor-neprilysin inhibitors (ARNIs) and so...
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JMIR Publications
2025-03-01
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| author | Sumanth Karamchand Tsungai Chipamaunga Poobalan Naidoo Kiolan Naidoo Virendra Rambiritch Kevin Ho Robert Chilton Kyle McMahon Rory Leisegang Hellmuth Weich Karim Hassan |
| author_facet | Sumanth Karamchand Tsungai Chipamaunga Poobalan Naidoo Kiolan Naidoo Virendra Rambiritch Kevin Ho Robert Chilton Kyle McMahon Rory Leisegang Hellmuth Weich Karim Hassan |
| author_sort | Sumanth Karamchand |
| collection | DOAJ |
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BackgroundChronic heart failure has high morbidity and mortality, with approximately half of the patients dying within 5 years of diagnosis. Recent additions to the armamentarium of anti–heart failure therapies include angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium/glucose cotransporter 2 inhibitors (SGLT2is). Both classes have demonstrated mortality and morbidity benefits. Although these new therapies have morbidity and mortality benefits, it is not known whether rapid initiation is beneficial when compared with the conventional, slower-stepped approach. Many clinicians have been taught that starting with low-dose therapies and gradually increasing the dose is a safe way of intensifying treatment regimens. Pharmacologically, it is rational to use a combination of drugs that target multiple pathological mechanisms, as there is potential synergism and better therapeutic outcomes. Theoretically, the quicker the right combinations are used, the more likely the beneficial effects will be experienced. However, rapid up-titration must be balanced with patient safety and tolerability.
ObjectiveThis study aims to determine if early addition of ARNIs, SGLT2is, β-blockers, and mineralocorticoid receptor antagonists (within 4 weeks), when compared with the same therapies initiated slower (within 6 months), will reduce all-cause mortality and hospitalizations for heart failure in patients with stable heart failure with reduced ejection fraction.
MethodsThis is a single-center, randomized controlled, double-arm, assessor-blinded, active control, and pragmatic clinical trial. Adults with stable heart failure with reduced ejection fraction and idiopathic dilated cardiomyopathy will be randomized to conventional sequencing (the control arm; over 6 months) of anti–heart failure therapies, and a second arm will receive rapid sequencing (over 4 weeks). Study participants will be followed for 5 years to assess the safety, efficacy, and tolerability of the 2 types of sequencing. Posttrial access and care will be provided to all study participants throughout their lifespan.
ResultsWe are currently in the process of obtaining ethical clearance and funding.
ConclusionsWe envisage that this study will help support evidence-based medicine and inform clinical practice guidelines on the optimal rate of sequencing of anti–heart failure therapies. A third placebo arm was considered, but costs would be too much and not providing study participants with therapies with known morbidity and mortality benefits may be unethical, in our opinion. Given the post–COVID-19 economic downturn and posttrial access to interventions, a major challenge will be acquiring funding for this study.
International Registered Report Identifier (IRRID)PRR1-10.2196/44027 |
| format | Article |
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| institution | OA Journals |
| issn | 1929-0748 |
| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-1b2f4f183fdb413aaa13a993b89955592025-08-20T01:57:35ZengJMIR PublicationsJMIR Research Protocols1929-07482025-03-0114e4402710.2196/44027Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled TrialSumanth Karamchandhttps://orcid.org/0000-0003-4435-6685Tsungai Chipamaungahttps://orcid.org/0000-0002-0986-3625Poobalan Naidoohttps://orcid.org/0000-0002-5950-1585Kiolan Naidoohttps://orcid.org/0000-0002-5435-8345Virendra Rambiritchhttps://orcid.org/0000-0002-3175-699XKevin Hohttps://orcid.org/0000-0003-2688-2606Robert Chiltonhttps://orcid.org/0000-0003-0195-5063Kyle McMahonhttps://orcid.org/0009-0003-0209-1479Rory Leiseganghttps://orcid.org/0000-0003-0810-4771Hellmuth Weichhttps://orcid.org/0000-0002-4283-0198Karim Hassanhttps://orcid.org/0000-0002-1141-9486 BackgroundChronic heart failure has high morbidity and mortality, with approximately half of the patients dying within 5 years of diagnosis. Recent additions to the armamentarium of anti–heart failure therapies include angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium/glucose cotransporter 2 inhibitors (SGLT2is). Both classes have demonstrated mortality and morbidity benefits. Although these new therapies have morbidity and mortality benefits, it is not known whether rapid initiation is beneficial when compared with the conventional, slower-stepped approach. Many clinicians have been taught that starting with low-dose therapies and gradually increasing the dose is a safe way of intensifying treatment regimens. Pharmacologically, it is rational to use a combination of drugs that target multiple pathological mechanisms, as there is potential synergism and better therapeutic outcomes. Theoretically, the quicker the right combinations are used, the more likely the beneficial effects will be experienced. However, rapid up-titration must be balanced with patient safety and tolerability. ObjectiveThis study aims to determine if early addition of ARNIs, SGLT2is, β-blockers, and mineralocorticoid receptor antagonists (within 4 weeks), when compared with the same therapies initiated slower (within 6 months), will reduce all-cause mortality and hospitalizations for heart failure in patients with stable heart failure with reduced ejection fraction. MethodsThis is a single-center, randomized controlled, double-arm, assessor-blinded, active control, and pragmatic clinical trial. Adults with stable heart failure with reduced ejection fraction and idiopathic dilated cardiomyopathy will be randomized to conventional sequencing (the control arm; over 6 months) of anti–heart failure therapies, and a second arm will receive rapid sequencing (over 4 weeks). Study participants will be followed for 5 years to assess the safety, efficacy, and tolerability of the 2 types of sequencing. Posttrial access and care will be provided to all study participants throughout their lifespan. ResultsWe are currently in the process of obtaining ethical clearance and funding. ConclusionsWe envisage that this study will help support evidence-based medicine and inform clinical practice guidelines on the optimal rate of sequencing of anti–heart failure therapies. A third placebo arm was considered, but costs would be too much and not providing study participants with therapies with known morbidity and mortality benefits may be unethical, in our opinion. Given the post–COVID-19 economic downturn and posttrial access to interventions, a major challenge will be acquiring funding for this study. International Registered Report Identifier (IRRID)PRR1-10.2196/44027https://www.researchprotocols.org/2025/1/e44027 |
| spellingShingle | Sumanth Karamchand Tsungai Chipamaunga Poobalan Naidoo Kiolan Naidoo Virendra Rambiritch Kevin Ho Robert Chilton Kyle McMahon Rory Leisegang Hellmuth Weich Karim Hassan Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial JMIR Research Protocols |
| title | Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial |
| title_full | Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial |
| title_fullStr | Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial |
| title_full_unstemmed | Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial |
| title_short | Novel Versus Conventional Sequencing of β-Blockers, Sodium/Glucose Cotransportor 2 Inhibitors, Angiotensin Receptor-Neprilysin Inhibitors, and Mineralocorticoid Receptor Antagonists in Stable Patients With Heart Failure With Reduced Ejection Fraction (NovCon Sequencing Study): Protocol for a Randomized Controlled Trial |
| title_sort | novel versus conventional sequencing of β blockers sodium glucose cotransportor 2 inhibitors angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists in stable patients with heart failure with reduced ejection fraction novcon sequencing study protocol for a randomized controlled trial |
| url | https://www.researchprotocols.org/2025/1/e44027 |
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