Dapagliflozin on Hypotensive Heart Failure Patients After Sacubitril/Valsartan Therapy

Study Overview
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Brief Summary
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The DAPA-HF trial demonstrated that dapagliflozin was able to reduce the risk of worsening heart failure events and cardiovascular death comparing to placebo in patients with reduced ejection fraction further to standard of care. However, hypotensive patients who generally have higher risks comparing to normotensive patients, were under represented in the DAPA-HF. The investigators aimed to evaluate clinical effects of dapagliflozin on hypotensive heart failure patients receiving chronic sacubitril/valsartan treatment.

Detailed Description
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The DAPA-HF trial demonstrated that dapagliflozin was able to reduce the risk of worsening heart failure (HF) events and cardiovascular death comparing to placebo in patients with reduced ejection fraction further to standard of care. However, hypotensive patients who generally have higher risks comparing to normotensive patients, were under represented in the DAPA-HF. The investigators aimed to evaluate clinical effects of dapagliflozin on hypotensive HFrEF patients receiving chronic sacubitril/valsartan (Sal/Val) treatment. This is an investigator-initiated, interventional, prospective. open-label study. The inclusion criteria were (1) chronic symptomatic HF with New York Heart Association (NYHA) class II-IV and LVEF less than 40%, (2) treatment with stable and maximal tolerable dose of Sac/Val, beta-blocker with or without mineralocorticoid receptor antagonist (MRA), (3) 6-minute walking-distance (6MWD)≥ 100meters and ≤425 meters at enrollment, (4) systolic blood pressure ≤100 mmHg at enrollment. The exclusion criteria were (1) type 1 diabetes mellitus, (2) patients previously treated with any sodium glucose co-transporter 2 inhibitor (SGLT2i). After applying the inclusion and exclusion criteria, if the participants had type 2 diabetes mellitus, the participants will receive dapagliflozin 10mg daily directly. If the participants did not have history of diabetes mellitus, the participants will be allocated to either receiving dapagliflozin 10mg daily or receiving standard heart failure treatment without dapagliflozin. Vital signs and laboratory tests were examined at baseline, 2-week, 4-week and 12-week. Six-minute-walking-test, five-level EuroQol five dimensions (EQ-5D-5L) questionnaire and visual analogue scale (VAS) were collected at baseline and at 12-week.

Official Title
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Effects of Dapagliflozin on Hypotensive Patients With Depressed Left Ventricular Ejection Fraction After Sacubitril/Valsartan Therapy

Conditions
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Hypotension, Heart Failure

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Sacubitril-Valsartan
* Drug: Beta blocker
* Drug: Mineralocorticoid Receptor Antagonist
* Device: Cardiac resynchronization therapy and/or implantable cardioverter defibrillator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: chronic symptomatic HF with New York Heart Association (NYHA) class II-IV and left ventricular ejection fraction (LVEF) less than 40% treatment with stable and maximal tolerable dose of Sac/Val, beta-blocker with or without mineralocorticoid receptor antagonist 6-minute walking-distance (6MWD)≥ 100meters and ≤425 meters at enrollment systolic blood pressure ≤100 mmHg at enrollment Exclusion Criteria: hemodialysis severe co-morbidities with life expectancy less than 1 year type 1 diabetes mellitus ever treated with any type of sodium glucose cotransporter 2 inhibitor (SGLT2i)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin with standard-of-care therapies for heart failure, including sacubitril/valsartan, beta-blocker, MRA, ICD and CRT | Drug: Dapagliflozin<br>* Dapagliflozin 10mg once daily<br>* Other names: Forxiga;Drug: Sacubitril-Valsartan<br>* Sacubitril-Valsartan, maximal tolerated dosage<br>* Other names: Entresto;Drug: Beta blocker<br>* Cardio-selective beta-blocker, including carvedilol, bisoprolol, metoprolol or nebivolol<br>* Other names: Concor, Betaloc zok, Nebilet, Carvedilol;Drug: Mineralocorticoid Receptor Antagonist<br>* Mineralocorticoid receptor antagonist, including spironolactone or eplerenone<br>* Other names: Aldactin, Inspra;Device: Cardiac resynchronization therapy and/or implantable cardioverter defibrillator<br>* CRT-P, CRT-D or ICD if clinically indicated<br>|
| Placebo Comparator: Standard of care<br>Standard-of-care therapies for heart failure, including sacubitril/valsartan, beta-blocker, MRA, ICD and CRT | Drug: Sacubitril-Valsartan<br>* Sacubitril-Valsartan, maximal tolerated dosage<br>* Other names: Entresto;Drug: Beta blocker<br>* Cardio-selective beta-blocker, including carvedilol, bisoprolol, metoprolol or nebivolol<br>* Other names: Concor, Betaloc zok, Nebilet, Carvedilol;Drug: Mineralocorticoid Receptor Antagonist<br>* Mineralocorticoid receptor antagonist, including spironolactone or eplerenone<br>* Other names: Aldactin, Inspra;Device: Cardiac resynchronization therapy and/or implantable cardioverter defibrillator<br>* CRT-P, CRT-D or ICD if clinically indicated<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-minute walking distance | Measuring walking distance within 6 minutes | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EQ-5D-5L | Measuring health status. Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.This version of EQ-5D has five-level scale, The number of levels of severity was classified into: having no problems, having slight problems, having moderate problems, having severe problems and being unable to do/having extreme problems. This version can define 3,125 (5x5x5x5x5) different health states. Valuation of the EQ-5D-5L was then calcuated by the Taiwanese hybrid model, range from -1.0259 to 1. [PLoS One 13(12):e0209344]. Higher score indicates better health status. | 12 weeks | 
| EQ-Visual analogue scale (EQ-VAS) | Evaluating the participants' overall health status. The participant would be asked to mark health status on the day of the interview on a 20 cm vertical scale with end points of 0 and 100. There are notes at the both ends of the scale that the bottom rate (0) corresponds to  the worst health you can imagine, and the highest rate (100) corresponds to the best health you can imagine. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Dapagliflozin, Sacubitril/valsartan