Heart Failure With Reduced Ejection Fraction
Conditions
Brief summary
Heart failure (HF) is a condition in which the heart does not contract (pump) or relax well, leading to insufficient perfusion of vital organs. Ankle swelling, fatigue, and breathlessness are some of the features of this syndrome. There are different causes for HF (e.g., infarct and hypertension) and two distinct types: HFpEF - HF with preserved ejection fraction - the heart pumps but does not relax well and HFrEF/HFmrEF - HF with reduced or mildly reduced ejection fraction - where the heart does not pump properly, here referred to as having HFrEF. Patients with HFrEF experience substantially shorter life expectancies compared with people in the general population of similar age. Compared to the different available therapeutics for HFrEF patients, angiotensin receptor-neprilysin inhibitor (ARNi), sacubitril/valsartan, has shown superiority for improving clinical outcomes. Furthermore, the new recently drug sodium-glucose cotransporter 2 inhibitor (SGLT2i) was proven to reduce mortality and morbidity on top of well-adapted background therapy. This work aims to test the safety of ARNi and SGLT2i initiation by comparing a strategy of simultaneous initiation of ARNi and SGLT2i versus sequential initiation of a SGLT2i first followed by an ARNi.
Detailed description
Sacubitril/valsartan and SGLT2i reduced HF hospitalizations and mortality in patients with heart failure and a reduced ejection fraction with a rapid onset of action, but the timing of initiation of each drug is uncertain. Clinicians may be reluctant to initiate both therapies simultaneously due to fear of adverse events (e.g., hypotension and worsening renal function) which may delay the initiation of (at least one) of these life-saving therapies. This study aims to fill this gap in knowledge by studying the initiation of sacubitril/valsartan and a SGLT2i simultaneously or in sequence. This study will better inform clinicians on their daily decisions.
Interventions
DRUGSacubitril-valsartan
Sacubitril-valsartan titration at the discretion of the treating physician
DRUGSGLT2 inhibitor
Either empagliflozin or dapagliflozin 10 mg/day
Sponsors
Unidade de Investigação e Desenvolvimento Cardiovascular (UnIC)
Rede de Investigação em Saúde
Universidade do Porto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Pragmatic study to be conducted in real-life routine practice conditions with a two-arm open randomization, to evaluate the efficacy (on surrogate markers) and safety of ARNi and SGLT2i combination in patients with HFrEF/HFmrEF and the doses of ARNi. 1. initiation of ARNi and SGLT2i simultaneously (same day or within ± 5 days); 2. initial SGLT2i initiation followed by ARNi between week 4 and 12 after randomization. Assuming a primary outcome frequency of 30% in the sequential group, if there is a true difference between the intervention groups (simultaneous vs sequential) of 10%, then 62 patients are required to be 80% certain that the upper limit of a one-sided 95% confidence interval will exclude a difference in favour of the sequential group of more than 20%.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Heart failure symptoms (NYHA II, III or IV) 3. Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram) 4. Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula) 5. Serum potassium (K+) ≤ 5.4 mmol/L 6. Systolic blood pressure ≥ 100 mmHg 7. Not treated with ARNi nor with SGLT2i within the previous month (30 days before inclusion, except if initiated 5 days before randomization; patients treated with an ACEi or ARB can be included and maintain their therapy until the switch to an ARNi is performed) 8. If female, she must not be a woman of childbearing potential. That is, she must be: 1. Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy) 2. Clinically diagnosed infertile 3. In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause 9. If female patient of childbearing potential, she must have a negative serum pregnancy test at Visit 1 (Day 0) and must agree to consistently and correctly use (from 28 days prior to first study treatment administration until at least 7 days after last study treatment administration) one of the following highly effective methods of contraception: 1. Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject) 2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) 3. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) 4. Intrauterine device 5. Intrauterine hormone-releasing system 6. Bilateral tubal occlusion 7. Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner
Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site) 2. Participation in another clinical study with an investigational product during the last month 3. Unwilling to sign inform consent 4. Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products 5. Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month 6. Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator's judgement) 7. Previously confirmed cardiac amyloidosis 8. History of angioedema 9. Implantable cardioverter-defibrillators or cardiac resynchronization therapy within 3 months prior to screening or if there is an intent to implant either device in the 3 months following screening 10. Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding 11. Severe valvulopathy according to the echocardiogram report 12. Previous history of ketoacidosis due to SGLT2i
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite outcome (time-to-first event' occurrence during the 6 months of follow-up): | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | * Symptomatic hypotension (systolic blood pressure \<100 mmHg with signs or symptoms compatible with hypoperfusion); * Hyperkalaemia (serum potassium \>6.0 mmol/L); * Hypokalemia (serum potassium \<3.0 mmol/L); * eGFR drop ≥50% from baseline or eGFR \<15 ml/min/1.73m2 or renal transplant or dialysis; * Increase in diuretic dose due to worsening heart failure; * Use of intravenous diuretics for worsening heart failure; * Heart failure hospitalization; * Death from cardiovascular causes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hyperkalaemia (serum potassium >6.0 mmol/L) | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| Hypokalemia (serum potassium <3.0 mmol/L) | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| eGFR drop ≥50% from baseline or eGFR <15 ml/min/1.73m2 or renal transplant or dialysis | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| Increase in diuretic dose due to worsening heart failure | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| Use of intravenous diuretics for worsening heart failure | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| Heart failure hospitalization | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| Death from cardiovascular causes | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| NT-pro BNP or BNP (log) | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| High sensitivity C-reactive protein | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Atrial fibrillation/flutter | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Electrocardiogram (yes/no) |
| Systolic and diastolic blood pressure | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Measure in the clinical appointments |
| High sensitivity Troponin | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Left atrial volume | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Transthoracic echocardiogram |
| Left ventricular systolic volume | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Transthoracic echocardiogram |
| Left ventricular diastolic volume | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Transthoracic echocardiogram |
| LV mass | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Transthoracic echocardiogram |
| LV ejection fraction | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Transthoracic echocardiogram |
| Pulmonary artery systolic pressure | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Transthoracic echocardiogram |
| Serum sodium | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Serum potassium | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Serum creatinine | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Glomerular filtration rate (eGFR) | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Calculated from the serum creatinine using the 2021 CKD-EPI creatinine-based formula |
| Urinary sodium | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Spot urine sample |
| Urinary potassium | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Spot urine sample |
| Microalbuminuria | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Spot urine sample |
| Total Cholesterol | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| LDL Cholesterol | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| HDL Cholesterol | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Triglycerides | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Glucose | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Measured in blood samples |
| Glycated hemoglobin (HbA1C) | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Uric acid | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| TSH | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Free thyroxin | visit 1 (day 0); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| ALAT | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| ASAT | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Gamma-GT | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Alkaline Phosphatase | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Total bilirubin | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Serum iron | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Symptomatic hypotension (systolic blood pressure <100 mmHg with signs or symptoms compatible with hypoperfusion) | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Time to event' occurrence during the 6 months of follow-up |
| Transferrin saturation | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
| Functional class (NYHA, New York Heart Association) | visit 1 (day 0); visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Assessed by the medical doctors in the clinical appointments (I / II / III / IV) |
| Quality of life (KCCQ, Kansas City Cardiomyopathy Questionnaire) | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | HR-QoL assessed by the Kansas City Cardiomyopathy Questionnaire a 12-item instrument. All items are measured on a Likert scale with 5-7 response options. KCCQ scores are scaled from 0 to 100 and summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent |
| Dosage titration of sacubitril/valsartan up to the dose 97/103 mg (b.i.d.) at 3 months | visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days) | Assessed by the medical doctors in the clinical appointments |
| Ferritin | visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days) | Concentration measured in blood samples |
Countries
Portugal
Outcome results
None listed