Initiation of Angiotensin Receptor-neprilysin Inhibitor (ARNi) and Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF): the INITIATE-HFrEF Randomized Open-label Trial
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 62
- 试验地点
- 5
- 主要终点
- Composite outcome (time-to-first event' occurrence during the 6 months of follow-up):
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Heart failure symptoms (NYHA II, III or IV)
- •Left ventricle ejection fraction ≤ 49% (assessed by transthoracic echocardiogram)
- •Glomerular filtration rate ≥ 25 ml/min/1.73m2 (CKD-EPI formula)
- •Serum potassium (K+) ≤ 5.4 mmol/L
- •Systolic blood pressure ≥ 100 mmHg
- •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)
- •If female, she must not be a woman of childbearing potential. That is, she must be:
- •Surgically sterilized (e.g., underwent hysterectomy, bilateral salpingectomy or bilateral oophorectomy)
- •Clinically diagnosed infertile
- •In a post-menopausal state, defined as no menses for 12 months without an alternative medical cause
- •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:
- •Abstinence of heterosexual intercourse (when this is in line with preferred and usual lifestyle of the subject)
- •Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
- •Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
- •Intrauterine device
- •Intrauterine hormone-releasing system
- •Bilateral tubal occlusion
- •Vasectomized partner, who has received medical assessment of the surgical success, or clinically diagnosed infertile partner
排除标准
- •Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
- •Participation in another clinical study with an investigational product during the last month
- •Unwilling to sign inform consent
- •Patients with a known hypersensitivity or intolerance to ARNi or SGLT2i or any of the excipients of the products
- •Hospitalization due to non-cardiovascular causes, surgical procedure, coronary, cerebral or peripheral vascular events or sepsis in the prior month
- •Cancer (life limiting with an estimated life expectancy of less than 2 years based on investigator's judgement)
- •Previously confirmed cardiac amyloidosis
- •History of angioedema
- •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
- •Female patients currently pregnant (confirmed by a positive pregnancy test) or intent to become pregnant or breast feeding
- •Severe valvulopathy according to the echocardiogram report
- •Previous history of ketoacidosis due to SGLT2i
研究组 & 干预措施
Simultaneous initiation
ARNi ((i.e. sacubitril/valsartan, irrespectively of brand name, at an initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (either empagliflozin or dapagliflozin or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10mg/d) on the same day or within ± 5 days.
干预措施: Sacubitril-valsartan (Drug)
Simultaneous initiation
ARNi ((i.e. sacubitril/valsartan, irrespectively of brand name, at an initial dose 24/26mg b.i.d. or 49/51mg b.i.d. titrated to 97/103mg b.i.d. preferably in the first 3-6 weeks, up to 3 months of follow-up) and SGLT2i (either empagliflozin or dapagliflozin or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10mg/d) on the same day or within ± 5 days.
干预措施: SGLT2 inhibitor (Drug)
Sequential initiation
Initial (at randomization day) SGLT2i prescription (either empagliflozin or dapagliflozin, or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10 mg/d) followed by an ARNi initiated between weeks 4 and 12 after randomization (sacubitril/valsartan at an initial dose of 24/26mg b.i.d. or 49/51mg b.i.d., and titrated to 97/103mg b.i.d. if tolerated, according to assistant physician decision)
干预措施: Sacubitril-valsartan (Drug)
Sequential initiation
Initial (at randomization day) SGLT2i prescription (either empagliflozin or dapagliflozin, or respective combinations with other substances, providing the total dose of SGLT2i is, at least, of 10 mg/d) followed by an ARNi initiated between weeks 4 and 12 after randomization (sacubitril/valsartan at an initial dose of 24/26mg b.i.d. or 49/51mg b.i.d., and titrated to 97/103mg b.i.d. if tolerated, according to assistant physician decision)
干预措施: SGLT2 inhibitor (Drug)
结局指标
主要结局
Composite outcome (time-to-first event' occurrence during the 6 months of follow-up):
时间窗: 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.
次要结局
- 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))
- Atrial fibrillation/flutter(visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- Left ventricular systolic volume(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- LV mass(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- LV ejection fraction(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- Triglycerides(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- 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))
- 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))
- 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))
- 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))
- 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))
- 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))
- Heart failure hospitalization(visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- 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))
- Death from cardiovascular causes(visit 2 (day 23 to 37); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- Microalbuminuria(visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- 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))
- 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))
- 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))
- 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))
- High sensitivity C-reactive protein(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- 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))
- Left ventricular diastolic volume(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- 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))
- 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))
- Urinary sodium(visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- Left atrial volume(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- Pulmonary artery systolic pressure(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- Urinary potassium(visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- Total Cholesterol(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- 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))
- 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))
- Ferritin(visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- 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))
- TSH(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- HDL Cholesterol(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- Glycated hemoglobin (HbA1C)(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- 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))
- 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))
- Transferrin saturation(visit 1 (day 0); visit 3 (visit 2 + 60 ±15 days); visit 4 (visit 3 + 90±15 days))
- 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))
- LDL Cholesterol(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- Free thyroxin(visit 1 (day 0); visit 4 (visit 3 + 90±15 days))
- 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))
- 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))
- 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))