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Delayed Initiation of ARNI and SGLT2i in Heart Failure With Corrected Aetiology (DELAY-HF), Pilot Study

2026年5月27日 更新者：Kyungsub Song

DELayed Initiation of ARNI and SGLT2i in Heart Failure With Corrected aetiologY (DELAY-HF), Pilot Study

In patients with heart failure due to a reversible underlying cause-such as valvular heart disease or coronary artery disease-surgical or procedural correction of the underlying lesion (valve repair/replacement, TAVI, PCI, or CABG) frequently leads to spontaneous recovery of cardiac function, even without neurohormonal modulators. In this clinical setting, a substantial proportion of patients may not require the full set of guideline-directed medical therapies routinely prescribed for chronic HFrEF. The purpose of this study is to determine whether ARNI (angiotensin receptor-neprilysin inhibitor) and SGLT2 inhibitors are truly necessary in patients whose left ventricular function recovers spontaneously after treatment of a correctable cause of heart failure.

The DELAY-HF trial (DELayed initiation of ARNI and SGLT2i in heart failure with corrected aetiologY) is a multi-center, randomized controlled non-inferiority trial evaluating whether a delayed-initiation strategy of ARNI and SGLT2i is non-inferior to immediate initiation in patients with heart failure whose underlying cause has been completely corrected by surgical or procedural intervention.

Adults with a preoperative left ventricular ejection fraction (LVEF) ≤40% who have undergone successful correction of a reversible cause of heart failure-either revascularization (PCI or CABG) for ischemic cardiomyopathy or valvular surgery (including TAVI) for left-sided valvular heart disease causing volume overload-will be randomized 1:1 to (1) delayed initiation, in which ARNI/SGLT2i are withheld for 6 months and started only in patients whose LVEF remains ≤40% at the 6-month assessment, versus (2) immediate guideline-directed medical therapy (GDMT) including ARNI/SGLT2i started shortly after the corrective procedure. All patients are followed for 12 months.

The primary outcome is the absolute change in LVEF from baseline at 12 months. Key secondary outcomes include cardiovascular mortality, heart failure hospitalization, additional echocardiographic indices, NT-proBNP, KCCQ quality-of-life score, 6-minute walk distance, and a cost-effectiveness analysis.

By comparing these two strategies, this trial will clarify the incremental contribution of ARNI and SGLT2i-both to further LVEF recovery and to clinical outcomes-in patients who have already demonstrated spontaneous improvement in cardiac function after correction of the underlying cause, and will thereby help define whether these agents are truly necessary in this population.

調査の概要

状態

募集

条件

介入・治療

詳細な説明

  1. Scientific Background and Rationale Contemporary heart failure (HF) guidelines recommend the early and simultaneous initiation of the four foundational pillars of guideline-directed medical therapy (GDMT)-ARNI (or ACEi/ARB), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor-in patients with a reduced left ventricular ejection fraction (LVEF). The pivotal trials supporting these recommendations, however, were conducted predominantly in patients with chronic HFrEF in whom the underlying aetiology was either non-correctable or had not been definitively addressed.

    A clinically distinct population is encountered when the underlying cause of heart failure is fully reversible: patients with ischaemic cardiomyopathy who undergo complete revascularization, and patients with left-sided valvular disease causing chronic pressure or volume overload (severe aortic stenosis, aortic regurgitation, primary mitral regurgitation) who undergo valvular surgery or transcatheter intervention. In these patients, removal of the haemodynamic insult itself drives a substantial portion of subsequent LVEF recovery, independent of neurohormonal blockade. Consequently, universal and immediate initiation of ARNI and SGLT2i in this population may expose patients who would have recovered spontaneously to drug-related adverse effects (symptomatic hypotension, hyperkalaemia, renal dysfunction, genitourinary infection, ketoacidosis), to the burden of polypharmacy, and to avoidable cost, with uncertain incremental benefit on cardiac function or clinical outcome.

    The optimal timing of ARNI and SGLT2i initiation in patients whose underlying cause of HF has been definitively corrected has not been prospectively examined.

  2. Study Hypothesis The central hypothesis of DELAY-HF is that, in patients in whom the underlying cause of heart failure has been surgically or procedurally corrected, the LVEF recovery attributable to treatment of the underlying cause is substantially greater than the incremental recovery attributable to ARNI and SGLT2i. A strategy of delayed initiation-in which ARNI and SGLT2i are withheld for 6 months and started only in patients without sufficient LVEF recovery-will therefore be non-inferior to immediate initiation with respect to the change in LVEF at 12 months.
  3. Pre-specified Analyses

Four pre-specified analyses are planned to fully characterise the contribution of ARNI/SGLT2i in this population:

  1. Effect of early ARNI/SGLT2i on LVEF recovery. Patients in the delayed-initiation arm who never received ARNI/SGLT2i during the 12-month follow-up (those without recovery at 6 months who were ultimately not started, plus those who recovered spontaneously) will be compared with the immediate-initiation arm to estimate the contribution of early ARNI/SGLT2i to LVEF recovery beyond the recovery driven by treatment of the underlying cause.
  2. Safety of delayed initiation. Within the delayed-initiation arm, patients who received delayed ARNI/SGLT2i and recovered will be compared with those who received delayed therapy without recovery, to evaluate whether postponing therapy by 6 months in non-recovering patients is associated with an attenuation of subsequent LVEF response.
  3. Twelve-month head-to-head comparison. The proportion of patients achieving LVEF recovery and the magnitude of LVEF improvement at the 12-month assessment will be compared directly between the delayed-initiation and immediate-initiation arms.
  4. Spontaneous versus pharmacologic recovery. Among patients in the delayed-initiation arm whose LVEF recovered spontaneously after correction of the underlying cause (without medication), the magnitude of LVEF recovery will be compared with that achieved in patients in the immediate-initiation arm whose recovery occurred while on ARNI/SGLT2i.

4. Exploratory Analyses A pre-specified exploratory aim of the trial is to estimate the proportion of patients in the delayed-initiation arm in whom ARNI and SGLT2i can ultimately be deemed unnecessary-that is, those whose cardiac function has recovered sufficiently at 6 months that initiation is not warranted under the trial protocol. A formal cost-effectiveness analysis (incremental cost-effectiveness ratio) will compare the two strategies from the healthcare-system perspective.

5. Expected Implications If the delayed-initiation strategy is shown to be non-inferior, the findings will support a more individualized prescribing approach in patients with a corrected cause of heart failure-reserving ARNI and SGLT2i for those who fail to recover spontaneously-and will reduce unnecessary drug exposure, adverse-effect burden, and cost in a population that is currently treated uniformly under generalized HFrEF guidelines.

研究の種類

介入

入学 (推定)

80

段階

  • フェーズ 4

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究連絡先

研究場所

  • 韓国
    • Daegu
      • Daegu、Daegu、韓国、42601
        • 募集
        • Keimyung University Dongsan Hospital
        • コンタクト：
        • 副調査官：
          • In-Cheol Kim, MD/PhD
    • Gyeonggi-do
      • Seongnam-si、Gyeonggi-do、韓国、13620
        • まだ募集していません
        • Seoul National University Bundang Hospital
        • コンタクト：
      • Suwon、Gyeonggi-do、韓国、16499
        • まだ募集していません
        • Ajou University Hospital
        • コンタクト：
    • Seoul
      • Seoul、Seoul、韓国、02841
        • まだ募集していません
        • Korea University Anam Hospital
        • コンタクト：

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

  • 大人
  • 高齢者

健康ボランティアの受け入れ

いいえ

説明

Inclusion Criteria:

  • Age ≥ 18 years.
  • Preoperative left ventricular ejection fraction (LVEF) ≤ 40% on echocardiography.
  • Successful surgical or procedural correction of a correctable underlying cause of heart failure: Valvular heart disease: mitral valve surgery, aortic valve surgery, transcatheter aortic valve implantation (TAVI), or tricuspid valve surgery, OR Ischemic cardiomyopathy: complete revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
  • Enrollment between 3 months before and 10 days after the corrective procedure.
  • Hemodynamically stable post-operative state with NYHA class I, defined at the time of randomization as: Systolic blood pressure ≥ 100 mmHg sustained for at least 6 hours; No up-titration of intravenous diuretics within the preceding 6 hours; No use of intravenous vasodilators within the preceding 6 hours; No use of intravenous inotropes within the preceding 24 hours; Heart rate 50-110 bpm and no clinical signs of volume overload.
  • Patients receiving ARNI or SGLT2 inhibitors prior to enrollment must complete a 1-week washout period before randomization.

Provision of written informed consent.

Exclusion Criteria:

  • Prior history of sustained ventricular tachycardia or ventricular fibrillation.
  • Greater-than-moderate paravalvular leak or residual mitral regurgitation after aortic or mitral valve surgery.
  • Incomplete revascularization in patients with coronary artery disease (residual significant disease in any major coronary territory: LAD, LCX, or RCA).
  • Graft occlusion documented on coronary CT angiography after CABG. Planned pregnancy during the study period.
  • Uncontrolled hypertension on medical therapy (systolic blood pressure > 160 mmHg).
  • Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m².
  • Inability to tolerate ARNI, defined as inability to take sacubitril/valsartan 25 mg twice daily (e.g., due to symptomatic hypotension, history of angioedema, or bilateral renal artery stenosis).
  • Inability to tolerate SGLT2 inhibitors (e.g., type 1 diabetes mellitus or history of recurrent diabetic ketoacidosis).
  • Any other condition that, in the opinion of the investigator, would interfere with study participation or follow-up.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

  • 主な目的：処理
  • 割り当て：ランダム化
  • 介入モデル：並列代入
  • マスキング：なし（オープンラベル）

武器と介入

参加者グループ / アーム
介入・治療
実験的：Delayed initiation of ARNI and SGLT2i
After surgical or procedural correction of the underlying cause of heart failure (valvular surgery/TAVI or PCI/CABG), ARNI and SGLT2 inhibitors are withheld and patients are observed for 6 months on background therapy excluding ARNI/SGLT2i. At the 6-month assessment, ARNI and SGLT2i are initiated only in patients whose LVEF remains ≤40%. Patients with LVEF >40% continue without ARNI/SGLT2i under observation. If symptomatic heart failure worsening or a ≥10 percentage-point decrease in LVEF occurs during the observation period, full guideline-directed medical therapy including ARNI and SGLT2i is started immediately as rescue therapy. All participants are followed for 12 months from randomization.
薬：Sacubitril / Valsartan

In the delayed-initiation arm, sacubitril/valsartan is withheld for 6 months after the corrective procedure; valsartan is used for blood pressure control and background heart failure therapy. At the 6-month assessment, sacubitril/valsartan is initiated only in patients with LVEF ≤40%. Patients with LVEF >40% continue their existing regimen without ARNI.

If heart failure worsens during observation (symptomatic deterioration or a ≥10 percentage-point drop in LVEF), sacubitril/valsartan is started immediately as rescue therapy. Patients on ARNI prior to enrollment undergo a 1-week washout before randomization.

薬：SGLT-2 inhibitor

In the delayed-initiation arm, the SGLT2 inhibitor (dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily) is withheld during the first 6 months and initiated at the 6-month assessment only in patients whose LVEF remains ≤40%; patients whose LVEF has recovered to >40% continue without SGLT2i under observation.

If heart failure worsens during the observation period, the SGLT2 inhibitor is started immediately as rescue therapy. Patients receiving SGLT2i prior to enrollment undergo a 1-week washout before randomization.

薬：Sacubitril / Valsartan
In the immediate-initiation arm, sacubitril/valsartan is started within 7 days after the corrective procedure, once the patient is hemodynamically stable and euvolemic. The starting dose is selected based on baseline blood pressure (25 mg to 200 mg twice daily) and titrated to the maximally tolerated dose (target 200 mg twice daily), continued throughout the 12-month follow-up.
アクティブコンパレータ：Immediate initiation of ARNI and SGLT2i (standard GDMT)
After surgical or procedural correction of the underlying cause of heart failure (valvular surgery/TAVI or PCI/CABG), full guideline-directed medical therapy including ARNI and SGLT2 inhibitors is initiated and titrated to the maximally tolerated doses according to current heart failure guidelines, and continued throughout the follow-up period. All participants are followed for 12 months from randomization.
薬：Sacubitril / Valsartan

In the delayed-initiation arm, sacubitril/valsartan is withheld for 6 months after the corrective procedure; valsartan is used for blood pressure control and background heart failure therapy. At the 6-month assessment, sacubitril/valsartan is initiated only in patients with LVEF ≤40%. Patients with LVEF >40% continue their existing regimen without ARNI.

If heart failure worsens during observation (symptomatic deterioration or a ≥10 percentage-point drop in LVEF), sacubitril/valsartan is started immediately as rescue therapy. Patients on ARNI prior to enrollment undergo a 1-week washout before randomization.

薬：Sacubitril / Valsartan
In the immediate-initiation arm, sacubitril/valsartan is started within 7 days after the corrective procedure, once the patient is hemodynamically stable and euvolemic. The starting dose is selected based on baseline blood pressure (25 mg to 200 mg twice daily) and titrated to the maximally tolerated dose (target 200 mg twice daily), continued throughout the 12-month follow-up.
薬：SGLT2 Inhibition
An SGLT2 inhibitor (dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily, at the discretion of the treating physician) is used as one of the foundational therapies of guideline-directed medical therapy for heart failure. In the immediate-initiation arm, the SGLT2 inhibitor is started after correction of the underlying cause of heart failure and continued throughout the 12-month follow-up.

この研究は何を測定していますか？

主要な結果の測定

結果測定
メジャーの説明
時間枠
Change in left ventricular ejection fraction (LVEF) at 12 months
時間枠：Baseline (at randomization) and 12 months after randomization

Absolute change in left ventricular ejection fraction (LVEF), expressed in percentage points, from baseline (at randomization) to the 12-month follow-up assessment. LVEF will be measured by transthoracic echocardiography using the biplane Simpson's method according to current ASE/EACVI guidelines, and analyzed by readers blinded to treatment assignment.

The primary hypothesis is non-inferiority of the delayed-initiation strategy compared with the immediate-initiation strategy. Non-inferiority will be declared if the lower bound of the two-sided 95% confidence interval for the between-group difference in LVEF change (delayed minus immediate) lies above -5 percentage points; that is, the LVEF improvement in the delayed-initiation arm is no more than 5 percentage points worse than in the immediate-initiation arm.
Baseline (at randomization) and 12 months after randomization

二次結果の測定

結果測定
メジャーの説明
時間枠
Cardiovascular mortality
時間枠：From randomization through 12 months
Incidence of death from cardiovascular causes, including death from heart failure, sudden cardiac death, myocardial infarction, stroke, and other cardiovascular causes, adjudicated by an independent clinical events committee blinded to treatment assignment.
From randomization through 12 months
Heart failure hospitalization
時間枠：From randomization through 12 months
Incidence of hospitalization due to worsening heart failure, defined as an unplanned admission with signs and symptoms of heart failure requiring intensification of decongestive therapy (intravenous diuretics, vasodilators, or inotropes), adjudicated by an independent clinical events committee blinded to treatment assignment.
From randomization through 12 months
Change in echocardiographic remodeling parameters at 12 months
時間枠：Baseline and 12 months after randomization
Change from baseline to 12 months in the following echocardiographic parameters measured by transthoracic echocardiography: left ventricular end-diastolic diameter (LVEDD), left ventricular end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), and right ventricular ejection fraction (RVEF).
Baseline and 12 months after randomization
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score
時間枠：Baseline and 12 months after randomization
Change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, a disease-specific health status measure for heart failure. Scores range from 0 to 100, with higher scores indicating better health status and quality of life.
Baseline and 12 months after randomization
Change in 6-minute walk distance (6MWD)
時間枠：Baseline and 12 months after randomization
Change from baseline to 12 months in the distance walked (in meters) during a standardized 6-minute walk test, conducted according to American Thoracic Society guidelines.
Baseline and 12 months after randomization
Non-cardiovascular hospitalization
時間枠：From randomization through 12 months
Incidence of hospitalization due to causes other than cardiovascular events.
From randomization through 12 months
Change in NT-proBNP from baseline
時間枠：Baseline and 12 months after randomization
Change from baseline to 12 months in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration (pg/mL), a biomarker of myocardial wall stress and heart failure severity.
Baseline and 12 months after randomization
Proportion of patients in whom ARNI/SGLT2i is deemed unnecessary
時間枠：6 months after randomization
Among patients in the delayed-initiation arm, the proportion whose LVEF has recovered to >40% at the 6-month assessment and who therefore do not require initiation of ARNI and SGLT2 inhibitors under the trial protocol. This is an exploratory outcome intended to estimate the fraction of patients who may safely avoid these therapies after correction of the underlying cause of heart failure.
6 months after randomization
LVEF recovery in patients with spontaneous recovery versus medication-treated recovery
時間枠：Baseline, 6 months, and 12 months after randomization
Among patients in the delayed-initiation arm whose LVEF recovers spontaneously (without ARNI or SGLT2i) by the 6-month assessment, the magnitude of LVEF recovery at 12 months will be compared with that in patients in the immediate-initiation arm whose recovery occurred while receiving ARNI and SGLT2i.
Baseline, 6 months, and 12 months after randomization
Cost-effectiveness analysis (Incremental Cost-Effectiveness Ratio, ICER)
時間枠：12 months after randomization
Cost-effectiveness of the delayed-initiation strategy compared with the immediate-initiation strategy, expressed as an incremental cost-effectiveness ratio (ICER) using cost per quality-adjusted life-year (QALY) gained, from the healthcare-system perspective. Direct medical costs (medications, hospitalizations, outpatient visits, procedures) and quality-of-life weights derived from the KCCQ will be incorporated into the analysis.
12 months after randomization

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Kyungsub Song

協力者

Korea University Anam Hospital
Seoul National University Bundang Hospital
Ajou University Medical Center

捜査官

  • スタディディレクター：Kyungsub Song, MD、Keimyung University Dongsan Medical Center

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

  • 1. Wilcox JE et al. Heart Failure With Recovered LVEF: JACC Scientific Expert Panel. JACC 2020;76(6):719-34. 2. Kodur N, Tang WHW. Management of HFimpEF: Current Evidence and Controversies. JACC Heart Fail 2025;13(4):537-53. 3. Velazquez EJ et al. Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy (STICH). N Engl J Med 2011;364:1607-16. 4. Myocardial Revascularization in Patients With Ischemic Cardiomyopathy. J Am Heart Assoc 2022. 5. Recovery of LV Function After Surgery for Aortic and Mitral Regurgitation With HF. J Cardiovasc Dev Dis 2024. 6. Halliday BP et al. Withdrawal of pharmacological treatment for HF in patients with recovered DCM (TRED-HF). Lancet 2019;393:61-73. 7. Cheng RK et al. Long-term follow-up of TRED-HF. Eur J Heart Fail 2025;27:113-21. 8. Heidenreich PA et al. 2022 AHA/ACC/HFSA Guideline for Management of Heart Failure. Circulation 2022;145:e895-e1032. 9. Bocchi EA et al. Carvedilol as Single Therapy for HFimpEF (CATHEDRAL-HF). JACC Heart Fail 2025;13(7):882-91. 10. Hawkins NM et al. Withdrawal of HF therapy after AF rhythm control with EF normalization (WITHDRAW-AF). Eur Heart J 2026;47(2):250-60. 11. ReReRe study: Withdrawal of GDMT in patients with recovered LV and reversible etiology in valvular regurgitation. Eur Heart J 2025;46(Suppl 1):ehaf784.1245. 12. Sauer AJ et al. How to Initiate and Uptitrate GDMT in Heart Failure. JACC Heart Fail 2023;11(1):21-30. 13. Early Initiation of GDMT for Heart Failure After Cardiac Surgery. Ann Thorac Surg 2024;118(4):887-94. 14. Whitehead AL et al. Estimating the sample size for a pilot randomised trial. Pilot Feasibility Stud 2016;2:17.

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始 (実際)

2026年5月20日

一次修了 (推定)

2028年5月20日

研究の完了 (推定)

2028年12月20日

試験登録日

最初に提出

2026年4月30日

QC基準を満たした最初の提出物

2026年4月30日

最初の投稿 (実際)

2026年5月7日

学習記録の更新

投稿された最後の更新 (実際)

2026年6月1日

QC基準を満たした最後の更新が送信されました

2026年5月27日

最終確認日

2026年5月1日

詳しくは

本研究に関する用語

キーワード

追加の関連 MeSH 用語

その他の研究ID番号

  • 2026-04-005-001 April 21, 2026
  • RS-2026-25475665 (その他の助成金/資金番号：National Research Foundation of Korea(NRF) grant funded by the South Korea government(MSIT))

個々の参加者データ (IPD) の計画

個々の参加者データ (IPD) を共有する予定はありますか?

はい

IPD プランの説明

Deidentified individual participant data (IPD) underlying the published results, including baseline demographic and clinical characteristics, echocardiographic parameters (LVEF, LV volumes, diastolic indices), laboratory values (NT-proBNP, eGFR, electrolytes), KCCQ-12 scores, 6-minute walk distance, randomization assignment, study drug exposure, and adjudicated clinical events (cardiovascular and all-cause mortality, heart failure hospitalization, MACE), will be made available. The full study protocol, statistical analysis plan, and informed consent form will also be shared. Only deidentified data without any direct or indirect identifiers will be released, in accordance with the Personal Information Protection Act of the Republic of Korea and the Bioethics and Safety Act.

IPD 共有時間枠

Beginning 6 months after publication of the primary study results, and ending 5 years after publication.

IPD 共有アクセス基準

Access will be granted to qualified investigators whose proposed use of the data has been reviewed and approved by an independent committee designated by the principal investigator. Requests must include: (1) a detailed research proposal with specific aims, methodology, and analysis plan; (2) the name and affiliation of the requesting investigator; and (3) a signed data access and confidentiality agreement. Requests should be submitted in writing to the principal investigator at the coordinating center (Keimyung University Dongsan Hospital). Approved investigators will receive deidentified data via a secure data transfer platform. The principal investigator and the steering committee retain the right to decline requests that conflict with patient privacy protections, applicable regulations, or the original informed consent provided by participants.

IPD 共有サポート情報タイプ

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • CSR

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いいえ

米国FDA規制機器製品の研究

いいえ

この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。

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