Rationale and Protocol of the Registry for Contemporary Medical Management of Chronic Heart Failure With Mildly Reduced and Preserved Ejection Fraction　― The PARACLETE Study ―

Abstract

Background: There is recent evidence for the medical treatment of heart failure (HF) with mildly reduced ejection fraction (EF) and preserved EF (HFmrEF/HFpEF). However, in real-world settings, information on how cardiologists treat patients with HFmrEF/HFpEF, especially those with chronic, mild, and stable HF or newly diagnosed HF, is lacking. In other words, we do not know when cardiologists should start and intensify medical treatment, which drugs they should choose, or why. To answer these questions, we will conduct an observational study of HFmrEF/HFpEF. Here, we describe the rationale and protocol of this observational study.

Methods and Results: This study will explore the therapeutic status of approximately 4,200 patients who were diagnosed or newly diagnosed with chronic HFmrEF/HFpEF (LVEF >40%) at approximately 70 cardiology clinics and hospitals. After enrolment, physicians will check whether the current medical therapy is appropriate for each patient and initiate or intensify HF medical therapy appropriately. The primary endpoints will be: (1) the proportion of patients within the categories of reasons for changing prescriptions at visit 1 of HF medical therapy and (2) a composite of unexpected HF hospitalization and all-cause death in a 2-year follow-up.

Conclusions: This registry will uniquely confirm the current treatment status of patients with HFmrEF/HFpEF in real-world settings.

Heart failure (HF) is characterized by high morbidity and mortality rates and is associated with significant social and economic burdens worldwide.^1–3 Compared with HF with reduced ejection fraction (HFrEF), treatment strategies for treating HF with mildly reduced EF and preserved EF(HFmrEF/HFpEF) are not well established. However, early diagnosis and appropriate intervention are essential for improved HF management.

Until recently, there has been little evidence regarding effective drugs for treating HFmrEF/HFpEF. However, several randomized clinical trials (RCTs) confirmed that sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce adverse events in patients with distinct HF and HFmrEF/HFpEF, and that angiotensin-receptor-neprilysin inhibitors (ARNI) reduce adverse events in patients with distinct HF and below-normal EF.^4–6 Thus, guideline-directed medical therapy is gradually being developed for the treatment of HFmrEF and HFpEF. In addition, the efficacy of mineralocorticoid-receptor antagonists (MRA) in HFmrEF/HFpEF has recently been demonstrated in patients with NT-proBNP levels >300 pg/mL in sinus rhythm and 600–900 pg in atrial fibrillation.^4–7

However, in the real-world setting, many patients with mild HF and HFmrEF/HFpEF do not meet the inclusion criteria for RCTs. The European Society of Cardiology (ESC) guidelines recommend measuring natriuretic peptide (NP) levels in patients with suspected HF and examining the cardiac echocardiogram to diagnose HF correctly in cases of BNP ≥35 pg/mL and NT-proBNP ≥125 pg/mL.⁸ However, information is lacking on how cardiologists treat these mild HF patients with mrEF or pEF; in other words, which drugs should cardiologists choose and why.

In this context, we have planned a nationwide, prospective, observational study that aims to recruit 4,200 patients with LVEF >40%, including those who would be excluded from recent RCTs, whose NP levels were lower, and those who had been newly diagnosed with HFmrEF/HFpEF at registration.

This study presents the rationale and protocol for an observational study titled “the registry of contemPorARy medical mAnagement of Chronic heart faiLurE wiTh non-reduced Ejection fraction (PARACLETE).”

Methods

Study Design

PARACLETE will be an ongoing prospective, observational, non-randomized study of adult outpatients with HFmrEF/HFpEF. An estimated 4,200 patients from approximately 50 outpatient clinics and 30 hospitals across Japan are required. These sites will enroll patients during outpatient visits. Patients will be followed for a maximum of 27 months or until death or withdrawal from the study. As this is a prospective observational cohort study, clinical practice will not be influenced (Figure A).

Figure.

Schematics of (A) the PARACLETE study schedule and (B) the inclusion criteria. BNP, B-type natriuretic peptide; HF, heart failure; LVEF, left ventricular ejection fraction; QOL, quality of life. NT-proBNP, N-terminal pro-BNP.

The study protocol has been approved by the Certified Review Board of Nara Medical University and registered under the Japanese UMIN Clinical Trials Registration (UMIN000046951). This study is being conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent will be obtained from each patient before enrolment. Personal information about potential and enrolled participants will be confidential, and their data will be identified using numbers.

Inclusion and Exclusion Criteria

The inclusion criteria are summarized in Figure B. We screened patients aged ≥20 years who were managed as or suspected of having stable HFmrEF/HFpEF, and among them, those who met the following inclusion criteria were enrolled. When HF-related treatment does not change for at least 8 weeks, HF is diagnosed as stable HF. The inclusion criteria are: (1) LVEF >40% to <50%; (2) in cases of LVEF ≥50%, we will include those with at least any one of the following: (a) history of hospitalization for worsening of HF, (b) BNP ≥100pg/mL or NT-proBNP ≥400 pg/mL in sinus rhythm, or (c) BNP ≥40 to <100 pg/mL or NT-proBNP ≥125 to <400 pg/mL in sinus rhythm and the presence of ≥1 echocardiographic structural criterion corresponding to high LV end-diastolic pressure. The echocardiographic structural criteria are: (a) interventricular septum or posterior wall thickness ≥11 mm, (b) left atrial (LA) diameter ≥38 mm or LA length ≥50 mm, (c) LA area ≥20 cm² or LA volume ≥55 mL, and (d) LA volume index ≥29 mL/m². In case of AF, the cutoff levels of natriuretic peptides were doubled. The most recent BNP or NT-proBNP values and echocardiographic data within 1 year of enrolment will be used as inclusion criteria.

The exclusion criteria are estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m² or dialysis, change in HF treatment within 8 weeks, severe valvular disease, and diagnosis of cardiac amyloidosis (Table 1).

Table 1.

Exclusion Criteria

Exclusion criteria

1) Severe renal dysfunction with the most recent eGFR <15 mL/min/1.73 m2 or on dialysis

2) Any change in HF-related treatment (including both pharmacological and nonpharmacological treatment) within 8 weeks prior to enrolment

3) Worsening HF requiring emergency hospitalization

4) Complications of severe valvular diseases

5) Dilated cardiomyopathy

6) Cardiac amyloidosis

7) Obstructive hypertrophic cardiomyopathy, or hypertrophic cardiomyopathy with family history

8) HF with recovered LVEF, having EF <40% in the past

9) Complications of pulmonary arterial hypertension

10) Complications of severe liver and lung diseases

11) Complications of malignant neoplasms with a prognosis of <1 year

12) Admission to a geriatric care facility or hospice

13) Participation in any clinical intervention

eGFR, estimated glomerular filtration rate; EF, ejection fraction; HF, heart failure; LVEF, left ventricular ejection fraction.

Trial Design and Follow-up

The investigational site will obtain written informed consent, determine patient eligibility, and enroll patients. At visit 0, the sites will collect baseline data, administer quality of life (QOL) questionnaires, and collect data such as medications and blood tests (Table 2). At visit 1 (within 12 weeks of visit 0), physicians will check whether the current medication regimen is appropriate for each patient and, if necessary, initiate or intensify the HF medication regimen based solely on medical reasons, as appropriate. In addition, changes in HF-related medications will be recorded. If the physician changes the medication, the reason for the change and the prescription will be documented. The reason for not changing a patient’s medication at visit 1 will be stated. In addition, if the medication is changed within the 6 months following visit 1, the reason for and prescription of the change will be examined. At visit 2 (2 years ±3 months after visit 1), sites will collect clinical outcomes, re-administer QOL questionnaires, and collect data such as medication and blood tests. Prognostic data on deaths and hospitalizations during follow-up will also be collected. Furthermore, within 3 months before and 6 months after visit 2, echocardiography will be performed and the measured values of the predetermined items will be recorded.

Table 2.

Data Collected in PARACLETE Study

Data type	Visit 0	Visit 1	Visit 1’	Visit 1a’	Visit 2	Visit 2’
	Baseline	Within 12 weeks of visit 0	Within 3 months of visit 1	Within 6 months of visit 1	2 years ±3 months after visit 1	Within 6 months of visit 2
Documented consent	•
Eligibility assessment	•
Registration	•
Background	•
Clinical history	•				•
Smoking status	•				•
Quality of life assessment (EQ-5D score, KCCQ-12)	•				•
Physical examination
Height	•
Weight	•				•
Physical findings	•				•
Physical characteristics	•				•
Echocardiography	•				• *
Blood and urine tests	•				•
Therapeutic drugs		•			•
Re-evaluation of HF medical therapy		•		•
Composite outcomes (Unexpected hospitalization for HF or all-cause death)					•
Exploratory echocardiography			•
Exploratory cardiac MRI			•			•

*Echocardiography should be performed within 3 months before and 6 months after visit 2. EQ-5D, EuroQol 5 dimensions; HF, heart failure; KCCQ-12, The Kansas City Cardiomyopathy Questionnaire-12; MRI, magnetic resonance imaging.

Exploratory studies including more detailed echocardiography (target: 500 patients) and cardiac magnetic resonance imaging (MRI; target: 100 patients) are also planned.

Endpoints

The primary outcomes include: (1) the proportion of patients who have their HF medication modified (including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ARNI, beta-blockers, MRA, SGLT2 inhibitors, vericiguat, and diuretics) and the reasons for prescription adjustments at visits 1 and 2 and (2) a composite outcome comprising unexpected HF hospitalization and all-cause deaths within 2 years of follow-up (Figure A). Secondary outcomes include adverse events (i.e., all-cause death, unexpected HF hospitalization, and all-cause hospitalization), transfer to care facilities, changes in HF-related medication, and changes in QOL (EQ-5D score or KCCQ-12) at the enrolment and 2 years later. Additional outcomes of interest will also be analyzed. Other patient data to be collected during the study include medical history, blood pressure, grip strength, nursing insurance, blood and urine biomarkers, echocardiographic findings, and cardiac MRI parameters (Table 3).

Table 3.

PARACLETE Study Endpoints

Primary endpoints

1) Proportion of patients who have their HF medication changed and the distribution of reasons for changing HF medication at visit

2) Composite of unexpected HF hospitalization and all-cause deaths in a 2-year follow-up

Secondary endpoints

1) During the 2-year follow-up: all-cause deaths, unexpected HF hospitalizations, all-cause hospitalizations, and transfers to nursing homes

2) Composite of unexpected HF hospitalization and all-cause death in the 2-year follow-up by sex and LVEF

3) Changes in medication between visits 1 and 2

4) Change in BNP or NT-proBNP levels between visits 1 and 2

5) Change in echocardiographic parameters, such as LVEF, E/A, IVS, PW, and LAV, between visits 1 and 2

6) Days of home-time

7) Changes in EQ-5D or KCCQ-12 scores between visits 1 and 2

8) Difference in HF medical therapy between cardiologists and non-specialists

9) Changes in HF medications within 6 months of visit 1 and the reasons for these changes

10) Reasons for the absence of a drug change in visit 1

11) Main medical intervals during the 2-year follow-up

Exploratory endpoints

1) Association between drug change at visit 1 and composite event (HF hospitalization or all-cause death)

2) Comparison of changes in treatment medications according to whether or not the patient received prior HF medications

3) Relationship between each drug and prognosis

4) Values at enrolment and changes during a 2-year follow-up for indices such as GLS and tissue Doppler in transthoracic echocardiography

5) Values at enrolment and changes during a 2-year follow-up for each indicator in cardiac MRI

BNP, B-type natriuretic peptide; GLS, global longitudinal strain; IVS, interventricular septum; LAV, left atrial volume; NT-proBNP, N-terminal pro-BNP; PW, posterior wall. Other abbreviations as in Tables 1,2.

Statistical Considerations

Sample Size Estimation The present study has 2 primary endpoints; therefore, we calculated the sample size to meet both primary endpoints.

For primary endpoint 1, we set an estimate because we could not find a similar study in the literature. We conservatively estimated that 50% of the enrolled patients would have a specific reason for treatment change at enrolment. A larger study population yields more precise estimates: 50% has a 95% confidence interval (CI) of ±4.4% for a sample size of 500 patients, ±2.0% for 2,500 patients, and ±1.4% for 5,000 patients. To obtain a half-width of 1.6% of the CI, a final evaluable sample size of 3,812 patients is needed.

In the case of primary endpoint 2, 30 independent variables will be evaluated in the multivariate analysis. Assuming 10 outcomes per independent variable, 300 outcomes will be observed. Our preliminary data assumes that the incidence rate of all-cause death or cardiac events within 2 years will be 8%. Therefore, the estimated sample size is 3,750 participants.

The 2 sample sizes based on the 2 endpoints are similar, and with an estimated 8% dropout rate, the necessary sample size has been calculated to be 4,144.

Statistical Analysis Plan Statistical considerations vary according to the specific analysis performed and will be detailed in a prespecified statistical plan for each analysis. In general, continuous data will be summarized using measures such as the mean, standard deviation, median, first and third quartiles, and minimum and maximum values. Categorical data will be presented as frequencies (percentages) or contingency tables. Descriptive techniques that account for the length of the observation time will be used as appropriate. Multivariate analyses will be conducted using appropriate regression models based on the parameter distribution. Healthcare utilization measures will be analyzed using negative binomial or logistic regression, depending on the frequency of events. Time-to-event data will be analyzed using the Cox proportional hazards regression.

Unless stated otherwise, two-sided P values <0.05 will be considered statistically significant.

Discussion

To our knowledge, the PARACLETE study is a unique cohort of patients with HFmrEF/HFpEF, considering the broad inclusion criteria, timing of enrolment, and primary endpoints. First, the inclusion criteria based on elevated NP levels and structural abnormalities noted on cardiac echocardiograms are similar to the diagnostic algorithm described in the ESC and AHA/ACC/AHFS guidelines.^8,9 Thus, PARACLETE includes patients with more stable and early-stage HFmrEF/HFpEF or those newly diagnosed at enrolment. These patients are excluded from cohort studies on acute decompensated HF or recent RCTs. Thus, the PARACLETE study includes patients similar to those encountered in real-world practice. We have already enrolled 4,387 patients (42.8% female, age 77.3 years) with a mean LVEF of 60.5% and a median NT-proBNP of 453 pg/mL. Our cohort is assumed to have milder HF and a better prognosis than other RCTs or cohorts.

Second, the enrolment period in the PARACLETE study was from February 2022 to April 2024, just after new evidence for the treatment of HFpEF using ARNI or SGLT2i was reported.^4,6 The observation period is scheduled to be from December 2023 to October 2026. During enrolment, new guidelines for the management of HF such as the 2022 ACC/AHA/AHFS guidelines and the 2023 focused update of the 2021 ESC guidelines were published to determine the usefulness of SGLT2i and ARNI in the treatment of HFpEF.^8,10 Moreover, a statement on the recommendation for the appropriate use of SGLT2 inhibitors in the treatment of HF was presented in Japan.¹¹ Therefore, this study is the first registry to include patients with HFmrEF/HFpEF in the new era of SGLT2i and ARNI and will provide new evidence.

Third, one of the primary endpoints is the proportion of patients who have their HF medication modified and the distribution of reasons for prescription adjustments at enrolment. This information will provide insight into the treatment of patients with stable, mild, or newly diagnosed HFmrEF/HFpEF.

This study will also analyze the effects of changes in medical treatment on all-cause death and hospitalization because of HF during a 2-year follow-up period. These results may provide clinical information for planning a new RCT to elucidate the effect of new drugs on patients in the early phase of HFmrEF/HFpEF, which is closer to Stage B or pre-HF.

Conclusions

The PARACLETE study will provide a unique research opportunity to investigate the current treatment status and strategies for patients with HFmrEF/HFpEF in Japan.

Disclosures

K.K. is a member of Circulation Reports’ Editorial Team.

Funding

The PARACLETE study was funded by Novartis Pharma K.K. as an investigator-initiated trial program.

Declaration of Interest

The following relationships exist related to this study:

T.U, D.Y, A.S, K.S, M.N, M.I, and A.K do not have any conflicts of interest associated with this study.

K.K. has received lecture fees from Astellas Pharma Inc., AstraZeneca K.K., MSD K.K., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Kowa Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd. (Sumitomo Pharma Co., Ltd.), Mitsubishi Tanabe Pharma Corp., Eli Lilly Japan K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., and Janssen Pharmaceutical K.K.; funded research or joint research expenses from Kowa Co., Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., Amgen, Janssen Pharmaceutical K.K., Parexel International Inc., and Astellas Pharma Inc. His affiliated institution (Shinshu University School of Medicine) has received grants from Otsuka Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., and Kyowa Kirin Co., Ltd., and his department has endowed chairs from Medtronic Japan Co. Ltd., Boston Scientific Japan K.K., Abbott Japan LLC, Japan Lifeline Co., Ltd., Biotronik Japan, Terumo Corporation, Nipro Corporation, and Cordis Japan G.K.

S.H. has received lecture fees from Novartis Pharma K.K. and has a family member who is an employee of Novartis Pharma K.K.

K.O. received lecture fees from Novartis Pharma K.K, Nippon Boehringer Ingelheim Co., Ltd., Amgen, Mitsubishi Tanabe Pharma Corp., AstraZeneca K.K., Kyowa Kirin Co., Ltd., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd. Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Tsumura & Co., GlaxoSmithKline K.K., Bristol-Myers Squibb K.K., and CureApp Inc.

Y.S. received research funds from Otsuka Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Novartis Pharma K.K.; research expenses from Novartis Pharma K.K.; and speakers’ bureau/honorarium from Otsuka Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Novartis Pharma K.K.

IRB Information

The study protocol was approved by the Certified Review Board of Nara Medical University (3187).

References

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