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Rationale and Design of the Proactive-HF Trial for Managing Patients With NYHA Class III Heart Failure by Using the Combined Cordella Pulmonary Artery Sensor and the Cordella Heart Failure System

Open AccessPublished:September 30, 2022DOI:https://doi.org/10.1016/j.cardfail.2022.09.006

      Highlights

      • The PROACTIVE-HF trial is designed to assess the benefit of personalized and proactive management of patients with class III heart failure (HF) guided by daily measurements of pulmonary artery pressure (PAP) pressures in combination with weight, blood pressure, heart rate, blood oxygen saturation, and symptoms.
      • The investigational Cordella Sensor System is designed to achieve high levels of patient engagement and compliance by the use of a small hand-held reader placed over an anteriorly implanted sensor, facilitating patient-friendly seated PAP measurements and a modern digital health app providing patients with timely education, real-time feedback and tools for easy 2-way communication with the care providers.
      • Key trial hypotheses are that HF management using PAP in combination with additional vital-sign parameters will provide the dual benefits of congestion management and GDMT optimization and that patient engagement and compliance will positively impact remote medical management decisions and patient outcomes.

      ABSTRACT

      Background

      Optimizing guideline-directed medical therapy (GDMT) and monitoring congestion in patients with heart failure (HF) are key to disease management and preventing hospitalizations. A pulmonary artery pressure (PAP)-guided HF management system providing access to body weight, blood pressure, heart rate, blood oxygen saturation, PAP, and symptoms, may provide new insights into the effects of patient engagement and comprehensive care for remote GDMT titration and congestion management.

      Methods

      The PROACTIVE-HF study was originally approved in 2018 as a prospective, randomized, controlled, single-blind, multicenter trial to evaluate the safety and effectiveness of the Cordella PAP Sensor in patients with HF and with New York Heart Association (NYHA) functional class III symptoms. Since then, robust clinical evidence supporting PAP-guided HF management has emerged, making clinical equipoise and enrolling patients into a standard-of-care control arm challenging. Therefore, PROACTIVE-HF was changed to a single-arm trial in 2021 with prespecified safety and effectiveness endpoints to provide evidence for a similar risk/benefit profile as the CardioMEMS HF System.

      Conclusion

      The single-arm PROACTIVE-HF trial is expected to further demonstrate the benefits of PAP-guided HF management of patients with NYHA class III HF. The addition of vital signs, patient engagement and self-reported symptoms may provide new insights into remote GDMT titration and congestion management.

      Key Words

      Approximately 6 million adult Americans live with heart failure (HF), and the projected prevalence is expected to increase to 8 million by 2030 as the population ages.
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      The economic burden of HF and related hospitalizations is substantial: 1%–2% of the total health care expenditures in the U.S. are allocated to HF, with inpatient admissions accounting for > 50% of this cost.
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      Once a patient has been diagnosed with HF, establishing appropriate pharmacological therapies and close monitoring of congestion development are key to management of the disease and preventing HF hospitalizations (HFHs).
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      The most common symptoms on admission for decompensated HF are dyspnea on exertion, orthopnea, fatigue, and peripheral edema. These symptoms reflect an acute or chronic increase in cardiac filling pressures or congestion.
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      It has been shown that in patients HF and with both reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF), a change in filling pressures can be detected weeks before hospitalization.
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      Persistent increases in filling pressures typically result in HF decompensation and HFH, whereas, when pressures remain stable, the risk of HFH is reduced.
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      Pulmonary artery pressure (PAP)-guided HF management has been shown to reduce HFH in patients with HF and New York Heart Association (NYHA) functional class III symptoms via a targeted treatment strategy of optimizing medical management to lower PAP actively.
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      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial.
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      • Brett ME
      • et al.
      Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF).
      • Shavelle DM
      • Desai AS
      • Abraham WT
      • Bourge RC
      • Raval N
      • Rathman LD
      • et al.
      Lower Rates of Heart Failure and All-Cause Hospitalizations During Pulmonary Artery Pressure-Guided Therapy for Ambulatory Heart Failure: One-Year Outcomes From the CardioMEMS Post-Approval Study.
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      The safety and effectiveness of PAP-guided HF management has been established in > 25,000 CardioMEMS device implants, including > 5000 patients in clinical trials from 2 randomized controlled trials,
      • Abraham WT
      • Adamson PB
      • Bourge RC
      • Aaron MF
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      • Stevenson LW
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial.
      ,
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      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      and > 2000 postmarket users; research results have been published in > 150 peer-reviewed journals. The 2021 European Society of Cardiology HF guidelines recommend (Class IIb) that monitoring of PAP by using a wireless hemodynamic monitoring system may be considered in symptomatic patients with HF to improve clinical outcomes.
      • McDonagh TA
      • Metra M
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      • Bohm M
      • et al.
      ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.
      The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines state that the usefulness of wireless monitoring of PAP to reduce the risk of subsequent HFHs in selected patients with NYHA class III symptoms is uncertain (Class IIb recommendation).
      • Heidenreich PA
      • Bozkurt B
      • Aguilar D
      • Allen LA
      • Byun JJ
      • Colvin MM
      • et al.
      AHA/ACC/HFSA Guideline for the management of Heart Failure.
      This less-certain recommendation incorporated the recent Hemodynamic-GUIDEd management of Heart Failure (GUIDE-HF) trial, which showed a significant benefit for PAP-guided treatment across all patient groups when a pre-COVID-19 analysis was performed, but it did not reach statistical significance when including post-COVID-19 follow-up.
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      In the CHAMPION trial, more than twice as many medication changes occurred in the treatment group compared with the control group during the 6-month follow-up, with diuretics being the most frequently adjusted medications in both groups (60.4% of all HF medication changes). Changes in direct vasodilators and GDMT neurohormonal antagonists also favored the treatment arm, although these medication changes were much less frequent than diuretic changes.
      • Costanzo MR
      • Stevenson LW
      • Adamson PB
      • Desai AS
      • Heywood JT
      • Bourge RC
      • et al.
      Interventions Linked to Decreased Heart Failure Hospitalizations During Ambulatory Pulmonary Artery Pressure Monitoring.
      Similarly, in the GUIDE-HF trial, more medication changes were made in the treatment group compared with the control group, although it is unclear whether this difference is significant, and individual medications were not reported. When examining the proportion of patients on GDMT at baseline and then after 12 months in the treatment arm, there was no significant difference in GDMT use over 1 year.
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      The Cordella PAP Sensor (Endotronix, Lisle, IL) was designed to enable patient-centric PAP-guided HF management and to assist clinicians in implementing GDMT titration and congestion management in a real-world setting (Fig. 1, A–F). Cordella provides comprehensive clinical information remotely, including PAP, body weight, blood pressure (BP), heart rate (HR), blood oxygen saturation (SpO2), and self-reported symptoms, and it has been shown to enable safe and accurate remote monitoring of PAP in the Head-to-Head Comparison of SIROlimus versus Paclitaxel Drug-Eluting BallooNAngioplasty in the Femoropopliteal Artery (SIRONA 1 [NCT03375710]) and SIRONA 2 (NCT04012944) trials.
      • Mullens W
      • Sharif F
      • Dupont M
      • Rothman AMK
      • Wijns W.
      Digital health care solution for proactive heart failure management with the Cordella Heart Failure System: results of the SIRONA first-in-human study.
      ,
      • Sharif F
      • Rosenkranz S
      • Bartunek J
      • Kempf T
      • Assmus B
      • Mahon NG
      • Mullens W.
      Safety and efficacy of a wireless pulmonary artery pressure sensor: primary endpoint results of the SIRONA 2 clinical trial.
      The system is designed to maximize patient engagement with modern digital health tools by providing both vital signs and PAP trends, timely feedback to the patient, and easy communication between patient and provider, all via a single smart tablet (Fig. 1, D–E) The PAP-reading experience has been enhanced by the design of a small, hand-held reader, held over the anterior right chest, which can be used in either a seated or a supine posture (Fig. 1, C). The implant procedure is similar to the CardioMEMS procedure
      • Shavelle D
      • Jermyn R.
      The CardioMEMS Heart Failure Sensor: A Procedural Guide for Implanting Physicians.
      with specific differences that enable anterior PAP readings from a seated posture.
      • Mullens W
      • Sharif F
      • Dupont M
      • Rothman AMK
      • Wijns W.
      Digital health care solution for proactive heart failure management with the Cordella Heart Failure System: results of the SIRONA first-in-human study.
      Besides showing safety and effectiveness, the clinical trials have established the patient-centric experience, demonstrating over 94% patient adherence to daily measurement and transmission of vital signs and PAP sensor readings.
      • Mullens W
      • Sharif F
      • Dupont M
      • Rothman AMK
      • Wijns W.
      Digital health care solution for proactive heart failure management with the Cordella Heart Failure System: results of the SIRONA first-in-human study.
      ,
      • Sharif F
      • Rosenkranz S
      • Bartunek J
      • Kempf T
      • Assmus B
      • Mahon NG
      • Mullens W.
      Safety and efficacy of a wireless pulmonary artery pressure sensor: primary endpoint results of the SIRONA 2 clinical trial.
      Furthermore, in the SIRONA 2 trial, patients were instructed to take daily seated and supine PAP readings for the first 3 months and, upon being surveyed about their postural preference, 84% preferred seated compared to supine readings.
      • Sharif F
      • Rosenkranz S
      • Bartunek J
      • Kempf T
      • Assmus B
      • Mahon NG
      • Mullens W.
      Safety and efficacy of a wireless pulmonary artery pressure sensor: primary endpoint results of the SIRONA 2 clinical trial.
      The PROACTIVE-HF study (NCT04089059) was designed to assess whether the favorable clinical results of previous PAP-guided HF management trials are replicable with the Cordella PA sensor system across diverse health care settings in the U.S. and Europe. PROACTIVE-HF trial is testing the hypothesis that targeted pharmacological intervention to lower and maintain a target range of PAP, combined with a comprehensive patient-centric design, can enable low rates of mortality and HFH in patients with New York Heart Association (NYHA) functional class III symptoms at high risk of congestion based on a history of HFH or elevated N-terminal (NT) pro B-type natriuretic peptide (NT-proBNP).
      This article outlines the original study design and rationale for the PROACTIVE-HF randomized control trial and, subsequently, the re-design and its associated rationale.

      Methods

      Original Randomized Control Trial Rationale

      The original FDA-approved investigational device exemption (IDE) study design in 2018 for PROACTIVE-HF was a prospective, randomized, controlled, single-blind, multicenter clinical trial designed to evaluate the safety and effectiveness of the Cordella PA Sensor in patients with NYHA functional class III HF. The Institutional Review Board of each participating center approved the study protocol, each patient provided written informed consent, and events are adjudicated by a Clinical Endpoint Committee. At the time of original study approval, CHAMPION-HF
      • Abraham WT
      • Adamson PB
      • Bourge RC
      • Aaron MF
      • Costanzo MR
      • Stevenson LW
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial.
      was the only prospective clinical trial available, necessitating PROACTIVE-HF to include randomized evidence to establish effectiveness in this patient population.
      All patients enrolled into PROACTIVE-HF received the Cordella PA sensor, implanted in their right pulmonary artery (PA) (Fig. 1, A). After the procedure, patients in the original trial were randomized to either a treatment or a control group at a ratio of 1:1. Both groups were instructed to take their daily PAP measurements along with their weight, BP, HR, SpO2, and symptoms by using Bluetooth-connected peripherals (Fig. 1, B). Readings were automatically uploaded by using a tablet. Patient information and daily readings were stored and accessed on a dedicated website, the myCordella Patient Management Platform (PMP), which is a secure cloud-based platform used by the health care providers to review data, manage patients and capture clinical decisions. All readings (weight, BP, HR, SpO2, symptoms, and PAP) were visible and accessible to the health care providers of the treatment-arm cohort, whereas only the vital signs were accessible to the patients. In the control arm, vital signs only (weight, BP, HR, SpO2, and symptoms) were visible and accessible to the patients and health care providers. After 12 months, providers in the control arm were unblinded to PAP data, and patients in both arms were able to see their own PAP measurements. In this initial design, the primary endpoint was all-cause mortality, HFH and the need for unscheduled emergency department/outpatient intravenous (IV) diuretic treatment at 12 months. The original PROACTIVE-HF trial assumed a 12-month mortality rate in the control group of 0.15 events per patient-year (EPPY) with an HFH rate of 0.60 EPPY with the expectation that treatment might lower the 12-month mortality rate to 0.14 EPPY and HFH to 0.45 EPPY. The sample size calculation for the study required 900 patients and a threshold of 970 enrolled subjects to account for possible early discontinuations. Calculation was based on 80% power and a 1-sided alpha of 0.025. The first subject was implanted in February 2020. As outlined below, blinding of patients and practitioners was removed from protocol in December 2021, and the above sample-size calculations were revised to meet the new trial design.

      Major Inclusion/Exclusion Criteria

      Major inclusion/exclusion criteria are listed in Table 1; they are similar to those previously reported for SIRONA 2 and GUIDE-HF.
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      ,
      • Sharif F
      • Rosenkranz S
      • Bartunek J
      • Kempf T
      • Assmus B
      • Mahon NG
      • Mullens W.
      Safety and efficacy of a wireless pulmonary artery pressure sensor: primary endpoint results of the SIRONA 2 clinical trial.
      In brief, adults with a diagnosis of HFrEF or HFpEF and NYHA functional class III symptoms are eligible for enrollment in PROACTIVE-HF if they are treated with optimal dosages of GDMT for a minimum of 3 months (stable dosages at least 30 days prior to enrollment), and the patient had either 1 HFH within the last year or a persistently elevated NT-proBNP level at the time of screening. The PROACTIVE-HF trial is designed to ensure the inclusion of moderately congested patients with HF and with higher risk of congestion-related events who have an NT-proBNP levels > 1500 pg/mL (for a left ventricular ejection fraction [LVEF] < 50%) and > 800 pg/mL (for an LVEF 50%). The congestion cut-off for NT-proBNP is higher than that of the GUIDE-HF trial,
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      which used NT-proBNP levels > 1000 pg/mL (for an LVEF ≤ 50%) and > 700 pg/mL (for an LVEF 50%). A correction for body mass index (BMI) is applied as a 4% reduction per BMI unit that exceeds 25 kg/m2. The study's eligibility committee reviews and approves all potential patients prior to enrollment and implant.
      Table 1Inclusion/Exclusion for PROACTIVE-HF
      Inclusion CriteriaExclusion Criteria
      1. Subject has given written informed consent.1. Intolerance to all neuro-hormonal antagonists (ie, ACE-I, ARB, ARNI, and beta-blockers due to hypotension or renal dysfunction
      2. ACC/AHA Stage D refractory HF (including having received or currently receiving pharmacological circulatory support with inotropes)
      2. Male or female, at least 18 years of age3. Subjects with history of recurrent pulmonary embolism (≥2 episodes within 5 years prior to screening visit) and/or deep-vein thrombosis (<3 months prior to screening visit)
      4. Subjects who have had a major cardiovascular (CV) event (eg, myocardial infarction, stroke) within 3 months of the screening visit
      3. Diagnosis and treatment of HF (regardless of LVEF) for ≥3 months and NYHA Class III HF at the time of screening5. Unrepaired severe valvular disease
      6. Subjects with congenital heart disease or mechanical/tissue right heart valve(s)
      4. Subjects should be on stable, optimally titrated medical therapy for at least 30 days, as recommended according to current American Heart Association (AHA)/American College of Cardiology (ACC) guidelines as standard-of-care for heart failure therapy in the United States, or current European Society of Cardiology (ESC) guidelines for heart failure treatment in Europe, with any intolerance documented.7. Subjects with known coagulation disorders
      8. Subjects with a hypersensitivity or allergy to platelet aggregation inhibitors, including aspirin, clopidogrel, prasugrel, and ticagrelor; or patients unable to take dual antiplatelet or anticoagulants for 1 month post implant
      5. HF-related hospitalization, HF treatment in a hospital day-care setting, or urgent outpatient clinic HF visit for IV diuretics within 12 months (last hospitalization should be 30 days before screening/enrollment) and/or N-terminal pro B-type Natriuretic Peptide (NT-proBNP) at time of screening/enrollment defined as:

      a. Subjects with LVEF ≤50%: NT-proBNP ≥1500 pg/mL.

      b. Subjects with LVEF >50%: NT-proBNP ≥ 800 pg/mL

      Thresholds for NT-proBNP (for both LVEF ≤50% and LVEF >50%) will be corrected for body mass index (BMI) using a 4% reduction per BMI unit over 25 kg/m2.
      9. Known history of life-threatening allergy to contrast dye
      10. Subjects whereby RHC is contraindicated
      6. Subjects should be on diuretic therapy.11. Subjects with an active infection at the Cordella PA sensor implant visit
      12. Subjects with a glomerular filtration rate (GFR) <25 mL/min or who are on chronic renal dialysis
      7. Subjects who are physically able to hold the myCordella Patient Reader unit (approximate weight 1.3 lb) against the ventral thoracic surface for up to 2 minutes per day while in a seated or standing position, as well as dock and undock the myCordella Patient Reader13. Implanted with cardiac resynchronization therapy (CRT)-pacemaker (CRT-P) or CRT-defibrillator (CRT-D) for fewer than 90 days prior to screening visit
      14. Received or are likely to receive an advanced therapy (eg, mechanical circulatory support or lung or heart transplant) in the next 12 months
      8. Subjects with sufficient eyesight, hearing and mental capacity to respond to the myCordella Patient Reader's audio/visual cues and operate the myCordella Patient Reader15. Subjects who are pregnant or breastfeeding
      16. Subjects who are unwilling or deemed by the investigator to be unwilling to comply with the study protocol or subjects with a history of noncompliance
      9. Subject has sufficient cellular and/or Wi-Fi Internet coverage at home.17. Severe illness, other than heart disease, that would limit survival to <1 year
      18. Subjects whose clinical condition, in the opinion of the investigator, makes them unsuitable candidates for the study
      10. Subject agrees to return to the investigator for all scheduled follow-up visits and can return to the hospital for follow-up.19. Subjects enrolled in another investigational trial with an active treatment arm
      20. Subject who is in custody by order of an authority or a court of law
      Following implant, patients are asked to measure their PAP daily (typically at the same time each morning), along with their weight, BP, HR, SpO2, and symptoms, and send them by secure wireless transmission. Clinicians are instructed to access the PMP at least once every 4 days and to treat patients per the trial-specific treatment guidelines. Patients are contacted weekly during the first month and then monthly thereafter and as needed for medication changes. Follow-up visits are performed in person at 1, 6, 12, 18, 24, and 36 months, with a virtual visit at 3 months. At each visit, patients undergo physical examination, including assessment of their concurrent medications, blood tests (full blood count, renal/liver function tests, coagulation profile, and NT-proBNP), urinalysis, reassessment of NYHA functional class, administration of the Kansas City Cardiomyopathy Questionnaire (KCCQ),
      • Spertus JA
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      Interpreting the Kansans City Cardiomyopathy Questionnaire in clinical trials and clinical care.
      a 6-minute walk test (6MWT),
      • Salzman SH.
      The 6-min walk test: clinical and research role, technique, coding, and reimbursement.
      and determination of adverse events. Echocardiography is performed at screening, 12 months and 36 months.
      A central element of the trial is the treatment guidelines or the management strategy used to optimize and maintain GDMT, with intervention designed to lower PAP to a target range representative of a state of euvolemia. The aim of treatment is the optimization of medical therapies (angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs] or angiotensin receptor-neprilysin inhibitors [ARNIs], beta-blockers, mineralocorticoid receptor antagonists [MRAs], diuretics, and sodium/glucose cotransporter-2 inhibitors [SGLT2is]), as appropriate for HF as classified by LVEF, which are then to be titrated against specific mean pulmonary artery pressure (mPAP) targets or mPAP trends (Fig. 2). For the purposes of patient management, changes in seated mPAP trends, defined as a 7-day average of daily means, are monitored with a target seated mPAP goal between 5–20 mmHg.
      • Kovacs G
      • Berghold A
      • Scheidl S
      • Olschewski H.
      Pulmonary arterial pressure during rest and exercise in healthy subjects: a systemic review.
      In order for the 7-day average to be calculated, there must be no more than 2 consecutive missed readings or 3 or fewer total missing readings in any 7-day moving window. Clinicians may observe and treat based on systolic PAP (sPAP), mPAP, and/or diastolic PAP (dPAP), or even PAP measurements in the supine posture,
      • Sharif F
      • Rosenkranz S
      • Bartunek J
      • Kempf T
      • Assmus B
      • Mahon NG
      • Mullens W.
      Safety and efficacy of a wireless pulmonary artery pressure sensor: primary endpoint results of the SIRONA 2 clinical trial.
      but the standardized treatment guideline notifications via the PMP are based on the 7-day average of seated mPAP only. As mentioned, clinicians are required to acknowledge data at least once every 4 days. It is expected that this approach, a moving average filter and the timeliness of data review, will address diurnal PAP variability
      • Sethi P
      • Lancaster P
      • Stack B
      • et al.
      Diurnal variation of pulmonary artery pressure in ambulatory heart failure patients.
      and be responsive to any trend toward rapid increases in mPAP, which may be observed in cases of HFpEF.
      • Anderson MJ
      • Borlaug BA.
      Invasive hemodynamic characterization of heart failure with preserved ejection fraction.
      ,
      • Hsu S
      • Fang JC
      • Borlaug BA.
      Hemodynamics for the Heart Failure Clinician: A State-of-the-Art Review.
      In PROACTIVE-HF, clinicians are encouraged to follow GDMT guidelines closely in order to titrate medical therapies to mPAP thresholds while considering the vital-sign measurements. This protocol differs from the CHAMPION
      • Abraham WT
      • Adamson PB
      • Bourge RC
      • Aaron MF
      • Costanzo MR
      • Stevenson LW
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial.
      and GUIDE-HF
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      trials, where the use of medications and the dosages prescribed to reach target PAP thresholds were based upon PAP alone. The automated web-based PMP data system used in PROACTIVE-HF flags those patients whose PAP falls outside of a predetermined range and in whom actionable interventions are required. Along with diuretic management, the addition of concurrent vital sign information available to PROACTIVE-HF providers may promote more favorable adjustments in GDMT.

      Subsequent Events and Rationale for Trial-Design Change

      Following the design of the trial, several events occurred necessitating a change in trial design. First, new prospective clinical evidence was published in 2019–2021, and it consistently demonstrated a positive clinical benefit in patients with NYHA functional class III.
      • Angermann CE
      • Assmus B
      • Anker SD
      • Asselbergs FW
      • Brachmann J
      • Brett ME
      • et al.
      Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF).
      • Shavelle DM
      • Desai AS
      • Abraham WT
      • Bourge RC
      • Raval N
      • Rathman LD
      • et al.
      Lower Rates of Heart Failure and All-Cause Hospitalizations During Pulmonary Artery Pressure-Guided Therapy for Ambulatory Heart Failure: One-Year Outcomes From the CardioMEMS Post-Approval Study.
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      Second, PAP-guided HF management therapy became more widely reimbursed and accessible to patients outside of a clinical-trial setting. Last, the COVID-19 pandemic altered the clinical-trial landscape, changing patients’ and human behavior broadly and impacting trial timelines and the willingness of patients to subject themselves to risk without the potential for immediate clinical benefit.
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      With the new evidence supporting the benefit of PAP-guided HF management in patients recently hospitalized as being in NYHA class III, there were equipoise challenges in the randomized trial from a clinical perspective, as practitioners wanted unblinded access to PAP measurements. Additionally, with a PAP-guided HF management technology widely and readily available (CardioMEMS), study recruitment was hampered by patients’ apprehension about enroll in a blinded trial.
      To this end, in December 2021, following consultation with the Food and Drug Administration (FDA), PROACTIVE-HF was changed to a single-arm trial with prespecified safety and effectiveness endpoints to provide objective evidence of a similar risk/benefit profile to the CardioMEMS HF system in patients in NYHA class III (Fig. 3).
      Fig 3
      Fig. 3Subject crossover from randomized, controlled to single-arm design.

      Former Control Group

      At the time of crossover to a single-arm trial, patients in the former control group (Cohort A) were unblinded, and both patients and clinicians immediately received access to daily PAP data. Patient-education material and a longitudinal survey to assess patients’ experience and knowledge of their PAP data were sent out. Follow-up of patients will occur through the 3-year study period. These patients will contribute to the safety but not the effectiveness endpoint. Patients enrolled in the former control group prior to crossover numbered 72.

      Former Treatment Group Plus Newly Enrolled Treatment Group

      Patients in the former treatment group (Cohort B) will continue follow-up per protocol. All newly enrolled patients are treatment patients (Cohort C). Former treatment-group patients plus newly enrolled patients (Cohort B plus Cohort C) will contribute to the safety and effectiveness endpoints. Seventy-six patients were enrolled in the former treatment group prior to crossover, and the event rates of this cohort will remain blinded through the primary endpoint of the single arm.
      All patients will maintain the same contact schedule as the original PROACTIVE-HF design: contacted weekly during the first month and then monthly thereafter and as needed for medication changes. Follow-up visits are performed in person at 1, 6, 12, 18, 24, and 36 months, with a virtual visit at 3 months.

      Statistical Considerations

      To establish effectiveness, the results of individual CardioMEMS studies and an internally derived meta-analysis were considered in determining the primary endpoint performance goal (PG) for the redesigned study. The meta-analysis was performed in the combined cohorts of CHAMPION-HF, CardioMEMS post-approval study, MEMS-HF, GUIDE-HF (NYHA Class III cohort), and LAPTOP-HF (control group only).
      • Abraham WT
      • Adamson PB
      • Bourge RC
      • Aaron MF
      • Costanzo MR
      • Stevenson LW
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial.
      • Angermann CE
      • Assmus B
      • Anker SD
      • Asselbergs FW
      • Brachmann J
      • Brett ME
      • et al.
      Pulmonary artery pressure-guided therapy in ambulatory patients with symptomatic heart failure: the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF).
      • Shavelle DM
      • Desai AS
      • Abraham WT
      • Bourge RC
      • Raval N
      • Rathman LD
      • et al.
      Lower Rates of Heart Failure and All-Cause Hospitalizations During Pulmonary Artery Pressure-Guided Therapy for Ambulatory Heart Failure: One-Year Outcomes From the CardioMEMS Post-Approval Study.
      ,
      • Abraham WT
      • Adamson PB
      • Costanzo MR
      • Eigler N
      • Gold M
      • Klapholz M
      • et al.
      Hemodynamic Monitoring in Advanced Heart Failure: Results from the LAPTOP-HF Trial.
      To meet the new objectives of the study, observed event rates in the single-arm PROACTIVE-HF should be similar to observed event rates in the treatment arm of CardioMEMS studies and lower than observed event rates in the control arm of CardioMEMS studies. Therefore, we set the PG below the meta-analysis upper bound 95% confidence interval of CardioMEMS-treated patients and below the meta-analysis estimates of CardioMEMS control patients and adjusted the goal downward to account for a potential impact of treatment with SGLT2i. Furthermore, we also required that the single-arm PROACTIVE-HF observed event rate be lower than both the meta-analysis estimate of CardioMEMS-treatment patients, and the lowest observed event rates of CardioMEMS control patients, further adjusted down by the potential impact of SGLT2i.
      • Nassif ME
      • Qintar M
      • Windsor SL
      • Jermyn R
      • Shavelle DM
      • Tang F
      • et al.
      Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial.
      Thus, for the primary endpoint of HFH and all-cause mortality (HFH/D) at 6 months, the PG is 0.43 events per patient per 6-months and the observed value must be lower than 0.37 events per patient at 6 months. For the powered secondary endpoint of HFH/D at 12 months, the PG is 0.70 EPPY, and the observed value must be lower than 0.59 EPPY.

      Primary Endpoint

      The assumed PROACTIVE-HF population 6-month event rate of HFH/D is expected to be 0.34. This assumed event rate is lower than all prior active CardioMEMS treatment rates except for GUIDE-HF.
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      Although the contemporary GUIDE-HF study observed a 6-month event rate of 0.31 in patients with NYHA class III, PROACTIVE-HF has higher NT-proBNP thresholds than the GUIDE-HF cohort, and we expect subjects with higher NT-proBNP levels to more closely align with subjects with recent HFHs who have higher event rates.
      • Bello NA
      • Claggett B
      • Desai AS
      • McMurray JJV
      • Granger CB
      • Yusuf S
      • et al.
      Influence of previous heart failure hospitalizations on cardiovascular events in patients with reduced and preserved ejection fraction.
      The null hypothesis will be rejected if the upper confidence bound for the rate is less than the PG of 0.43 or, equivalently, that the corresponding P value from the hypothesis test is less than 0.025. An observed event rate of fewer than 0.37 events per patient at 6 months and rejection of the null hypothesis indicate that the observed rate is statistically less than the PG, indicating clinically acceptable results and study success. The added requirement for the observed event rate to be less than 0.37 provides further assurance that results are comparable to the results of studies of prior CardioMEMS treatment. The study will implant 450 subjects (Cohort B + Cohort C), leading to an expected evaluable cohort of 406 subjects. With a PG of 0.43 events per patient 6-months and a 1-sided 0.025 alpha level, the study will have greater than 80% power, assuming a population treatment rate of 0.34 events per patient 6-months.

      Secondary Endpoint

      Similarly, the assumed single-arm PROACTIVE-HF population 12-month HFH/D event rate is expected to be 0.55. This assumed event rate is lower than all prior active CardioMEMS treatment rates except for GUIDE-HF (where the event rate was 0.52 EPPY).
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      The rationale for this is the same as for the primary endpoint analysis. A value of 0.70 EPPY will be used for the PG. The null hypothesis will be rejected if the upper confidence bound for the rate is less than the PG or, equivalently, that the corresponding P value from the hypothesis test is less than 0.025. An observed value of less than 0.59 EPPY and rejection of the null will indicate that the observed rate is statistically less than the PG, indicating clinically acceptable results. Analysis will use the same method as used in the primary endpoint.

      Safety Assessments

      There are 2 primary safety endpoints. First, freedom from device- or system-related complications at 6 months will be tested against the null rate of 90%. Second, freedom from pressure-sensor failure at 6 months will be tested against the null rate of 95%. Both primary safety endpoints are assessed as binary (Y/N) through 6 months. In addition to the 2 primary safety endpoints with hypothesis tests, the following secondary safety endpoints will be summarized: pressure-sensor failure rate throughout the study, frequency of serious adverse events (SAEs) throughout the study, and frequency of implant procedure and procedure-related adverse events (Aes) and SAEs.
      In addition to the above, several secondary endpoints will also be investigated. Notably, HFH rate, all-cause mortality rate, and emergency department/outpatient intravenous diuretic visits will be assessed separately and in various combinations at the 6-, 12-, 18-, 24-, and 36-month time points. Additionally, changes in NT-proBNP, days alive out of hospital, all medication changes, change in PAP from baseline, and change in PAP before and after exercise will be analyzed. Finally, KCCQ, NYHA, 6MWT will be assessed at each time point, and an overall health-economic analysis will be made.

      Discussion

      Optimization of GDMT involves titration of multiple evidence-based medications at proven target dosages and yields a reduction in HFH and mortality when fully implemented.
      • Srivastava PK
      • DeVore AD
      • Hellkamp AS
      • Thomas L
      • Albert NM
      • Butler J
      • et al.
      Heart Failure Hospitalizations and Guideline-Directed Prescribing Patterns Among Heart Failure With Reduced Ejection Fraction Patients.
      ,
      • Packer M
      • Poole-Wilson PA
      • Armstrong PW
      • Cleland JG
      • Horowitz JD
      • Massie BM
      • et al.
      Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group.
      Despite directives regarding GDMT use, the CHAMP-HF registry, which assessed outpatient management of patients with stable HFrEF, confirmed that in the majority of patients, significant gaps in the use and dosage of GDMT remain.
      • Greene SJ
      • Butler J
      • Albert NM
      • DeVore AD
      • Sharma PP
      • Duffy CI
      • et al.
      Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry.
      Even in patients whose treatment tolerance is challenging, titration to the highest possible dosage is still critical, and lack of such implementation has been associated with poorer outcomes.
      • Srivastava PK
      • DeVore AD
      • Hellkamp AS
      • Thomas L
      • Albert NM
      • Butler J
      • et al.
      Heart Failure Hospitalizations and Guideline-Directed Prescribing Patterns Among Heart Failure With Reduced Ejection Fraction Patients.
      Hence, the aim of the single-arm PROACTIVE-HF trial is to use PAP-guided HF management plus vital-sign measurement and self-reported symptoms as a multisystem care delivery model rather than just a reactive PAP remote-monitoring measurement tool.
      Treatment guidelines that combine GDMT with diuretic management, as enabled by the Cordella PA sensor system, provide a more comprehensive approach to the management of patients’ health. PROACTIVE-HF is similar to prior studies of PAP-guided HF management,
      • Abraham WT
      • Adamson PB
      • Bourge RC
      • Aaron MF
      • Costanzo MR
      • Stevenson LW
      • et al.
      Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomized controlled trial.
      ,
      • Lindenfeld J
      • Zile MR
      • Desai A
      • Bhatt K
      • Ducharme A
      • Horstmanshof D
      • et al.
      Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.
      where active pharmacological management is suggested to reduce PAP to a euvolemic target range, with some important differences. The treatment guidelines in PROACTIVE-HF are designed around seated mPAP instead of supine PAP, although the Cordella system enables either posture. The majority of patients prefer the seated position,
      • Sharif F
      • Rosenkranz S
      • Bartunek J
      • Kempf T
      • Assmus B
      • Mahon NG
      • Mullens W.
      Safety and efficacy of a wireless pulmonary artery pressure sensor: primary endpoint results of the SIRONA 2 clinical trial.
      which may lead to higher levels of sustained engagement and compliance. In addition to patients’ preferences and engagement, the seated posture represents a different physiological state, which may be more closely representative of daily living.
      • Raeside DA
      • Chalmers G
      • Clelland J
      • Mafhok R
      • Peacock AJ.
      Pulmonary artery pressure variation in patients with connective tissue disease: 24 hour ambulatory pulmonary artery pressure monitoring.
      Unlike prior PAP-guided HF management trials in which PAP is the sole physiological metric available from the patients’ homes, PROACTIVE-HF patients also transmit vital signs (weight, BP, HR, and SpO2) and symptoms, along with daily PAP. Preventing and managing congestion events by targeting treatment to lower PAP is still the aim in PROACTIVE-HF and, therefore, PAP remains the main trigger of action driving proactive therapy delivery. However, with the additional knowledge of vital signs and symptoms, the appropriate treatment may not always be an immediate diuretic change, which was the usual course of therapy in prior studies of PAP-guided HF management.
      • Costanzo MR
      • Stevenson LW
      • Adamson PB
      • Desai AS
      • Heywood JT
      • Bourge RC
      • et al.
      Interventions Linked to Decreased Heart Failure Hospitalizations During Ambulatory Pulmonary Artery Pressure Monitoring.
      Treatment guidelines in PROACTIVE-HF are triggered by PAP levels, yet clinicians are first encouraged to address precipitating factors underlying congestion, such as lifestyle issues and noncompliance with medications, in addition to targeted medication adjustments. Additionally, the inclusion of chemistry panels following medication changes, as outlined in Fig. 2, will also factor into clinical decision making. To better understand how and why clinicians may adjust medications differently with both PAP and vital-sign information available, PROACTIVE-HF is capturing documented reasons behind deviations from the recommended treatment guidelines.
      Another important component of the Cordella system is patients’ engagement. The system was designed to improve patients’ engagement with modern digital health tools by providing both vital-sign and PAP trends, feedback to the patients, and easy communication between patients and providers, all via a single smart tablet. The PAP reading experience has also been enhanced with the design of a small, hand-held reader, held at the anterior chest, easing PAP readings. The former control group (Cohort A) will further investigate patient engagement once patients have access to daily PAP and vital sign trend data.

      Conclusion

      The PROACTIVE-HF trial is expected to demonstrate further the benefits of PAP-guided HF management in patients in NYHA Class III by providing new insights into the effects of patients’ engagement and comprehensive care, including vital signs and patients’ symptoms, on remote medical-management decisions and patients’ outcomes.

      Author headshot photograph

      Liviu Klein

      Funding

      Endotronix.

      Conflicts of Interest

      Omid Forouzan, Nicholas J. Hiivala, Andrea Sauerland, and Katrin Leadley are employees of Endotronix. All other authors report no financial relationships or conflicts of interest regarding the content herein.

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