How Medtronic’s Global Heart Failure Trial Explores Personalized Pacing for HFpEF

Heart failure with preserved ejection fraction (HFpEF) is one of cardiology’s most persistent clinical challenges. Despite accounting for about half of all heart failure cases globally and an estimated 32 million people worldwide, effective therapies remain limited.

Unlike heart failure with reduced ejection fraction (HFrEF), where the heart’s pumping capacity is diminished, HFpEF patients have a preserved ejection fraction but a stiff ventricle that prevents proper filling between beats. This leads to elevated filling pressures, fatigue, exercise intolerance and reduced quality of life.

The condition’s heterogeneity makes it particularly difficult to treat. It can arise from chronic hypertension, obesity, diabetes, infiltrative diseases, or the effects of aging, creating multiple disease pathways under one diagnosis. As a result, what works for one patient population may fail in another.

heart failure trial — Robert Kowal, MD, PhD
Vice President and General Manager
Cardiac Pacing Therapies
Medtronic

“It’s almost like HFpEF is a final common pathway for a lot of different things,” said Robert Kowal, MD, PhD, Vice President and General Manager of Medtronic’s Cardiac Pacing Therapies business. “Because of that heterogeneity, a one-size-fits-all approach doesn’t work. If you’re too broad, you can’t find an effective therapy; if you’re too restrictive, you’ll never find enough patients.”

That’s the challenge at the heart of Medtronic’s ELEVATE-HFpEF pivotal study, a first-of-its-kind global clinical trial exploring whether cardiac pacing, a well-established technology, can be harnessed in a new way to improve symptoms and quality of life in patients with preserved ejection fraction heart failure.

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Investigating a New Role for an Established Technology

For decades, pacemakers have been used to manage bradycardia and certain arrhythmias, and cardiac resynchronization therapy (CRT) has been effective in patients with HFrEF. But for HFpEF, pacing has not been part of the treatment conversation.

Dr. Kowal sees this as an opportunity to extend a mature, well-understood therapy into a completely new domain. “It’s incredibly exciting because it offers a fairly mature technology to be used in a different way,” he said.

Unlike CRT, which requires an additional lead to stimulate both ventricles, the ELEVATE-HFpEF study uses conduction system pacing (CSP).

CSP is a technique that activates the heart through its natural electrical pathways, producing a more physiologic beat. The pacing can occur at different, specific locations within the heart. When a pacemaker stimulates the left bundle branch area or the His bundle, for example, it coordinates the heart’s ventricles. When it stimulates the Bachmann’s bundle area, it coordinates the atria. Overall, CSP can, result in a more coordinated and efficient heartbeat.

“If it turns out to yield positive results, it offers the opportunity to bring the first new indication for pacing or for dual-chamber pacemakers in 30 to 40 years,” Dr. Kowal explained. “It could substantially grow the population of patients who benefit from pacing.

The Science Behind Personalized Pacing

Traditionally, HFpEF management has focused on slowing the heart rate to allow for more filling time. The ELEVATE-HFpEF trial flips that paradigm, testing whether slightly increasing the heart rate could reduce filling pressures and improve symptoms.

“What this trial is actually testing is the opposite,” said Dr. Kowal. “Do we actually want to speed up the heart rate, not too much, but enough to shorten filling time and lower pressures?”

What makes this approach distinctive is its personalized design. Each patient’s pacing rate is tailored to their ejection fraction and body size, recognizing that smaller individuals naturally require faster heart rates. This personalization is not only physiologically logical but also essential for ensuring appropriate treatment across genders.

“Women are often underrepresented and undertreated in cardiology trials. The way this trial is designed, because it’s a personalized heart rate, means that women are treated appropriately. Since there are more women with HFpEF, we’re hoping we will enroll more women than men and actually find an appropriate therapy.”

– Robert Kowal

Rigor and Innovation: Inside the ELEVATE-HFpEF Trial Design

The ELEVATE-HFpEF study will enroll up to 700 patients across North America, Europe, the Middle East, Africa, Australia, and Asia Pacific, representing one of the most geographically diverse heart failure studies to date.

The trial is also sham-controlled, a rare but rigorous design for device studies. Every participant receives a dual-chamber pacemaker, but only half are programmed to a personalized elevated pacing rate, while the other half receive a non-personalized backup pacing rate if needed.

After one year, the control group will cross over to the personalized program. This structure minimizes placebo effects and ensures all participants have access to potential benefits.

“It’s also important because we’re dealing with a quality-of-life endpoint,” Dr. Kowal said. “We didn’t want an artifactual benefit caused by the procedure itself. The sham control helps us ensure the outcomes are real.”

The study endpoints reflect a shift toward clinically meaningful outcomes beyond mortality, emphasizing quality of life factors like exercise capacity that matter most to patients living with chronic HFpEF.

Embedding Implementation Science from the Start

Dr. Kowal highlighted a concept often overlooked in trial design: implementation science. The goal is to design a study that can transition smoothly from research to clinical practice if successful.

“As you’re designing the trial, whether it’s endpoints, inclusion criteria or how you find patients, you’re trying to design it in a way that actually facilitates implementation of the workflow if and when the trial is positive and approved for broader use.”

– Robert Kowal

That meant keeping diagnostic and procedural criteria aligned with standard HFpEF guidelines and using common tools such as Holter monitoring to measure heart rates. “We’re not doing anything that requires a new diagnostic pathway afterward,” he noted.

By building real-world applicability into the trial itself, Medtronic hopes to accelerate the path from potential positive results to clinical implementation, a crucial step in ensuring patients benefit faster from innovation.

Conducting a Truly Global Study

Running a multinational study brings logistical challenges: coordinating regulatory submissions, navigating institutional review boards (IRBs) across regions and ensuring protocol consistency among dozens of countries.

“The challenges are real. You’ve got to have this footprint all around the world,” said Dr. Kowal. “But the benefit is that if the trial is positive, you can bring the therapy to patients globally, not piecemeal.”

By enrolling diverse populations from multiple continents, Medtronic aims to generate data that are representative and applicable worldwide. A unified trial design also helps prevent fragmentation of clinical guidelines. “You’re less likely to get into a situation where a US guideline says one thing and a European guideline says another,” he explained. “It can unify and make therapy much more consistent around the world.”

Rethinking Clinical Research for Speed and Relevance

Traditional randomized controlled trials remain the gold standard, but in medtech, where technology can evolve faster than data, speed and adaptability are essential.

Dr. Kowal emphasized that Medtronic is leveraging hierarchical endpoint design with a win-ratio model, ensuring every patient’s data contributes meaningfully. “Endpoints like quality of life, exercise capacity and other similar metrics are really important endpoints for these patients.”

He noted that in other Medtronic trials, the company has collaborated closely with the FDA to use advanced modeling and virtual patient groups, enabling adaptive designs that reduce sample size requirements and accelerate results

Digital health integration is another pillar of Medtronic’s approach. “In another trial called DEFINE-AF, we used a smartphone app to collect both objective and subjective patient data,” he shared. “There are a lot of ways we protect the rigor of the science while improving the speed at which we can get the data and reducing cost.”

Patient-Centered Design and Informed Participation

The ELEVATE-HFpEF trial was shaped directly by patient input. Medtronic convened panels of individuals with heart failure to discuss what mattered most to them, such as how long they would be comfortable remaining blinded before crossing over to therapy. “When we talked to regulatory agencies, we showed them the patient input,” Dr. Kowal said.

Beyond input, the company also prioritized reducing patient burden, limiting unnecessary follow-ups and procedures while maintaining rigorous data collection.

And because pacemakers are an established technology with well-characterized risk profiles, patient consent discussions are more transparent. “When you consent a patient, you can really give them a good sense of what the benefits might be and what the risks are,” said Dr. Kowal.

The Next Era of Cardiac Pacing

The ELEVATE-HFpEF trial is part of a larger wave of studies rethinking the role of pacing in cardiovascular care.

“About three and a half years ago, I switched from being the Medical Officer for the cardiac rhythm group to running the pacing business,” said Dr. Kowal. “This is exactly why I wanted to do that.”

Advances such as leadless pacing and conduction system pacing have improved pacing benefits and reduced risks, making new indications like HFpEF possible to explore.

Beyond ELEVATE-HFpEF, Medtronic is supporting additional investigational studies:

A strategic collaboration with Orchestra BioMed on BACKBEAT, a global pivotal trial evaluating pacing’s role in treating uncontrolled hypertension among patients who are already indicated for dual-chamber pacemakers.
Grant funding for studies on pacing for longstanding atrial fibrillation.

“The technology improvements drive this ability to expand pacing well beyond the reach of bradycardia,” he said. “If these investigational studies are positive, I think we’re going to see a kind of renaissance of pacing. In five to ten years, you could imagine a world where bradycardia is a minority of what pacemakers are used for, and there are many other applications.”

Advancing Cardiovascular Treatment Innovation Worldwide

If successful, Medtronic’s ELEVATE-HFpEF study could represent the first new pacing indication in four decades, and potentially a breakthrough for millions living with HFpEF.

“It’s incredibly exciting because it offers a mature technology used in a new way,” said Dr. Kowal.

By combining personalized pacing, global trial design and patient-informed science, Medtronic is not only testing a therapy but also reimagining how cardiovascular innovation reaches patients worldwide.