Beta blockers, the standard treatment after a heart attack, may offer no benefit for heart attack patients and women can have worse outcomes
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"REBOOT Trial" shows beta blockers—drugs commonly prescribed for heart attacks—may offer no clinical benefit for these patients
view moreCredit: Mount Sinai Health System
Beta blockers—drugs commonly prescribed for a range of cardiac conditions, including heart attacks—provide no clinical benefit for patients who have had an uncomplicated myocardial infarction with preserved heart function. Beta blockers have been the standard treatment for these patients for 40 years.
This is a breakthrough discovery from the “REBOOT Trial” with senior investigator Valentin Fuster, MD, PhD, President of Mount Sinai Fuster Heart Hospital and General Director of Spain’s Centro Nacional de Investigaciones Cardiovasculares (CNIC). The study results, which could overturn a standard treatment paradigm, were presented on Saturday, August 30, during a “Hot Line” session at the European Society of Cardiology Congress in Madrid, and simultaneously published in The New England Journal of Medicine.
Additionally, a REBOOT substudy, published Saturday, August 30, in the European Heart Journal, shows that women treated with beta blockers had a higher risk of death, heart attack, or hospitalization for heart failure compared to women not receiving the drug. Men did not have this increased risk.
“This trial will reshape all international clinical guidelines. It joins other previous landmark trials led by CNIC and Mount Sinai—such as SECURE with the polypill and DapaTAVI, with SLT2 inhibition associated to TAVI—that have already transformed some global approaches to cardiovascular disease,” says Dr. Fuster.
The SECURE trial showed a polypill, a single pill that that combines three medications - which contains aspirin, ramipril, and atorvastatin – reduces cardiovascular events by 33 percent in patients treated with this after a heart attack. The DapaTAVI trial showed both dapagliflozin and the related medication empagliflozin - drugs used to treat diabetes- improves the prognosis of patients with aortic stenosis treated by transcatheter aortic valve implantation.
“REBOOT will change clinical practice worldwide,” says Principal Investigator Borja Ibáñez, MD, CNIC’s Scientific Director, who presented the results. “Currently, more than 80 percent of patients with uncomplicated myocardial infarction are discharged on beta blockers. The REBOOT findings represent one of the most significant advances in heart attack treatment in decades.”
Although generally considered safe, beta blockers can cause side effects such as fatigue, bradycardia (low heart rate), and sexual dysfunction. For more than 40 years, beta blockers have been prescribed as a standard treatment after a heart attack, but their benefit in the context of modern treatments was unproven. The REBOOT trial, is the largest clinical trial on this subject. The international study was coordinated by CNIC in collaboration with the Mario Negri Institute for Pharmacological Research in Milan.
Researchers enrolled 8,505 patients across 109 hospitals in Spain and Italy. Participants were randomly assigned to receive or not receive beta blockers after hospital discharge. All patients otherwise received the current standard of care and were followed for a median of nearly four years. The results showed no significant differences between the two groups in rates of death, recurrent heart attack, or hospitalization for heart failure.
A REBOOT subgroup analysis found that women treated with beta blockers experienced more adverse events. Results show women treated with beta-blockers had a 2.7 percent higher absolute risk of mortality compared to those not treated with beta-blockers during the 3.7 years of follow-up of the study. The elevated risk when treated with beta-blockers was restricted to women with a complete normal cardiac function after a heart attack (left ventricular ejection fraction of 50 percent or higher). Those with a mild deterioration in cardiac function did not have an excess risk of adverse outcomes when treated with beta-blockers.
“After a heart attack, patients are typically prescribed multiple medications, which can make adherence difficult,” explains Dr. Ibáñez. “Beta blockers were added to standard treatment early on because they significantly reduced mortality at the time. Their benefits were linked to reduced cardiac oxygen demand and arrhythmia prevention. But therapies have evolved. Today, occluded coronary arteries are reopened rapidly and systematically, drastically lowering the risk of serious complications such as arrhythmias. In this new context—where the extent of heart damage is smaller—the need for beta blockers is unclear. While we often test new drugs, it's much less common to rigorously question the continued need for older treatments.”
That was the motivation behind REBOOT.
“The trial was designed to optimize heart attack care based on solid scientific evidence and without commercial interests. These results will help streamline treatment, reduce side effects, and improve quality of life for thousands of patients every year,” Dr. Ibanez adds.
REBOOT was conducted without pharmaceutical industry funding.
Mount Sinai Is a World Leader in Cardiology and Heart Surgery
Mount Sinai Fuster Heart Hospital at The Mount Sinai Hospital ranks No. 2 nationally for cardiology, heart, and vascular surgery, according to U.S. News & World Report®. It also ranks No. 1 in New York and No. 6 globally according to Newsweek’s “The World’s Best Specialized Hospitals.”
It is part of Mount Sinai Health System, which is New York City's largest academic medical system, encompassing seven hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. We advance medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 9,000 primary and specialty care physicians; 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 48 multidisciplinary research, educational, and clinical institutes. Hospitals within the Health System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report's® “Best Hospitals” Honor Roll for 2025-2026.
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About the CNIC
The CNIC is a center of the Carlos III Health Institute (ISCIII), executive agency of the Spanish Ministry of Science, Innovation, and Universities. Directed by Dr. Valentín Fuster, the CNIC is dedicated to cardiovascular research and the translation of the knowledge gained into real benefits for patients. The CNIC has been recognized by the Spanish government as a Severo Ochoa center of excellence (award CEX2020-001041-S, funded by MICIN/AEI/10.13039/501100011033). The center is financed through a pioneering public-private partnership between the government (through the ISCIII) and the Pro-CNIC Foundation, which brings together 11 of the most important Spanish private companies.
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Journal
New England Journal of Medicine
Method of Research
Randomized controlled/clinical trial
Subject of Research
People
Article Title
Beta-Blockers after Myocardial Infarction without Reduced Ejection Fraction
Article Publication Date
30-Aug-2025
CNIC-led REBOOT clinical trial challenges 40-year-old standard of care for heart attack patients
image:
Women and beta-blocker treatment after a heart attack
view moreCredit: CNIC
Madrid, August 30, 2025. An international clinical trial coordinated by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), in collaboration with the Mario Negri Institute for Pharmacological Research in Milan, has found that beta-blockers—drugs commonly prescribed for a range of cardiac conditions—offer no clinical benefit for patients who have had an uncomplicated myocardial infarction (i.e., without deterioration of the heart function after the event).
The findings—published in two articles in The New England Journal of Medicine and The Lancet and presented today during a “Hot Line” session at the European Society of Cardiology (ESC) Congress in Madrid—overturn a treatment paradigm that has shaped clinical practice for more than four decades.
The REBOOT trial (Treatment with Beta-Blockers after Myocardial Infarction without Reduced Ejection Fraction) enrolled 8,505 patients with a left ventricular ejection fraction above 40% after a heart attack, across 109 hospitals in Spain and Italy. Participants were randomly assigned to receive or not receive beta-blockers after hospital discharge. All patients received current standard of care and were followed for a median of nearly four years. The results showed no significant differences between the two groups in rates of death, recurrent heart attack, or hospitalization for heart failure.
Although generally considered safe, beta-blockers can cause side effects such as fatigue, bradycardia (low heart rate), and sexual dysfunction.
“REBOOT will change clinical practice worldwide,” says principal investigator Dr. Borja Ibáñez, CNIC Scientific Director, cardiologist at Hospital Universitario Fundación Jiménez Díaz, and a group leader in the Spanish cardiovascular research network CIBERCV. “Currently, more than 80% of patients with uncomplicated myocardial infarction are discharged on beta-blockers. The REBOOT findings represent one of the most significant advances in heart attack treatment in decades.”
After a heart attack, cardiac contractile function can be overtly deteriorated (left ventricular ejection fraction below 40%), moderately reduced (40-50%), or preserved (above 50%). The vast majority patients these days (approx. 70%) survive the heart attach with a preserved cardiac function, a smaller proportion (approx. 20%) with a moderately reduced function, and 10% with overtly reduced cardiac function. REBOOT enrolled patients from the 2 former groups since there was no evidence of the benefits of beta-blockers on these types of patients. While the trial results showed no benefit of beta-blockers for the study population overall, the treatment did appear to benefit the patient subgroup with moderately reduced contractile function. However, this subgroup constituted a relatively small proportion of the study population, and the small sample size prevented the team from drawing firm conclusions on this subgroup.
To address this question in this specific subgroup of patients, the researchers carried out a joint meta-analysis with other smaller trials that also included patients with these characteristics. The meta-analysis, published in The Lancet, confirms that beta-blockers significantly reduce the risk of death, recurrent heart attack, or heart failure only in post-infarction patients with moderately reduced cardiac contractile function.
Dr. Xavier Rosselló—CNIC scientist, cardiologist at University Hospital Son Espases in Mallorca, and one of the REBOOT study leaders—explains: “Taken together, these two studies provide compelling evidence that post-infarction patients with fully preserved contractile function (ejection fraction above 50%) do not benefit from beta-blockers, whereas those with moderate or greater dysfunction (ejection fraction below 50%) do.”
Dr. Borja Ibáñez, who led the meta-analysis, adds: “These findings will form the basis for future treatment of myocardial infarction and will drive a major shift in clinical practice guidelines.”
Every year, more than 2 million people in Europe suffer a heart attack, including around 70,000 in Spain. Until now, the majority were discharged on beta-blockers—a practice now called into question.
“After a heart attack, patients are typically prescribed multiple medications, which can make adherence difficult,” explains Dr. Ibáñez. “Beta-blockers were added to standard treatment early on because they significantly reduced mortality at the time. Their benefits were linked to reduced cardiac oxygen demand and arrhythmia prevention. But therapies have evolved. Today, occluded coronary arteries are systematically reopened rapidly, drastically lowering the risk of serious complications such as arrhythmias. In this new context—where the extent of heart damage is smaller—the need for beta-blockers is unclear. While we often test new drugs, it's much less common to rigorously question the continued need for older treatments.”
That was the motivation behind REBOOT-CNIC. “The trial was designed to optimize heart attack care based on solid scientific evidence and without commercial bias,” said Dr. Ibáñez. “These results will help simplify and streamline treatment, reduce adverse effects, and improve the quality of life for thousands of patients every year.”
Importantly, REBOOT was conducted without pharmaceutical industry funding.
A landmark in European cardiovascular research
More than 500 researchers from across Spain and Italy participated in REBOOT on a voluntary basis. A total of 109 hospitals—74 in Spain and 35 in Italy—recruited 8,505 patients. The Italian arm was coordinated by the Mario Negri Institute in Milan under the leadership of cardiologist Roberto Latini, through a collaboration agreement with the CNIC.
As Dr. Rosselló explains: “The credit for carrying out the largest clinical trial ever conducted on this question belongs not only to CNIC, but above all to the more than 100 participating hospitals and their teams, who worked tirelessly for six years with the sole aim of improving care for heart attack patients worldwide.”
Through its Clinical Trials Coordination Unit (CTCU), the CNIC led the logistics and management of the trial, showcasing the Spanish research system’s capacity to deliver clinical studies with global impact. The CTCU has become a key hub for coordinating large-scale cardiology trials with a purely scientific mission.
The success of REBOOT also relied on the collaboration between the CNIC, the Spanish Society of Cardiology (SEC), and CIBERCV. According to SEC president Dr. Luis Rodríguez Padial, “REBOOT not only changes heart attack treatment—it also changes how clinical trials are designed and run in Spain.”
Underlining this point, Dr. Ibáñez emphasizes that the joint leadership by CNIC, SEC, and CIBERCV “reflects Spain’s enormous potential when a transformative project is combined with strong scientific leadership.”
Dr. Valentín Fuster, CNIC General Director, President of Mount Sinai Fuster Heart Hospital, and one of the senior investigators on REBOOT, notes: “This trial will reshape all international clinical guidelines. It joins other landmark trials led by CNIC—such as SECURE with the polypill and DapaTAVI, which links SGLT2 inhibition to TAVI—that have already transformed the global approach to cardiovascular disease.”
The trial was funded by the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) an affiliate center of the Carlos III Health Institute (ISCIII), an executive agency of the Spanish Ministry of Science, Innovation and Universities. The clinical trial was carried out with the collaboration of the Spanish Society of Cardiology (SEC), and CIBERCV.
About the CNIC
The CNIC is an affiliate center of the Carlos III Health Institute (ISCIII), an executive agency of the Spanish Ministry of Science, Innovation, and Universities. Directed by Dr. Valentín Fuster, the CNIC is dedicated to cardiovascular research and the translation of the knowledge gained into real benefits for patients. The CNIC has been recognized by the Spanish government as a Severo Ochoa center of excellence (award CEX2020-001041-S, funded by MICIN/AEI/10.13039/501100011033). The center is financed through a pioneering public-private partnership between the government (through the ISCIII) and the Pro-CNIC Foundation, which brings together 11 of the most important Spanish private companies.
Journal
New England Journal of Medicine
Method of Research
Meta-analysis
Article Title
CNIC-led REBOOT clinical trial challenges 40-year-old standard of care for heart attack patients
New study finds that, after a heart attack, women have worse prognosis when treated with beta-blockers
A substudy from the REBOOT trial published at the European Heart Journal shows that women treated with Beta-blockers had a higher risk of death, reinfarction, or hospitalization for heart failure compared to women not receiving the drug
A major new analysis from REBOOT (Treatment with Beta-blockers after Myocardial Infarction without Reduced Ejection Fraction) clinical trial, an international study coordinated by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), published at the European Heart Journal has revealed important sex-specific differences in the effects of beta-blockers following heart attacks, raising questions about long-standing treatment practices.
REBOOT, presented in a Hotline session of the ESC congress in Madrid, is the largest contemporaneous trial testing the effect of beta-blockers in patients who survive myocardial infarction without a moderate or severe deterioration of their cardiac function (i.e. left ventricular ejection fraction greater than 40%). 8,505 patients were included across 109 hospitals in Spain and Italy. While the proportion of women in the trial was not high (something common in most myocardial infarction trials), the total number of women is the largest ever included in a trial testing beta-blockers after infarction, providing high power to the analysis performed. Patients were randomly assigned to receive Beta-blockers—a commonly prescribed drug—or no beta-blocker, while continuing to receive standard post-heart attack care. Patients were followed for a median of nearly four years.
The analysis uncovers notable sex-specific differences: while men experienced no benefit or risk when treated with beta-blockers, women treated with Beta-blockers had a significant increased risk of death, reinfarction, or hospitalization for heart failure compared to women not receiving the drug. Women treated with beta-blockers had a 2.7% higher absolute risk of mortality than those not treated with beta-blockers during the 3.7 years of follow-up of the study. The elevated risk when treated with beta-blockers was restricted to women with a complete normal cardiac function after infarction (i.e. left ventricular ejection fraction of 50% or higher). Those with a mild deterioration in cardiac function did not have an excess risk of adverse outcomes when treated with beta-blockers.
Another important finding from this pre-specified analysis of the REBOOT trial is that women presenting with infarction had a worse cardiovascular profile. They were older, had more comorbidities (including higher prevalence of hypertension diabetes and dyslipidemia), and more frequently experienced heart attacks without obstructive coronary arteries (6% vs 2% in men). In addition, while overall prescription rates of secondary prevention interventions were high for all patients in the trial, women were less often prescribed some guideline-recommended therapies such as antiplatelets, statins, angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARBs) or cardiac rehabilitation. Of note, overall, women had a significantly worse prognosis than men (mortality across study duration was 4.3% in women vs. 3.6% in men). The Principal Investigator of the REBOOT trial, Dr. Borja Ibáñez, CNIC Scientific Director, cardiologist at Hospital Universitario Fundación Jiménez Díaz, and member of the CIBERCV, says “these findings confirm previous observational data but in a rigorous prospective trial: women presenting with infarction have worse cardiovascular profile and, more importantly, have worse prognosis than men. Our data also shows that they respond differently to a commonly prescribed intervention, beta-blockers in this case”.
Xavier Rosselló, scientist at CNIC, cardiologist at University Hospital Son Espases in Mallorca and another leader of the REBOOT trial emphasizes that "Our findings suggest that a one-size-fits-all approach may not be appropriate and that sex-specific considerations are crucial for cardiovascular interventions prescriptions."
The REBOOT trial was coordinated by the CNIC, in collaboration with the Mario Negri Institute for Pharmacological Research in Milano, Italy. As the largest independent study of its kind, it provides critical insights into how modern post-heart attack treatments should consider patient sex, heart function, and dosing strategies. "In many cases, prescribing Beta-blockers to women after uncomplicated heart attack may do more harm than good," Dr. Ibáñez added. "Clinicians should carefully weigh the risks and benefits, and consider dose adjustments or alternative therapies when treating female patients."
The trial’s results underscore the importance of personalizing post-heart attack therapy. By highlighting how sex-specific factors influence the safety and effectiveness of commonly used drugs, REBOOT could reshape guidelines and improve outcomes for women worldwide.
Dr. Valentín Fuster, CNIC General Director, President of Mount Sinai Fuster Heart Hospital, and another investigator of REBOOT trial, notes: “We have been investigating sex-differences in cardiovascular disease for a long time. We already knew that cardiovascular disease presentation is different in women and men, and this study significantly adds to this knowledge by showing that response to medications is not necessarily equal in women and men. This study should spark the much-needed sex-specific approach for cardiovascular disease”. The REBOOT trial was funded by the CNIC, an affiliate center of the Carlos III Health Institute (ISCIII), an executive agency of the Spanish Ministry of Science, Innovation and Universities. The clinical trial was carried out with the collaboration of the Spanish Society of Cardiology (SEC), and CIBERCV.
About the CNIC
The CNIC is an affiliate center of the Carlos III Health Institute (ISCIII), an executive agency of the Spanish Ministry of Science, Innovation, and Universities. Directed by Dr. Valentín Fuster, the CNIC is dedicated to cardiovascular research and the translation of the knowledge gained into real benefits for patients. The CNIC has been recognized by the Spanish government as a Severo Ochoa center of excellence (award CEX2020-001041-S, funded by MICIN/AEI/10.13039/501100011033). The center is financed through a pioneering public-private partnership between the government (through the ISCIII) and the Pro-CNIC Foundation, which brings together 11 of the most important Spanish private companies.
Journal
European Heart Journal
Article Title
New study finds that, after a heart attack, women have worse prognosis when treated with beta-blockers
Article Publication Date
30-Aug-2025
