CNIC-led REBOOT clinical trial challenges 40-year-old standard of care for heart attack patients

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.

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