Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are now commonly used medications to improve patient outcomes after a myocardial infarction (MI). Due to the groundwork on ACE inhibitors and ARB research that began at the Brigham in the 1970s, clinicians today have made great progress reducing post-myocardial infarction mortality.
Marc Pfeffer, MD, PhD, and Eugene Braunwald, MD, both of the Division of Cardiovascular Medicine, have devoted decades of their careers to pursuing new treatment strategies for patients.
“The bar for cardiovascular research is very high and the number of people who have been saved is staggering,” said Pfeffer. “The tempo of progress continues to quicken as evidence by incremental improvements in prognosis.”
From discoveries made in a basic research lab through large-scale cardiovascular disease clinical trials, the Brigham has helped lead the field. Recently, both Pfeffer and Braunwald authored a paper published in The New England Journal of Medicine that examined use of the medication combination sacubitril/valsartan among patients with MI. They view the findings in the larger context of work that traces back to 1970s in the basement level of the Peter Bent Brigham Hospital, where their research first began.
“This is a story that takes us from bench to bedside to ultimately help patients,” said Braunwald.
The “Pre-Clinical” Era
Beginning in 1976, Marc Pfeffer’s late wife, Janice Pfeffer, PhD, who served for 25 years as a member of the hospital’s Cardiovascular Division, began to study the effects of ACE inhibitors in a rat model under the guidance of Braunwald. After a myocardial infarction, the heart’s left ventricle will enlarge, increasing the risk of a second infarction and potentially, heart failure. To understand if ACE inhibitors—which are classically used to treat hypertension—could prevent detrimental post-MI ventricular remodeling, Janice Pfeffer administered captopril, an ACE inhibitor, in rats with coronary artery ligation-induced myocardial infarctions. Through Janice Pfeffer’s landmark study, it was found that therapy with captopril slowed the adverse, time-dependent post-myocardial infarction ventricular remodeling and improved ventricular function.
“Janice Pfeffer did extraordinarily important work in the rat and has influenced how acute MI is managed today worldwide. She was rare and we are grateful for her,” said Braunwald.
A Courtship Leading to the Clinical Era
Gervasio A. Lamas, MD, who now serves as the chair of Medicine at Mount Sinai Medical Center in Miami Beach and Professor of Medicine at Columbia University Medical Center, recalls his early days at the Brigham, where he completed his residency and cardiology training. Though significant advancements in cardiology like valve replacements were being made at the time, the overarching practice of cardiology was still rudimentary when he began his residency.
“When I first joined, finding a mentor was like a courtship amongst the attendings and fellows: attendings wanted hard-working collaborators and residents wanted a mentor to learn from. My courtship ended as I walked out of the library and ran into Marc Pfeffer,” says Lamas.
After learning that Marc Pfeffer wanted to build upon Janice Pfeffer’s initial studies and move towards clinical trials, Lamas agreed to join this historic research team. Together, Marc Pfeffer, Lamas and Braunwald designed the Survival and Ventricular Enlargement (SAVE) clinical trial to test the effects of captopril on ventricular remodeling in anterior-MI heart attack survivors. It was found that anterior MIs increase the size of the heart in a linear fashion and treatment with captopril attenuated the dilation of the heart. Both Janice Pfeffer’s pilot studies in a murine model and later Pfeffer, Lamas and Braunwald’s clinical trial provided strong evidence that administration of ACE inhibitors after a heart attack significantly improved patient survival.
“Studies that began in our Peter Bent Brigham basement have now shaped what we consider standard practice,” said Marc Pfeffer.
Head-to-Head with the Gold-Standard Therapy
Progress, according to Pfeffer and Braunwald, is defined separately in the lab and clinical setting.
“We want to know if X is better than Y in the lab, whereas in human beings we must ask if X is better than what we already have,” said Pfeffer.
In the early 2000s, ARBs were developed and soon found to be equivalent rather than superior to ACE inhibitors. Scott Solomon, MD, of the Division of Cardiovascular Medicine, and John McMurray, MD, of the British Heart Foundation Cardiovascular Research Centre, University of Glasgow, who spent a year at the Brigham, led the 2014 PARADIGM-HF trial, the largest study conducted of heart failure with reduced ejection fraction that shaped today’s standard of practice. In the trial, it was shown that sacubitril/valsartan, composed of an ARB (valsartan) and neprilysin inhibitor (sacubitril), was clearly superior to the two current standards of care, ACE inhibitors and ARBs.
In blocking neprilysin, an enzyme responsible for the breakdown of natriuretic peptides (ANP, BNP), sacubitril/valsartan augmented these and other beneficial endogenous peptides, and improved patient health significantly. The PARADIGM-HF trial was conducted for 27 months, had over 8,400 patients enrolled, and was stopped early due to efficacy, with substantial reductions in mortality and heart failure hospitalization. Furthermore, patients were found to have fewer side-effects with the drug combination, less renal dysfunction, hyperkalemia, and cough that had complicated the use of ACE inhibitors.
Solomon notes that neprilysin inhibitors cannot be coupled with an ACE inhibitor due to an increased risk of swelling beneath the skin. “We are very proud of the tremendous efficacy sacubitril-valsartan has shown in going head-to-head with a gold standard therapy,” said Solomon.
Solomon and McMurray further teamed up to test sacubitril/valsartan in patients with heart failure with preserved ejection fraction in 4700 patients in the PARAGON-HF trial. While PARAGON-HF just missed statistical significance, there was clear evidence of benefit in patients whose ejection fraction was below normal, and on the basis of this trial, the FDA awarded the first indication for any therapy for heart failure with an ejection fraction greater than 40%. In a subsequent article, Solomon along with Muthu Vaduganathan, MD, MPH, also in the Division of Cardiovascular Medicine, estimated that up to 1.8 million Americans would be newly eligible for sacubitril/valsartan based on the new indication which could result in up to 180,000 heart failure hospitalizations per year prevented.
Building on PARADIGM
Stemming from the success of the PARADIGM-HF trial, investigators have designed large-scale, randomized trials, including PIONEER-HF and PARADISE-MI to further evaluate sacubitril-valsartan.
Braunwald and colleagues conducted the 2019 PIONEER-HF clinical trial among heart failure patients with acute decompensation and found that initiation of sacubitril-valsartan improved markers of poor prognosis, compared to ACE inhibitor therapy.
Pfeffer, Braunwald, Solomon and their colleagues continue to look for ways to improve patient outcomes, but the leaps in progress are now much harder to achieve. A recent example of this is the 2021 PARADISE-MI Trial led by Pfeffer and Braunwald, which tested whether sacubitril-valsartan could reduce the incidence of death from cardiovascular causes or hospitalization among heart failure among patients who had experienced a heart attack. Results of the trial indicated that new onset of heart failure could be prevented, but the trial did not meet its primary endpoint of showing a significant improvement over giving an ACE inhibitor alone.
“Our most important observation from PARADISE MI, reflecting care given by the cardiovascular community, was the dramatic reductions in mortality from acute myocardial infraction during this time period from SAVE to the present,” said Pfeffer.
Bringing it back to the Brigham
With an emphasis on moving from bench to beside to populations, researchers have saved a staggering number of lives thanks to more than forty years of ACE inhibitor and ARB-related research at Brigham.
“Helping patients globally, even those we may never see, is truly gratifying,” said Braunwald.