Author + information
- Christopher M. O'Connor, Editor-in-Chief, JACC: Heart Failure∗ ()
- ↵∗Address for correspondence:
Dr. Christopher M. O’Connor, Editor-in-Chief, JACC: Heart Failure, American College of Cardiology, Heart House, 2400 N Street NW, Washington, DC 20037.
The recent publication of the RELAX-AHF-2 trial by Metra et al. (1), and the subsequent editorial by Packer (2), bring considerable doubt to the investigative field, as to whether short-term pharmacotherapy with novel molecules can produce enough of a benefit in patients presenting with acute decompensated heart failure, and whether it merits integration into clinical practice. Today, we face an increase in the burden of heart failure, with >1 million hospitalizations per year resulting in the number 1 reason for patients older than 65 years being admitted to the hospital, with considerable morbidity and mortality. This poses an economic burden on the ecosystem and those who serve to ameliorate this condition.
In 1990, as a young junior faculty member serving under Dr. Robert Califf, I learned that acute compensated heart failure should be studied like acute coronary artery syndromes. Because of this, I embarked on a 30-year career to investigate therapies that might benefit patients with acute decompensated heart failure.
We started this journey with the intravenous beta blocker esmolol, which seemed to improve hemodynamics in patients. We quickly moved to an investigator-initiated trial, with Dr. Mihai Gheorghiade, Dr. Michael Cuffe, me, and Dr. Califf, to study intravenous milrinone in patients with acute decompensated heart failure. With a sample size of such significance, we tested important clinical outcomes, such as days out of hospital and freedom from death over a 60-day period (3). One of the early lessons of why we do clinical trials was learned from this outcome trial. Not only did we not see an advantage in clinical outcomes, but we learned that the drug had significant hypotensive-inducing properties and pro-arrhythmic properties. Furthermore, it increased the risk of myocardial infarction, atrial fibrillation, ventricular tachycardia, and sustained hypotension. Over the next 3 decades, we studied a number of acute decompensated heart failure drugs without success.
Pure vasodilators and venodilators have shown no significant improvement or advantage. As a result, we were left with how to develop good quality drugs. Therefore, I am recommending that we pursue a different course for vasodilatory therapies and acute decompensated heart failure. They should be studied only in patients who have refractory heart failure following acute decompensation or in which prolonged therapy can be given.
Patients who come into the hospital with heart failure and are unresponsive to aggressive diuretic therapy within the first 48 h, as evidenced by urine sodium, increase in serum creatinine, or decreased urine output during a 4-h period, would be candidates for randomization to rescue therapy with a new vasodilator therapy or placebo. The therapy would be continued for 48 to 96 h, measuring each component per day of dyspnea: decongestive symptoms, in-hospital heart failure, weight loss, renal function, natriuretic peptide levels, and troponin. When the patient obtains a degree of decongestion, the therapy would be stopped, and patients would be discharged within 24 to 48 h. An important additional endpoint, perhaps the primary endpoint, would be length of stay.
In this capacity, if a drug could improve outcomes in refractory acute decompensated heart failure and had an impact on worsening in-hospital heart failure and length of stay without increasing 30-day events, it would be a success (4). Payment agencies, such as Centers for Medicare and Medicaid Services and private sector insurance, would compensate for treatment. There would be evidence that the patient has done better and that they would have a shorter hospital stay, which shows an improved quality of life. Although Dr. Packer may argue decompensated heart failure is misguided, I would argue, in contrast, that we have learned a lot from our decades of investigations, and now understand where the sweet spot is. It is important that we remain focused on development in these specific areas. Our patients deserve it.
- 2019 American College of Cardiology Foundation
- Metra M.,
- Teerlink J.R.,
- Cotter G.,
- et al.
- Packer M.
- Food and Drug Administration