Interview With Milton Packer, MD: Rapid Sequencing of the Four Pillars of Heart Failure Treatment

Milton Packer, MD: For years, the conventional approach to implementing the 4 foundational drugs for heart failure with reduced ejection fraction [HFrEF] was based purely on the historical sequence in which these 4 classes of drugs were developed. If you let history guide practice, then you start a renin-angiotensin-aldosterone system inhibitor first, titrate up to target dose, start a β-blocker, titrate up to target dose, and then start an MRA [mineralocorticoid receptor antagonist] and titrate up to target dose. Then you start an SGLT2 [sodium-glucose cotransporter-2] inhibitor, which doesn’t require up-titration. If you do that according to a certain deliberate pathway, it takes 6 to 12 months to achieve treatment with the 4 foundational drugs. Six to 12 months! HFrEF progresses in 6 to 12 months.

The difference between being on an ACE [angiotensin-converting enzyme] inhibitor and β-blocker and being on all the foundational drugs is an incremental 50% to 60% reduction in the risk of death and the reduction in the risk of hospitalization. We’re not talking a small, incremental treatment effect. We’re talking about a doubling or more of the benefit of some of the early drugs. If we follow a deliberate slow titration historical approach, we will have a lot of people with HFrEF who will have progression of disease, who will be hospitalized, and who will die. That will happen unnecessarily.

[Coinvestigator John McMurray and I] think physicians should use all the foundational drugs.1 It’s 4 drugs interfering with 5 pathways. They should do it as rapidly as possible. How rapidly is that? We think that most patients can get to 4 drugs in 4 weeks. It’s a catchy phrase, but it’s a nice way of framing the goal.

We think that certain drugs can be started on the same day, either because we know that they can be safely initiated at the same time, or because their actions mutually reinforce each other’s safety. For instance, we propose starting a β-blocker and an SGLT2 inhibitor on the same day, because β-blockers cause a little bit of fluid retention, and SGLT2 inhibitors counteract that fluid retention. When you combine the 2, you actually have a combination that is safer than if you had used only 1 drug. There are synergies across these 4 foundational drugs that allow them to be put into combined use much more rapidly.

There have been 2 major trials of SGLT2 inhibitors in patients with HFrEF. The first of these was the DAPA-HF trial with dapagliflozin, and the second was the EMPEROR-Reduced trial with empagliflozin.2,3 The 2 trials came out with results that were almost superimposable on top of each other. The biggest benefit of these drugs is to reduce hospitalizations for HF. It’s about a 35% reduction in risk of hospitalization of HF, which is a sizeable treatment effect. That was the reason that the addition of SGLT2 inhibitors to foundational drugs was supported both in the European [Society of Cardiology] guidelines and in the recent [American College of Cardiology/American Heart Association/Heart Failure Society of America] guidelines that were issued in the United States.4,5

There is now a recognition that a slower approach doesn’t get people to where they need to be, either at all or rapidly enough. We now know where we need to be, we have to get there as soon as possible, and now we have support across the globe.

This transcript has been edited for clarity.


1. Packer M, McMurray JJV. Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction. Eur J Heart Fail. 2021;23(6):882-894. doi:10.1002/ejhf.2149

2. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303

3. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190

4. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. doi:10.1093/eurheartj/ehab368

5. Writing Committee Members; ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Card Fail. 2022;e1-e167. doi:10.1016/j.cardfail.2022.02.010

For other articles and videos in this AJMC® Perspectives publication, please visit “Implementing the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: SGLT2 Inhibitors, Treatment Sequencing, and Value Statements.