Rapid Sequencing of the Four Pillars of Heart Failure Treatment

Supplements and Featured PublicationsImplementing the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: SGLT2 Inhibitors, Treatment Sequencing, and Value Statements

A Q&A With Milton Packer, MD

Click here to view video highlights from this interview.

AJMC®: Could you describe the conventional approach to combining all 4 “pillars” of therapy for heart failure with reduced ejection fraction [HFrEF]?

PACKER: For years, the conventional approach to implementing the 4 foundational drugs for HFrEF was based purely on the historical sequence in which these 4 classes of drugs were developed. Initially, in the early 1980s, ACE [angiotensin-converting enzyme] inhibitors were developed. Other inhibitors in the angiotensin system were developed thereafter. Then β-blockers were developed in the early 1990s, mineralocorticoid receptor antagonists (MRAs) were developed in the late 1990s, and neprilysin inhibitors were developed in about 2014. SGLT2 [sodium-glucose cotransporter-2] inhibitors were developed only in the past 2 or 3 years.

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 and titrate up to target dose. Then you start an SGLT2 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.

However, there’s a bigger problem: if you tell people this therapy will take 6 to 12 months, a very large proportion of people will not do it at all. Many people with HFrEF are on an ACE inhibitor and a β-blocker and that’s it. They’re not on any of the other foundational drugs. They’re not on MRAs. They’re not on a neprilysin inhibitor. They’re not on an SGLT2 inhibitor. Patients are not only getting delayed therapy; they’re not getting all the therapy they need. The result is that a large part of the benefit—mortality benefit, hospitalization benefit—of these drugs is lost.

The difference between being on an ACE 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.

AJMC®: In a recent review article, you and coinvestigator John McMurray, MD, argue that all 4 pillars should be used in the first 4 weeks of treatment.1 What is the rationale for this recommendation?

PACKER: We think physicians should use all the foundational drugs. 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. There are several reasons for this approach.

First, the clinical trial data show that so much of the benefit of these drugs is seen at the initial dose. β-blockers, which really do require up-titration, are an exception. But for the other classes of drugs, the low starting dose gets you 70%, 80%, or more of the total treatment effect. It is much better to have all the foundational drugs at a starting dose than to have 1 drug at a maximal dose. You’re not covering all the systems you should be covering with 1 drug at a maximal dose. However, you’re covering almost everything you want to cover with low starting doses across the board.

Second, our approach is evidence-based. Most new drugs for HF were developed while patients were on background therapy with other drugs that were at low doses, not at target doses. We know, for example, that β-blockers work, because they were tested in patients getting low doses of an ACE inhibitor, not target doses. We know that spironolactone works in people getting low doses of ACE inhibitors and β-blockers. The same with neprilysin inhibitors and SGLT2 inhibitors. Almost none of the patients in the big major trials were getting target doses of all of the previous drugs before they got the new one. Our proposed framework is exactly the way that the clinical trials were conducted. The patients were already getting low doses, and they did not up titrate the background therapy during the trial. We’re closely mimicking how the trials were conducted.

Third, with this approach, we can determine in a reasonably short period of time whether a patient tolerates these drugs. You can pretty much know if someone tolerates a drug within a week.

AJMC®: In what order should these 4 drugs be introduced into HFrEF therapy?

PACKER: 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.

We proposed a sequence that begins with a β-blocker and SGLT2 inhibitor, adds an ARNI [angiotensin receptor-neprilysin inhibitor], and then adds an MRA. However, a different order would be fine; it really doesn’t matter which 2 to start. At the end of 4 weeks, everyone’s going to be at the same place. The sequence can be tailored to the personal preferences of the physician and the circumstances of the patient. The key is to get all 4 drugs on board in 4 weeks.

AJMC®: In the article you recommend determining priority of treatment based upon relative efficacy, safety, and ease of use and emphasizes evidence-based treatment. Could you speak to the place of evidence-based medicine in HFrEF therapy?

PACKER: It seems axiomatic that all physicians should practice evidence-based medicine, but there are lots of reasons why they don’t. For one, other types of medicine compete for attention. For instance, there’s so-called “eminence-based medicine,” which is doing what experts say. There’s story-based medicine, which is giving drugs according to an idea of what the drugs are doing to the body rather than to evidence. And then there’s practical medicine: it can be difficult to prescribe certain drugs, because they’re expensive, or because they require authorization forms, or because a patient’s insurance doesn’t cover them.

Certain mistaken beliefs also hinder the practice of evidence-based medicine. For instance, there’s an idea that a patient can look okay and can have “stable HF.” Well, there’s no such thing as “stable HF.” Even if a patient says they feel the same as they did 3 months ago, their condition is not stable. HF inherently progresses, even if it is not noticeable to the patient or if the patient has adapted to that progression.

Finally, physicians have time constraints. Often, their exposure to a patient is less than 15, or even 10, minutes. Patients may have more than just HF. They may have 5, 6, 7 comorbid conditions. They all have to be managed in 10 minutes. All of these factors get in the way of practicing evidence-based medicine.

AJMC®: The aim is to get patients on all 4 of these pharmacotherapies in the first 4 weeks. However, you recommend getting HFrEF patients started on both a β-blocker and an SGLT2 inhibitor. Why should treatment start there?

PACKER: John McMurray and I thought that the combination of a β-blocker and an SGLT2 inhibitor was a good starting point for 2 reasons. We wanted to start with a β-blocker because β-blockers have dramatic effects on mortality; we’re talking a 35% reduction in risk of death. They reduce mortality more than any other class of drugs does, and they particularly reduce sudden death. You really want a β-blocker on board as early as possible for someone with HF. The earlier the better. β-blockers may require some up-titration so getting them on board early also gives you some time to then get them up to the right dose.

The biggest disadvantage of β-blockers is that, in some people, they cause fluid retention. So the first reason to add an SGLT2 inhibitor is that SGLT2 inhibitors counteract that fluid retention. The second reason is that SGLT2 inhibitors reduce hospitalization for HF. You can easily combine a β-blocker and an SGLT2 inhibitor. They mutually reinforce each other. They’re both given once daily. You can achieve an enormous amount of what you’re trying to achieve, because the effect size, the magnitude of benefit, is so large, and they reinforce each other’s safety, which is really nice.

AJMC®: In 2021, the European Society of Cardiology recommended SGLT2 inhibitors for frontline treatment in HFrEF based upon the EMPEROR-Reduced trials.2,3 In their April 2022 guideline, the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Failure Society of America (HFSA) recommended SGLT2 inhibitors to reduce hospitalization for HF and cardiovascular mortality in patients with symptomatic chronic HFrEF, citing the same trials.4 Can you describe how these trials have influenced the use of SGLT2 inhibitors in HFrEF?

PACKER: 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.3,5 We’ve been speaking of the 4 drugs in 4 weeks paper that John McMurray and I collaborated on.1 John McMurray led the DAPA-HF trial, and I led the EMPEROR-Reduced trial. The 2 trials came out with results that were almost superimposable on top of each other. It’s almost as if the numerical result in 1 trial was exactly replicated in the other trial. There were a few differences but amazingly similar results, both in terms of the nature of the benefit and the magnitude of the benefit. 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 guidelines and in the recent guidelines that were issued in the United States.2,3

AJMC®: At the AHA Scientific Sessions 2021 in November, results of the EMPULSE trial were published; they demonstrated that SGLT2 inhibitors were beneficial in reducing adverse events among patients hospitalized with acute decompensated HF.6 How might the results of the EMPULSE trial influence future guidance regarding the use of SGLT2 inhibitors?

PACKER: No one was surprised by the results of EMPULSE. In EMPULSE, investigators initiated SGLT2 inhibitors in the hospital. Previously, we had had trials where we initiated ACE inhibitors in the hospital, β-blockers in the hospital, MRAs in the hospital. We knew that SGLT2 inhibitors should be initiated as early as possible.

The results of the EMPULSE trial jibe with our recommendations for rapid sequencing. When we say 4 drugs in 4 weeks, we don’t mean just outpatient 4 drugs in 4 weeks. We mean whenever you see the patient, and the patient is sufficiently out of their acute phase of their hospitalization—which is usually in the first 24 to 48 hours of therapy—after that, then it’s time to initiate 4 foundational drugs with the intent of achieving them in the next 4 weeks.

AJMC®: Recommendations in the ACC/AHA/HFSA guideline are in accord with points made by you and Dr McMurray in your review that simultaneous initiation or sequencing should not be delayed. What is the takeaway from this consensus?

PACKER: I was really impressed by the enthusiasm to get all 4 foundational drugs onboard as quickly as possible. Recommendations in the guideline give a sense that time is of the essence. That represents a meaningful change, because past guidelines took a slower approach. 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, and we have to get there as soon as possible.

The issuance of a guideline represents an opportunity for physicians to remember what is important. It reminds physicians, every physician who cares for patients with HF, what they should be thinking about, what their goals are, what they should be doing. We need reminders about that all the time, because, as of just a few years ago, the number of people getting evidence-based medicine with 4 foundational drugs for HFrEF in the United States was less than 5%. It’s a really disappointing number. If the guidelines serve as a reminder that we need to do better, that is exactly what their goal should be.

Dr Packer is distinguished scholar in cardiovascular science at Baylor University Medical Center.


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. 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

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. Heidenreich PA, Bozkurt B, Aguilar D, et al. 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

5. 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

6. Voors AA, Angermann CE, Teerlink JR, et al., for the EMPULSE Trial Investigators. Empagliflozin in patients hospitalized for acute heart failure: the EMPULSE trial. Presented at the 2021 American Heart Association Scientific Sessions; November 14, 2021; Virtual. Late-breaking session 5.

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.

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