They are known as the Fantastic Four — the powerful drug quartet now recommended for most cases of heart failure with reduced ejection fraction. At Penn Medicine, the heart failure team is promoting their adoption, following major revisions to guideline-directed medical therapy (GDMT) in spring 2022.
“These are life-sustaining drugs,” says Lee Goldberg, MD, section chief of Advanced Heart Failure and Cardiac Transplant. “It’s important to recognize that stacking them together actually gives us the best chance of changing outcomes.”
Among the four drugs used for heart failure with left ventricular ejection fraction (LVEF) of 40 percent or less, beta-blockers remain a standby; so do mineralocorticoid receptor antagonists (MRAs), an option not always pursued in the past.
Change has come to the third mainstay, renin-angiotensin-aldosterone system (RAAS) inhibitors. Guidelines call for using the newest such option, an angiotensin receptor-neprilysin inhibitor (ARNi), whenever possible. If a patient cannot tolerate taking it — perhaps due to developing angioedema or hypotension or having a history of these conditions — doctors can turn to older drugs, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs).
Perhaps the greatest GDMT difference lies in the addition of a fourth pillar with the promise to further change the course of heart failure. Unlike the other drug classes, sodium-glucose cotransporter-2 (SGLT2) inhibitors use a new, non-neurohormonal pathway. Strong trial evidence shows the drugs can significantly reduce morbidity and mortality.
When taken with other GDMT drugs, an ARNI and an SGLT2 inhibitor can help patients live longer, with a better quality of life. They can even reverse existing remodeling of the heart, to improve left ventricular function and delay or even avoid invasive procedures.
That potential represents a clear call for physicians to get patients on full GDMT as soon as possible.
“We recognize there will be barriers, and that it won’t happen for 100 percent of patients,” Goldberg says. “But we want to get as close to that as we can.”
Impressive Trial Results Lead to Approvals for ARNi and SGLT2 Inhibitors
Penn’s push follows a significant guidelines update from the American Heart Association, the American College of Cardiology and the Heart Failure Society of America.
As with existing GDMT pillars, the ARNi switch and the SGLT2 inhibitor addition come with Class I recommendations. Their inclusion follows remarkable results from a series of clinical trials, part of a wave of advances in heart failure therapy since 2015.
For ARNi, the PARADIGM-HF trial showed the superiority of sacubitril-valsartan over valsartan alone. The combination more effectively reduced heart failure hospitalizations and risk of cardiovascular death. The PRIME study also showed the pairing spurred a greater reduction in functional mitral regurgitation.
SGLT2 inhibitors took a more circuitous path, but have shown a remarkable benefit across the heart failure spectrum.
The compounds were initially designed to manage diabetes mellitus by reducing reabsorption of filtered glucose and increasing urinary excretion. When researchers also discovered cardiovascular benefits, randomized, placebo-controlled trials opened specifically for heart failure with reduced ejection fraction (HFrEF).
Both the EMPEROR-Reduced trial and the DAPA-HF trial reduced the risk of heart failure progression or cardiovascular death. The results were similar whether participants had diabetes or not. Dapagliflozin gained FDA approval for HFrEF in 2020 and empagliflozin followed in 2021.
Further trials — EMPEROR-Preserved and DELIVER — showed benefits for heart failure with preserved ejection fraction (HFpEF, defined as LVEF above 49 percent). They also demonstrated benefits for mildly reduced ejection fraction (HFmrEF, or LVEF 41 percent to 49 percent). The revised heart failure guidelines give a Class 2a recommendation for prescribing SGLT2 inhibitors in such cases. For now, though, only empagliflozin has specific FDA approval for these uses.
While the exact mechanism of cardiovascular benefit remains unidentified, Goldberg says the collective trial results should prompt clinicians to adjust their SGLT2 inhibitor mindset.
“Rather than thinking of them as glucose-lowering drugs, we must think of them as cardiovascular drugs that also lower blood glucose,” he says.
Given the benefits, Penn Medicine team members constantly consider a question, says Hansie Mathelier, MD, attending heart failure cardiologist at Penn Presbyterian Medical Center. “What can we do to help get patients on the drugs?” she asks.
New Heart Failure Guidelines for HFrEF Come With Great Promise and New Demands
In some ways, GDMT implementation is now more streamlined. Currently, each of the main SGLT2 inhibitors is given as a predetermined daily dose, rather than adjusted over time for each patient. Step therapy for GDMT has also been replaced. Instead, patients should get on all four drug classes as soon as possible, before up-titration to maximum tolerated doses.
Still, the Penn Medicine team acknowledges new challenges for community physicians. Switching existing patients to an ARNi takes time and effort. SGLT2 inhibitors represent another drug class to balance, one that is costly and requires additional follow-up.
While generally well tolerated, the new drugs feature occasional contraindications and adverse reactions. They also prompt questions about how to get patients on them, what side effects to monitor and how they fit with drugs not part of GDMT.
The added tasks get piled on other heart failure demands placed on community physicians — managing comorbidities, controlling heart rhythm, and deciding when to pursue devices and procedures.
The Penn heart failure team feels it can help because of its involvement with revising guidelines and experience with the new drugs. The program participated in all the trials that led to their approval, and it had SGLT2 inhibitor protocols ready to go when the FDA signoff came.
The team also has the infrastructure to ease the transition. It can consult with other Penn specialties, such as endocrinology. The heart failure pharmacist and social worker can work on insurance approvals and find ways for patients to lower costs. Nurse practitioners and certified heart failure nurse coordinators can educate patients and follow up with them about reactions to the drugs.
Penn embraces a shared care model, Goldberg said. For example, community physicians can send patients for a one-time consult, with care then continuing back at their practices. They can also ask the program to get patients up-titrated on all four GDMT drugs over a series of visits. Labs can take place at Penn or in the community.
“How can we partner with you?” Goldberg asks. “How can we better support you and your patients?"
Penn team members say they are happy to speak at any point about HFrEF care and GDMT, but offer some advice for now:
Establishing Drug Order for GDMT
For de novo patients, physicians do not yet have evidence whether the order of drug initiation matters. For the recent trials, many participants were already on the original “triple therapy,” so the Penn team suggests starting there. SGLT2 inhibitors could also get added sooner if desired.
Regardless of the order, the Penn team tries to get the patient on all four drugs within six weeks, then adjusts each dose.
Accounting for Renal Function
While sacubitril-valsartan is generally protective of kidney health, it can also harm renal function in certain vulnerable patients. Physicians should take caution when glomerular filtration rate (GFR) is lower than 30 milliliters per minute.
For SGLT2 inhibitors, empagliflozin can be given when GFR is as low as 20 milliliters per minute. The floor for dapagliflozin is 30 milliliters.
Avoiding SGLT2 Inhibitors in Certain Populations
SGLT2 inhibitors are currently contraindicated for patients with Type 1 diabetes.
For Type 2 diabetes, an endocrinology consult is recommended for patients taking insulin or multiple diabetes medications or who have a history of ketoacidosis. Patients with Type 2 diabetes should also take a medication break if not eating or drinking, such as during an illness or in preparation for a medical procedure.
Separately, patients with current or previous critical limb ischemia should avoid SGLT2 inhibitors because of the risk of amputation. Physicians should take caution with other cases of peripheral artery disease.
Choosing an SGLT2 Inhibitor
The decision could come down to insurance approval. If kidney function is a concern, empagliflozin can be given for a lower GFR, as discussed.
Adjusting Diuretics
In addition to GDMT, patients should still take diuretics as needed for congestion. Physicians can consider lowering doses up to 25 percent for patients who are euvolemic when they receive their SGLT2 inhibitor.
Watching for Side Effects
Side effects from sacubitril-valsartan and SGLT2 inhibitors can include:
- Hypotension: Sacubitril-valsartan lowers blood pressure, as do SGLT2 inhibitors. Physicians can respond by lowering diuretics, and the Penn team has not found hypotension to pose a significant barrier.
- Skewed potassium levels: SGLT2 inhibitors can potentially reduce potassium levels, though clinical trials didn’t show significant impacts. On the other hand, hyperkalemia remains a risk with MRAs and RAAS inhibitors, including ARNi. Results from the DIAMOND trial show that patiromer may help manage this risk.
- Hypovolemia: While side effects were relatively infrequent during SGLT2 inhibitor trials, volume depletion was one of the more common. Physicians should warn patients to watch for the signs, with the possibility of lowering diuretics.
- Urinary tract infections: Participants in SGLT2 inhibitor trials also developed genital mycotic infections more frequently. The vast majority were effectively treated with over-the-counter medications. Still, physicians should warn patients and hold off on therapy when a GMI is already present.
Continuing GDMT
Once a patient is on all four GDMT drugs, the best results come from raising each dose to maximum tolerance, the Penn team says. This approach holds true even when symptoms are mild or disease appears stable.
“It might seem like the patient is doing ‘fine,’” Goldberg says. “The reality is that they’re likely not getting the full benefit of all the drugs and their disease is probably slowly progressing over time.”
Once all drugs are up-titrated, therapy should continue even if LVEF improves and symptoms dissipate. The TRED-HF trial showed the harm that can result from stopping.
Considering Additional Drugs
In addition to GDMT, physicians can choose from several other drugs for certain patients:
- Vericiguat (2021 approval after the VICTORIA trial): Physicians can prescribe vericiguat when LVEF remains below 40 percent and symptoms persist despite GDMT. It was specifically evaluated in patients with a recent heart failure hospitalization or need for IV diuretic therapy. It may help prevent further hospitalizations.
- Ivabradine (2015 approval after the SHIFT trial): Ivabradine can lower the risk of hospitalization in certain cases. It is intended for patients who continue to experience symptoms despite GDMT and need to lower their heart rate despite maximally tolerated beta blocker.
- Isosorbide dinitrate/hydralazine (2005 approval after the A-HeFT trial): African Americans can add this medication to GDMT to improve function, reduce hospitalizations and prolong survival. It can also be used in patients who are unable to tolerate any RAAS inhibitor due to renal insufficiency or persistent hyperkalemia.
To learn more about the Penn Heart Failure Program, please contact 215-615-0800.