For patients with heart failure with reduced ejection fraction (HFrEF), four foundational medications have been proven to substantially decrease hospitalizations and improve survival rates and patient-reported quality of life. In 2022, the American College of Cardiology (ACC) and American Heart Association (AHA) updated the heart failure guidelines. UT Southwestern’s Clinical Chief of Cardiology Mark Drazner, M.D., and Section Chief of Electrophysiology Mark Link, M.D., were members of that guideline-writing committee.
One of the key recommendations in those updated guidelines was the addition of SGLT2 inhibitors to three other medications previously recommended to treat patients with HFrEF. With this addition, a combination of four medications was recommended and is now affectionately known as the “Fantastic Four”:
- ARNI (or ACE/ARB): Angiotensin receptor/neprilysin inhibitor (or angiotensin-converting enzyme/angiotensin receptor blockers), which blocks an unfavorable hormone (angiotensin) and increase the levels of favorable natriuretic peptides.
- Beta blockers, to block the effect of the hormones adrenaline and noradrenaline.
- Mineralocorticoid receptor antagonists (MRAs), which blocks an adrenal hormone called aldosterone.
- Sodium-glucose cotransporter-2 inhibitors (SGLT2i), originally developed to treat diabetes and proven to reduce the risk of hospitalization or death when given with a background of contemporary medications in patients with HFrEF, regardless of whether they have diabetes.
These four pillars of guideline-directed medical therapy (GDMT) are game changers for patients. That’s the good news. The bad news is that despite a substantial body of research showing the benefits of GDMT, implementation has remained stagnant, and many patients don’t get the treatment they need.
For example, data from the Get With The Guidelines-Heart Failure Registry showed that from 2021 to 2022, just 9% of eligible patients with HFrEF were discharged from the hospital with quadruple therapy of GDMT. This is consistent with findings from another registry demonstrating significant underuse of GDMT in patients with HFrEF in the U.S. Furthermore, a recent study published Oct. 2, 2023, evaluating the use of GDMT following a first hospitalization for heart failure showed a similar situation around the world.
Even hospitalization – a pivotal moment in the trajectory of a patient with heart failure – does not seem to change this troubling trend, which is most often fueled by clinical inertia and a lack of knowledge among some providers about the benefits of GDMT for heart failure patients. Education for both patients and providers about the long-term benefits of GDMT is a potential area for improvement.
At UT Southwestern, our heart failure specialists put a premium on getting patients on GDMT quickly and titrating them up to the proper dosage for long-term benefits. We know that we do a great job of getting patients on good medicines to treat heart failure, so we have launched a Strong Heart Clinic (housed in our Heart and Lung Clinic) to help get all patients with heart failure on optimal doses of the four medications proven to reduce their risk of death and hospitalization, improve their symptoms, and better their overall health and quality of life.
Proven benefits of GDMT
GDMT has been proven to extend survival, decrease risk of being admitted to the hospital, and improve symptoms so that patients feel better. In fact, compared with use of no medications, if a patient takes all of the four types of medications included in GDMT, they can reduce the risk of dying over two years by an estimated 73%!
The benefits of all four medications are additive, which means each one gives additional benefit to the patient. Also, each of these medicines starts to work very quickly to provide this benefit -- within weeks of initiation. For example, the EMPEROR-Reduced study showed a 58% relative decrease in risk of death and hospitalization for heart failure or urgent visit to the doctor for heart failure within 12 days of initiating an SGLT2 inhibitor. Delaying or not starting any of these medicines can put patients at unnecessary risk.
The STRONG-HF trial, used a strategy of simultaneous and rapid up-titration of GDMT for patients who were hospitalized with HF compared with the usual method of slower adjustments to medications. This randomized controlled trial demonstrated that the strategy of starting medicines at the same time and increasing the doses rapidly was effective, with more patients likely to be on target doses at 90 days and greater use of all medications at six months. It also showed this method was well-tolerated and safe – there was virtually no difference in adverse events among participants who underwent the rapid up-titration of GDMT or routine care.
In fact, the STRONG-HF results were so compelling the Data Safety and Monitoring Board ended the trial early due to overwhelming efficacy.
Related reading: Fighting heart failure with ‘Fantastic Four,’ new guidelines
'Thank you for not giving up on me'
Jennifer Thibodeau, M.D., Medical Director of UT Southwestern's Heart Failure Program and ECMO Program, talks about the strong connection she makes with her heart failure patients, and how she is determined to find innovative ways to improve their heart function and quality of life.
How we approach heart failure treatment
In UT Southwestern’s Strong Heart Clinic, our physicians have earned American Board of Internal Medicine subspecialty certification in Advanced Heart Failure and Transplant Cardiology, giving our team the expertise to treat even the most complex and challenging conditions.
In the Strong Heart Clinic, our clinicians see patients who may be referred by a primary care provider or a general cardiologist. We work with them to start the four foundational GDMT medications (initiate) and increase the dosages (uptitrate) until they are at the maximum tolerated or target doses indicated from clinical trials known to improve morbidity and mortality. This is important, because we know that as we increase the dose of the medicine, there is a larger effect on the health of the heart.
While some patients note an improvement in symptoms very quickly, the medications do more than just help with symptoms. They work “behind the scenes” to improve heart health, decrease the need to come to the hospital, and help patients live longer and healthier. Once patients are on the appropriate doses of medications, they “graduate” back to their regular provider’s care.
During the COVID-19 pandemic, we introduced telehealth in our heart failure clinic and have been successful in using it to effectively care for our patients who have heart failure.
We have also implemented strategies in EPIC, our electronic health records system, that remind providers to discuss GDMT medications with patients who have HFrEF. This way, we can intercept any gaps in medical therapy and help HF patients get on track sooner.
Every eligible patient with heart failure with reduced ejection fraction should be on all four medications, unless they have a documented contraindication. If you aren’t on these medications at the appropriate doses, talk with your primary care provider or cardiologist. Getting the right medications and right doses can give you added support – and years of happier, healthier life.