November 08, 2019
10 min read

HF pharmacotherapy in midst of paradigm shift

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Dramatic results of the recent DAPA-HF and PARAGON-HF trials have prompted the cardiology community to rethink pharmacotherapy for patients with HF with reduced or preserved ejection fraction. Changes to clinical practice and to guidelines could be forthcoming, but there is a lot to sort out before that happens.

In DAPA-HF, the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca), approved for the treatment of type 2 diabetes, reduced the primary endpoint of CV death or worsening of HF by 26% in patients with HFrEF with and without diabetes. In PARAGON-HF, the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) narrowly missed its primary endpoint of reduction of CV death and HF hospitalizations in patients with HFpEF compared with valsartan alone, but the treatment effect was greater in women and in patients on the lower end of the EF range. Both studies were presented at the European Society of Cardiology Congress and published in The New England Journal of Medicine in September.

For patients with HFrEF, there are a number of medication options that need to be prioritized, while for patients with HFpEF, there are no medical therapies known to be effective across the board. Much more needs to be learned, experts told Cardiology Today.

Mary Norine Walsh, MD, MACC, from St. Vincent Heart Center in Indianapolis, said more research is needed to refine medical therapy strategies for patients with HF.
Source: St. Vincent Heart Center. Printed with permission.

“There should be a call for the scientific community to get together to develop the ground rules of how we are going to make pharmacotherapy decisions for heart failure,” Cardiology Today Editorial Board Member Javed Butler, MD, MPH, MBA, FACC, FAHA, professor and chairman of the department of medicine at the University of Mississippi Medical Center, said in an interview. “Therapy decisions with multiple drugs in complex multimorbid patients could have potential mortality impact.”

Diabetes drug shows promise

In DAPA-HF, in addition to meeting the primary outcome, dapagliflozin treatment was also associated with a 30% reduction in worsening HF, an 18% reduction in CV mortality and a 17% reduction in all-cause mortality. The primary outcome did not differ across subgroups, and dapagliflozin reduced CV death or worsening HF by 25% in patients with diabetes and by 27% in patients without diabetes. In October, the FDA expanded the indication for dapagliflozin to include reduction of HF hospitalization in patients with type 2 diabetes who have CVD or are at high risk for it.


The results show the potential for dapagliflozin to become “one of the foundational therapies for heart failure with reduced ejection fraction irrespective of a medical history of diabetes being present or absent,” Gregg C. Fonarow, MD, FACC, FAHA, FHFSA, director of the Ahmanson-UCLA Cardiomyopathy Center, co-director of the UCLA Preventive Cardiology Program, co-chief of the division of cardiology at UCLA and Eliot Corday Chair in Cardiovascular Medicine and Science, told Cardiology Today. “This is a very important therapeutic advancement for heart failure.”

Gregg C. Fonarow

The DAPA-HF findings were then reinforced by DEFINE-HF, presented at the Heart Failure Society of America Scientific Meeting and published in Circulation in September. In DEFINE-HF, dapagliflozin improved HF-related health status with placebo at 12 weeks in patients with HFrEF with or without diabetes despite no significant effect on N-terminal pro-B-type natriuretic peptide.

While dapagliflozin is the first diabetes drug to demonstrate benefit in patients with HF without diabetes, other SGLT2 inhibitors have shown HF-related benefits in diabetes populations, so many experts believe there is a class effect.

“One thing I think we can embrace without much hesitancy at all is that for the SGLT2 inhibitor class overall, there are sufficient signals to argue that as a means of preventing the onset of HF, that evidence base appears to be incontrovertible and moving quickly toward endorsement of the use of SGLT2 inhibitors in people at risk for HF with and without diabetes,” Clyde W. Yancy, MD, MSc, MACC, FAHA, MACP, FHFSA, vice dean of diversity and inclusion, Magerstadt Professor of Medicine, professor of medical social sciences and chief of the division of cardiology at Northwestern University Feinberg School of Medicine, associate director of Bluhm Cardiovascular Institute, Northwestern Memorial Hospital and past president of the American Heart Association, told Cardiology Today. “It appears to be an actionable item.”

A limitation, however, is that only approximately 10% of the patients in DAPA-HF were taking sacubitril/valsartan, which has demonstrated superior outcomes in HFrEF over other renin-angiotensin-aldosterone system inhibitors.

“What role will SGLT2 inhibitors have in treating HF patients who are not diabetic? We have yet to see until we have a bigger study that includes patients who are on [sacubitril/valsartan],” Cardiology Today Editorial Board Member Mary Norine Walsh, MD, MACC, medical director of the HF and cardiac transplantation programs at St. Vincent Heart Center in Indianapolis and past president of the American College of Cardiology, said in an interview. “The DAPA-HF results are very intriguing, but we need to see better what the effect of this particular agent is on patients who are fully treated, including with [sacubitril/valsartan].”


Sacubitril/valsartan data mixed

Sacubitril/valsartan was proven superior to enalapril in chronic HFrEF in the PARADIGM-HF trial and in stabilized acute decompensated HFrEF in the PIONEER-HF trial, results of which were both previously reported. The outlook of sacubitril/valsartan in HFpEF is more complicated, after it narrowly missed the primary endpoint compared with valsartan in PARAGON-HF. Scott D. Solomon, MD, Edward D. Frohlich Distinguished Chair and professor of medicine at Harvard Medical School, senior physician at Brigham and Women’s Hospital and executive committee co-chair of PARAGON-HF, said during the HFSA Scientific Meeting that the study would have been positive had there been seven more events favoring the sacubitril/valsartan group.

Experts told Cardiology Today that sacubitril/valsartan may eventually have a role in HFpEF, but further analyses must be performed.

“There was a lot of encouraging information from PARAGON-HF with the exception that sacubitril/valsartan didn’t meet the prespecified primary endpoint,” Randall C. Starling, MD, MPH, FACC, FESC, FHFSA, professor of medicine at Cleveland Clinic and immediate past president of HFSA, said in an interview. “It also shows there were no safety concerns. It shows us potentially, depending on how you interpret the data, that it may actually be beneficial for renal function. The subgroup analyses contain some other very interesting findings, which include odds ratios suggesting that if you are a woman and if your ejection fraction is lower than the median, which was 57%, the drug may have significant benefit.”

Randall C. Starling

Walsh agreed that more research in women is necessary, but noted that immediate use of sacubitril/valsartan in HFpEF is unlikely, especially given that many insurers have been reluctant to pay for it in HFrEF despite strong favorable data and guideline recommendations.

“The benefit in women was very clear and one can’t help but wonder if the endpoint would have been met if more women had been enrolled in the trial,” Walsh told Cardiology Today. “At the current time, we can postulate a role. However, the ability to get payment through insurers for this drug for HFrEF is limited. So, as an off-label use, I can’t imagine that this is something we would be able to use at this time.”

Strategies for HFrEF

The pharmacology strategy for HFrEF has been pretty straightforward, but is now in flux because of the potential of SGLT2 inhibitors (Graphic), experts said.

Barry H. Greenberg

“For HFrEF, the background is clear. We have a cornerstone of therapies in form of neurohormonal modulating agents,” Cardiology Today Editorial Board Member Barry H. Greenberg, MD, FACC, FHFSA, distiguished professor of medicine and director of the Advanced Heart Failure Treatment program at the University of California, San Diego, said in an interview. “Those would include ACE inhibitors, angiotensin receptor blockers or preferably an angiotensin receptor/neprilysin inhibitor (ARNI) because the ARNIs have now been shown to be superior to the ACE inhibitor or the angiotensin receptor blocker. These patients should also receive a beta-blocker and a mineralocorticoid receptor antagonist.”


In addition, experts said, diuretics should be administered when there are symptoms of congestion.

It will be a challenge to figure out where SGLT2 inhibitors fit into the overall scheme, Butler said.

Javed Butler

“The bigger debate is, now you have a patient on an ACE inhibitor, a beta-blocker and mineralocorticoid receptor antagonist, and they can only afford one more medication or have insurance issues or have lower blood pressure or whatever, what do you give preference to, sacubitril/valsartan or dapagliflozin?” he said. “The reason why that discussion is really important today is that on the heels of these drugs are omecamtiv mecarbil (Cytokinetics/Amgen) and vericiguat (Merck/Bayer). Results from those pivotal trials are coming out in the next year or so. None of the patients in those trials are on SGLT2 inhibitors and very few are on ARNI. What if those are positive? This question is not going away.”

In addition, Walsh said, ivabradine (Corlanor, Amgen) is appropriate for patients with HFrEF who are in sinus rhythm but have an elevated heart rate and “for our HF patients with diabetes, we need to think about the SGLT2 inhibitor.”

Strategies for HFpEF

There is no formula for HFpEF pharmacotherapy, in part because no single drug has been shown to be effective across the entire syndrome and because the population is extremely heterogeneous, with a variety of causes for their condition. The best approach at this juncture is to treat each patient based on their individual phenotype.

“It is much more difficult with HFpEF because there are no good, compelling clinical trial data that support the use of anything other than medications that are either for the control of symptoms like diuretics for salt and water overload, controlling heart rates in atrial fibrillation, controlling blood pressure if they’re hypertensive, or if they have coronary disease with active ischemia, being a little bit more aggressive in intervening on them,” Greenberg told Cardiology Today.

The signal from PARAGON-HF will have to be explored more deeply before sacubitril/valsartan can be considered routinely for this population.

Debate continues over the appropriateness of spironolactone in HFpEF years after the mixed results of the TOPCAT trial, experts said.

“We are still in our infancy of understanding HFpEF, and we thus have this heterogenous population whom we have enrolled in trials of therapies that have not yet demonstrated full benefit,” Walsh said. “What we need is to try therapies based on the phenotype of the HFpEF. We need to narrow down which patients we are using which therapies on.”


Starling noted it is important that HFpEF not be mistaken for another condition, lest medical therapy be prescribed that is ineffective or harmful.

“If a patient is labelled as having HFpEF and they actually have amyloid cardiomyopathy, hypertrophic cardiomyopathy or Fabry’s disease, you are going to do that patient a great disservice no matter how you treat them if you have not uncovered what the real etiology is of their heart disease,” he said.

In a viewpoint published in JAMA in September, Butler and colleagues noted that PARAGON-HF, TOPCAT and other trials have called into question the traditional definitions of HFrEF and HFpEF, as patients in low range of EF for HFpEF appear to benefit from HFrEF therapies. The traditional definition of HFrEF as EF 40% or lower was not based on physiology and may have unintentionally led to patients with EF 41% to 50%, currently classified as HFpEF, being deprived of beneficial therapies, Butler and colleagues wrote.

Fonarow said more research in this area is urgently needed.

“The reality is, right now, we are left with treating the volume status and targeting comorbid conditions by doing additional research to find therapies that are really going to make meaningful impact on clinical outcomes for heart failure with preserved EF,” he said.

Next frontier of research

Several areas are ideal targets for future research, especially for patients with HFpEF.

“This is half our patient population and we need to put a focus on identifying this patient population, sorting through the various phenotypes of patients who have HFpEF,” Walsh said.

Researchers should also focus on the differences between men and women with current therapies, as shown in PARAGON-HF, experts said.

In addition, treatment with SGLT2 inhibitors outside of diabetes requires further investigation, particularly in patients with HFpEF.

There is some interest in other agents that may potentially benefit this patient population including autonomic nervous system modulation and biologic agents such as gene therapy and cell transplant therapy.

“There are still issues related to vector toxicity, ability of the vector to deliver the genes to the appropriate place, for determining how long gene expressions actually persist after therapy,” Greenberg said. “Those need to be worked out, but we’re getting closer than we were in the past. It is very promising.”

More research is needed on how to operationalize precision medicine, especially since therapies for patients with HFpEF need to be aligned with the presentation of the disease. This can also be done for patients with HFrEF in an attempt to prevent patients from taking numerous medications or to even prevent the disease altogether, experts said.


“For HFrEF, we have this surfeit of therapies and the polypharmacy that exists tells us that the next iteration of discovery necessarily needs to be upstream, where we can prevent the onset of the disease and avoid this polypharmacy,” Yancy said. “Or, it needs to be downstream, where we can take advantage of a better understanding of the biology behind the dysfunction, so that we might mitigate the need to proceed onto invasive procedures, LVADs and transplants.”

Clyde W. Yancy

New ideas about implementation of effective therapies are also greatly needed, experts said.

Focus on prevention

As challenges continue in achieving the best outcomes in HF, the focus should be on prevention, especially since it has a solid evidence base, experts told Cardiology Today. Certain dietary patterns such as the Southern diet have been shown to increase the incidence of HF, whereas the ability to control hypertension can reduce the prevalence of HF.

“The better we can achieve BP reduction, the more likely we are to reduce the incidence of hospitalized HF by as much as 40%,” Yancy said.

He elaborated on the importance of preventive strategies such as Life’s Simple 7, which is endorsed by the AHA.

“We have actional steps we can take today to prevent heart failure,” Yancy said. “Nothing could be more important from a public-health standpoint and a personal quality-of-life standpoint. No person should want to be exposed to polypharmacy and devices unless it is absolutely necessary. Taking proactive steps at the early stages ... might be incredibly valuable.” – by Darlene Dobkowski and Erik Swain

Disclosures: Butler reports he consults or serves on an advisory board for Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Relypsa, SC Pharma, Stealth Peptide and Vifor. Fonarow reports he consults for Abbott, Amgen, Bayer, Janssen, Medtronic and Novartis. Greenberg reports he consults or serves on an advisory board for Actelion, Akcea, Amgen, Bayer, Cellular Dynamics, EBR Systems, Janssen, Merck, Myokardia, Novartis, Sanofi, Tenaya and Viking and servers on the speakers’ bureau for Novartis and Zoll. Starling reports his institution received research grants from Novartis. Walsh reports no relevant financial disclosures. Yancy reports his spouse is a non-clinical employee of Abbott Vascular.