Clinical trialist John J.V. McMurray has a top 5 list

In a special ESC session, “Celebration of the Last Decade of Cardiac Innovation What Has Been Achieved and What Are the Unmet Needs” conducted jointly with the International Society for Cardiovascular Translational Research, John J. V. McMurray, MD, of the University of Glasgow, was asked to come up his top five heart failure innovations for the past decade.

To set-up his take on breakthroughs in heart failure, McMurray pointed out that earlier decades had provided evidence for three foundational treatments for heart failure: angiotensin system blockers (ACEi/ARB), beta-blockers, and mineralocorticoid receptor agonist (MRA) therapy.

That established, McMurray focused on breakthroughs of the last 10 years, saying, “it was easy to come up with the top three innovations of the decade. I put them in chronological order, so the first of these was a sinus node inhibitor — a drug called ivabradine—the only known effect of it was to reduce heart rate. It was studied in a very large morbidity and mortality trial called SHIFT and shown to be effective when added to conventional IV therapy. It reduced the composite outcome of cardiovascular death or heart failure by 18%—a benefit driven mostly by heart rate, but that of course is itself a very important thing for our patients.”

The next innovation was the use of a neprilysin inhibitor “that we hoped would have beneficial effects in patients with heart failure and reduced ejection fraction. And, of course, we demonstrated that that was indeed the case in the PARADIGM-HF trial.”

And then, in 2019 came “the third big breakthrough: SGLT2-inhibitors… These drugs, originally introduced as glucose lowering therapy for patients with type 2 diabetes… reduced cardiovascular death or worsening heart failure substantially in patients with reduced ejection fraction… We could probably give SGLT2 inhibitors two places for innovation, because they also have been very important in the prevention of the development of heart failure in patients with type 2 diabetes.”

At the ESC, the benefit of SGLT2-inhibitors has been a major theme for two consecutive congresses. In 2019, DAPA-HF results overshadowed all heart failure discussions, and this year EMPEROR-Reduced was the number one Hot Line presentation. For those who may have doubted the relevance, The Lancet published a meta-analysis of the two trials.

Faiez Zannad, MD, PhD, professor of Therapeutics and Cardiology, Université de Lorraine, and Director of the INSERM Clinical Investigation, and colleagues wrote:

“Among 8,474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0.87, 95% CI 0.77–0.98; p=0.018) and 14% reduction in cardiovascular death (0.86, 0.76–0.98; P=0.027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalization for heart failure (0.74, 0.68–0.82; P<0.0001), and by a 25% decrease in the composite of recurrent hospitalization for heart failure or cardiovascular death (0.75, 0.68–0.84; p<0.0001). The risk of the composite renal endpoint was also reduced (0.62, 0.43–0.90; P=0.013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. [Emphasis added].”

Moving beyond those three pharmacological innovations meant that clinicians are “now in a fantastic position, when it comes to treating patients with heart failure and reduced ejection fraction, of having a choice of therapies… And I think the two that most people would recognize as being particularly important are neprilysin inhibition and SGLT2 inhibition, because of course they both reduce mortality. So, we have five life-saving treatments for patients with heart failure and reduced ejection fraction, which we can give in four pills because of course, two of these [neprilysin inhibition and angiotensin system blockers] are combined in sacubitril/valsartan.”

McMurray said he had to move away from the medicine chest to come up with two more heart failure breakthroughs of the last decade. He asked his colleagues who deal with patients with advanced heart failure for help in choosing the fourth innovation.

“They couldn’t make up their minds, so we put two innovations (under the heading of surgery) as number four: The introduction of a new left ventricular assist device that gives superior outcomes to existing left ventricular assist devices —HeartMate 3. It demonstrated superiority in the MOMENTUM 3 trial. And, sharing the fourth place is the introduction of a technique to harvest hearts after a donor has experienced circulatory death, and that has greatly increased the supply of donor hearts in many countries as a result of this technology.”

Finally, McMurray said he couldn’t select a single innovation to fill the fifth slot — and, when he asked colleagues for suggestions, there was no consensus.

So, he listed all of the suggestions this way:

  • “Intravenous iron: clinical observation leading to a simple inexpensive therapy (but awaiting mortality/morbidity trials).
  • “DANISH trial—less is more; challenging existing paradigms for IICD use.
  • “Tafamadis — precision cardiology.
  • “Handheld echocardiography.
  • “Natriuretic peptides — evolution to revolution.
  • “Genetic testing— evolution to revolution.”

That said, McMurray predicted that the list will change very soon, and he included a list of likely additions based on already reported findings, as well as findings that are expected over the next 18 months or so.

Heading the list are the soluble guanylate cyclase inhibitor vericiguat for HFrEF, which reported positive results in VICTORIA, and mavacamten, an inhibitor of cardiac myosin for hypertrophic obstructive cardiomyopathy (EXPLORER-HCM) that was reported Aug. 29 at ESC. Two more possible additions are omecamtiv mecarbil, a selective cardiac myosin activator (GLALACTIC-HF) and finerenone, a non-steroidal MRA being testing in preserved ejection fraction heart failure (FINEARTS-HF).

McMurray summed up with a word of caution: “I think it’s also important to highlight that very few things are a revolution — most things occur as an evolution over time. For example, the introduction of genetic testing [and] the use of natriuretic peptides are very good examples of [treatments that have] become established in the past 10 years, but it’s taken decades really of research to take them to that point.”

  1. Be aware that this report discusses some drugs that are not yet approved for clinical use.

  2. Note that there are currently four classes of oral medications recommended for treatment of heart failure with reduced ejection fraction: ACEi/ARB/ARNI, beta-blockers, mineralocorticoid receptor agonists (MRAs) and SGLT2 inhibitors.

Peggy Peck, Editor-in-Chief, BreakingMED™

PARADIGM-HF was funded by Novartis.

DAPA-HF was funded by AstraZeneca.

EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly.

VICTORIA was funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer.

GALACTIC-HF was funded by Amgen, Cytokinetics, and Servier.

FINEARTS-HF was funded by Bayer.

McMurray is supported by the University of Glasgow Institute of Cardiovascular and Medical Sciences and the British Heart Foundation.

Cat ID: 204

Topic ID: 74,204,730,204,3,192,925,203