Your Health Checkup: Heart Failure and the Four Horsemen

“Your Health Checkup” is our online column by Dr. Douglas Zipes, an internationally acclaimed cardiologist, professor, author, inventor, and authority on pacing and electrophysiology. Dr. Zipes is also a contributor to The Saturday Evening Post print magazine. Subscribe to receive thoughtful articles, new fiction, health and wellness advice, and gems from our archive. 

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Living in Indiana, one of my favorite football teams is Notre Dame. In 1924, sportswriter Grantland Rice immortalized four outstanding backfield players, coached by the legendary Knute Rockne, by labeling them the Four Horsemen of Notre Dame, a takeoff of the biblical Four Horsemen of the Apocalypse. During the three-year tenure of the Four Horsemen, Notre Dame lost only two games, once in 1922 and once in 1923, both to Nebraska.

Below, I am proposing the Four Horsemen of Heart Failure Treatment.

In a previous Saturday Evening Post column, I discussed dramatic therapeutic advances that have improved the lives of patients with several types of heart problems, including catheter-based valve replacement and repair, new approaches to managing heart rhythm issues, novel stents for clogged arteries, and innovative drugs to reduce abnormal lipids. I briefly mentioned a unique category of drugs called SGLT2 inhibitors that began as treatment for diabetes but resulted in spectacular outcomes for heart failure patients with or without diabetes.

Heart failure is a disease that affects more than 26 million people worldwide and is expected to increase as the population ages. Heart failure with reduced ejection fraction (that is, a heart that can’t pump blood as efficiently due to a weakened heart muscle from such ailments as heart attacks) accounts for approximately half of all cases of heart failure in the United States, causing significant illness and death. Shortness of breath, exercise intolerance, and fluid accumulation are some of the symptoms responsible for reduced quality of life in heart failure patients.

Despite treatment including drugs and devices, heart failure has remained incurable, with a poor prognosis. However, recent advances including a combination of four drugs — the Four Horsemen — has revolutionized care, leading to outstanding success and prolongation of life.

A new publication investigated a host of heart failure drugs used in 75 relevant trials representing 95,444 participants. The authors analyzed which drug combinations had the greatest impact in reducing all-cause mortality.

They found that the quadruple combination of ARNI (Angiotensin Receptor Neprilysin Inhibitor), BB (beta blocker), MRA (mineralocorticoid antagonist), and SGLT2i (sodium–glucose cotransporter 2 inhibitor) exerted the greatest reduction in mortality, giving the average 70-year-old patient an additional 5.0 years (2.5-7.5 years) of life compared with no treatment.

While the analysis was performed appropriately, it is important to remember the limitations of such a study, including selection bias and confounding issues and that the patient populations may not fully mirror those treated by the average physician in the U.S. Also, the magnitude of the survival benefit — a 61 percent reduction in all-cause mortality — must be considered with caution and may not be reproducible in all clinical practice settings. Finally, quadruple therapy is expensive.

Despite these reservations, this is a major advance in heart failure therapy and will likely rewrite the guidelines for treatment. Because non-physicians are not likely to remember the names of these four drugs, I hope they will remember the Four Horsemen of Heart Failure Treatment and take that information to their physicians to be sure this therapy is considered whenever and in whomever it is feasible to treat heart failure caused by a weakened heart muscle.

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