Current and New Pharmacologic Therapies for Heart Failure

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– by Dr. Irving Loh, MD

Heart failure is one of the most prevalent and expensive conditions in the U.S., affecting 6 million Americans and increasingly other populations around the world as well. It is estimated to account for approximately 1 million annual hospitalizations (with up to 50% re-hospitalization rates at 1 month post discharge) at cost of $21 billion ($53 billion by 2030) in the U.S. Part of this is simply attributable to increasing longevity as nutrition and infection control improves worldwide, but also because we physicians are getting better at our jobs and people are living long enough to get heart failure and cancer. Although ischemic heart disease is a common cause of heart failure, uncontrolled hypertension and inadequately managed valvular disease also significantly contribute. Ethnic and socio-economic differences also exist.

The primary therapy for heart failure (for this discussion limited to heart failure due to reduced ejection fraction, in contrast to the less frequent, but not uncommon, heart failure with preserved ejection fraction, or diastolic heart failure) remains identifying and mitigating the risk factors that caused the heart failure, which means those that exacerbate ischemic heart disease, diabetes, hypertension, valvular disease, etc. An echocardiogram is the least expensive and most information-dense diagnostic tool you can use next to a good history and physical, to help confirm or deny the diagnosis.

When you all were getting your medical training (depending on your age and when that was, of course), the fundamentals of heart failure drug management were inculcated into your curriculum whether or not you intended to do primary care or other non-cardiology fields. First was digitalis, a very dangerous and tricky drug used as a poison centuries ago, but very useful in skilled clinician’s hands for its inotropic effect, mitigated by an unfortunate LD50 of 50%! Next up was the advent of diuretics (for preload reduction) with the toxic mercuhydrin in the late 1940s, but then the loop diuretics in different flavors and potency appeared, and have remained as a mainstay since. As the role of the adrenergic nervous system in heart failure was postulated in the late 1960s, the heroic Scandinavians led the way with beta-blockers with almost incredibly good outcome data validated in large trials over the next few decades. Then the impact of manipulating basic cardiovascular pathophysiology by impedance (or afterload) reduction with direct vasodilators like hydralazine and nitrates showed benefit (and are quite underutilized), with the additional benefit of lowering pulmonary artery pressures. Impedance reduction became even more prevalent by elucidating the role of the renin-angiotensin-aldosterone system, which led to the use of angiotensin-converting enzymes, angiotensin receptor blockers, and direct aldosterone antagonists like spironolactone and eplerenone. These validated evidence based pharmacologic therapies when implemented in skilled heart failure disease management programs have radically altered the quality and quantity of life for heart failure patients to the good, and have positively impacted the health economic implications for society by reducing the cost of care by fewer unexpected encounters with their doctors and fewer hospitalizations.

Indeed, good heart failure therapy has allowed the management of many patients to shift from cardiologists and heart failure specialists towards a primary care environment. This would be great were it not for the very counterproductive reality of overworked primary care providers with inadequate time and resources to do the job they know how to do. The increased use of superbly trained mid-level providers like advanced practice nurses working at the top of their licenses in an integrated healthcare environment could further improve all outcome metrics. But that’s a topic for a future post.

What I want to do in this post is to give my SERMO colleagues a heads up on a couple of pharmacologic innovations that may further positively impact this equation, although the degree and cost are yet to be determined. One agent, ivabradine, has just been approved by the FDA. The other, LCZ696, will likely be approved in the not too distant future.

The first agent, ivabradine, has been available outside the U.S. for several years. It plays to the observation that adequately and traditionally treated heart failure patients with a persistently increased heart rate despite maximally tolerated beta-blocker therapy did less well compared to those with lower heart rates. Ivabradine is the first agent approved in the U.S. to target the sinus node through modulating the appropriately named “funny” channel and thus reducing the heart rate. So what’s the impact of this maneuver? In a 6500 patient multi-national trial published in 2010 called the SHIFT study (1), an 18% reduction in HF hospitalization was demonstrated, though no benefit in all cause or cardiovascular mortality was seen. Despite the lack of impact on mortality, the improved quality of life for patients and positive health-economic benefit to society apparently was sufficient to garner FDA approval. Save your questions for the intense detailing to begin as we speak.

The second agent, known as LCZ696, is actually a compound combining a work-horse angiotensin receptor blocker, valsartan, with a novel agent called sacubitril, which is a prodrug that is activated to another product that inhibits the enzyme neprilysin. Neprilysin is responsible for the degradation of both atrial and brain natriuretic peptide, two peptides that work primarily by reducing blood volume. In the PARADIGM HF study (2), 8400 heart failure patients were randomized to LCZ696 vs. enalapril. The study was terminated early for positive outcome. Benefit was seen for cardiovascular death (13.3% vs. 16.5%, p <0.001), all-cause death (17% vs. 19.8%, p = 0.0009), and heart failure hospitalization (12.8% vs. 15.6%, p <0.001). Given that LCZ696 was superior to full dose enalapril which itself has been shown to improve HF outcomes in many prior trials, this agent has the potential to replace ACE inhibitors and ARBs for HF management. However, the cost proposition will need to be carefully calculated to the payers to avoid pricing itself into a corner.

Interesting times in heart failure pharmacotherapy! The role of devices, intravascular monitoring, and consumer wearable technologies in heart failure may be subject for future posts.

If you are an M.D. or D.O. in the US or UK, please join us on SERMO.

References

1. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; on behalf of the SHIFT Investigators (2010). “Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study”. The Lancet 376 (9744): 875–885. doi:10.1016/S0140-6736(10)61198-1

2. John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., and Michael R. Zile, M.D. for the PARADIGM-HF Investigators and Committees “Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure” N Engl J Med 2014; 371:993-1004September 11, 2014DOI: 10.1056/NEJMoa1409077

 

Bio:

Irv Loh MDDr. Irving Kent Loh MD, FACC, FAHA (Epidemiology & Prevention), FCCP, FACP is a board certified internist and sub-specialty board certified cardiac specialist with an emphasis on preventive cardiology. He founded and directs the Ventura Heart Institute, which conducts education, research and preventive cardiovascular programs. Dr. Loh is a former Assistant Professor of Medicine at UCLA School of Medicine. He is Chief Medical Officer and Co-founder of Infermedica, an artificial intelligence company for enhancing clinical decision support for patients and healthcare providers.

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