Shining light or shipwreck

There have been no novel medications for decades, and exisiting therapies don’t have enough of an impact on morbidity and mortality rates

The clinical guidelines for the treatment of heart failure were completely revised by the American College of Cardiology Foundation and the American Heart Association (ACCF/AHA), to emphasize the role of medication therapy as the foremost approach to managing this high profile condition (

Approximately 5.1 million people in the United States have heart failure and it is the leading cause of hospitalization among people over age 65. The Agency for Healthcare Research and Quality projects there were 928,000 heart failure admissions in 2012, far exceeding those for heart attack (594,000), coronary artery disease (480,000) or atrial fibrillation (466,000). Hospitalization for acute heart failure is prognostic of a 50% risk for readmission within six months and a one-year mortality rate of approximately 30%, according to the ACCF/AHA.

Of the proportion of people under age 65 who were hospitalized for any reason, those hospitalized for heart failure rose from 23% in 2000 to 29% in 2010.

“Serelaxin may be an important advance, but we have been excited about other drugs in the past and they have been disappointing in larger studies,” says Mariell Jessup, MD, of the University of Pennsylvania.

“One of the most important updates is the formal definition of the concept of guideline-directed medical therapy, GDMT,” says Mariell Jessup, MD, vice chairwoman of the writing committee that wrote the guideline and professor of medicine at the University of Pennsylvania. “GDMT is the current optimal therapy for each stage of heart failure.”

The focus on GDMT reflects the advances that have been made in medical therapy for many cardiovascular disorders, and the ACCF/AHA intends to use this term throughout its long list of guidelines.

GDMT for heart failure has progressed from digitalis and diuretics to vasodilators and to the current neurohormonal agents in which rennin-angiotensin-aldosterone system antagonists are the drugs of choice. There have been no novel heart failure medications for decades.

Furthermore, existing therapies reduce morbidity or mortality only in 50% of heart failure patients — those affected by heart failure with reduced ejection fraction, HFrEF. Disease modifying medication therapy that has not yet been demonstrated conclusively for individuals with heart failure with preserved ejection fraction, HFpEF. Ejection fraction is the percent of the ventricular volume that is pumped out with each heartbeat. The revised guidelines define HFrEF as an ejection fraction ≤ 40% and HFpEF as an ejection fraction ≥ 50%. Borderline HFpEF has an ejection fraction of 41% to 49%.

Problems for health plans

Heart failure is expensive for Medicare Advantage plans. A recent article in Health Affairs reports that heart failure generates higher per-patient Medicare expenditures than diabetes or chronic obstructive pulmonary disease. A study reported online by the American Journal of Managed Care says the average annual cost for Medicare members is $33,000 with hospitalizations accounting for more than half of those costs. Late-stage heart failure patients may face substantial hospital costs in the form of implantation of expensive cardioverter defibrillators or ventricular-assist devices.

In addition, Medicare Advantage plans are penalized for readmissions, and in 2010 the heart failure readmission rate was 24.7%.

Many CHF readmissions are related to inadequate medication therapy.

Part D plans are able to escape penalties for readmissions, many of which are related to inadequate medication therapy.

“CMS is starting to have issues around readmissions in stand-alone Part D programs because they are not assigned financial responsibility in the same way health plans are penalized,” says Brian Solow, MD, chief medical officer at OptumRX, UnitedHealthcare’s captive PBM. CMS has finally realized it needs to start to look at this.” Solow says CMS has not figured out if or how it will deal with this issue.

Part D plans face another important challenge in heart failure. In 2013, 95% of Part D programs targeted heart failure for a medication therapy management program. In 2014, CMS will include a star rating for the completion of comprehensive medication reviews, CMRs, thus encouraging Part D plans to get them done for heart failure patients. The American College of Cardiology says in 2009 heart failure patients had an average of 5.91 comorbidities which increase the number of medications and greatly complicate CMRs.

The guideline revision pays special attention to HFpEF, which affects approximately 50% of patients and lacks proven effective pharmacological therapies. It received increased attention for several reasons.

The diagnosis of HFpEF is more challenging than the diagnosis of HFrEF because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of heart failure. Patients with HFpEF are usually older women with a history of hypertension, atrial fibrillation, obesity, and diabetes mellitus.

HFpEF poses serious therapeutic challenges, as drugs that are efficacious in HFrEF — angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), and beta blockers — have produced disappointing results for morbidity and for mortality.

These patients are often treated for underlying risk factors and comorbidities, using GDMT similar to that used in patients with HFrEF.

Medications may affect the comorbidities surrounding heart failure but they do not improve heart failure morbidity and mortality.

The challenge in HFpEF is Stage C, which entails structural heart disease and symptoms. The pharmacologic treatment recommendations vary by New York Heart Association (NYHA) functional classification, which describes exercise capacity and the symptomatic status of the disease. Treatment in this stage includes blood pressure medications, diuretics, management of atrial fibrillation, and use of beta blockers, ACE inhibitors, and ARBs in patients with hypertension.

Blood pressure control is the most important recommendation in patients with HFpEF. The guidelines recommend aggressive treatment — often with several drugs with complementary mechanisms of action. ACE inhibitors and/or ARBs are often considered as first-line agents.

Increasing hospitalizations are another challenge for HFpEF patients. Among 6,076 consecutive acute heart failure admissions at Mayo Clinic Hospitals from 1987 to 2001, the prevalence of HFpEF increased from 38% in the first five years to 54% in the final five years, according to a recent study in Current Heart Failure Reports.

In addition, the survival of hospitalized HFrEF patients improved over the study period, but there was no improvement in acute heart failure patients with HFpEF.

“We need new medicines for patients with HFpEF, given that 50% of all hospital admissions are for patients with preserved ejection fraction,” says Jessup. “This is a poorly understood syndrome, and there are no evidence based therapies that modify its overall course.”

The need for new medical therapies is widely recognized. In June, the FDA granted breakthrough status for Novartis’s serelaxin, which produced a 37% reduction in death at six months for hospitalized acute heart failure patients.

“Serelaxin may be an important advance, but we have been excited about other drugs in the past and they have been disappointing in larger studies,” says Jessup. Serelaxin missed at least one endpoint in its phase 3 trial.

Complex nature

“Heart failure is a common, high-profile condition because of its complex nature, with many comorbidities and frequent hospitalizations,” says Solow. “Disease management programs don’t work as well as we would like them to. People end up with dyspnea or fluid buildup, or in the worse case are back in the hospital for many different reasons that are hard to control.”

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