Chronic Heart Failure

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Chronic Heart Failure

Chronic heart failure (often simply termed heart failure or HF in the scientific literature) is categorized into three broad types: left-sided heart failure, right-sided heart failure, and congestive heart failure. Pharmacological progress in treating this disease has been frustratingly slow, with only two new drugs gaining FDA approval in the last ten years: ivabradine, marketed as Corlanor, and a sacubitril/valsartan mix marketed as Entresto. This is in large part because the biomarkers of chronic heart failure are still being mapped out, making it difficult to demonstrate the efficacy of new drugs. However, there are some promising candidates currently in clinical trials, including omecamtiv mecarbil and testosterone therapy. Below is a deep dive into the current and possible future trends in the treatment of chronic heart failure.

THE FIRST USE OF A HCN BLOCKER TO TREAT CHRONIC HEART DISEASE

Corlanor (ivabradine) was approved by the FDA in 2015, specifically for chronic heart failure. It is a drug that is typically prescribed for patients with heart failure that is caused by problems in the heart’s lower left chamber, patients with normal heart rates, and patients whose heart rate is not controlled by beta-blockers or patients that cannot take beta-blockers. It is the first HCN channel blocker. The drug works to treat chronic heart failure by inhibiting specific channels in the SA node, which slows the patient's heart rate.

THE FIRST USE OF AN ANGIOTENSIN RECEPTOR NEPRILYSIN INHIBITORS TO TREAT CHRONIC HEART DISEASE

Sacubitril/Valsartan (Entresto) is a new medicine that is prescribed to shorten a patient's time in the hospital. It was approved by the FDA in 2015 and is the "first in a new class of drugs called angiotensin receptor neprilysin inhibitors, or ARNIs." However, it cannot be used with ACE inhibitors. It was approved specifically for chronic heart failure. Sacubitril inhibits an enzyme called neprilysin, which is used to reduce blood volume. Lower blood volume results in lower blood pressure. Note that though valsartan has received FDA approval, studies continue to, for example, "evaluate the tolerability and safety of valsartan in patients with stable, chronic heart failure."

NEW BLOOD THINNER FOR CHRONIC HEART DISEASE BEING PRESCRIBED BY PHYSICIANS

In 2018, Xarelto (rivaroxaban) was approved by the FDA. It is used to treat "chronic coronary or peripheral artery disease." It can reduce the effect of major cardiac events by 24%, when used in combination with aspirin. Data also showed, "a 42% reduction in stroke, 22% reduction in CV death and 14% reduction in heart attack." Xarelto reduces the formation of fibrin (which binds platelets together), which means the patient is less likely to get a blood clot.

BIOMARKER RESEARCH

Much of the cutting-edge research into chronic heart failure (and heart failure in general) is focused on identifying biomarkers which can be used to diagnose the disease early. Currently, "the natriuretic peptides appear to be the gold standard biomarker against which the other biomarkers are compared." The search for new biomarkers continues in various studies by organizations like the prestigious Mayo Clinic. For reasons that will be explained below, a better understanding in this area is vital for the pharmaceutical industry and the lack thereof is hindering

CURRENT CLINICAL TRIALS

One possible biomarker is the presence of certain hormonal deficiencies, particularly androgen depletion in men. This has led to investigations into using testosterone to treat the disease, which a review paper published in September 2018 called "a promising topic that requires further investigation."

One of the most promising new drugs, currently in the second round of its phase 3 trials, is omecamtiv mecarbil. Omecantive was originally developed by Cytokinetics but is now under a joint venture between Amgen and Servier. The medication is designed "to increase the duration of cardiac muscle contractility and improve cardiac muscle performance in heart failure," which would hopefully extend the patient's time to death or even to their first heart attack, as well as improve the patient's tolerance to exertion and exercise.

There are currently 441 recruiting or active clinical trials for therapies (not all of them drugs) for chronic heart failure or related conditions. However, we have little information in most cases about how the medication is expected to work. For example, dapansutrile capsules are among the drugs currently being tested, though the results of this clinical trial are still pending, which prevents us from having much visibility into the mechanics of the drug. We are therefore unable to determine if certain pathways to treatment are receiving more attention than others.

NON-PHARMACEUTICAL TREATMENTS

 Cardiac resynchronization is currently being used with drug therapy to achieve maximum patient results. Cardiac resynchronization therapy (CRT) involves a small pacemaker that is implanted into the patient and helps the patient's heart rhythms stay regular. It can send electric pulses on the patient's ticker surface, meaning fewer adjustments. CRT is intended for heart failure patients with moderate to severe symptoms and whose left and right heart chambers do not beat in unison. It is not effective for diastolic failure. It treats arrhythmia, especially atrial fibrillation by improving ventral synchrony. According to NCBI, " a number of technological advances have already contributed to achieve some objectives of modern CRT. They include novel lead design (the left ventricular quadripolar lead, and multipoint pacing), or the possibility to go beyond conventional delivery of CRT (left ventricular endocardial pacing, His bundle pacing)."

In fact, a lot of the anticipated progress in the treatment of chronic heart failure is in the domain of the Internet of Things (IoT), with in-home and wearable devices currently being studied for this disease. As this subject appears to be outside the intent of the report criteria, we did not pursue this avenue further, but it might be worth further study in order to better understand the future trends in this area.

SLOW PROGRESS BY THE PHARMACEUTICAL INDUSTRY

As we studied the available literature, we found a consistent tone of frustration over the "lack of new drug treatment options" to reverse chronic heart failure's "stubbornly low" survival rates. In a similar vein, a 2018 study concluded that there is "a large unmet need for new therapies in the treatment of heart failure with reduced ejection fraction (HFrEF)." The authors recommend a balanced approach to determining a relatively small "number of parameters, indices, or biomarkers indicative of a clinical benefit" in developing new drugs. Whether this will result in more drugs being developed specifically for HFrEF remains to be seen.

Due to the lack of recent FDA approvals (only two in the past 10 years), many older medications are still being prescribed by doctors to treat chronic heart failure. These include anticoagulants, antiplatelet agents and dual antiplatelet therapy, ACE Inhibitors II, receptor blockers, angiotensin-receptor neprilysin inhibitors, beta blockers, calcium channel blockers, cholesterol-lowering medications, digitalis preparations, diuretics, and vasodilators are currently the most common medications prescribed to treat chronic heart failure. A full list with descriptions can be viewed here.

Incidentally, and perhaps slightly off-topic, researchers at UCLA have published a study which found that only 25% of patients were being prescribed all three of the current categories of heart failure medicine and that this has not improved in at least the last decade. "The report says new strategies are needed to more effectively achieve and maintain recommended doses of heart failure medications and that there is a substantial opportunity to improve dosing of heart failure medications, which would improve the care and outcomes for people with heart failure." It will be interesting to see whether this report is used by the pharmaceutical industry to broaden their reach.

CONCLUSION

For a variety of reasons, including our current poor understanding of the associated biomarkers, pharmacological treatments of chronic heart failure have been extremely slow in both development and FDA approval for the last decade. This has resulted in numerous papers published even in just the last year calling for more studies and clinical trials in the hopes of increasing the survivability of the disease. While it's difficult at best to predict which treatments will ultimately be approved, omecamtiv mecarbil and testosterone replacement therapy look promising. Other drugs, like dapanstrile, are simply too early in the testing stage to judge properly. The most often cited future trends in the treatment of this disease, however, are not strictly pharmacological, but rather the use of other technologies, like cardiac resynchronization therapy (CRT) and the Internet of Things (IoT) to supplement existing drug therapies. Further research into IoT technological trends is recommended for the sake of a more complete picture of the future of chronic heart failure treatment.

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