Heart Failure Research Paper

Heart Failure is a disease state caused by a dysfunction or structural deviation in the cardiac system that inhibits the heart’s ventricles from filling and ejecting blood in its fullest capacity. When the heart’s ability to effectively pump blood decreases it lacks the ability to meet the need for blood in all other areas of the body. 1-3 Heart failure is considered a progressive condition that originates from a cardiovascular event that damages the function of the heart to contract and relax.1 This results in a decrease in cardiac output which leads to various types of compensation mechanisms such as tachycardia, increased preload, vasoconstriction, and ventricular hypertrophy and remodeling. There are currently about 5.1 million people in
the U.S. that are diagnosed with heart failure.1 The prevalence of heart failure is large and growing due to the increasing number of elderly people living longer and being effected with multiple comorbidities.2 There are about 670,000 new cases of heart failure diagnosed each year and we spend approximately 39 billion dollars as a country for the treatment of HF.2 The population at the most risk for developing heart failure are African Americans, people over the age of 65, and co-morbidities such as hypertension, diabetes, coronary disease, and obesity.1-3
There are 4 classes of heart failure ranging from I to IV used by patients to describe their symptoms.
Where I is no symptoms, II is mild symptoms with activity, III is limitation with activity, and IV is limitation in activity and at rest.3 There are also four stages of heart failure ranging from A to D, used by health care professionals, where A indicates a high risk for heart failure development but no signs or symptoms, B indicates heart disease without signs and symptoms, C indicates heart disease with signs and symptoms, and D indicates refractory heart failure that includes signs and symptoms at rest or without exertion and require specialized treatment.1-3 Each stage has different therapeutic recommendations with moderate overlap. For each stage it is recommend to stop smoking, get regular exercise, and limit sodium intake to 1500mg per day. The treatment for Stage A heart failure depends mostly on the other health conditions the patient has.1 Common risk factors include, coronary heart disease, smoking cigarettes, hypertension, obesity, diabetes, dyslipidemia,and valvular heart disease. 1,2 The best way to aid in the progression of heart failure is to treat the co-morbidities. 1 Many patients will be on anti-hypertensives to control their blood pressure and statins to control their high cholesterol. If patients have multiple risk factors relating to their cardiovascular system, they will be put on ACE inhibitors or ARBs to prevent the progression of their heart
failure. For Stage B patients already have a cardiac disorder that is putting them at an extremely high risk of developing heart failure signs and symptoms. Some examples of cardiac disorders in this population are left ventricular hypertrophy, MI, valvular disease, and reduced left ventricular ejection fraction. The treatment goal with these patients is to avoid further damage and limit the process of cardiac remodeling. It is recommended that these patients be on ACE inhibitors and beta- blockers. For Stage C patients, who have heart disease and symptoms, the goal is to reduce morbidities and mortality. It is recommended that all stage C patients are on a diuretic, a beta- blocker, and an ACE inhibitor. Other add on therapies for stage C patients include: aldosterone receptor antagonist, ARBs, digoxin, and hydralazine-isosorbide dinitrate. 1,3 At this stage, implantable cardioverter-defribillators (ICD) and cardiac resynchronization therapy (CRT) can be added as a nonpharmacologic treatment option. Stage D patients have the most advanced form of heart failure and require specialized care and management, such as mechanical circulatory support, continuous IV positive iontropic therapy, and cardiac transplant. These patients are also on high dose diuretics to control their water retention. It is recommended that Stage D patients restrict sodium and fluid intake, start on a loop and thiazide diuretic, continue on ACEs and beta-blockers. It is also recommended for all stages to obtain social support from peers, family, or friends to increase medical adherence, create a less stressful environment, and maintain a healthy lifestyle.3 Overall there are many aspects and factors that play a role in heart failure including add on drugs, which can be extremely useful in the maintenance of heart failure.
Eplerenone is a potassium sparing diuretic, aldosterone receptor antagonist, and common add on therapy used in heart failure.4-6 In addition to heart failure Eplerenone is also indicated for hypertension. The typical dosage for an adult with heart failure is initially 25 mg daily to be titrated up to a goal of 50 mg daily. Eplerenone acts competitively on mineralocorticoid aldosterone receptors to block the binding of aldosterone. Aldosterone is a part of the renin-angiotensin-aldosterone- system (RAAS) pathway and promotes retention of water and sodium, ultimately increasing blood pressure. 4,6 When Eplerenone binds to the aldosterone receptor it prevents the aldosterone from binding. If aldosterone doesn’t bind to the receptor, water and sodium is not retained and it goes through the kidney for excretion. Eplerenone only comes in a tablet form and taken orally with or without food.
Eplerenone has a good oral bioavailability (69%) and is not effected by food.4-6 It is approximately 50 % bound to proteins, mostly alpha-1-acid glycoproteins and has a time to peal of about 1.5 to 2 hours. For doses of Eplerenone between 25 mg and 100 mg, Cmax and AUC are dose proportional. The volume of distribution for Eplerenone ranges from 42 to 90 L. Eplerenone is metabolized extensively in the liver by cytochrome P450 3A4 into inactive metabolites. Eplerenone is excreted through the kidneys and has a half-life of 3 to 6 hours.
Eplerenone’s most dangerous adverse effect is hyperkalemia and is contraindicated in patients whose serum potassium is about 5.5 mEq/L.4-6 Other adverse effects include hypercholesterolemia, cough, diarrhea, headache, angina, raised serum creatinine, and abnormal vaginal bleeding. Eplerenone should not be used in patients with renal disease or renal failure, a CrCl under 30 mL/min, or with current hyperkalemia. Several drug interactions occur with the use of Eplerenone due it its metabolism by CYP3A4. Eplerenone cannot be used with CYP3A4 inhibitors such as clarithromycin and ketoconazole, as well as potassium supplements. Patients on ACE inhibitors and Eplerenone must also monitor closely for signs and symptoms of hyperkalemia. Eplerenone is a common add-on therapy to patients with heart failure. Studies have shown it can help promote positive health care outcomes.
A recent study from 2011 was conducted by the EMPHASIS-HF Study Group in order to test the effects of Eplerenone on heart failure patients.7 The study contained 2,723 patients who were randomly put into a placebo group or a test group that received up to 50mg of Eplerenone per day.
The study was double-blinded and placebo controlled. The patients were classified as having class II heart failure, where patient’s experience signs and symptoms of physical activity, at least 55 years of age, having an ejection fraction under 30%, being treated with an ACE or ARB as well as a beta-blocker, and a recent hospitalization. Patients with acute MI, classified as class III and IV heart failure patients, having a serum potassium level of over 5 mmol/L, or having a GFR under 30 mL were excluded from the study. There were 1,364 patients in the study group who received Eplerenone and 1,373 patients in the placebo group. Patients who were assigned to the study group were initially started on Eplerenone 25 mg daily and then titrated up to 50 mg daily after 4 weeks. The primary study measure outcome was death from cardiovascular causes or hospitalization for heart failure. There were several secondary outcomes including, but not limited to: death from any cause or hospitalization for any reason, hospitalization for cardiovascular causes, hospitalization for any reason, etc. This study utilized a two-sample t-test for variables that were considered continuous and a Fisher’s test for variables
that were categorical. Kaplan-Meier estimates and Cox proportional-hazards models were used to calculate hazard ratios, confidence intervals, and P values.
Of the patients who participated in the study the average age was 68.7 year old with a standard deviation of 7.7 years.7 A majority of the participants were male, with about 22% being female, and about 83% of the participants were white. It was found, that in the primary outcome result 18.3% of patients on the Eplerenone experienced death from a cardiovascular cause or hospitalization due to heart failure compared to 25.9% of patients on the placebo. The hazard ratio was 0.63, 95% CI ,0.54 to 0.74; P<0.001] were monitored during the study. Overall, the authors concluded that Eplerenone, used as an add on therapy to other recommended heart failure therapies, was successful in reducing mortality and hospitalizations in heart failure patients.
I believe this trial is helpful and served a purpose in determining a use for Eplerenone in heart failure patients, but there were also many weaknesses in this study. In my opinion the study would have been much stronger if it was not placebo controlled and Eplerenone was being compared to a different drug that is intended for a similar purpose such as Spironolactone. I think the study was also limited when it came to safety and efficacy. Some strengths of the study were that there was a large sample size, it was a randomized control trial, it was double-blinded, and the study was measuring health outcomes rather than specific surrogate parameters. The study had high interval validity because the methodology was specific and followed closely, there were no other variable present in the study other than the drug regimen, and the study measured ended up measuring what it intended to, which was the effect of Eplerenone of heart failure events and mortality. The external validity was weaker due to the study population having so many specific criteria to be met for participation such as, age, ejection fraction deficiency, and a recent hospitalization. Therefore, the results and outcomes of the study cannot be easily generalized to all heart failure patients. Overall, I do agree with the author. I believe that the effects of Eplerenone in heart failure patients can lead to a decrease in mortality and hospitalizations in these patients. I believe that Eplerenone can be useful in patients older than 65, with low ejection fraction, and recent hospitalizations and should be utilized in these patients whenever it is possible. The results from this study solidify the belief that Eplerenone is effective in heart failure patients and it should be used frequently in order to promote more positive health outcomes.
Eplerenone is a commonly used add-on drug for patients suffering from heart failure. It is an aldosterone receptor antagonist and potassium-sparing diuretic that helps decrease blood pressure and slows the progression of heart failure. When observing the results of the clinical trial by EMPHASIS-HF it is clear to see that events of hospitalization and death are significantly decreased when patients are taking Eplerenone. Although not a first line therapy, Eplerenone is effective in treating heart failure.