Please select the eligibility criteria that correspond to the clinical trial below.
Title: The Effect Of Eplerenone Versus Placebo On Cardiovascular Mortality And Heart Failure Hospitalization In Subjects With NYHA Class II Chronic Systolic Heart Failure
Brief Summary: In an earlier study, eplerenone was shown to improve survival in patients who had heart failure immediately following a heart attack. However, it is not known how patients with established mild-to-moderate heart failure (NYHA Class II), who have the additional risk of sudden death, will respond if treated with eplerenone. In this trial, eplerenone plus standard heart failure medicines is being compared to placebo plus standard heart failure medicines in terms of an additional ability to prolong life and prevent re-hospitalizations for worsening heart failure in these patients.

The Data Safety Monitoring Committee (DSMC) observed during its conduct of the protocol-specified second interim analysis on the 6th of May, 2010 that the efficacy of eplerenone had met the pre-specified stopping rules in the protocol. As a result of the discussion between the DSMC and the Executive Steering Committee (ESC), the ESC recommended that EMPHASIS-HF should be terminated, Based on the convincing efficacy and the consideration that it would be unethical not to offer this treatment to patients, the ESC recommended that all the patients in the trial should be transferred to open-label eplerenone. The Open Label Extension eplerenone arm will last for 12 months. Eplerenone is not currently approved for the indication studied in this patient population.

On May 26, 2010, further enrollment into EMPHASIS-HF was stopped. The amendment is considered to be the most appropriate way to ensure that all the subjects who participated in the double-blind phase of the EMPHASIS-HF trial can be offered treatment with eplerenone


Options:
A: Inclusion Criteria:

* History (Hx) of chronic systolic heart failure of ischemic or non-ischemic etiology of at least 4 weeks duration; Currently, New York Heart Association (NYHA) functional Class II and on optimal dose, or maximally tolerated dose of standard heart failure medicines (advisable to include ACE-I/ARBs; beta-blockers) and diuretics if indicated for fluid overload. Should have participated in the double-blind phase of the EMPHASIS-HF trial

Exclusion Criteria:

* Severe chronic systolic heart failure symptomatic at rest despite optimal medical therapy; estimated glomerular filtration rate (eGFR) \<30 ml/min/1.73m2.
B: Inclusion Criteria:

* Male or female patient ≥21 years old
* Admitted to hospital for AHF with at least 1 symptom (dyspnea, orthopnea, or fatigue) and 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography) of congestion
* Patient must be randomized within 24 hours of first IV diuretic dose administered for the current episode of decompensation (regardless of where the diuretic was given e.g. office, ED, ambulance, hospital etc.)
* Estimated GFR of ≥30 mL/min/1.73m2 determined by the MDRD equation
* Serum K+ ≤5.0 mmol/L at enrollment
* NT-proBNP ≥1000 pg/mL or BNP ≥250 pg/mL, measured within 24h from randomization
* Not on MRA or on low-dose spironolactone (12.5 mg or 25 mg daily) at baseline

Exclusion Criteria:

* Taking eplerenone or \>25 mg spironolactone at baseline
* eGFR \< 30 ml/min/1.73m2
* Serum K+ \>5.0 mmol/L. If a repeat measurement within the enrollment window is \<5.0, the patient can be considered for inclusion.
* Systolic blood pressure \<90 mmHg
* Hemodynamically significant arrhythmias or defibrillator shock within 1 week
* Acute coronary syndrome currently suspected or within the past 4 weeks
* Severe liver disease (ALT or AST \>3 x normal, alkaline phosphatase or bilirubin \>2x normal)
* Active infection (current use of oral or IV antimicrobial agents)
* Active gastrointestinal bleeding
* Active malignancy other than non-melanoma skin cancers
* Current or planned mechanical circulatory support within 30 days
* Post cardiac transplant or listed for transplant and expected to receive one within 30 days
* Current inotrope use
* Complex congenital heart disease
* Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade
* Previous adverse reaction to MRAs
* Enrollment in another randomized clinical trial during index hospitalization
C: Inclusion Criteria:

* Adult male and female subjects aged 20-65 of all ethnic backgrounds.
* Type I diabetes mellitus defined as sudden onset of insulin requiring diabetes prior to age 20 and at least 5 years duration
* Type 2 diabetes mellitus defined as onset \> 20 years of age and treatment with oral hypoglycemic agent and/or insulin and increased C-peptide level.
* Seated SBP \> 130 mmHg documented at one screening visit or treated SBP \< 130 mmHg with a documented history of SBP \> 130 mmHg on more than one previous occasion
* Proteinuria defined as a 24-hour urine albumin/creatinine ratio \> 300 mg/g while on an ACE inhibitor with or without non-ARB, non-aldosterone antagonist treatment
* Ongoing treatment (\> 3 months) with an ACE inhibitor or ARB with or without additional antihypertensive therapy (e.g. CCB, a-blocker, b-blocker, clonidine).

Exclusion Criteria:

* BMI \> 45 kg/m2
* Baseline serum creatinine \> 3.0 mg/dl in females and \> 4.0 mg/dl in males or creatinine clearance \<20 ml/min estimated by Cockcroft-Gault equation (based on age, fasting serum creatinine concentration and ideal body weight in kilograms).
* Secondary cause of kidney disease other than diabetic nephropathy
* Serum potassium concentration \>5.5 mEq/L on ACE inhibitor therapy 7-10 days prior to randomization
* Poorly controlled diabetes, i.e. HgbA1C \> 11 mg/dl 7-10 days prior to randomization
* History of allergy to iothalamate or history of renal failure due to contrast nephropathy
* Stroke or myocardial infarction within the preceding 12 months prior to randomization
* Coronary revascularization procedure within past 6 months
* Clinically apparent congestive heart failure defined as clinical signs of heart failure or an ejection fraction of \< 40% (and/or depressed LV systolic function by echocardiogram).
* Terminal disease including cancer and AIDS
* Documented increase in serum creatinine \> 50% of baseline within 3 months prior to the run-in period
* Renal disease known or in the opinion of the investigator caused by a condition other than diabetes
* Known adverse reaction to study medications including ACE inhibitors, ARB and spironolactone
* History of chronic or intermittent gross hematuria
* Spontaneous 24-hour urine sodium excretion rate exceeding 350 mEq/day
* AST or ALT greater than 2.5 the upper limit of normal for the laboratory
* Pregnancy
* History of autoimmune disease, connective tissue disease or multiple drug allergies
* Anticipated need for renal replacement therapy within 12 months Inclusion criteria for normal subjects
* Adult male and female subjects aged 20-65 of all ethnic backgrounds Exclusion criteria for normal subjects
* Chronic medical conditions, including but not limited to diabetes mellitus, hypertension, chronic kidney disease, and hyperlipidemia.
* Use of medications for antihypertensive
* Inability to follow study protocol for any reason
D: Inclusion Criteria:

* Age \< 75 years
* Type-2 diabetes
* Therapy resistant hypertension (by ABPM)
* Treatment with at least 3 antihypertensives

Exclusion Criteria:

* HbA1c \> 10.0
* BP \> 180/110 mmHg
* Secondary hypertension
* Intolerance to spironolactone
* Permanent treatment with nonsteroidal antiinflammatory drugs or systemic glucocorticoids
* Total cholesterol 10 mmol/l
* New York Heart Association class III and IV
* Pregnancy or planned pregnancy
* Psychiatric disease
* Malignant disease
* Insufficient adherence

Answer: A