Chapter 280 - Heart Failure: Management Flashcards
Name the therapies that are considered disease-modifying in those with heart failure (HF) with reduced ejection fraction (HFrEF).
“Early management evolved from symptom control to disease-modifying therapy in HFrEF with the advent of renin-angiotensin-aldosterone system-directed therapy, beta receptor antagonists, mineralocorticoid receptor antagonists, resynchronization therapy, and implantable cardio-defibrillators.”
Therapeutic advantagens in those with HF with preserved ejection fraction (HFpEF) and acute decompensated HF (ADHF) have remainded devoided of convincing therapeutic advances to alter their natural history.
True or False?
True.
Compare the clinical features and outcomes in those with advanced HF to those with early-stage asymptomatic left ventricle (LV) dysfunction.
“In advanced heart failure, a stage of disease typically encountered in HFrEF, the patient remains markedly symptomatic with demonstrated refractoriness or inability to tolerate full-dose neurohormonal antagonism, often requires escalating doses of diuretics, and exhibits persistent hyponatremia and renal insufficiency with frequent episodes of heart failure decompensation requiring recurrent hospitalizations. Such individuals are at the highest risk of sudden or progressive pump failure-related deaths. In contrast, early-stage asymptomatic left ventricular dysfunction is amenable to preventive care, and its natural history is modifiable by neurohormonal antagonism.”
Regarding those with HFpEF, addressing surrogate targets, such as regression of ventricular hypertrophy in hypertensive heart disease, and use of lusitropic agents, such as calcium channel blockers and beta receptor antagonists, have been disappointing. Experience has demonstrated that lowering blood pressure alleviates symptoms more effectively than targeted therapy with specific agents.
True or False?
True.
Summarize the evidence on therapeutics for HFpEF, namely the main results of the CHARM, I-PRESERVE, DIG, and SENIORS trials. Also, discuss the evidence regarding the use of ACE inhibitors in those with HFpEF.
“The Candesartan in Heart Failure-Assessment of Mortality and Morbidity (CHARM) Preserved study showed a statistically significant reduction in hostapilizations but no difference in all-cause mortaity in patients with HFpEF who were treated with the angiotensin receptor blocker, candesartan. Similarly, the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial demonstrated no differences in meaningful endpoints in such patients treated with irbesartan. An earlier analysis of a subset of the Digitalis Investigation Group (DIG) trial found no role for digoxin in the treament of HFpEF. In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) trial of nebivolol, a vasodilating beta blocker, the subgroup of elderly patients with prior hostapilization and HFpEF did not appear to benefit in terms of all-cause or cardiovascular mortality. Much smaller mechanistic studies in the elderly with the angiotensin-converting enzyme inhibitor enalapril showed no effect on peak exercise oxygen consumption, 6-minute walk distance, aortic distensibility, left ventricular mass, or peripheral neurohormone expression.”
What are the main findings of the RELAX trial? What was the rationale for this study?
“A small trial demonstrated that the phosphodiesterase-5 inhibitor sildenafil improved filling pressures and right ventricular function in a cohort of HFpEF patients with pulmonary venous hypertension. This finding led to the phase II trial, Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX), in HFpEF patients (left ventricular ejection fraction [LVEF] >50%) with NYA functional class II or III symptoms, who received sildenafil at 20mg three times daily for 3 months, followed by 60 mg three times daiy for another 3 months, compared with placebo. There was no improvement in functional capacity, quality of life, or other clinical and surrogate parameters.”
Compare the findings of TOPCAT and ALDO-DHF studies.
“Conceptually targeting myocardial fibrosis in HFpEF, the large-scale Aldosteonse Antagonist Therapy in Adults with Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) trial has been completed. This trial demonstrated no improvement in the primary composite end-point, but did show a secondary signal of benefit on HF hospitalizations, counterbalanced, however, by an increase in adverse effects, particularly hyperkalemia. However, pessimism has been generated by the negative outcome of the Alodsteronse Receptor Blockade in Diastolic Heart Failure (ALDO-DHF) study wherein spironolactone improved echocardiographic indices of diastolic dysfunction but failed to improve exercise capacity, symptoms, or quality-of-life measures.”
What might the usefulness of LCZ696 in patients with HFpEF?
“A unique molecule that hybridez an ARB with an endopeptidase inhibitor, LCZ696, increases the generation of myocardial cyclic guanosine 3’,5’-monophospahte, enhances myocardial relaxation, and reduces ventricular hyeprtrophy. This dual blocker has been shown to reduce circulating natriuretic peptides and reduce left atrial size to a significantly greater extent than valsartan alone in patients with HFpEF.”
Some investigators have suggested that the exercise intolerance in HFrEF is a manifestation of chrotropic insuffiiency and that such aberrations could be corrected with use of rate responsive pacemakers, but this remains an inadequately investigated contention.
True or False?
False.
The argument applies only for those with HFpEF.
Summarize the epidemiology of ADHF regarding short- and long-term mortality, as well as major events incidence at 12 months after hospitalization.
“Admission with a diagnosis of ADHF is associated with excessive morbidity and mortality, with nearly half of these patients readmitted for management with 6 months, and a high short-term (5-8% in-hospital) and long-term mortality (20% at 1 year). Importantly, long-term aggregate outcomes remain poor, with a combined incidence of cardiovascular deaths, heart failure hospitalizations, myocardial infarction, strokes, or sudden deaths, heart failure hospitalizations, myocardial infarction, strokes, or sudden death reaching 50% at 12 months after hospitalization.”
Name all the precipitant factors known to be associated with decompensation of chronic HF.
“The first principle of managemnt of [ADHF] patients is to identify and tackle down precipitants of decompensation. Identification and management of medication nonadherence and use of prescribed medicines such as nonsteroidal anti-inflammatory drugs, cold and flu preparations with cardiac stimulants, and herbal preparations, including licorice, ginseng, and ma huang (an herbal form of ephedrine now banned in most places), are required. Active infection and overt or covert pulmonary thromboembolism should be sought, identified, and treated when clinical clues suggest such direction. When possible, arrhythmias should be corrected by controlling heart rate or restoring sinus rhythm in patients with poorly tolerated rapid atrial fibrillation and by correcting ongoing ischemia with coronary revascularization or by correcting offenders such as ongoing bleeding in demand-related ischemia.”
The routine use of pulmonary artery catheter is not recomended in those with ADHF and should be restricted to those who respond poorly to diuresis or experience hypotension or signs and symptoms suggestive of a low cardiac output where therapeutic targets are unclear.
True or False?
True.
Name the parameters associated with worser outcomes in those with hospitalization due to ADHF.
Blood urea nitrogen >43mg/dL, systolic blood pressure less than 115 mmHg, serum creatinine level >2,75mg/dL, and elevated troponin I level.
Digoxin might reduce hospitalizations in those with HFpEF.
True or False?
True.
Although this result has not been shown in the mentioned subset DIG trial. It is mentioned in the therapeutic algorithm for HFpEF.
What is the best diuretic regimen for those admitted with ADHF?
“Randomized clinical trials of high-versus low-dose or bolus versus continuous infusion diuresis have not provided clear justification for the best diuretic strategy in ADHF, and as such, the use of diuretic regimnes remains an art rather than science.”
Which diuretic is most commonly used in those with ADHF?
Furosemide.
“Addition of a thiazide diuretic agent such as metolazone in combination provides a synergistic effect and is often required in patients receiving long-term therapy with loop diuretic agents.”
How should one monitorize patients with ADHF regarding their volemic status and optimal euvolemia achievement for discharge planning?
“Physical examination findings, speifically the jugular venous pressure coupled with biomarker trends, are useful in timing discharge planning.”
Summarize the definition, incidence and pathophysiology of cardiorenal syndrome.
“The cardiorenal syndrome is being recognized increasingly as a complication of ADHF. Multiple definitions have been proposed for the cardiorenal syndrome, but at its simplest it can bge thought to reflect the interplay between abnormalities of heart and kidney function, with deteriorating function of one organ while therapy is administered to preserve the other. Approximately 30% of patients hospitalized with ADHF exhibit abnormal renal function at baseline, and this is associated with longer hospitalizations and increased mortality. However, mechanistic studies have been largely unable to find correlation between deterioration in renal function, cardiac ouput, left-sided filling pressures, and reduced renal perfusion; most patients with cardiorenal sndrome demonstrate a preserved cardiac output. It is hypothesized that in patients with established heart failure, this syndrome represents a complex interplay of neurohormonal factors, potentially exacerbated by “backward failure” resulting from increased intra-abdominal pressure and impairment in return of renal venous blood flow. Continued use of diuretic therapy may be associated with a reduction in glomerular filtration rate and a worsening of the cardiorenal sydrome when right-sided filling pressures remain elevated.”
Inotropic therapy in those with late stages of HF has been shown to preserve or improve renal function in selected individuals in the short term.
True or False?
True.
Summarize the rationale of using ultrafiltration in patients with ADHF, as well as the evidence available for this therapy.
“Ultrafiltration (UF) is an invasive fluid removal technique that may supplement the need for diuretic therapy. Proposed benefits of UF include controlled rates of fluid removal, neutral effects on serum electrolytes, and decreased neurohormonal activity. This technique has also been referred to as aquapheresis in recognition of its electrolyte depletion-sparing effects. Current UF systems function with two large-bore, peripherally inserted venous lines. In a pivotal study evaluating UF versus conventional therapy, fluid removal was improved and subsequent heart failure hospitalizations and urgent clinic vists were reduced with UF, however, no improvement in renal function and no subjective differences in dyspnea scores or adverse outcomes were noted. More recently, in the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, 188 patiets with ADHF and worsening renal failure were randomized to stepped pharmacologic care or UF. The primary endpoint was a change in serum creatinine and change in weight (reflecting fluid removal ) at 96 hours. Although similar weight loss occurred in both groups (approximately 5,5 Kg) there was worsening in creatinine in the UF group. Deaths and hospitalizations for heart failure were no different between groups, but there were more severe adverse evets in the UF group, mainly due to kidney falure, bleeding complications, and intravenous catheter-related complications.”
What are the main results of the ASCEND-HF trial? What was the rationale for this study?
“[Nesiritide] was introduced in a fixed dose for therapy after a comparison with intravenous nitrates suggested more rapid and greater reduction in pulmonary capillary wedge pressure. Enthusiasm for nesiritide wanned due to concerns within the pivotal trials for development of renal insufficiency and an increase in mortality. To address these concerns, a large-scale morbidity and mortality trial, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study was completed in 2011 and randomly enrolled 7141 patients with ADHF to nesiritide or placebo for 24 to 168 hours in addition to standard care. Nesiritide was not associated with an increase or a decrease in the rates of death and rehospitalization and had a clinically insignigificant benefit on dyspnea. Renal function did not worsen, but increased rates of hypotension were noted. Although this trial established the safety for this drug, the routine use cannot be advocated due to lack of significant efficacy.”
Summarize the evidence regarding serelaxin.
“Recombinant human relaxin-2, or serelaxin, is a peptide upregulated in pregnancy and examined in ADHF patients with a normal or elevated blood pressure. In the Relaxin in Acute Heart Failure (RELAX-AHF trial), serelaxin or placebo was added to a regimen of standard therapy in 1161 patients hospitalized with ADHF, evidence of congestion, and systolic pressure >125 mmHg. Serelaxin improved dyspnea, reduced signs and symptoms of congestion, and was associated with less early worsening of HF. Exploratory endpoints of hard outcomes at 6 months suggest positive signals in favor of mortality reduction.”
Compare dobutamine to milrinone.
Both are inotropic therapies that act via direct or indirect pathways, more specifically, dobutamine is a sympathomimetic amine while milrinone is a phosphodiesterase-3 inhibitor. “Their activity leads to an increase in cytoplasmic calcium. Inotropic therapy in those with a low-output state augments cardiac output, improves perfusion, and relieves congestion acutely. Although milrinone and dobutamine have similar hemodynamic profiles, milrinone is slower acting and is renally excreted and thus requires dose adjustments in the setting of kidney dysfunction. Since milrinone acts downstream from the b1-adrenergic receptor, it may provide an advantage in patients receiving beta blockers when admitted to the hospital.”
Studies are in agreement that long-term inotropic therapy increases mortality, while short-term usage is also associated with increased arrhythmia, hypotenson, and no beneficial effects on hard outcomes.
True or False?
True.
Compare the RELAX study to RELAX-AHF.
- RELAX: this study randomized patients to sildenafil versus placebo. Patients on the sildenafil arm were taking 20mg three times a day for 3 months and 60mg three times a day in the following 3 months. No differences on outcomes were shown (namely quality-of-life measurements, as well as surrogate outcomes);
- RELAX-AHF: this study enrolled patients with ADHF, congestive symptoms and systolic pressure >125mmHg,
taking seralaxin (recombinant human relaxin-2). Patients on seralaxin had improvement on dyspnea, reduzed signs and symptoms of congestion, and less early worsening of HF. Exploratory endpoints of hard outcomes at 6 months suggested positive signals in favor of mortality reduction.
What are the main results of the REVIVE II and SURVIVE trials?
“Two trials, the second Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE II) and Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE), have tested [levosideman] in ADHF. SURVIVE compared levosimendan with dobutamine, and despite an initial reduction in circulating B-type natriuretic peptide levels in the levosimendan group compared with patients in the dobutamine group, this drug did not reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. The second trial compared levosimendan against traditional noninotropic therapy and found a modest improvement in symptoms with worsened short-term mortality and ventricular arrhythmias.”
What are the main findings of the ATOMIC-HF study?
“Another drug that functions as a selective myosin activator, omecamtiv mecarbil, prolongs the ejection and increases fractional shortening. Distinctively, the force of contraction is not increased, and as such, this agent does not increase myocardial oxygen demand. In a 600-patient trial called ATOMIC-HF (A Trial of Omecamtiv Mecarbil to Increase Contractility in ACute Heart Failure), this agent showed improvement in dyspnea scores in the highest dose cohort, but no across all enrolled patients.”
Summarize the findings of PROTECT and EVEREST trials.
“The Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT) trial of selective adenosine antagonism and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial of an oral selective vasopressin-2 antagonist in ADHF were both negative with respect to hard outcomes.”
Individuals with a lower exposure to ACE inhibitors and beta blockers due to inability to tolerate optimal doses represent a high-risk cohort with poor prognosis.
True or False?
True.
