B P6 C50 Management of Heart Failure Patients with Reduced Ejection Fraction Flashcards by Shadow Fox

In industrialized countries, _____ is the predominant cause in etiology in men and women and is responsible for 60% to 75% of cases of HF.

CAD

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_____ is an important cause of HF in the African and African American population.

Hypertension

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_____ is still a major cause of HF in South America.

Chagas disease

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As developing nations undergo socioeconomic development, the epidemiology of HF is becoming similar to that of Western Europe and North America, with _____ emerging as the single most common cause of HF.

CAD

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In _____% of the cases of HFrEF, the exact etiologic basis is not known. These patients are referred to as having dilated or idiopathic cardiomyopathy if the cause is unknown

20-30%

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Most of the forms of familial dilated cardiomyopathy are inherited in an _____ fashion

Autosomal dominant

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___ is one of the stronger and most consistent predictors of adverse outcome in HF

Age

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Risk Factors for Cardiac Failure (Olmstead County): Odds ratio for CAD

3.05

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Risk Factors for Cardiac Failure (Olmstead County): Odds ratio for Hypertension

1.44

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Risk Factors for Cardiac Failure (Olmstead County): Odds ratio for Diabetes

2.65

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Risk Factors for Cardiac Failure (Olmstead County): Odds ratio for Obesity

2.00

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Risk Factors for Cardiac Failure (Olmstead County): Odds ratio for Ever smoker

1.37

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Strong inverse correlations have been reported between survival and plasma levels of these biomarkers/inflammatory markers:

Norepinephrine
Renin
Arginine vasopressin (AVP)
Aldosterone
Atrial and brain natriuretic peptides (BNP and NT-proBNP)
Endothelin-1

Inflammatory markers:
Tumor necrosis factor (TNF)
Soluble TNF receptors
C reactive protein
Galactin-3
Pentraxin-3
Soluble ST2

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The _____ Trial was designed to prospectively study the relationship between change in natriuretic peptide concentration, cardiac remodeling, and clinical events in HFrEF patients. Although this was stopped prematurely because biomarker-guided treatment was not more effective than usual care in improving outcomes, the Echocardiographic Substudy showed that lowering NT-proBNP to less than 1000 pg/mL by 12 months was associated with reverse LV remodeling and improved outcomes, regardless of the treatment strategy employed. These findings suggest the response to treatment as assessed by change in NT-proBNP is more important than the treatment strategy.

GUIDE-IT trial (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure)

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Markers of oxidative stress, such as _____, have also been associated with worsening clinical status and impaired survival in patients with chronic HF.

Oxidized LDL
Serum uric acid

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_____, sensitive markers of myocyte damage, may be elevated in patients with non- ischemic HF and predict adverse cardiac outcomes, as well as the development of incident HF.

Cardiac troponin T and I

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In general, anemia is associated with ______. However, it is unclear whether anemia is a cause of decreased survival, or simply a marker of more advanced disease.

(1) More HF symptoms
(2) Worse NYHA functional status
(3) Greater risk of HF hospitalization
(4) Reduced survival

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The underlying cause for anemia is likely multifactorial, including _____ given as possible explanations.

(1) Reduced sensitivity to erythropoietin receptors
(2) Presence of a hematopoiesis inhibitor
(3) Defective iron supply for erythropoiesis

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Although a “transfusion threshold” for maintaining the hematocrit greater than ____% in patients with cardiovascular disease has been generally been accepted, this clinical practice has been based more on expert opinion rather than on direct evidence that documents the efficacy of this form of therapy.

> 30%

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Treatment of anemic HF patients with mild to moderate anemia (hemoglobin level 9.0 to 12.0 g/dL) with the erythropoietin analog darbepoetin alpha was evaluated in the _____ trial. There was no significant difference in the primary outcome variable of death from any cause or hospitalization for worsening HF (hazard ratio [HR] in the darbepoetin alfa group, 1.01; 95% confidence interval [CI] 0.90−1.13; P = 0.87), nor the secondary outcome of cardiovascular death or time to first hospitalization for worsening HF (HR in the darbepoetin alfa group 10.01, 95% CI 0.89 to 1.14; P = 0.2). The lack of effect of darbepoetin alfa was consistent across all prespecified subgroups. Importantly, treatment with darbepoetin alfa led to an early (within 1 month) and sustained increase in the hemoglobin level throughout the study.

RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure)

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The definition of iron deficiency in HF differs from other conditions of chronic inflammation and is defined as:

(1) Ferritin less than 100 μg/L

(2) Ferritin of 100 to 299 μg/L + transferrin saturation < 20%

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The one randomized clinical trial that used an oral iron polysaccharide (_____), did not show an improvement in peak VO2 by cardiopulmonary exercise testing at 16 weeks. Based on the results of the randomized trials with intravenous iron supplementation, the current ACC/AHA/HFSA guidelines recommend (class IIb, LOE B-R) that intravenous iron replacement might be reasonable in patients with NYHA class II and III HF and iron deficiency (ferritin <100 ng/mL or 100 to 300 ng/
mL if transferrin saturation is <20%) to improve functional status and quality of life.

Oral Iron Repletion Effects 0 On Oxygen Uptake in Heart Failure [IRONOUT]; NCT02188784

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In the _____, impaired renal function was a stronger predictor of mortality than impaired LV function and NYHA class in patients with advanced HF. Thus, renal insufficiency is a strong, independent predictor of adverse out- comes in HF patients. As will be discussed, below, treatment with sodium-glucose transporter-2 (SGLT2) inhibitors stabilizes renal function in patients with HFrEF.

Second Prospective Randomized Study of Ibopamine on Mortality and Efficacy (PRIME II)

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___________ includes patients who are at high risk for developing HF, but without structural heart dis- ease or symptoms of HF (e.g., patients with diabetes or hypertension)

Stage A

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____________ includes patients who have structural heart disease but without symptoms of HF (e.g., patients with a previous myocardial infarction [MI] and asymptomatic LV dysfunction)

Stage B

___________ includes patients who have structural heart disease who have developed symptoms of HF (e.g., patients with a previous MI with short- ness of breath and fatigue)

Stage C

_________ includes patients who refractory HF requiring special interventions (e.g., patients with refractory HF who are awaiting cardiac transplantation)

Stage D

Transient Left Ventricular Dysfunction can be the result of

The general pathophysiologic m anism involved is either some form of “stunning” of functional myocardium or activation of proinflammatory cytokines that are capable of suppressing LV function Emotional stress can also precipitate severe, reversible LV d function that is accompanied by chest pain, pulmonary edema, and cardiogenic shock in patients without coronary disease (Takotsubo syndrome [stress cardiomyopathy]). In this setting LV dysfunction is thought to occur secondary to the deleterious effects of catecholamines following heightened sympathetic stimulation.

For patients who have developed LV systolic dysfunction, but who remain asymptomatic (class I), the goal should be to slow disease progression by ______________________ that lead to cardiac remodeling

Blocking neurohormonal systems

For patients who have developed symptoms (class II to IV), the primary goal should be to ___________________

Alleviate fluid retention, lessen disability, and reduce the risk of further disease progression and death.

Framingham criteria - Major criteria

Paroxysmal nocturnal dyspnea or orthopnea Neck-vein distention RALES Cardiomegaly Acute pulmonary edema S3 gallop Increased venous pressure >16 cm H2O Hepatojugular reflux

Framingham criteria - Minor criteria

Ankle edema Night cough Dyspnea on exertion Hepatomegaly Pleural effusion Vital capacity decreased one third from maximal capacity Tachycardia (rate >120/min)

Major or minor criteria

Weight loss >4.5 kg in 5 days in response to treatment

Major or minor criteria

Weight loss >4.5 kg in 5 days in response to treatment

Among the most common causes of acute decompensation in a previously stable patient are ________________ and ______________, either from patient self-discontinuation of medication, or alternatively from physician withdrawal of effective pharmacotherapy

Dietary indiscretion and inappropriate reduction of HF therapy

Routine _____________ has been shown to be beneficial in selected patients with NYHA class I to III HFrEF.

Modest exercise

Large multicenter randomized controlled study whose primary endpoint was a composite of all-cause mortality and all-cause hospitalization. Secondary endpoints included all-cause mortality, all-cause hospitalization, and the composite of cardiovascular mortality or HF hospitalization Failed to show a significant improvement in all-cause mortality or all-cause hospitalization (HR, 0.93; 95% CI 0.84 to 1.02; p = 0.13) in patients who received a 12-week (3 times/wk) exercise training program followed by 25 to 30 minute, 5 days/wk home-based, self-monitored exercise workouts on a treadmill or stationary bicycle There was a trend towards decreased cardiovascular mortality or HF hospitalizations (HR, 0.87; 95% CI 0.74 to 0.99 p = 0.06) and quality of life was significantly improved in the exercise group

HF-ACTION trial (Controlled Trial Investigating Outcomes of Exercise Training) There was no difference in all-cause mortality (HR, 0.96; 95% CI 0.79 to 1.17 Exercise training is not recommended, however, in **HFrEF patients who have had a major cardiovascular event or procedure within the last 6 weeks**, in patients receiving **cardiac devices that limit the ability to achieve target heart rates**, and in patients with **significant arrhythmia or ischemia during baseline cardiopulmonary exercise testing**.

Dietary restriction of sodium (____________) is recommended in all patients with the clinical syndrome of HF and preserved or depressed EF. F

2 to 3 g daily

Fluid restriction is generally unnecessary unless the patient is __________________, which may develop because of activation of the renin angiotensin system, excessive secretion of AVP, or loss of salt in excess of water from prior diuretic use.

Hyponatremic (<130 mEq/L)

Fluid restriction (__________) should be considered in hyponatremic patients (<130 mEq/L), or for those patients whose fluid retention is difficult to control despite high doses of diuretics and sodium restriction.

<2 L/day

Diuretic-induced negative sodium and water balance can _____________

Decrease LV dilation Functional mitral insufficiency, Decrease mitral wall stress and subendocardial ischemia.

_____________ increase sodium excretion by up to 20% to 25% of the filtered load of sodium, enhance free water clearance, and maintain their efficacy unless renal function is severely impaired.

Loop diuretic

_________ increase the fractional excretion of sodium to only 5% to 10% of the filtered load, tend to decrease free water clearance, and lose their effectiveness in patients with impaired renal function (creatinine clearance <40 mL/ min)

Thiazide diuretic

_________________ have emerged as the preferred diuretic agents for use in most patients with HF

Loop diuretics

______________ act by competing with chloride for binding to the Na+ -K+ -2Cl − symporter (NKCC2) on the apical membrane of epithelial cells in the thick ascending loop of Henle

Loop diuretic

The efficacy of loop diuretics is dependent upon sufficient ____________________ and proximal tubular secretion to deliver these agents to their site of action

Renal plasma blood flow

___________ shifts the plasma concentration-response curve for furosemide to the right by competitively inhibiting furosemide excretion by the organic acid transport system.

Probenecid

Bioavailability of Furosemide Bumetanide/Torsemide

Furosemide - 40-70% Bumetanide/Torsemide - >80%

______________ may be safely used in sulfa-allergic HF patients.

Ethacrynic acid

Furosemide acts as a ______________ and reduces right atrial and pulmonary capillary wedge pressure within minutes when given intravenously (0.5 to 1.0 mg/kg)

Venodilator

There have also been reports of an acute rise in systemic vascular resistance with in response to loop diuretics, which has been attributed to transient activation of the ______________

Systemic or intravascular renin-angiotensin system (RAS) The potentially deleterious rise in LV afterload reinforces the importance of initiating **vasodilator therapy** with diuretics in patients with acute pulmonary edema and adequate blood pressure (

__________ block the Na+-Cl −t porter in the cortical portion of the ascending loop of Henle and the distal convoluted tubule

Thiazide diuretic

____________ quinazoline sulfonamide, is a thiazide-like diuretic that is used in combination with furosemide, in patients who become resistant to diuretics

Metolazone Because thiazide and thiazide-like diuretics prevent maximal dilution of urine, they decrease the kidney’s ability to increase free water clearance and may therefore contribute to the development of hyponatremia

Thiazides increase ______ resorption in the distal nephron

Ca2+

_____________ synthetic MRA receptors that act on the distal nephron to inhibit Na+ /K + exchange at the site of aldosterone action

Spironolactone and Eplerenone

____________ has antiandrogenic and progesterone-like effects, which may cause gynecomastia or impotence in men, and menstrual irregularities in women.

Spironolactone

______________ has greater selectivity for the MRA receptor than for steroid receptors and has less sex hormone side effects than does spironolactone.

Eplerenone Eplerenone is further distinguished from spironolactone by its shorter half-life and the fact that it does not have any active metabolites.

_________ referred to as potassium sparing diuretics. These agents share the common property of causing a mild increase in NaCl excretion, as well as having antikaluretic properties.

Triamterene and amiloride

The use of these agents in patients with HF is c fined to temporary administration to correct the metabolic alkalosis that occurs as a “contraction” phenomenon in response to the administration of other diuretics.When used repeatedly, these agents can lead to metabolic acidosis as well as severe hypokalemia.

Carbonic anhydrase inhibitor - Acetazolamide inhibit carbonic anhydrase, resulting in near-complete loss of NaHCO 3 resorption in the proximal tubule.

_________ accounts for 90% of glucose reabsorption by the kidney; responsible for proximal tubular reabsorption of sodium, and the passive absorption of chloride that is driven by the resulting electrochemical gradient in the proximal tubule lumen.

SGLT2

result in a 1:1 stoichiometric inhibition of sodium and glucose uptake in the proximal tubule of the kidney. This leads to contraction of the plasma volume and modest lowering of blood pressure, without activation of the sympathetic nervous system.

SGLT2 inhibitors

________ antagonists block the vasoconstricting effects of AVP in peripheral vascular smooth muscle cells, whereas _________ selective receptor antagonists inhibit recruitment of aquaporin water channels into the apical membranes of collecting duct epithelial cells, thereby reducing the ability of the collecting duct to resorb water.

V1 - vascular V2 - renal

Two vasopressin antagonists are Food and Drug Administration (FDA)-approved (_____________ and ____________) for the treatment of **clinically significant hypervolemic and euvolemic hyponatremia (serum Na + ≤125) that is symptomatic and which resisted correction with fluid restriction in patients with HF;** however, neither of these agents is currently specifically approved for the treatment of HF.

Conivaptan and tolvaptan

Typical starting dose of furosemide for patients with systolic HF and normal renal function

20 - 40mg

Diuretic use can lead to ___ which can predispose the patient to significant cardiac arrhythmias. Renal potassium losses from diuretic use can be also exacerbated by the increase in circulating levels of aldosterone observed in patients with advanced HF

Potassium depletion

Serum K +should be maintained between ____ because HF patients are often treated with pharmacologic agents that are likely to provoke proarrhythmic effects in the presence of hypokalemia (e.g., digoxin, type III antiarrhythmics, beta-agonists, or phosphodiesterase inhibitors)

4.0 and 5.0 mEq/L

The normal daily dietary K + intake is approximately 40 to 80 mEq. Therefore, to increase this by 50% requires an additional 20 to 40 mEq K + supplementation daily. However, in the presence of ____, hypokalemia is quite unresponsive to increased dietary intake of KCL, and more aggressive replacement is necessary.

Alkalosis, hyperaldosteronism, or Mg 2+ depletion

Potassium supplementation is generally stopped after the initiation of ____, and patients should be counseled to avoid high potassium–containing foods.

Aldosterone antagonists

Two new potassium binders, patiromer and sodium zirconium cyclosilicate, have been studied in HF patients with hyperkalemia. This is a nonabsorbed, cation-exchange polymer that contains a calcium-sorbitol counterion, and works by binding potassium in the lumen of the gastrointestinal tract, resulting in a reduction of serum-potassium levels within 7 hours of the first dose; FDA-approved for the treatment of hyperkalemia, but should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action.

Patiromer

Metabolic and electrolyte disturbances with Loop diuretics

Hyponatremia Hypomagnesemia Metabolic alkalosis Hyperglycemia Hyperlipidemia Hyperuricemia

In this instance reductions in the diuretic dose are not necessary, particularly if the patient remains edematous. In some patients with advanced, chronic HF, ____ may be necessary to maintain control of congestive symptoms.

Elevated BUN and creatinine concentrations

Diuretics may increase the activation of _____ in HF patients, which can lead to disease progression unless patients are receiving treatment with a concomitant neurohormonal antagonist (e.g., ACEI or beta-blocker).

Endogenous neurohormonal systems

Ototoxicity, which is more frequent with ____ than the other loop diuretics, can manifest as tinnitus, hearing impairment, and deafness.

Ethacrynic acid Hearing impairment and deafness are usually, but not invariably, reversible. Ototoxicity occurs most frequently with rapid intravenous injections, and least frequently with oral administration.

In normal subjects the magnitude of natriuresis following a given dose of diuretic declines over time as a result of the so-called ____

“Braking phenomenon”

Studies have shown that the time-dependent decline in natriuresis for a given diuretic dose is critically dependent upon __, which leads to an increase in solute and fluid reabsorption in the proximal tubule. In addition, contraction of the extracellular volume can lead to stimulation of ___, which reduces urinary Na + excretion by reducing renal blood flow, stimulating renin (and ultimately aldosterone) release, which in turn stimulates Na +reabsorption along the nephron

Reduction of the extracellular fluid volume Efferent sympathetic nerves

Although the bioavailability of these diuretics is generally not decreased in HF, the potential ___ may result in peak drug levels within the tubular lumen in the ascending loop of Henle that are insufficient to induce maximal natriuresis.

Delay in their rate of absorption

However, even with intravenous dosing, a ____ of the dose-response curve is observed between the diuretic concentration in the tubular lumen and its natriuretic effect in HF. Moreover, the maximal effect (ceiling) is ___ in HF. This rightward shift has been referred to as ___ and is likely due to several factors in addition to the braking phenomenon described above.

Rightward shift Maximal effect - lower “diuretic resistance”

First, most loop diuretics (with the exception of torsemide) are ___. Accordingly, after a period of natriuresis, the diuretic concentration in plasma and tubular fluid declines below the diuretic threshold. In this situation, renal Na+ reabsorption is no longer inhibited and a period of antinatriuresis or postdiuretic NaCl retention ensues. If dietary NaCl intake is moderate to excessive, postdiuretic NaCl retention may overcome the initial natriuresis in patients with excessive activation of the adrenergic nervous system and RAS. This observation forms the rationale for administering shortacting diuretics several times per day to obtain consistent daily salt and water loss.

Short-acting drugs

Second, there is a loss of renal responsiveness to endogenous ___ as HF advances

Natriuretic peptides

Third, diuretics increase solute delivery to distal segments of the nephron, causing epithelial cells to undergo both hypertrophy and hyperplasia. Chronic loop diuretic administration ___ in the distal collecting duct and cortical collecting tubule, as well as ___ in the distal nephron, which increases the solute resorptive capacity of the kidney as much as threefold.

Increases the Na-K-ATPase activity Increases the number of thiazide sensitive Na-Cl cotransporters

Apart from these more obvious causes, it is importannt to query the patient with regard to the concurrent use of drugs that adversely affect renal function, such as ____ and certain antibiotics (trimethoprim and gentamicin).

NSAIDs and COX-2 inhibitors

A patient with HF may be considered to be resistant to diuretic drugs when ____ doses of a loop diuretic do not achieve the desired reduction of the extracellular fluid volume.

Moderate

In outpatients, a common and useful method for treating the diuretic-resistant patient is to administer two classes of diuretic concurrently. Adding a proximal tubule diuretic or a distal collecting tubule diuretic to a regimen of loop diuretics is often dramatically effective (______).

“Sequential nephron blockade”

As a general rule, when adding a second class of diuretic the dose of loop diuretic should ____, because the shape of the dose-response curve for loop diuretics is not affected by the addition of other diuretics, and the loop diuretic must be given at an effective dose for it to be effective.

Dose should not be altered

The combination of loop and ___ has been shown to be effective through several mechanisms. Mechanisms?

Distal collecting tubule diuretics One is that distal collecting tubule diuretics have longer half-lives than loop diuretics and may thus prevent or attenuate postdiuretic NaCl retention. A second mechanism by which distal collecting tubule diuretics potentiate the effects of loop diuretics is by inhibiting Na + transport along the proximal tubule, insofar as most thiazide diuretics also inhibit carbonic anhydrase. They also inhibit NaCl transport along the distal renal tubule, which may counteract the increased solute resorptive effects of the hypertrophied and hyperplastic distal epithelial cells.

Distal collecting tubule diuretics may be added in full doses (50 to 100 mg/day hydrochlorothiazide or 2.5 to 10 mg/day metolazone) when a rapid and robust response is needed. However, such an approach is likely to lead to excessive fluid and electrolyte depletion if patients are not followed up extremely closely.

One reasonable approach to combination therapy is to achieve control of fluid overload by initially adding full doses of distal collecting tubule diuretic on a daily basis and then decreasing the dose of this diuretic to three times weekly to avoid excessive diuresis.

Another common reason for diuretic resistance in advanced HF is the development of the ___, which is recognized clinically as worsening renal function that limits diuresis in patients with obvious clinical volume overload.

Cardiorenal syndrome

Drugs that interfere with the excessive activation of renin angiotensinaldosterone system and the adrenergic nervous system can relieve the symptoms of HFrEF patients by stabilizing and/or reversing LV remodeling. In this regard ____ and ____ have emerged as cornerstones of modern HF therapy for patients with a depressed EF.

ACEIs/ARBs and beta-blockers

There is overwhelming evidence that ACEIs should be used in __ (class I indication).

Symptomatic and asymptomatic patients with a reduced EF (<40%) ACEIs interfere with the renin angiotensin system by i iting the enzyme that is responsible for the conversion of angiotensin I to angiotensin II. However, because ACEIs also inhibit kininase II, they may lead to the upregulation of bradykinin, which may further enhance the effects of angiotensin suppression.

Because fluid retention can attenuate the effects of ACEIs, it is preferable to optimize the dose of ____ first, before starting the ACEI. However, it may be necessary to reduce the dose of diuretic during the initiation of an ACEI, in order to prevent symptomatic hypotension. ACEIs should be initiated in low doses, followed by increments in dose if lower doses have been well tolerated. Titration is generally achieved by doubling doses every ___.

Diuretic 3 to 5 days The dose of ACEI should be increased until the doses used are similar to those that have been shown to be effective in clinical trials

For stable patients, it is acceptable to add therapy with beta-blocking agents before full target doses of either ACEIs are reached. Blood pressure (including postural changes), renal function, and potassium should be evaluated ____ after initiation of ACEIs, especially in patients with preexisting azotemia, hypotension, hyponatremia, diabetes mellitus, or in those taking potassium supplements.

Within 1 to 2 weeks Abrupt w drawal of treatment with an ACEI may lead to clinical deterioration and should, therefore, be avoided in the absence of life-threatening complications (e.g., angioedema, hyperkalemia).

Evaluated the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional **class IV**. Randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127) The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group--a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001).

CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) The addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.

Multicenter, randomized, placebo-controlled study, conducted at 83 different hospitals in 3 different countries, randomized 2,569 patients with left ventricular ejection fraction (LVEF) ≤35% to receive either enalapril or placebo (regardless of NYHA class) Demonstrated that treatment with enalapril significantly reduced mortality (35.2% vs. 39.7%; p<0.0036) and the frequency of hospitalizations for heart failure (25.8% vs. 36.6%; p<0.001) in patients with CHF when compared with placebo

SOLVD Rx trial (Studies of Left Ventricular Dysfunction (SOLVD)

Studied the effect of an angiotensin-converting--enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure **(asymptomatic)** Randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial Enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril.

SOLVD Asx (Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions)

Within 3 to 16 days after myocardial infarction, 2231 patients with ejection fractions of 40 percent or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive double-blind treatment with either placebo (1116 patients) or captopril (1115 patients) In patients with **asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril was associated with an improvement in survival and reduced morbidity and mortality due to major cardiovascular events**. These benefits were observed in patients who received thrombolytic therapy, aspirin, or beta-blockers, as well as those who did not, suggesting that treatment with captopril leads to additional improvement in outcome among selected survivors of myocardial infarction

SAVE trial (Effect of Captopril on Mortality and Morbidity in Patients with Left Ventricular Dysfunction after Myocardial Infarction — Results of the Survival and Ventricular Enlargement Trial)

2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, <35 percent). On days 3 to 7 **after infarction**, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients) Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.

TRACE trial (A Clinical Trial of the Angiotensin-Converting–Enzyme Inhibitor Trandolapril in Patients with Left Ventricular Dysfunction after Myocardial Infarction)

Taken together, these observations support the conclusion that the effects of ACEIs on the natural history of chronic HF, post-MI LV dysfunction, or patients at high risk of developing HF represent a “___” of these agents.

Class effects

The majority of the adverse effects of ACEIs are related to suppression of the renin angiotensin system. The decreases in blood pressure and mild azotemia often seen during the initiation of therapy are, in general, well tolerated and do not require a decrease in the dose of the ACEI. The side effects of ACEIs that are related to kinin potentiation include a ___ (10% to 15% of patients) and angioedema (1% of patients).

Nonproductive cough In patients who cannot tolerate ACEIs because of cough or angioedema, **ARBs** are the next recommended line of therapy. Patients intolerant to ACEIs because of hyperkalemia or renal insufficiency are likely to experience the same side effects with ARBs. The combination of hydralazine and an oral nitrate should be considered for these latter patients

___ are well tolerated in patients who are intolerant of ACEIs because of cough, skin rash, and angioedema and should, therefore, be used in symptomatic and asymptomatic patients with an EF less than 40% who are ACE intolerant for reasons other than hyperkalemia or renal insufficiency (class I indication).

ARBs

Although ACEIs and ARBs inhibit RAAS, they do so by a different mechanism. Whereas ACEIs block the enzyme responsible for converting angiotensin I to angiotensin II, ARBs block the effects of angiotensin II on the ___

Angiotensin type 1 receptor

Enrolled 2028 patients with **symptomatic heart failure and left-ventricular ejection fraction 40% or less who were not receiving ACE inhibitors because of previous intolerance.** Patients were randomly assigned candesartan (target dose 32 mg once daily) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. During a median follow-up of 33·7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had **cardiovascular death or hospital admission for CHF (unadjusted hazard ratio 0·77 [95% CI 0·67–0·89], p=0·0004; covariate adjusted 0·70 [0·60–0·81], p<0·0001).** **Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic heart failure and intolerance to ACE inhibitors.**

CHARM - ALTERNATIVE trial (Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors)

A total of 5010 patients with heart failure of New York Heart Association **(NYHA) class II, III, or IV were randomly assigned to receive 160 mg of valsartan or placebo twice daily**. The primary outcomes were mortality and the combined end point of mortality and morbidity, defined as the incidence of cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least four hours. The incidence of the combined end point, however, was 13.2 percent lower with valsartan than with placebo (relative risk, 0.87; 97.5 percent confidence interval, 0.77 to 0.97; P=0.009), predominantly because of a lower number of patients hospitalized for heart failure. Overall mortality was similar in the two groups

VAL-Heft Trial (A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure) Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure, when added to prescribed therapy. However, the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan, an ACE inhibitor, and a beta-blocker raises concern about the potential safety of this specific combination.

3846 patients with heart failure of New York Heart Association **class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors** were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919) Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit

HEEAL trial (Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial)

Enrolled 2548 patients with New York Heart Association functional **class II-IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors.** Randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction. However, the addition of candesartan to an ACE inhibitor resulted in an increase in the incidence of hyperkalemia increased from 0.7% to 3.4%.

CHARM ADDED trial

Compared outcomes with: (1) angiotensin-converting enzyme inhibition (ACEI) with the reference agent captopril; (2) angiotensin-receptor blockade (ARB) with valsartan; or (3) both in patients with heart failure (HF) and/or left ventricular systolic dysfunction (LVSD) after myocardial infarction (MI). Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival.

VALIANT trial (Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both)

The ACC/AHA/HFSA guidelines recommend that _____ remain first line therapy (class I indication) for the treatment of HFrEF, whereas ARBs were recommended for ACE-intolerant patients (class IIa indication). The guidelines also indicate that ARBs may be considered in persistently symptomatic patients with HFrEF who are already being treated with an ACE inhibitor and a beta-blocker in whom an aldosterone antagonist is not indicated or tolerated (class IIb indication).

ACE inhibitors - first line

The combination of an ARNI slows the degradation of ____, bradykinin and adrenomedullin, thereby enhancing diuresis, natriuresis and myocardial relaxation, as well as ____ while selectively ____ reduces vasoconstriction, sodium, and water retention and myocardial hypertrophy

Slows degradation of natriuretic peptides Inhibiting renin and aldosterone secretion - blocking the AT1 receptor

Double-blind trial, we randomly assigned 8442 patients with and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. Class II, III, or IV heart failure - characterized by either mildly elevated natriuretic peptide levels (BNP greater than 150 pg/mL or NT-proBNP ≥ 600 pg/mL), or a prior hospitalization in the preceding 12 months and elevated natriuretic peptide levels (BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL) The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure

PARADIGM HF trial (Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure) ARNIs should be administered in low doses (sacubitril 24 mg/ valsartan 26 mg twice daily) in ACEI/ARB naïve patients, or at moderate doses (sacubitril 49 mg/valsartan 51 mg twice daily) in patients who are tolerating ACEIs/ARBs. The target dose of sacubitril/valsartan in PARADIGM-HF was 97/103 mg twice daily.

Given that less than 1% of the patients in the PARADIGM-HF had ___, ARNIs are not currently recommended for patients with advanced HF symptomatology.

NYHA class IV HF

Oral neprilysin inhibitors, used in c bination with ACE inhibitors, can lead to angioedema; accordingly, the concomitant use of ACEIs and ARNIs is contraindicated (class III recommendation). For patients who are switching from ACEIs to sacubitril/valsartan, the ACEI should be withheld for at least ___ before initiating sacubitril/valsartan in order to minimize the risk of angioedema caused by overlapping ACE and neprilysin inhibition.

36 hours

Administration of beta-blockers may be associated with an early, short-term deterioration in cardiac function, consistent with the ____ of withdrawing adrenergic drive.

Negative inotropic effects

However, when given in concert with ACE inhibitors, treatment with beta-blockers is associated with decrease in LV volumes (___), favorable changes in LV shape, as well as improved LVEF.

Reverse LV remodeling

____ are indicated for patients with symptomatic or asymptomatic HF and a depressed EF less than 40% (class I indication).

Beta blockers

The dose of beta-blocker should be increased until the doses used are similar to those that have been reported to be effective in clinical trials. However, unlike ACEIs, which may be up-titrated relatively rapidly, the dose titration of beta-blockers should proceed no sooner than ___, because the initiation and/or increased dosing of these agents may lead to ___ because of the abrupt withdrawal of adrenergic support to the heart and the circulation.

Two-week intervals Worsening fluid retention

Therefore, it is important to optimize the dose of diuretic before starting therapy with beta-blockers. If worsening fluid retention does occur, it is likely to occur within ___ of initiating therapy, and will be manifest as increase in body weight and/or symptoms of worsening HF. The increased fluid retention can usually be managed by increasing the dose of diuretics.

3 to 5 days Patients need not be taking high doses of ACEIs before being considered for treatment with a beta-blocker, because most patients enrolled in the beta-blocker trials were not taking high doses of ACEIs. Furthermore, in patients taking a low dose of an ACEI, the addition of a beta-blocker produces a greater improvement in symptoms and reduction in the risk of death than an increase in the dose of the ACEI. Studies have shown that beta-blockers can be safely started before discharge, even in patients hospitalized for HF, provided that the patient is stable and does not require intravenous HF therapy.

1990 patients were randomly assigned **metoprolol CR/XL 12·5 mg (NYHA III-IV) or 25·0 mg once daily (NYHA II) and 2001 were assigned placebo**. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7·2%, per patient-year of follow-up]) vs 217 deaths [11·0 %], relative risk 0·66 [95% CI 0·53–0·81]; p=0·00009 or adjusted for interim analyses p=0·0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0·59 [0·45–0·78]; p=0·0002) and deaths from worsening heart failure (30 vs 58, 0·51 [0·33–0·79]; p=0·0023).

MERIT HF trial (Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure)

Multicentre double-blind randomised placebo-controlled trial in Europe, we enrolled 2647 symptomatic patients in New York Heart Association class III or IV, with left-ventricular ejection fraction of 35% or less receiving standard therapy with diuretics and inhibitors of angiotensin-converting enzyme. We randomly assigned patients *8bisoprolol 1·25 mg (n=1327) or placebo (n=1320) daily, the drug being progressively increased to a maximum of 10 mg per day.** All-cause mortality was significantly lower with bisoprolol than on placebo (156 [11·8%] vs 228 [17·3%] deaths with a hazard ratio of 0·66 (95% CI 0·54–0·81, p<0·0001). There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3·6%] vs 83 [6·3%] deaths), with a hazard ratio of 0·56 (0·39–0·80, p=0·0011). Treatment effects were independent of the severity or cause of heart failure.

CIBIS II trial (The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial)

Randomly assigned 1133 patients to **placebo and 1156 patients to treatment with carvedilol** for a mean period of 10.4 months, during which standard therapy for heart failure was continued. There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol.

COPERNICUS trial (Effect of Carvedilol on Survival in Severe Chronic Heart Failure)

Multicentre, randomised, placebo-controlled trial, 1959 patients with a proven **acute myocardial infarction and a left-ventricular ejection fraction of

CAPRICORN trial (Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction)

In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with **carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily).** Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. **Carvedilol was associated with a significant 33% reduction in all-cause mortality when compared with metoprolol tartrate (33.9% versus 39.5%, HR 0.83, 95% CI 0.74 to 0.93, P = 0.0017)**.

Based on the results of the COMET trial, short-acting metoprolol tartrate is not recommended for use in the treatment of HF.

Nebivolol is a selective β1 receptor antagonist with ancillary vasodilatory properties that are mediated, at least in part, by ___

Nitric oxide (NO)

Randomly assigned 2128 patients aged >/=70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction

SENIORS trial (Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure) Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

Although ACEI may transiently decrease aldosterone secretion, with chronic therapy there is a rapid return of aldosterone to levels similar to those before ACEI, which is referred to as _____ The administration of an MRA is recommended for patients with ____ HF who have a depressed EF (≤35%), and who are receiving standard therapy including diuretics, ACEIs, and beta-blockers (class I indication)

Aldosterone breakthrough NYHA class II to IV

Potassium supplementation is generally stopped after the initiation of aldosterone antagonists, and patients should be counseled to avoid high-potassium foods. Potassium levels and renal function should be rechecked ____ and again at ___ after initiation of an aldosterone antagonist.

Within 3 days and 1 week

Total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo in NYHA class III or IV HF patients with a LVEF less than 35%, who were being treated with an ACEI, a loop diuretic, and, in most cases, digoxin. The primary end point was death from all causes Spironolactone led to a 30% reduction in total mortality when compared with placebo (p = 0.001). The frequency of hospitalization for worsening HF was also 35% lower in the spironolactone group than in the placebo group. Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure

RALES (Randomized Aldactone Evaluation Study)

Randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. Eplerenone (titrated to 50 mg/day) led to a significant 27% decrease in cardiovascular death or HF hospitalization (HR 0.63; 95% CI 0.54 to 0.74; P < 0.001) (see Fig. 50.7B). 9 , 15 There were also significant decreases in all-cause death (24%), cardiovascular death (24%), all-cause hospitalization (23%), and HF hospitalizations (43%). Importantly, the effect of eplerenone was consistent across all prespecified subgroups

EMPHASIS - HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)

Randomly assigned to eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day; 3313 patients) or placebo (3319 patients) in addition to optimal medical therapy. The study continued until 1012 deaths occurred. The primary end points were death from any cause and death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia Evaluated the effect of eplerenone (titrated to a maximum of 50 mg/day) on morbidity and mortality among patients with acute MI complicated by LV dysfunction and HF. Treatment with eplerenone led to 15% decrease in all-cause death

EPHESUS trial (Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure

Based on the results of the RALES and EMPHASIS-HF trials, aldosterone antagonists are currently recommended for all patients with persistent ____, in addition to treatment with an ACEI (or an ARB if an ACEI is not tolerated) and a beta-blocker (class I indication).

NYHA class II to IV symptoms and an EF ≤35%

Aldosterone antagonists are not recommended when the serum creatinine is ____ (or creatinine clearance is <30 mL/min) or serum K ____ The development of worsening renal function should lead to consideration regarding stopping aldosterone antagonists because of the potential risk of hyperkalemia. ___ may develop in 10% to 15% of patients who use spironolactone, in which case eplerenone may be substituted.

Creatinine greater than 2.5 mg/dL Potassium is greater than 5.5 mmol/L Painful gynecomastia

____ is an orally active direct renin inhibitor that appears to suppress RAS to a degree similar to ACE inhibitors. Although the benefits of ACEIs and ARBs in HF have been clearly established, these agents provoke a compensatory increase in renin and downstream intermediaries of the renin-angiotensin-aldosterone system, which may attenuate the effects of ACEIs and ARBs (“aldosterone breakthrough”)

Aliskiren

However, both the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT)44 and the Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbi-mortality in Patients With Chronic Heart Failure (ATMOSPHERE) clinical trials failed to improve outcomes in HFrEF patients. Aliskiren is not currently recommended as an alternative to an ACEI, ARBs, or in combination with ACEIs for the treatment of HFrEF.

The combination of H-ISDN is recommended (class I indication) for ____ with NYHA class III to IV HFrEF who remain symptomatic despite concomitant use of ACE inhibitors, beta blockers, and aldosterone antagonists The combination of H-ISDN is used in patients who are intolerant to ACEI/ARBs/ARNIs (class IIa recommendation).

African Americans

_____ is a heart rate-lowering agent that acts by selectively blocking the cardiac pacemaker I f (“funny”) current that controls the spontaneous diastolic depolarization of the sinoatrial node. Ivabradine blocks If channels in a concentration-dependent manner by entering the channel pore from the intracellular side, and thus can only block the channel when it is open. The magnitude of If inhibition is directly related to the frequency of channel opening and would therefore be expected to be most effective at ____

Ivabradine Higher heart rates

Randomised, double-blind, placebo-controlled, parallel-group study if they had symptomatic heart failure and a left-ventricular ejection fraction of 35% or lower, were in sinus rhythm with heart rate 70 beats per min or higher, had been admitted to hospital for heart failure within the previous year, and were on stable background treatment including a β blocker if tolerated Ivabradine (up-titrated to a maximal dosage of 7.5 mg twice daily) reduced the primary composite outcome of cardiovascular death or HF hospitalization by 18% (HR 0.82, 95% CI 0.75 to 0.90, (p < 0.0001) Endpoint was driven primarily by reducing hospital admissions for worsening HF (HR 0.74, CI 0.66 to 0.83; (p < 0.0001), insofar as there was no decrease in cardiovascular deaths (HR 0.91; 95% CI 0.80 to 1.03), (p = 0.13) or all-cause deaths. Given that ivabradine lowered heart rate by approximately **10 beats/min** and that only 26% of the patients in the trial were on optimal doses of beta-blockers, it is possible that titrating beta-blockers to recommended disease may have reduced the HF hospitalizations to a similar degree.

SHIFT trial (Systolic Heart failure treatment with the IF inhibitor ivabradine Trial) Among patients with moderate to severe heart failure, the use of the heart rate reducing agent ivabradine was beneficial. This agent reduced the composite outcome of cardiovascular mortality or heart failure hospitalization compared with placebo.

Ivabradine is recommended by the ACC/AHA/HFSA guidelines (class IIa recommendation) to reduce HF hospitalization in HFrEF patients in sinus rhythm with a HR greater than ____ who are receiving guideline-directed medical therapy (GDMT).

70 beats/min

The landmark ___ demonstrated that empagliflozin reduced death from CV causes by 38%, hospitalization for HF by 35%, and progression to end-stage kidney disease in patients with type 2 DM and established CV disease

EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients)

4744 patients with **NYHA class II, III, or IV HF and an LVEF of ≤ 40% were randomized to receive either dapagliflozin (10 mg once daily) or placebo, in addition to GDMT**. The primary outcome was a composite of worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or cardiovascular death. After a follow-up of 18.2 months, dapagliflozin was associated with a **26% reduction in risk** (HR, 0.74; 95% CI, 0.59 to 0.83; p = 0.00001). Importantly, event rates for all the components of the composite outcome favored dapagliflozin; hospitalizations for worsening HF were reduced (HR 0.70; 95% CI, 0.59 to 0.83), as well as **death from CV cause** (HR 0.82; 95% CI 0.69 to 0.98). **The outcomes were similar in patients with and without diabetes.** There was no difference in a composite of worsening renal function.

DAPA-HF trial (Effect of Dapagliflozin on the Incidence of W ening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure)

3730 patients with NYHA class II, III, or IV HF and an ejection fraction of LVEF of ≤ 40% were randomized to receive empagliflozin (10 mg once daily) or placebo, in addition to standard guideline-directed medical therapy. The primary outcome was a composite of CV death or hospitalization for worsening HF. After a median follow-up of 16 months, empagliflozin was associated with **25% reduction in risk** (HR 0.75; 95% CI, 0.65 to 0.86; P < 0.001) The primary outcome was similar in patients with or without diabetes. In contrast to DAPA-HF, the primary endpoint in EMPEROR-Reduced was driven by **decreased HF hospitalization** (HR, 0.70; 95% CI, 0.58 to 0.85); whereas there was **no significant difference in CV mortality (HR 0.92; 95% CI, 0.75 to 1.12)**. **Composite renal outcome was significantly reduced with the use of empagliflozin**

EMPEROR-Reduced (Empagliflozin outcome trial in Patients with Chronic Heart Failure With Reduced Ejection Fraction)

Class 1 indication for SGLT2 inhibitors

In patients with symptomatic chronic HFrEF, SGLT2i are recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes

____ is a novel oral soluble guanylate cyclase stimulator that enhances the cyclic guanosine monophosphate (GMP) production pathway, by directly stimulating soluble guanylate cyclase activity, as well as sensitizing soluble guanylate cyclase to endogenous NO.

Vericiguat

In the ___ trial, 5050 patients with chronic NYHA class II to IV HF and an LVEF less than 45% were randomized to receive vericiguat (target dose,10 mg once daily) or placebo, in addition to GDMT. The primary outcome was a composite of CV death or first hospitalization for HF. At 10.8 months of follow-up there were fewer CV death and HF hospitalizations in the vericiguat group than in the placebo group (HR 0.90; 95% CI 0.82 to 0.98; P = 0.02). There was, however, no significant difference in CV death in the vericiguat group when compared with the placebo group (HR 0.93; 95% CI 0.81 to 1.06).

Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA)

Cardiac myosin activators represent a new mechanistic class of therapeutic agents designed to increase myocardial contractility without increasing intracellular concentrations of cyclic adenosine monophosphate and calcium, and without increasing myocardial oxygen consumption, thus avoiding the major toxic effects of classic inotropic agents. ____ is a small-molecule activator of myosin that prolongs myocardial systole by increasing the fraction of sarcomeric myosin molecules that are strongly bound to actin thereby leading to increased myocardial force generation and increased contractility.

Omecamtiv mecarbil

Trial which enrolled 8200 patients with HFrEF, showed that treatment with omecamtiv mecarbil significantly reduced the composite of CV death or HF hospitalization and other urgent treatment for HF compared to placebo in patients treated with standard of care

GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure trial [NCT02929329]

In a phase 2 trial, 448 patients with HFrEF were randomized to receive placebo or omecamtiv mecarbil (25 mg twice daily with pharmacokinetic-guided dose selection to 50 mg twice daily) for 20 weeks. In patients who received omecamtiv mecarbil, systolic ejection time and stroke volume both increased, while diastolic filing parameters were not worsened

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF)

___ is recommended for patients with symptomatic HFrEF to reduce hospitalizations despite receiving standard therapy, including ACEIs (or ARBs), ARNIs, betablockers, and MRA receptor antagonists (class IIa indication).

Digoxin

Digoxin exerts its effects by inhibiting the sodium potassium adenosine trisphosphate (Na+ -K + ATPase) pump in cell membranes, including the sarcolemmal Na+-K +ATPase pump of cardiac myocytes Mechanism of Digoxin to HF patients is to sensitize ____ activity in vagal afferent nerves, leading to an increase in vagal tone that counterbalances the increased activation of the adrenergic system in advanced HF. Digoxin also inhibits Na+ -K + ATPase activity in the kidney and may therefore blunt renal tubular resorption of sodium.

Na+-K +ATPase

The ___ showed that long-term administration of 1 g/day of omega n-3 PUFA resulted in a significant reduction in both all-cause mortality and all-cause mortality and cardiovascular admissions (adjusted HR 0.92; 99% CI 0.850 to 0.999; p = 0.009), in all the predefined subgroups, including HF patients with nonischemic cardiomyopathy. 5

Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca-Heart Failure (GISSI-HF)

The ____ showed that CABG did not reduce all-cause death (HR 0.86 [95% CI 90.7 to 1.04]; P = .12), which was the primary endpoint of the trial; CABG did, however, **reduce the composite endpoint of cardiovascular death, death from any cause, or hospitalization for cardiovascular causes which was a prespecified secondary analysis**. The **10-year follow-up to the original STICH trial demonstrated a significantly lower mortality** in patients who underwent CABG when compared to medical therapy.

Surgical Treatment for Ischemic Heart Failure (STICH) trial

Current ACC/AHA/HFSA guidelines (class I indication) recommend revascularization with ___ for HFrEF patients on appropriate medical therapy, who have angina and suitable coronary anatomy for revascularization, especially left main stenosis (>50%) or left main equivalent disease.

CABG or PCI

Functional mitral regurgitation secondary to LV dysfunction and LV remodeling in HFrEF is powerful predictor of adverse clinical outcomes. ____ trial showed a significant decrease in all hospitalizations for HF (HR 0.53; 95% CI 0.40 to 0.70; P < 0.001). In the COAPT trial, death from any cause (prespecified secondary outcome) within 24 months occurred in significantly fewer patients in the device group when compared to the control group (HR 0.62; 95% CI 0.46 to 0.82; P < 0.001).

Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT)

Anticoagulation is also recommended for all patients with a history of systemic or pulmonary emboli, including stroke or transient ischemic attack. Patients with symptomatic or asymptomatic ischemic cardiomyopathy and documented recent large anterior MI or recent MI with documented LV thrombus should be treated with ____ (goal INR 2.0 to 3.0) for the initial 3 months after MI unless there are contraindications.

Warfarin

In ___ trial, a strategy of **rhythm control (pharmacologic or electrical cardioversion) was superior to a strategy of controlling ventricular rate with respect to reducing death from cardiovascular causes** (HR rhythm-control group 1.06; 95% CI 0.86 to 1.30; P = 0.59). Secondary outcomes were also similar in the rate and rhythm control groups, including death from any cause, stroke, worsening HF, and the composite of death from cardiovascular causes, stroke, or worsening HF.

Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial

Accordingly, a ____ is best suited for patients with a reversible secondary cause of AF, or in patients who are not amenable to a rate strategy.

Rhythm control strategy

For control of heart rate in HFrEF patients with AF, ____ are preferred over digoxin, insofar as digoxin does not provide rate control during exercise.

Beta-blockers Although the effectiveness of beta-blockers in HFrEF patients with coexisting AF was cast in doubt by a patient-level metaanalysis, a recent substudy of the AF-CHF trial showed that the use of beta-blockers was associated with significantly lower mortality, but no difference in CV and non-CV hospitalization in patients with HFrEF and AF. Importantly, the combination of digoxin and a beta-blocker is more effective than a beta-blocker alone in controlling the ventricular rate at rest.

The optimum control of ventricular rate in patients with HF and AF is unclear at present. Although a resting ventricular response of ____ and a ventricular response between _____ during moderate exercise has been suggested by some experts The____ **did not show a difference in a composite of clinical outcomes when a strategy of strict rate control (<80 beats/min at rest and <110 beats/min during a 6 minute walk) was compared with lenient rate control**

Resting: 60 to 80 beats/min Moderate exercise: 90 and 115 beats/min RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation: a Comparison between Lenient versus Strict Rate Control II)

____ is the preferred drug for restoring and maintaining sinus rhythm and may improve the success of electrical cardioversion in patients with HF.

Amiodarone

Randomized, parallel-group, multicenter study. Patients with persistent AF, dual-chamber implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator, New York Heart Association II to III, and left ventricular ejection fraction <40% within the past 6 months were randomly assigned (1:1 ratio) to undergo CA for AF (group 1, n=102) or receive AMIO (group 2, n=101). Recurrence of AF was the primary end point. All-cause mortality and unplanned hospitalization were the secondary end points. This multicenter randomized study shows that CA of AF is superior to AMIO in achieving freedom from AF at long-term follow-up and reducing unplanned hospitalization and mortality in patients with heart failure and persistent AF.

AATAC trial (Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial)

Randomly assigned patients with symptomatic paroxysmal or persistent atrial fibrillation who did not have a response to antiarrhythmic drugs, had unacceptable side effects, or were unwilling to take these drugs to undergo either catheter ablation (179 patients) or medical therapy (rate or rhythm control) (184 patients) for atrial fibrillation in addition to guidelines-based therapy for heart failure Catheter ablation reduced death from any cause or hospitalization for worsening HF (primary endpoint) in NYHA class II to IV HFrEF patients (HR 0.62; 95% CI 0.43 to 0.87; P = 0.007) with symptomatic paroxysmal or persistent AF.

CASTLE-AF (Catheter Ablation versus Standard Conventional Treatment in Patients with Left Ventricular Dysfunction and Atrial Fibrillation)

CRT should be considered for patients in NYHA class II to IV HF with a depressed EF less than 30% to 35% and a wide QRS who are on GDMT, and may be considered in select patients with NYHA class I HF with a wide QRS. For eligible patients, consideration should be given for implantation of CRT with an ICD (CRT-ICD).

Implantation of an ICD should be considered for patients in NYHA class II to III HF with a depressed EF less than 30% to 35%, who are on are on GDMT, and who have a reasonable expectation of survival with a good functional status for more than 1 year (class I indication}. CRT-ICD should be considered for NYHA class IV patients.

B P6 C50 Management of Heart Failure Patients with Reduced Ejection Fraction Flashcards

(160 cards)