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Most evidence-based treatment strategies have focused on patients with systolic rather than diastolic heart failure; hence, stage-specific outpatient management of patients with chronic systolic heart failure (left ventricular systolic dysfunction) is the focus of the discussion that follows. Although stages A–D of the ACC/AHA heart failure classification represent progressive cardiac risk and dysfunction, the treatment strategies recommended at earlier stages are applicable to and recommended for later stages (see Table 21-2).
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A. Systolic Heart Failure
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1. High risk for systolic heart failure (stage A)
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Individuals with conditions and behaviors that place them at high risk for heart failure but who do not have structurally abnormal hearts are classified as ACC/AHA stage A and should be treated with therapies that can delay progression of cardiac dysfunction and development of heart failure. Optimizing hypertension treatment based on the current national guidelines, such as the Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) and JNC VIII panel members’ recommendations can reduce new-onset heart failure by 50%. Therapies such as diuretics, β-blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs) are proven to be more effective than calcium channel blockers and doxazosin in preventing heart failure. The use of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors or statin therapy in CAD patients based on current hyperlipidemia guidelines [the updated Adult Treatment Panel III (ATP III)] can also reduce the incidence of heart failure by 20%.
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Evidence-based disease management strategies for diabetes mellitus, atherosclerotic vascular disease, and thyroid disease, as well as patient avoidance of tobacco, alcohol, cocaine, amphetamines, and other illicit drugs that can be cardiotoxic, are also important components of early risk modification for prevention of heart failure. In diabetic patients, both ACEIs and ARBs (specifically losartan and irbesartan) have been shown to reduce new-onset heart failure compared with placebo. In CAD or atherosclerotic vascular disease patients without heart failure, reviews of the EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) and HOPE (Heart Outcomes Prevention Evaluation) results show a 23% reduction in heart failure with ACEI therapy as well as reduced mortality, MIs, and cardiac arrest.
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ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA[JAMA and JAMA Network Journals Full Text]. 2002;288:2981.
[PubMed: 12479763]
+
Brenner
BM
et al.. Effects of
losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
N Engl J Med. 2001;345:861.
[PubMed: 11565518]
+
Fox
KM. Efficacy of
perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Lancet. 2003;362:782.
[PubMed: 13678572]
+
Yusuf
S
et al.. Effects of an angiotensin-converting-enzyme inhibitor,
ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.
N Engl J Med. 2000;342:145.
[PubMed: 10639539]
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2. Asymptomatic with cardiac structural abnormalities or remodeling (stage B)
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Patients who do not have clinical symptoms of heart failure but who have a structurally abnormal heart, such as a previous MI, evidence of left ventricular remodeling (left ventricular hypertrophy or low ejection fraction), or valvular disease, are at a substantial risk of developing symptomatic heart failure. Prevention of further progression in these at-risk patients is the goal, and appropriate therapies are dependent on the patient’s cardiac condition.
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In all patients with a recent or remote history of MI, regardless of ejection fraction, ACEIs and β-blockers are the mainstay of therapy. Both therapies have been demonstrated in randomized control trials to cause a significant reduction in cardiovascular death and symptomatic heart failure. These therapies are vital in post-MI patients, as is evidence-based management of an ST elevation MI and chronic stable angina, to help further achieve reduction in heart failure morbidity and mortality.
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In asymptomatic patients who have not had an MI but have a reduced left ventricular ejection fraction (nonischemic cardiomyopathy), clinical trials reported an overall 37% reduction in symptomatic heart failure when treated with ACEI therapy. The SOLVD (Studies of Left Ventricular Dysfunction) trial and a 12-year follow-up study confirmed the long-term benefit of ACEIs regarding the onset of symptomatic heart failure and mortality. A substudy of the SOLVD trial showed how enalapril attenuates progressive increases in left ventricular dilation and hypertrophy, thus inhibiting left ventricular remodeling. Despite a lack of evidence from randomized controlled trials, the ACC/AHA guidelines recommend β-blockers in patients with stage B heart failure, given the significant survival benefit that these agents provide in worsening stages of heart failure. The RACE (Ramipril Cardioprotective Evaluation) trial provided a clue as to why ACEIs are advantageous over β-blockers for nonischemic cardiomyopathy by demonstrating that ramipril is more effective than the β-blocker atenolol in reversing left ventricular hypertrophy in hypertensive patients.
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There is no clear outcome evidence for the use of ARBs in asymptomatic patients with reduced left ventricular ejection fraction. ARB therapy is, however, a guideline recommended alternative in ACEI-intolerant patients. VALIANT (VALsartan In Acute myocardial iNfarcTion) was one trial that showed that the ARB valsartan was as effective as but not superior to captopril, an ACEI, in reducing cardiovascular morbidity and mortality in post-MI patients with heart failure or a reduced left ventricular ejection fraction. The combination of both therapies was no better than captopril alone.
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Agabiti-Rosei
E
et al.. ACE inhibitor
ramipril is more effective than the beta-blocker
atenolol in reducing left ventricular mass in hypertension. Results of the RACE (
ramipril cardioprotective evaluation) study on behalf of the RACE study group.
J Hypertens. 1995; 13:1325.
[PubMed: 8984131]
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Flather
MD
et al.. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocar-dial Infarction Collaborative Group.
Lancet. 2000; 355:1575.
[PubMed: 10821360]
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Greenberg
B
et al.. Effects of long-term
enalapril therapy on cardiac structure and function in patients with left ventricular systolic dysfunction. Results of the SOLVD echocardiography substudy.
Circulation. 1995; 91:2573.
[PubMed: 7743619]
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Maggioni
AP, Fabbri
G. VALIANT (
VALsartan In Acute myocardial iNfarcTion) trial.
Expert Opin Pharmacother. 2005; 6:507.
[PubMed: 15794740]
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3. Symptomatic systolic heart failure (stage C)
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Patients with a clinical diagnosis of heart failure have current or prior symptoms of heart failure and structural heart disease with a reduced left ventricular ejection fraction comprise ACC/AHA stage C. This stage encompasses NYHA classes II, III, and IV, excluding patients who develop refractory end-stage heart failure (see Table 21-2). In patients with symptomatic heart failure and left ventricular dysfunction, neurohormonal activation creates deleterious effects on the heart, leading to pulmonary and peripheral edema, persistent increased afterload, pathologic cardiac remodeling, and a progressive decline in cardiac function. The overall goals in this stage are to improve the patient’s symptoms, slow or reverse the deterioration of cardiac functioning, and reduce the patient’s long-term morbidity and mortality.
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Accurate assessment of the cause and severity of heart failure; the incorporation of previous stage A and B treatment recommendations; and correction of any cardiovascular, systemic, and behavioral factors (Table 21-5) are important to achieve control in patients with symptomatic heart failure. Moderate dietary sodium restriction (3–4 g daily) with daily weight measurement further enhance volume control and allow for lower and safer doses of diuretic therapies. Exercise training is beneficial and should be encouraged to prevent physical deconditioning, which can contribute to exercise intolerance in patients with heart failure.
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Patients with symptomatic heart failure should be routinely managed with a standard therapy of a diuretic, an ACEI (or ARB if intolerant), and a β-blocker (see Table 21-2). The addition of other pharmacologic therapies should be guided by the need for further symptom control versus the desire to enhance survival and long-term prognosis. A stepwise approach to therapy is presented in Table 21-6 and expanded on later.
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Patients with heart failure who present with common congestive symptoms (pulmonary and peripheral edema) are given a diuretic to manage fluid retention and achieve and maintain a euvolemic state. Diuretic therapy is specifically aimed at treating the compensatory volume expansion driven by renal tubular sodium retention and activation of the renin-angiotensin-aldosterone system.
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Loop diuretics are the treatment of choice because they increase sodium excretion by 20–25% and substantially enhance free water clearance. Furosemide is most commonly used, but patients may respond better to bumetanide or torsemide because of superior, more predictable absorptions and longer durations of action. To minimize the risk of over- or underdiuresis, the diuretic response should guide the dosage of loop diuretics (Table 21-7), with dose increases until a response is achieved. Frequency of dosing is guided by the time needed to maintain active diuresis and sustained volume and weight control.
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Thiazide diuretics also have a role in heart failure, principally as antihypertensive therapy, but they can be used in combination with loop diuretics to provide a potentiated or synergistic diuresis. As a lone treatment, however, they increase sodium excretion by only 5–10% and tend to decrease free water clearance overall.
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Symptom improvement with diuretics occurs within hours to days, as compared with weeks to months for other heart failure therapies. For long-term clinical stability, diuretics are not sufficient, and exacerbations can be greatly reduced when they are combined with ACEI and β-blocker therapies.
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ACEIs are prescribed to all patients with symptomatic heart failure unless contraindicated and have proven benefit in alleviating heart failure symptoms, reducing hospitalization, and improving survival. Current ACC/AHA guidelines recommend that all patients with left ventricular systolic dysfunction be started on low-dose ACEI therapy to avoid side effects and raised to a maintenance or target dose (see Table 21-7). There is, however, some uncertainty regarding target doses achieved in clinical trials, and whether these are more beneficial than lower doses. For ACEIs as a class, there does not appear to be any difference in agents in terms of effectiveness at improving heart failure outcomes.
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In patients with NYHA class II or III heart failure, the β-blockers bisoprolol, metoprolol succinate (sustained release), and carvedilol have been shown to improve mortality and event-free survival. These benefits are in addition to ACEI therapy and support the use of β-blockers as part of standard therapy in these patients. A similar survival benefit has been shown for patients with stable NYHA class IV heart failure.
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β-blocker therapy should be initiated near the onset of a diagnosis of left ventricular systolic dysfunction and mild heart failure symptoms, given the added benefit on survival and disease progression. Titrating ACEI therapy to a target dose should not preclude the initiation of β-blocker therapy. Starting doses should be very low, given their effectiveness (see Table 21-7) but doubled at regular intervals, every 2–3 weeks as tolerated, toward target doses to achieve heart rate reductions. Individual studies indicate that there might be a dose-dependent outcome improvement, but recent meta-analysis concluded that the magnitude of heart rate reduction (5 bpm reductions) was associated with an 18% reduction in the risk of death whereas the β-blocker dose was not.
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Traditionally the negative inotropic effects of β-blockers were considered harmful in heart failure, but this impact is outweighed by the beneficial effect of inhibiting sympathetic nervous system activation. Current evidence suggests that these beneficial effects may not necessarily be equivalent among proven β-blockers. The COMET (Carvedilol or Metoprolol European Trial) findings showed that carvedilol (an α1-, β1-, and β2-receptor inhibitor) is more effective than twice-daily dosed immediate-release metoprolol tartrate (a highly specific β1-receptor inhibitor) in reducing heart failure mortality (40% vs 34%, respectively). Previous trials had investigated metoprolol succinate (sustained-release, once-daily dosing), but the COMET trial showed a mortality reduction even with metoprolol tartrate, a very cost-effective alternative. A recent systematic review and meta-analysis suggests, however, that the benefits may be a class effect with no superior agent over others.
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Because β-blockers may cause a 4–10-week increase in symptoms before improvement is noted, therapy should be initiated when patients have no or minimal evidence of fluid retention. Relative contraindications include bradycardia, hypotension, hypoperfusion, severe peripheral vascular disease, a P-R interval of >0.24 seconds, second- or third-degree atrioventricular block, severe COPD, or a history of asthma. Race or gender differences in efficacy of β-blocker therapy have not been noted.
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D. angiotensin ii receptor blockers
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Certain ARBs (see Table 21-7) have been shown in clinical trials to be nearly as effective as, but not consistently as and not superior to, ACEIs as first-line therapy for symptomatic heart failure. The use of ARBs is recommended in ACEI-intolerant patients but not preferentially over ACEIs given the volume of evidence validating ACEIs. Despite unclear evidence, the ACC/AHA guidelines recommend that ARB therapy be considered in addition to ACEI and standard therapy for patients who have persistent symptoms of heart failure. A recent systematic review that analyzed the benefit of ARBs in heart failure found no mortality or morbidity benefit when compared to placebo or ACEI and no benefit to combination with an ACEI.
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E. aldosterone antagonists
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For selected patients with moderately severe to severe symptoms who are difficult to control (NYHA class III with decompensations or class IV), additional treatment options include the aldosterone antagonists spironolactone and eplerenone (see Table 21-7) to improve mortality and reduce hospitalizations. A recent trial also proved the same outcome benefit of eplerenone in milder symptomatic heart failure, NYHA class II, and reduced ejection fraction of 35%.
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The addition of aldosterone antagonist therapy can cause life-threatening hyperkalemia in patients with heart failure, who are often already at risk because of reduced left ventricular function and associated renal insufficiency. Current guidelines recommend careful monitoring to ensure that creatinine is <2.5 mg/dL in men or <2.0 mg/dL in women and that potassium is maintained below 5.0 mEq/L (levels >5.5 mEq/L should trigger discontinuation or dose reduction). Higher doses of aldosterone antagonists and ACEI therapy should also raise concern for possible hyperkalemia, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX2) inhibitors, and potassium supplements should be avoided if possible. If the clinical situation does not allow for proper monitoring, the risk of hyperkalemia may outweigh the benefit of aldosterone antagonist therapy.
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Digoxin therapy is indicated only to reduce hospitalizations in patients with uncontrolled symptomatic heart failure or as a ventricular rate control agent if a patient has a known arrhythmia. The DIG (Digitalis Investigation Group) trial proved the benefit of digoxin added to diuretic and ACEI therapy in improving heart failure symptom control and decreasing the rate of hospitalization by 6%, but there was no overall mortality benefit. Subsequent retrospective subgroup analysis of the trial discovered some survival improvement at a serum digoxin concentration of 0.5–0.8 ng/mL in men. A similar but nonsignificant survival trend was also noted in women. Because survival is clearly worse when the serum digoxin concentration is >1.2 ng/mL, patients are best managed within the range noted to avoid potential adverse outcomes given the narrow risk/benefit ratio. Digoxin should be used cautiously in elderly patients, who may have impaired renal function that adversely affects drug levels.
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The combination of hydralazine and isosorbide dinitrate (H-I) is a reasonable treatment in patients, particularly African Americans, who have persistent heart failure symptoms with standard therapy. In V-HeFT I (Vasodilator Heart-Failure Trial), the mortality of African-American patients receiving H-I combination therapy was reduced, but mortality of white patients did not differ from that of the placebo group. In V-HeFT II, a reduction in mortality with the H-I combination was seen only in white patients who had been receiving enalapril therapy. No effect on hospitalization was found in either trial.
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The A-HeFT (African-American Heart Failure Trial) findings further supported the benefit of a fixed dose H-I combination (see Table 21-7) by showing a reduction in mortality and heart failure hospitalization rates as well as improved quality-of-life scores in patients with moderate to severe heart failure (NYHA class III or IV) who self-identified as African-American. The H-I combination was in addition to standard therapies that included ACEIs or ARBs, β-blockers, and spironolactone.
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It is well established that patients with heart failure are at an increased risk of thrombosis from blood stasis in dilated hypokinetic cardiac chambers and peripheral blood vessels. Despite this known risk, the yearly incidence of thromboembolic events in patients with stable heart failure is between 1% and 3%, even in those with lower left ventricular ejection fractions and evidence of intracardiac thrombi. Such low rates limit the detectable benefit of warfarin therapy, and retrospective data analysis of warfarin with heart failure show conflicting results, especially given the major risk of bleeding. Warfarin therapy is indicated only in heart failure patients with a history of a thromboembolic event or those with paroxysmal or chronic atrial fibrillation or flutter. Likewise, the benefit of antiplatelet therapies, such as aspirin, has not been clearly proved, and these therapies could possibly be detrimental because of their known interaction with ACEIs. Aspirin can decrease ACEI effectiveness and potentially increase hospitalizations due to heart failure decompensation.
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Therapies that adversely affect the clinical status of patients with symptomatic heart failure should be avoided. Other than for control of hypertension, calcium channel blockers offer no morbidity or mortality benefit in heart failure. Nondihydropyridine calcium channel blockers (eg, diltiazem and verapamil) and older, short-acting dihydropyridines (eg, nicardipine and nisoldipine) can worsen symptoms of heart failure, especially in patients with moderate to severe heart failure. The newer long-acting dihydropyridine calcium channel blockers amlodipine and felodipine are safe but do not have a role in heart failure treatment and improving outcomes. NSAIDs can also exacerbate heart failure through peripheral vasoconstriction and by interfering with the renal effects of diuretics and the unloading effects of ACEIs. Most antiarrhythmic drugs (except amiodarone and dofetilide) have an adverse impact on heart failure and survival because of their negative inotropic activity and proarrhythmic effects. Phosphodiesterase inhibitors (cilostazol, sildenafil, vardenafil, and tadalafil) can cause hypotension and are potentially hazardous in patients with heart failure. Thiazolidinediones and metformin, both used in treatment of diabetes, can be detrimental in patients with heart failure because they increase the risk of excessive fluid retention and lactic acidosis, respectively.
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J. implantable devices
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Nearly one-third of all heart failure deaths occur as a result of sudden cardiac death. The ACC/AHA recommendations include the use of implantable cardioverter-defibrillators (ICDs) for secondary prevention of sudden cardiac death in patients with symptomatic heart failure; a reduced left ventricular ejection fraction; and a history of cardiac arrest, ventricular fibrillation, or hemodynamically destabilizing ventricular tachycardia. ICDs are recommended for patients with NYHA class II or III heart failure, a left ventricular ejection fraction of <35%, and a reasonable 1-year survival with no recent MI (within 40 days).
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As heart failure progresses, ventricular dyssynchrony can also occur. This is defined by a QRS duration of >0.12 ms in patients with a low left ventricular ejection fraction (usually <35%) and NYHA class III or IV heart failure. Clinical trials have shown that cardiac resynchronization therapy with biventricular pacing can improve quality of life, functional class, exercise capacity, exercise distance, left ventricular ejection fraction, and survival in these patients. Patients who meet criteria for cardiac resynchronization therapy and an ICD should receive a combined device, unless contraindicated.
+
Chatterjee
S, Biondi-Zoccai
G, Abbate
A
et al.. Benefits of beta blockers in patients with heart failure and reduced ejection fraction: network meta-analysis. Br Med J. 2013;346:f55.
+
Heran
BS, Musini
VM, Bassett
K, Taylor
RS, Wright
JM. Angiotensin receptor blocker for heart failure. Cochrane Database Syst Rev. 2012;4:CD003040.
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Jong
P
et al.. Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials.
J Am Coll Cardiol. 2002; 39:463.
[PubMed: 11823085]
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Jong
P
et al.. Effect of
enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.
Lancet. 2003; 361:1843.
[PubMed: 12788569]
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McAlister
FA, Wiebe
N, Ezekowitz
JA, Leung
AA, Armstrong
PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150(11):784–794.
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Rochon
PA
et al.. Use of angiotensin-converting enzyme inhibitor therapy and dose-related outcomes in older adults with new heart failure in the community.
J Gen Intern Med. 2004; 19:676.
[PubMed: 15209607]
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Taylor
AL
et al.. Combination of isosorbide dinitrate and
hydralazine in blacks with heart failure.
N Engl J Med. 2004; 351:2049.
[PubMed: 15533851]
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Yan
AT, Yan
RT, Liu
PP. Narrative review: pharmacotherapy for chronic heart failure: evidence from recent clinical trials. Ann Intern Med. 2005;142(2):132–145.
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Zannad
F, McMurray
JJ, Krum
H
et al..
Eplerenone in patients with systolic heart failure and mild symptoms.
N Engl J Med. 2011;364(1):11–21.
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4. Refractory end-stage heart failure (stage D)
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Despite optimal medical therapy, some patients deteriorate or do not improve and experience symptoms at rest (NYHA class IV). These patients can have rapid recurrence of symptoms, leading to frequent hospitalizations and a significant or permanent reduction in their activities of daily living. Before classifying patients as being refractory or having end-stage heart failure, providers should verify an accurate diagnosis, identify and treat contributing conditions that could be hindering improvement, and maximize medical therapy.
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Control of fluid retention to improve symptoms is paramount in this stage, and referral to a program with expertise in refractory heart failure or referral for cardiac transplantation should be considered. Other specialized treatment strategies, such as mechanical circulatory support, continuous intravenous positive inotropic therapy, and other surgical management can be considered, but there is limited evidence in terms of morbidity and mortality to support the value of these therapies. Careful discussion of the prognosis and options for end-of-life care should also be initiated with patients and their families. In this scenario, patients with ICDs should receive information about the option to inactivate defibrillation.
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B. Diastolic Heart Failure
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Clinically, diastolic heart failure is as prevalent as LVSD, and the presentation of diastolic heart failure is indistinguishable from LVSD. Nearly 40–50% of patients with symptomatic heart failure experience diastolic failure. Patients with diastolic heart failure are more likely to be women, older, and have hypertension, atrial fibrillation, and left ventricular hypertrophy, but no history of CAD. Diastolic heart failure remains a diagnosis of exclusion in which a thorough differential of heart failure needs to be considered. Compared to systolic heart failure, the treatment of diastolic heart failure lacks validated evidence-based therapies. Management focuses on controlling systolic and diastolic blood pressure, ventricular rate, volume status, and reducing myocardial ischemia, because these entities are known to exert effects on ventricular relaxation. Diuretics are used to control symptoms of pulmonary congestion and peripheral edema, but care must be taken to avoid overdiuresis, which can cause decreased volume status and preload, manifesting as worsening heart failure.
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King
M, Kingery
J, Casey
B. Diagnosis and evaluation of heart failure. Am Fam Physician. 2012;85(12):1161–1168.