Clinical Features
Chronic Management

Treatments to Lower Heart Rate
ACE Inhibitors

Angiotensin receptor blockers
Hydralazine + Isosorbide dinitrate
Calcium Channel Blockers
Growth Hormone
Hormone Replacement Therapy
Coenzyme Q
Intravenous Immune Globulin


Implantable Cardioverter-Defibrillators

Cardiac resynchronization

Left Ventricular Assist Devices
Enhanced External Counterpulsation (EECP)
Surgical Treatment
Cardiac transplant

Management of HF with normal LVEF
Treatment of acute decompensated HF

I. Epidemiology

  1. Prevalence about 1%
  2. Highest mortality is in those with highest Renin-AII activation, which is suggested by moderate hyponatremia (<137) (Circ. 73:257, 1986)

II. Clinical features

  1. Dyspnea on exertion
  2. Orthopnea (dyspnea worsened with recumbency)
  3. Paroxysmal nocturnal dyspnea
  4. Occasionally, cough (usually productive of frothy sputum, usually white, sometimes pink)
  5. Anemia can occur, for unclear reasons; tx with Erythropoietin increased LVEF and reduced NYHA class in one uncontrolled study (JACC 35:1737, 2000--JW)
  6. Px: Bibasilar rales; S3 gallop
  7. Pedal edema, jugular venous distention, hepatomegaly, hepatojugular reflux (with right-sided CHF)
New York Heart Association (NYHA) Classification Scheme:
  • I--no limit of activity, no sx of CHF (fatigue, palps, dyspn) or angina
  • II-sl. limit of activity, sx of CHF/ang with ordinary activity; no sx at rest
  • III-marked limiting of activity, sx with less than ordinary activity, no sx at rest
  • IV-no activity without discomfort, sx at rest

ACC-AHA stages:
  • Stage A: High risk for HF but no structural or functional abnormality or symptoms
  • Stage B: Structural heart changes associated with development of HF but no signs or symptoms
  • Stage C: Structural heart changes + symptomatic HF
  • Stage D: Advanced structural heart changes + marked HF symtpoms at rest

III. Etiology

Note that Vitamin E supplementation may increase the risk of heart failure--Click on link for details

  1. With low LVEF
  1. Cardiomyopathy
  1. Idiopathic
  2. Chronic ischemic heart disease
  3. Hypertension-more likely with high pulse pressures (JAMA 281:634, 1999--AFP)
  4. Chronic aortic regurgitation
  5. Alcoholism
  6. Infectious: viral (coxsackie, echo, rubella); bacterial (diptheria), fungal (aspergillus); parasitic (toxo, Chagas')
  1. Acute myocardial infarction
  2. Acute hypertension
  3. Acute myocarditis
  4. Thyrotoxicosis
  5. Exacerbations may be triggered by factors which increase intravascular volume, e.g. high dietary sodium intake or use of NSAIDS and COX-2 Inhibitors
  1. With normal LVEF
  1. Transient ischemia ("flash pulmonary edema")
  2. Mitral stenosis
  3. Volume overload, e.g. acute or chronic renal failure
  4. Transient arrhythmias
  5. "Diastolic Dysfunction"
    1.  A purported phenomenon of failure of ventricles to relax & enlarge adequately during diastole
    2. Some controversy as to whether this is a real phenomenon or not
      1. In a case series, many pts diagnosed with "diastolic dysfunction" had other explanations for their symptoms (BMJ 321:215, 2000--JW)
      2. Cardiac catheterization studies have confirmed abnormal pressure-volume relationships in pts with heart failure and normal LVEF which suggest incomplete ventricular relaxation during diastole (NEJM 350:1953, 2004--AFP)
  1. With elevated LVEF
  1. Hypertrophic Cardiomyopathy
  2. Aortic regurgitation; early mitral regurgitation

IV. Diagnosis

  1. Echocardiogram traditionally used to evaluate systolic function and/or diastolic function
  2. ECG may be an appropriate pre-screening tool for pts with suspected HF
  1. Prospective evaluation of 534 pts (ages 17-94) whose primary care doc had ordreed Echo for suspected LV dysfunction
  2. All pts had EKG evaluated by someone blind to outcome of the Echo
  3. 96 pts had Echo's showing LV dysfunction
  1. None had nl EKG's!
  2. 90 had major EKG abnormalities (AFib, prev. MI, LVH, BBB, LAD)
  1. Using EKG as a screening tool would reduce # of Echos by 50% without decreasing sensitivity!
  1. Brain-type ("B-type") Natriuretic Peptide level
    1. Released when LV is stretched e.g. in left-sided heart failure
    2. Can also be elevated with:
      1. Left ventricular diastolic dysfunction
      2. Right ventricular hypertrophy/cor pulmonale
      3. Prolonged myocardial ischemia
    3. In a study of 250 pts presenting to ER with signs/sx of CHF, a BNP > 80 pg/mL was 98% sensitive and 92% specific for an ultimate dx of CHF made by chart review done by cardiologists (J. Am. Coll. Cardiol. 37:379, 2001--JW)
    4. In a study of 321 pts presenting to an ER w/dyspnea, a BMP of > 94 pg/mL was 86% sensitive and 98% specific for an eventual clinical dx of CHF (J. Am. Coll. Cardiol. 39:202, 2002--JW)
    5. Using cutoff of 100pg/mL, sensitivity and specificity of BNP level were 90% and 76%, respectively; cutoff of 50pg/mL ass'd with sensitivity of 97% and specificity of 62% in a study of 1586 pts presenting to an emergency department with acute dyspnea not obviously caused by CHF (NEJM 347:161, 2002--JW)
    6. In a population study of 3177 people, using ROC analysis and echocardiographic estimate of LVEF as the gold standard, plasma B-type natriuretic peptide level did not do very well; at 95% specificity had a sensitivity of only about 33%  (JAMA 288:1252, 2002--abst)
    7. Specificity of elevated BNP in determining elevations of pulmonary artery pressure may be reduced in the presence of shock (Crit. Care Med. 32:1643, 2004--abst)
    8. Chronic renal failure is not associated with elevation in serum BNP levels independent of left ventricular ejection fraction (Am. J. Kid. DIs. 44:420, 2004--JW)
  2. Resting heart rate > diastolic blood pressure ass'd with odd ratio of 9.0 for CHF in a population study of 2158 pts (BMJ 320:220, 2000--JW)
  3. Physical exam findings-S3 and S4 "gallop" heart sounds
    1. When measured objectively with phonocardiography and processed using a computer algorithm, S3 and S4 had sensitivity/specificity of 52%/87% and 43%/72%, respectively, compared with transthoracic echocardiography-measured LVEF (JAMA 293:2238, 2005--abst)

V. Chronic management

note--Consider sleep study in pts with CHF; in one series of 81pts with stable CHF, 51% were found to meeet criteria for Obstructive Sleep Apnea (Circ. 97:2154, 1998--JW)

note--Implantable left atrial pressure sensors may help with heart failure management by providing early detection of exacerbation.

note--Using BNP to guide therapy may be associated with improved outcomes

  1. ACE Inhibitors (see also under "CHF with normal LVEF" below)-First line for all patients with reduced LVEF even if they are asymptomatic
  1. Improve hemodynamics, sx, LVH, arrhythmias, LVEF, survival; may cause cough, secondary fluid retention or tolerance; helps avoid hypokalemia due to hyperaldo in CHF. May take 4-12 weeks for clinical improvement
  1. Adequate dosing is important!
  1. 3000 pts with class II-IV CHF randomized to low (2.5-5mg/d) vs. high (32.5-35mg/d) doses of lisinopril; Over 39-48mo f/u, sig. less risk of combined endpoint of hospitalization or death in high-dose group (78% vs. 84%; Circ. 100:2312, 1999--JW)
  2. Pts (summary doesn't state how many) with mod-severe CHF randomized to enalapril titrated to 20mg/d vs. titrated to 60mg/d; there were no sig. diffs. in 12mo incidence of mortality, hospitalization for CHF exacerbations, or NYHA class (J. Am. Coll. Cardiol. 36:2090, 2000--AFP)
  3. Recc'd target daily doses of ACEI's for tx of CHF per AHCPR are 20mg for enalapril, 150mg of captopril, or 20mg of lisinopril
  1. African-Americans may not have the same benefit from ACEI's as members of other racial/ethnic groups
    1. In a subgroup analysis of 800 black enrollees in two of the trials mentioned below (summary doesn't mention which), over avg. 3y f/u, BP reduction and hospitalization rates were no different in Enalapril vs. placebo groups (NEJM 344:1351, 2001--JW)
  1. CONSENSUS I (NEJM 316:1429,87)
  1. 253 pts (70% male) in class IV CHF
  2. Meds at entry were continued: 93% on Dig; 98% on diuretics
  3. 73% had CAD, 48% had prev. MI
  4. Randomized to enalapril 1.25-20mg BID (mean dose 18mg/d) vs placebo for avg 6mo f/u
  5. 16% of pts on enalapril had to withdraw due to sxatic hypotn, inc. [Cr], etc; us. occured after 1st wk of tx
  6. Enalapril reduced mortality by 40%@6mos, 31%@1yr; also sig. improv in NHYA class, LVH
  7. All reduction in mort among deaths due to CHF; no change in mortality due to sudden cardiac death
  1. SOLVD (Treatment trial) (NEJM 325:293, 8/91)
  1. 2569 pts (avg. 61yo, 80% men, 80% white) with overt CHF & LVEF < 35% (avg 25%; 57% class II CHF; 30% class III); avg f/u 41mo
  2. Placebo vs. enalapril tapered from 2.5-5mg BID to 10mg BID if tolerated (avg. mainenance dose 16.6mg/d)
  3. Enalapril group showed
  1. 16% risk reduction in mort. over total f/u period
  2. 26% risk red. in overall death or hosps for CHF
  3. For both, greatest red. @ 3mos & grad. thereafter, though still sig. @ end of study
  4. 22% risk red. in deaths from CHF
  5. No sig. risk red. in deaths from MI
  6. Evidence for sxatic benefit: almost twice the pts in placebo group had to switch to open-label tx for worsening CHF; other vasodilators added for CHF tx more often in placebo group
  1. Benefit from Enalapril not affected by
  1. Baseline serum [Na]
  2. Use of vasodilators other than ACEIs
  3. Cause of CHF
  4. NYHA functional status
  1. SOLVD (Prevention trial) (NEJM 327:685, 9/92)
  1. 4200 pts (Avg. 59y, 89% male) with asymptomatic, untx'd LVEF <35% but no overt CHF; Avg f/u 3y
  2. Enalapril 5-10mg BID (Avg 17mg/d) vs. placebo showed
  1. 12% risk red. in CV mort (nonsig.), though many started open-label ACEI after dx with CHF
  2. 20% risk red. in deaths or hosps from CHF (sig.)
  3. 29% risk red. in devel. of CHF or death (sig.)
  4. 6% risk inc. in death for LFEV 33-35% (nonsig.)
  5. Pts on enalapril had 46% dizz/fainting; 34% cough
  1. Beta-blockers
  1. Benefit may derive from downregulation of catecholamine receptors that results from the chronic hyperadrenergic state of CHF.
  2. In a meta-analysis of 23 randomized studies of beta-blockers in pts with heart failure (usually involving dose titration to a particular resting heart rate), nearly all of whom had systolic dysfunction and were on ACEIs, the benefits of beta-blockers was closely correlated with reduction in resting heart rate but NOT with beta-blocker dose used.  (Ann. Int> Med. 150:784, 2009-JW)
  3. Carvedilol
  1. A nonselective beta-blocker with some vasodilatory effects (alpha-blocking) effects, the latter most prominent at start of therapy
  2. Approved for tx of NYHA class II or III CHF stabilized on other drugs (an "add-on" drug); start at 3.125 BID and gradually increase gradually to 25 BID (50 BID if > 85kg) if tol'd; take w/food to slow absorption and dec. risk of hypotension. No studies as of 1997 in pts with NYHA class IV or hosp'd pts.
  1. JACC 25:1225, 1995
  1. 60 pts with CHF & LVEF <35% randomized to carvedilol or placebo; other CHF meds were continued
  2. Carvedilol dose started low & then carefully titrated up
  3. After 4mos, carvedilol group had decrease in sx and increase in LVEF, while placebo group remained unchanged
  1. NEJM 334:1349, 1996
  1. Multicenter, randomized trial of carvedilol vs. placebo; mean followup 6.5 mos
  2. 1094 Pts with CHF and low LVEF (avg 23%)
  3. Almost all pts were already on dig, diuretics, and ACEI's
  4. Excluded if had recent MI, hyper- or hypo-tension, bradycardia, renal or hepatic disease
  5. Mort. rate 3.2% vs 7.8% with placebo (sig.); mainly due to reductions in CHF progression and sudden death
  6. Rate of death or cardiac hosp (combined) 15.8% vs 24.6% with placebo (sig)
  1. Circulation 94:2793, 2800, and 2807, 1996-JW
  1. Three studies each involving 366pts comparing carvedilol 6.25-25mg BID with placebo over 1y in pts with mild, mod, and severe CHF on standard Rx, including ACEIs
  2. Associated with sig. increase in LVEF, sx and functional class, and sig. decrease in mortality
  1. Lancet 349:375, 1997-JW, ML
  1. 415 pts with stable mild-mod CHF due to CAD randomized to carvedilol up to 25 BID vs. placebo
  2. 85% were on ACEI; 75% on diuretics; 38% on dig
  3. RR for death or hosp. admission over 19mos of f/u was 0.74 in carvedilol group
  4. No difference in activity, exercise, and sx scores at 12mos
  5. Carvedilol group had sl. worse sx at 6mos!!! (summary didn't say which sx or if statistically sig.)
  1. 2289 pts with class III or IV CHF  and LVEF < 25% randomized to carvedilol titrated to max 25mg BID vs. placebo ; over avg. 10.4mo f/u, carvedilol group had sig. lower mortality (11.2% vs. 16.8%); benefit was sig. for subgroup of pts with LVEF < 20% (NEJM 344:1651, 2001--JW)
  1. 63 pts with class IV CHF treated with carvedilol; 71% were able to tolerate it long-term and 59% improved by at least one functional class; "serious nonfatal" adverse events occurred in 43% (e.g. worsening CHF), more likely in pts with low baseline BP and low serum Na levels (JACC 33:924, 1999--JW)
  1. Adverse effects: like other beta-blockers, may cause hypotension (us. stops after 1 week, either spontaneously or after temp. decr. in diuretic or ACEI), fluid retention requiring increased dose of diuretics, aggravation of bronchospasm, bradycardia and heart block, and can increase serum levels of dig. (Med. Letter 39:90, 1997)
  1. Beta-blockers other than carvedilol
  1. Prospective study of 3,225 pts with NYHA Class II or III CHF; 1,109 were on some kind of beta-blocker at time of enrollment. Mortality over 4y was 9% in beta-blocker pts vs. 17% in those not on beta-blockers. The diff. remained sig. after adjustment for sex, h/o previous MI, NYHA class, or concommittant tx with dig, diuretics, nitrates, and ACEIs (Am. J. Cardiol. 81:1455, 1998--AFP)
  1. "Cardiac Insufficiency Bisoprolol Study" (CIBIS)--641 pts with mod-severe CHF randomized to bisoprolol (up to 5mg/d) vs. placebo on top of "conventional therapy--Over avg. 23mo f/u, mortality nonsig. less in bisoprolol group (17% vs. 21%; Circ. 90:1765, 1994--Med. Lett.)
  1. "Cardiac Insufficiency Bisoprolol Study II" (CIBIS-II)--2,647 pts with NYHA Class III or IV CHF (with LVEF < 35% and on diuretics and ACEIs) randomized to bisoprolol (1.25mg/d titrated to 10mg/d as tolerated) vs. placebo. Over avg. 16mo f/u; sig. less all-cause mortality in bisoprolol group (11.8% vs. 17.3%) (CIBIS-II; Lancet 353:9, 1999--JW)
  1. "Metoprolol in Dilated Cardiomyopathy" (MDC) study--383 pts with NYHA Class II or III CHF randomized to immediate-release Metoprolol titrated up to 150mg/d; over 12-18mo f/u, % of pts dying or needing cardiac transplantation was 13% in bisoprolol group c/w 20% w/placebo (nonsig; Lancet 342:1441, 1993--Med. Lett.)
  1. 3,991 pts with CHF (NYHA class II-IV, most class II-III) & LVEF < 40%, randomized to QD Metoprolol XR started at 25mg QD (12.5mg QD if class IV) titrated to target dose of 200mg/d vs. placebo; sig. decrease in mortality in metoprolol group at 1y (7% vs. 11%); also symptomatic benefit as measured by McMaster Overall Treatment Evaluation score was sig. better in metoprolol group ("MERIT-HF" Trial Lancet 353:2001, 1999, JAMA 283:1295, 2000--JW; abst)
  1. 2708 pts with severe CHF (mean LVEF 23%) randomized to bucindolol vs. placebo.  Over mean 2y f/u, mortality rate was not sig. different in two groups but incidence of hospitalization for CHF was sig. lower (35% vs. 42%). (NEJM 344:1659, 2001--JW)
  1. Carvedilol vs. other beta-blockers
    1. Meta-analysis of 3,000 pts, from 17 randomized clinical trials (from 1975 to 1997) of beta-blockers vs. placebo in CHF (ischemic or non-ischemic) with avg. f/u about 9mos (JACC 30:27, 1997-JW)
  1. Use of beta-blockers ass'd with OR of 0.69 for death
  2. Trend for greater mortality reduction with carvedilol than with other beta-blockers, but didn't take into account sig. death rate with carvedilol during initial, open-label phases of those trials
  1. Meta-analysis of 3,023 pts, mostly with mild-mod CHF, from 18 randomized trials showed RR 0.68 for mortality and 0.59 for hospitalization, both sig. Mortality reduction 49% for non-selective beta-blockers e.g. carvedilol vs. 18% with beta-selective agents, e.g. metoprolol (Circ. 98:1184, 1998--JW)
  2. 67 pts with symptomatic CHF on dig, diuretics, and ACEI's randomized to carvedilol vs. metoprolol x 6mos. No sig. differences seen in symptomatic improvement, exercise tolerance, or LVEF (Circ. 99:2645, 1999--JW)
  3. In a randomized trial of 3029 pts with chronic heart failure randomized to Carvedilol (titrated to 25mg BID) vs. metoprolol (titrated to 50mg BID), over mean 58mo f/u, incidence of mortality was sig. lower with carvedilol (34% vs. 40%); significance held in analysis of subgroups based on age > 65yo vs. < 65yo and LVEF < 25% vs. > 25% (Lancet 362:7, 2003--JW)
  1. Beta-blockers vs. ACEIs for initial treatment of HF
    1. In a study in 1,010 pts > 65yo with NYHA class II-III HF and LVEF < 36% randomized to bisoprolol 10mg/d vs. enalapril titrated to 10mg BID, over mean 1.2y f/u, incidence of (death or hospitalization) was not sig. diff. between the two groups in intention-to-treat analysis but was in the per-protocol analysis (33.1% vs. 32.4%) ("CIBIS III" Trial; Circ. 112:2426, 2005--JW)
  1. Angiotensin receptor blockers-Alternative first-line to ACEIs if ACEIs are contraindicated or not tolerated
    1. Comparisons with ACEIs
      1. 700 pts > 65yo w/NYHA class II-IV CHF and LVEF < 40% randomized to losartan (titrated 50 mg QD) vs. captopril (titrated to 50mg TID) x 48wks. Combined risk of death and/or admission for CHF was 9.4% w/losartan vs. 13.2% w/captopril (p = 0.075); all-cause mortality 4.8% w/losartan vs. 8.7% w/captopril (p = 0.035). No diff. in admissions for CHF (5.7%) or improvement in functional class from baseline. 12% of losartan pts d/c'd tx b/c of adverse f/x, c/w 21% in captopril group (Evaluation of Losartan in the Elderly ("ELITE") study; Lancet 349:747, 1997-UW drug supplement)
      2. 116 pts with CHF and LVEF < 45% already on ACEIs randomized to losartan vs. enalapril (non-enalapril ACEI's were d/c'd). At 12 weeks; exercise capacity, sx, and LVEF were similar in both groups
      3. 768 pts with CHF (NYHA Class II-IV) randomized to candesartan vs. enalapril vs. both; at 43wks there were no sig. diff's in exercise tolerance, functional status, quality of life, or mortality (Circ. 100:1056, 1999--JW)
      4. 3152 pts with NYHA Class II-IV CHF and LVEF < 41% randomized to Captopril (titrated up to 50mg TID) vs. Losartan (titrated up to 50mg/d). Over median 1.5y f/u, no sig. diff. in all-cause mortality, sudden death, or hosp. admission ("ELITE II"; Lancet 355:1582, 2000--JW)
      5. See also under Acute MI Management for data on use in acute MI patients with low LVEF
    2. Comparisons of one ARB to another
      1. In a retrospective study using a heart failure registry with 5,139 pts with HF treated with candesartan or losartan, pts treated with candesartan had sig. higher 1y survival (90% vs. 83%) and 5-year survival (61% vs. 44%).  The diff. between the two drugs was sig. after adjustment for potential confounders (JAMA 305:175, 2011-abst)
    3. Addition of ARBs to an ACEI-including regimen
      1. 5,010 pts > 18yo with mild-severe CHF and LVEF < 40% randomized to Valsartan up to 160mg BID vs. placebo while continuing "usual care" including ACEI's in 93% of pts. Over f/u period, combined endpoint of "mortality & morbidity" from CHF was sig. lower in Valsartan group (28.8% vs. 32.1%); total mortality no diff. in the two groups; in pts on ACEI + Beta-blockers at baseline, valsartan was ass'd with sig. higher mortality than placebo ("Val-HeFT" trial; NEJM 345:1667, 2001--JW)
      2. Combination may increase risk of hyperkalemia
    4. Use of ARBs in pts with HF, heterogeneous as to ACEI use
      1. In a study in 7,599 pts with NYHA class II-IV HF (3023 had LVEF > 40%; 41% also on an ACEI) randomized to Candesartan (titrated to 32mg/d) vs. placebo, over median 38mo f/u, incidence of overall mortality was 23% in candesartan group and 25% in placebo group (nonsig. but sig. after adjustment for possible confounders); incidence of (CV death or unplanned hospitalization for worsening heart failure) was sig. lower with candesartan (30% vs. 35%).  This benefit was sig. for pts with LVEF < = 40% and not on ACEI, < = 40% AND on ACEI.  The benefit was NOT sig. in pts with LVEF > 40%.  No diff. in this benefit based on use or non-use of beta-blockers, diuretics, spironolactone, or digoxin. ("CHARM" trial; Lancet 362:759, 2003--JW)
      2. In a follow-up report in the same cohort of patients, the incidence of (cardiovascular death or nonfatal MI) was sig. lower in candesartan group (20.4% vs. 22.9%); similar reductions seen in various subgroup analyses (JAMA 294:1794, 2005--abst)
    5. Dosing of ARBs in heart failure
      1. In a study in 3,846 pts with NYHA class II-IV CHF, LVEF of 40% or below, and intolerance to ACEIs, randomized to losartan with target dose of 50mg/d vs. 150mg/d, after median 4.7y f/u, the high-dose gorup had sig. lower incidence of (death or hospitalization for heart failure) (RR 0.90) though no sig. diff. in all-cause mortality; high-dose group had sig. more hyperkalemia, hypotension, and angioedema (Lancet 374:1840, 2009-JW)
  1. Vasopressin antagonists
    1. May help alleviate both edema (both pulmonary and peripheral) and hyponatremia without disrupting eleecolyte levels as diureti may do
    2. Specific drugs
      1. Tolvaptan
      2. Several others in development as of 2005
    3. Studies of clinical efficacy
      1. 319 pts hospitalized with HF exacerbation and LVEF < 40% randomized to tolvaptan 30-90mg PO QD vs. placebo; all also received "standard therapy"; at 24h, all 3 active-tx groups had sig. greater median decreases in body weight c/w placebo; at 60d, no sig. diff. in incidence of worsening HF (JAMA 291:1963, 2004--JW)
      2. In a study in 4,133 pts hospitalized with heart failure randomized to tolvaptan 30mg QD vs. placebo x 2mos; over median 9.9mo f/u, there was no sig. diff. in incidence of (all-cause mortality) or (cardiovascular eath or hospitalization for heart failure) ("EVEREST Outcome Trial"; JAMA 297:1319, 2007--Abst)
  1. Diuretics
    1. Potassium-Sparing Diuretics
      1. Spironolactone 25mg/d ass'd with 27% mortality reduction (sig.) and 32% reduction in hospitalization for cardiac causes (sig.) c/w placebo in one trial of 1,663 pts with class III or IV CHF and LVEF < 35% with serum Cr < 2.5 and K < 5.0 with avg. 2y f/u; all were on ACEIs ("RALES" trial, NEJM 341:709, 1999--Med. Lett. & JW)
      2. 6632 pts 3-14d post-MI with LVEF 40% of less and (heart failure or DM) randomized to Eplerenone 25-50mg/d vs. placebo.  Over mean 16mo f/u, eplerenone recipients has sig. lower incidence of all-cause mortality (14.4% vs. 16.7%) and (cardiovascular death or first cardiovascular hospitalization) (26.7% vs. 30.0%) ("EPHESUS" trial, NEJM 348:1309, 2003--JW)
    2. Non-Postassium sparing diuretics
      1. Loop diuretics, e.g. furosemide-helpful for sx; not shown to improve survival
      2. Non-potassium sparing diuretic use ass'd with RR of 1.33 for arrhythmic death (sig.) c/w no diuretic use, after adjustment for counfounders in a retrospective study of 6,797 pts with CHF and LV dysfunction--no different if potassium supplements co-administered; no increased risk with use of potassium-sparing diuretics or combined use of potassium- and non-potassium-sparing diuretics ("SOLVD" trial, Circ. 100:1311, 1999--JW)
  1. Digoxin can decrease sx and reduce hospitalizations but not shown to improve survival
    1. Can be helpful in pts with Low LVEF & poor response to diuretics--many studies show sig. hemodynamic/symptomatic improvements (e.g. NEJM 303:1443, 1980; NEJM 306:699, 1982--14/25 pts responded); ACEIs may be better, though (JAMA 259:539, 1988)
    2. Reduces risk of hospitalization but very slightly (64% vs. 67% over 3y in randomized placebo-controlled trial w/6800 pts; no change in mortality; NEJM 336:525, 1997-JW)
    3. In AFib (34% of CHF pts) or other SVT, to control rapid ventr. rate
    4. Dose of 0.25mg/d no better than 0.125mg/d in terms of improvement of LC function in a study involving 19 pts with CHF and reduced LV fn (JACC 29:1206, 1997-JW)
    5. In a 3y randomized trial in pts with CHF of digoxin vs. placebo looking at subgroups by gender, the all-cause mortality rates in digoxin recipients vs. placebo was not sig. different among men but among women, dig recipients had higher mortality rates, approaching statistical significance (33.1% vs. 28.9%, P=0.078) ( ("DIG" study; NEJM 347:1403--JW)


  2. Hydralazine + Isosorbide dinitrate-Alternate first-line if neither ACEIs nor ARBs can be used
    1. Less effective than ACEI (NEJM 325:303, 1991)
    2. n.b. Vasodilators are contraindicated in pts with severe aortic stenosis
    3. In a study in 642 men avg 58yo, w/mild-mod CHF (mean LVEF 30%; low exercise tolerance), already on dig & diuretics, randomized to (hydralazine 75mgQID + isosorbide dinitrate 40mgQID) vs. (Prazosin 5 mg QID) vs. placebo, the former combination wsa associated with sig. mortality reduction at 2y but not at 3y; Prazosin was associated with similar mortality to placebo.  Subgroup analysis showed no diff. in findings based on presence vs. absence of CAD  ("VHeFT 1" Trial; NEJM 314:1547, '86) 
    4. May be particularly beneficial in people of African ancestry
      1. In a study in 1,050 black pts with HF and LVEF < 35% (mean 24%), most already on ACEIs and beta-blockers, randomized to isosorbide-hydralazine vs. placebo, after mean 10mo f//u, the isosorbide-hydralazine group had sig. lower mortality (6% vs. 10%), hospitalization for heart failure (16% vs. 24%), and sig. better mean quality-of-life scores ("A-HEFT" Trial; NEJM 351:2049, 2004-JW)

  3. Calcium channel blockers-with nonischemic CHF, may be good for pts who can't tolerate ACEI's!
  1. NEJM 335:1107, 1996-JW
  1. 1153 pts with NYHA Class III-IV CHF and LVEF < 30%, all on "standard drug therapy" randomized to Amlodipine 5-10mg/d vs. placebo; median f/u 14mos
  2. In pts with ischemic cardiomyopathy (63% of pts), similar morbidity & mortality
  3. In pts with nonischemic cardiomyopathy, amlodipine group had 18% mort vs. 31% with placebo (sig.); sig. morbidity 28% vs. 37%
  1. Inotropics
    1. In a randomized trial in 30 pts with symptomatic HF despite tx with dig, enalapril, spironolactone, and diuretics s/p a single 72-hour infusion of dobutamine randomized to to dobutamine 8mcg/kg/min x 8h Q14d vs. placebo; at 1y, dobutamine group had sig. lower mortality at 1y (31% vs. 72% with placebo) and 2y (56% vs. 79%) (Chest 125:1198, 2004--AFP)
  2. Warfarin anticoagulation
    1. In a nonrandomized, 3y prospective study of 6,800 pts with LVEF of 35% of less enrolled in a randomized trial of ACEIs, overall mortality no diff. between users & nonusers of warfarin, but users had lower mean LVEF and worse mean NYHA functional class and used more antiarrhythmics. Afger adjusting for these & other factors, use of warfarin was ass'd with RR of death of 0.76 during the study period. No different when pts w/o AFib were excluded. (JACC 31:749, 1998--JW)
  1. Etanercept (soluble TNF receptor that inactivates TNF)
    1. Improved sx, exercise tolerance, and LVEF in one small randomized trial of pts with class III CHF (Circ. 99:3224, 1999--JW)
    2. However, in a randomized trial involving about 1,500 pt with heart failure, didn't improve sx or survival (FP News 9/15/2005, no reference given)
  1. Recombinant human growth hormone
    1. Seems to have an inotropic effect
    2. Improves ventricular function in pts with idiopathic dilated cardiomyopathy and mild CHF (NEJM 334:809, 1996--UW Pharm letter)
    3. Improved functional class and cardiac output in an uncontrolled trial of 7 pts with ischemic cardiomyopathy and average LVEF of 31% (Circ. 99:18, 1999-JW)
  1. Surgical treatment
    1. "Batista operaton"--for severe dilated cardiomyopathy; resection of a large wedge of myocardium to reduce size of LV. Promising results (in terms of LVEF) in uncontrolled trials in pts with severe HF (Circ. 97:839, 1998--JW)
    2. Surgical ventricular restoration
      1. Reduces LV volume and restores to some degree the elliptical shape of the LV
      2. Promising results in pts with heart failure s/p MI in uncontrolled trials (e.g. J. Am. Coll. Cardiol. 44:1439, 2004--abst)
  1. Endothelin receptor antagonists
    1. Bosentan (a nonselective endothelin A & B antagonist) didn't reduce sx or mortality in one placebo-controlled trial (Int. J. Cardiol. 85:195, 2002--JW)
    2. Darusentan (a selective endothelin A antagonist) x 6mos, c/w placebo in a randomized trial in 642 pts with NYHA class II-IV heart failure, there were no sig. .diffs in LV end-systolic volume or incidence of worsening HF or death ("EARTH" Trial; Lancet 364:347, 2004--JW)
    3. In a study in 1,435 pts with acute left ventricular failure and dyspnea (but no acute MI), randomized to tezosentan (an endothelin receptor antagonist) vs. placebo x 24-72h, there was no sig. diff. in dyspnea, length of hospital stay, or 30d or 6mo mortality ("VERITAS" Trial; JAMA 298:2009, 2007--JW)
  2. Treatments to lower heart rate
    1. Rapid heart rate in pts with HF is associated with adverse outcomes

    2. In a study in 6,505 adults with symptomatic HF, LVEF 35% or less, and baseline HR 70 or greater randomized to ivabradine (a sinus-node inhibitor) vs. placebo, over median 22.9 f/u, incidence of (cardiovascular death or hospitalization fo HR) was sig. lower in active-treatment group (24% vs. 29%); diff. was not sig. in subgroup of pts with HR 70-77. ("SHIFT" Trial; Lancet 376:875, 2010-JW)

  3. Coenzyme Q--no effect on hemodynamic parameters or sx in one study in pts with CHF and low LVEF (JACC 33:1549, 1999--JW)
  4. Hormone Replacement Therapy ass'd with reduced risk of death in patients with HF--Click on link for detals
  5. Hawthorn (Crataegus spp.)
    1. Associated with improvements in exercise capacity c/w placebo in pts with HF per a meta-analysis of 13 randomized trials (Am. J. Med. 114:665, 2003--AFP)
  1. Plasmapheresis-Some improvement in sx in anectodal cases as of 2005 (FP News 9/15/2005-no citation)
  2. IV Immune Globulin-Some improvement in uncontrolled studies as of 0205 (FP News 9/15/2005-no citation)
  3. Iron
    1. In a study in 459 pts with systolic HF (NYHA class II-III) and iron deficiency (half had normal baseline Hb levels) randomized to ferric carboxymaltose vs. placebo IV x 24wks, iron recipients had sig. greater likelihood of clinical improvement and improved exercise tolerance ("FAIR-HF" Trial; NEJM 361:2436, 2009-JW)
  4. Left-Ventricular Assist Devices
    1. In a randomized trial in 129 NYHA Class IV pts, implantable LVAD vs. optimized medical management was ass'd with sig. higher 1y survival (52% vs. 25%) (NEJM 345:1435, 2001--JW)
  1. Cardiac transplantation-If otherwise favorable prognosis and end-stage heart failure despite use of all appropriate treatments
  1. Cardiac resynchronization through biventricular pacing
    1. Uses atrial-synchronized pacing of both left and right ventricles, theoretically restoring electrical synchrony between the left and right ventricles and, it is intended, increasing ventricular function, particularly in patients with intraventricular conduction delay
    2. Improves outcomes in patients with HF with low LVEF (particularly at NYHA class III-IV) with  prolonged QRS duration
    3. Clinical trials
      1. 453 pts with chronic NYHA Class III or IV HF and QRS duration > 130ms randomized to biventricular pacing vs. no pacing x 6mos.  At 6mo f/u, pacing group had sig. better exercise tolerance, quality of life, LVEF, and incidence of hospitalization for worsening heart failure than control group; no sig. diff. in mortality ("MIRACLE" study, NEJM 346:1845, 2002--JW)
      2. In a study of 1,520 pts with chronic HF (mean LVEF 21%) and prolonged QRS duration randomized  to "optimal" medical therapy alone, medical therapy + cardiac resynchronization, or medical therapy + cardiac resynchronization + ICD, both groups that had the resynchronization had sig. lower 1y incidence of death or hospitalization (56% in both groups) than the medical-therapy-only group (68%). ("COMPANION" trial; NEJM 350:2140, 2004--JW)
      3. 369 pts with NYHA class III-IV heart failure, LVEF < 35%, and QRS duration > 130ms, all with ICDs, randomized to resynchronization vs. no resynchronization.  At 6mos, resynchronization group had sig. greater improvement in median quality of life scores and NYHA functional class but no sig. diff. in overall mortality ("MIRACL ICD" Trial; JAMA 289:2685, 2003--abst)
      4. In a study in 813 pts with NYHA III-IV heart failure, LVEF < 36%, and evidence of cardiac dyssynchrony (e.g. QRS > 150msec) randomized to implantation of a resynchronization device + medical therapy vs. medical therapy alone, over mean 29mo f/u, incidence of (death or unplanned hospitalization for a cardiac event) was 39% in resynchronization group vs. 55% in control group (sig.) ; all-cause mortality was 20% vs. 30% (sig.)(Cardiac Resynchronisation Heart Failure Study ("CARE-HF"), Reported by John Cleland at an ACC meeting; reported in Family Practice News, 7/2005)
      5. In a study in 1,820 pts with Class I-II HF, LVEF < 31%, and QRS durations of > 129ms randomized to (resynchronization therapy vs. no resynchronization therapy) along with an implantable defibrillator that all were receiving.  Over mean 2.4y f/u, incidence of (acute HF or death) was sig. lower in the resynchronization group (17.2% vs. 25.3%) ("MADIT-CRT" trial; NEJM e-pub, 9/1/2009-10.1056/NEJMoa0906431)
      6. In a study in 610 pts with NYHA class I or II HF and LVEF < 41% who all had cardiac resynchronization devices implanted and were randomized to having the devices set on or off, there was no sig. diff. in incidence of HF worsening (based on a clinical score) but pts with the device turned on had sig. greater improvement of LVEF (J. Am. Coll. Cardiol. 52:1834, 2008-JW)
      7. In a meta-analysis of 4 randomized trials (with 3-6mo f/u) with total 1634 pts with heart failure & LV dysfunction randomized to cardiac resynchronization vs. placebo was ass'd with sig. lower risk of death from progressive HF (1.7% vs. 3.5%, OR 0.49) and hospitalization for HC (OR 0.71) and nonsig. reduction in all-cause mortality (OR 0.77). (JAMA 289:730, 2003--abst)
      8. In a meta-analysis of data from nine randomized trials involving 3,216 pts (mostly with NYHA class III-IV HF), all-cause mortality with resynchronization was sig. lower than medical therapy alone (RR 0.8) and sig. higher likelihood of functional status improving by at least one class (RR 1.6) (Ann. Int. Med. 141:381, 2004--JW)
      9. In a meta-analysis of  14 randomized trials in pts with LV systolic dysfunction (LVEF 21-30%) and prolonged QRS duration (91% of the pts had NYHA class III-IV HF despite optimal pharmacotherapy), CRT was associated with a sig. improvements in LVEF (mean absolute improvement 3%), quality of life, and and functional status, and sig. decreases in incidence of hospitalization and all-cause mortality. (JAMA 297:2502, 2007--abst)
  2. Implantable Cardioverter-Defibrillators
    1. Associated with reduced mortality in patients with heart failure after Myocardial Infarction (click link for details)
    2. ICDs were associated with nonsig. lower all-cause mortality (RR 0.65) and sig. lower incidence of arrhythmia-related sudden death but no diff. in incidence of death from heart failure over mean 29mo f/u in a randomized trial in 458 patients with NYHA class I-III nonischemic dilated cardiomyopathy with LVEF < 36%, all of whom also received "standard" medical therapy.  All-cause mortality was sig. lower (RR 0.37) in subgroup of pts with class III heart failure ("DEFINITE" trial; NEJM 350:2151, 2004--JW)
    3. In a meta-analysis of 5 randomized trial of ICDs vs. medical therapy alone in patients with low LVEF but no h/o ischemic coronary disease, ICDs were ass'd with sig. reduced all-cause mortality (RR 0.69) (JAMA 292:2874, 2004--abst)
    4. ICDs vs. Amiodarone or placebo
      1. In a study in 2,521 pts with NYHA class II-III heart failure and LVEF 35% randomized to amiodarone, placebo, or placebo + ICD (all also received "conventional" HF therapy), over median 46mo f/u, ICD group had sig. lower all-cause mortality than amiodarone or placebo groups (22%, 28%, and 29% respectively) ("Sudden Cardiac Death in Heart Failure" Trial ("SCD-HeFT"); NEJM 352:225, 2005-JW)
  3. Enhanced External Counterpulsation (EECP)
    1. Usually used for refractory angina (see link above)
    2. In a study in 187 pts with optimally-treated NYHA class II-III heart failure and LVEF < 35% randomized to EECP (35 sessions, each 1h, over 8wks) vs. medial tx alone, at 6mos, incidence of improvement in exercise time and NYHA class was sig. greater in the EECP group (35% vs. 25% and 31% vs. 14%, respectively).  No sig. diff. in quality of life, however.  ("Prospective Evaluation of Enhanced External Counterpulsation in Congestive Heart Failure" ("PEECH") J. Am. Coll. Cardiol. 48:1198, 2006--JW)
  1. Management of CHF with nl LVEF
  1. Prevalence nll LVEF among pts with CHF 35-45% in various studies
  2. Associated, in 2 different prospective studies, with similar mortality to pts with HF and reduced LV at 1y (NEJM 355:260, 2006--JW), though at 5y there was a slight but sig. reduced mortality (65% vs. 68%, NEJM 355: 251, 2006--JW)
  3. Treatment
    1. ACEIs
      1. Enalapril improved NYHA class, LV mass, and LVEF in 21 elderly pts with class III CHF, nl LVEF, prior MI, already on furosemide (Am.J.Cardiol. 71:602, 1993)
      2. In a study in 850 pts > 70yo with heart failure and evidence of diastolic dysfunction on echocardiography randomized to perindopril (up to 4mg/d) vs. placebo, 1y incidence of (death or unplanned hospitalization for heart failure), the primary outcome, was not sig. diff. in the two groups, though perindopril had sig. greater improvements in NYHA class and 6-minute walking distance at 1y  ("PEP-CHF" trial; Eur. Heart J. 27:2338, 2006--JW)
    2. Digoxin
      1. In a study in pts with HF and LVEF > 45% randomized to dig (adjusted by study personnel, from 0.125mg/d to 0.5mg/d) vs. placebo, over mean 3y f/u, there was no sig. diff. between the groups in incidence of (hospitalization for or death from HF) or all-cause mortality ("Digitalis Investigation Group" ("DIG") Trial; 114:397, 2006--JW)
    3. Beta-blockers
      1. In a study in 2752 pts > 70yo with heart failure and LVEF > 35% (82% were on ACEIs) randomized to nebivolol vs. placebo.  This was actually a subgroup analysis of a larger study tha talso included pts with low LVEF.  This study found a similar significant treatment effect from nebivolol, i.e. reduction in (death or cardiovascular horpialization) ("Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure" ("SENIORS") trial; J. Am. Coll. Cardiol. 53:2150, 2009-JW)
      2. Japanese Diastolic Heart Failure study-800 pts with normal LV systolic function, looking at effects of carvedilol; ongoing as of 2009.
  1. VHEfT 1 study showed improvement with isosorbide dinitrate + hydralazine
  2. Other appropriate Tx include Ca-blockers (1 study) & diuretics
  3. Dig may increase mortality in pts with CHF & normal LVEF
  4. Prevention of sudden cardiac death in pts with CHF and LVEF
  1. 704 pts with known CAD and LVEF < 40%, h/o asymptomatic nonsustained VT who, on electrophysiologic testing, had inducible sustained VT randomized to EP-guided antiarrhythmic drug therapy (or AICD if no drug therapy worked; 50% of this group got AICD) vs. no antiarrhythmic therapy. Over median f/u of 39mos, sig. less cardiac arrest or arrhythmic death in tx group (25% vs. 32%)--benefit confined to those who had AICD's (NEJM 341:1882, 1999--JW)

VI. Treatment of acute decompensated CHF

  1. Mechanical Ventilation if indicated
    1. Noninvasive posiitve-pressure ventilation  (NIPPV)
      1. Can be delivered through CPAP or bilevel (inspiratory and expiratory) ventilation
      2. May reduce risk for invasive mechanical ventilation compared with standard treatment (including face-mask oxygen)
      3. In a meta-analysis of 23 randomized trials of NIPPV vs. standard care, NIPPV through CPAP was associated with sig. lower incidence of in-hospital mortality (RR 0.59) c/w standard care though the same was not true of bilevel mechanical ventilation (Lancet 367:1155, 2006--JW)
  2. IV vasodilators, e.g. Nitroglycerin or Nitroprusside
    1. Reduce preload & afterload
    2. Lower pulmonary capillary wedge pressure & relieve symptoms
    3. May cause hypotension
  3. Loop diuretics, e.g. furosemide
  4. IV Nesiritide (Natrecor), recombinant B-type natriuretic peptide
    1. A vasodilatory hormone secreted by the heart in response to heart failure
    2. Associated with better symptom control and lowering of PCWP than IV Nitroglycerin in a randomized trial in 489 pts with decompensated CHF (Vasodilation in the Management of Acute Congestive Heart Failure "VMAC" trial; JAMA 287:1531, 2002--abst)
    3. However, a meta-analysis of three randomized trials found that nesiritide was associated with nonsig. increased 30d mortality vs. placebo (7.2 vs. 4.0%) (JAMA 293:1900, 2005--AFP)
    4. Can cause hypotension, nausea, vomiting, and confusion
  5. Inotropic agents, e.g. IV Milrinone or Dobutamine
    1. In a randomized trial in 951 pts with acute exacerbation of CHF randomized to IV milrinone x 48h vs. placebo, there was no sig. diff. in duration of hospitalization, in-hospital mortality, or 60d mortality (JAMA 287:1541, 2002--abst)
  6. Vasopressin antagonists
    1. In a randomized trial in 319 pts with LVEF < 40% hospitalized for heart failure and persistent signs/sx of systemic congestion despite standard therapy, tolvaptan (a vasopressin antagonist) 30-90mg/d PO vs. placebo, x 60d, was ass'd with no sig. difference in incidence of (death, hospitalization, or unscheduled visits for heart failure) at 60d (JAMA 291:1963, 2004--abst)
  7. Relaxin
    1. A naturally-occurring vasodylator
    2. Administered by continuous IV infusion
    3. Associated with symptomatic improvement in acute HF in early trials
  8. Peripheral ultrafiltration of the blood
    1. A way to remove excess water without using diuretics
    2. In a study in 40 hospitalized patients with heart failure and volume overload randomized to ultrafiltration x 8h vs. no ultrafiltration (all pts received "usual care"), the ultrafiltration group had sig. greater mean fluid removal at 24h ("RAPID-CHF" Trial; J. Am. Coll. Cardiol. 46:2047, 2005--JW)
    3. In a study in 200 patients with acute decompensated heart failure and volume overload randomized to peripheral ultrafiltration vs. high-dose IV loop diuretics, ultrafiltration pts had sig. greater fluid loss and sig. fewer 90d incidence of rehospitalization (18% vs. 32% or urgent ED or office visits (21% vs. 44%). However, no sig. diff. in dyspnea scores at 48h ("IV Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure" ("UNLOAD") Trial; J. Am. Coll. Cardiol. 49:675, 2007--JW)