TABLE 1.

Summary of CHF studies by standard medical therapy

Study	Study Design	Study Population	Medication	Outcome	Tolerability	Efficacy	Adverse Drug Events	Comments
Beta Blockers
Baxter et al. (2002)	Observational Study Mean follow-up of 13 weeks	N=51 Mean age 78 years Systolic dysfunction	Bisoprolol Mean dose 7.6 mg/day	Tolerability	69% (35/51) patients	N/A	Symptomatic hypotension, hypotension, fatigue, GI disturbance, worsening CHF, bronchospasms, rash, insomnia	Improved GHQ and HAD scores No differences in Guyatt CHF, CMSS, 6-minute walk test
Sin et al. (2002)	Population-based Cohort Study Median follow-up 21 months	N=11,942 Mean age 79 years, Charlson score >2 Systolic dysfunction	Beta blockers Metoprolol	Morbidity Mortality	N/A	Reductions in all cause mortality (HR=0.72), mortality due to heart failure (HR=0.65), hospitalizations for heart failure (HR=0.82)	N/A
Witham et al. (2004)	Retrospective Study Heart failure clinic	N=226 Mean age 73.3 years Systolic dysfunction	Beta blockers Carvedilol > Bisoprolol > Atenolol > Metoprolol, Sotalol	Tolerability	69.7% Age >75 80% Age <75	N/A	Breathlessness, fatigue, bradycardia, light headedness, dizziness, hypotension	Predictors of tolerability included NYHA status and LV function via univariate analysis
Lawless et al. (2005)	Observational study No follow-up	N=360 Mean age 75.5 vs. 52.7 years Systolic dysfunction	Carvedilol	Tolerability	84.7% Age >70 79.9% Age <70	N/A	Dyspnea and weakness (age >70), hypotension, bradycardia, heart block, worsening heart failure, syncope, dizziness, gastrointestinal symptoms
Cioffiet al. (2005)	Observational Study Italian heart failure units 1-year follow-up	N=240 Mean age 76.6 years Systolic dysfunction Chronic atrial fibrillation	Carvedilol	Tolerability	87.9% (29/33) Stable sinus rhythm 93.1% (95/102) Chronic atrial fibrillation	N/A	Worsening heart failure, bradycardia, bronchospasms, ventricular arrhythmias
Flather et al. (2005) SENIORS Study	Randomized Controlled Trial Mean follow-up of 21 months	N=2128 Mean Age 76 years Systolic and Diastolic Dysfunction	Nebivolol Mean dose 7.7 mg/daily	Composite all cause mortality and cardiovascular hospital admission	N/A	31.1% (332/1067) vs. 35.3% (375/1061) All cause Mortality and cardiovascular hospital admission; HR 0.86; 95 CI 0.74–0.99	Bradycardia, decreased angina and unstable angina	Benefits appears after 6 months of treatment
Krum et al. (2006) COLA II	Observational Study 6-month follow-up	N=1030 Systolic dysfunction	Carvedilol Mean dose 31.2 mg/day, although varied with age, with progressive diminution in dose with advancing age	Tolerability	80% Overall, with age 70–75 years 84.3%, 76–80 years 76.8%, and >80 years 76.8% Significant diminution of tolerability with advanced age and NYHA class (62.7% NYHA IV)	Improvements in NYHA class, LVEF	Worsening heart failure, symptomatic hypotension, bradycardia, amiodarone use	Subgroup analysis according to age Predictors of tolerability included advanced age, low diastolic BP, LVEF, obstructive airways, diabetes
Sindaco et al. (2007)	Observational Study Specialized heart failure clinics 1-year follow-up	N=252 Mean age 76.5 years Systolic dysfunction	Carvedilol Mean dose 23.5 mg/day	Safety Tolerability, Efficacy in diabetics and non diabetics	93.7% Diabetic 92.2% Nondiabetic	Improvements in NYHA Class, MR severity LVEF (more in non-diabetics) No differences in incidence of hospitalizations or mortality	Bradycardia, acute bronchospasm, worsening functional status (nondiabetics)	No metabolic difference in FBS, HbA1C, Creatinine
ACE Inhibitors
Schwartz et al. (1991)	Observational Study Hospitalization	N=20 Mean age 76 years Severe CHF	Enalapril 20 mg/Day Furosemide maintenance	Safety Creatinine	16/20 No effect on kidney function 4/20 had rapid renal dysfunction	N/A	N/A
Mets et al. (1992)	Observational Study 3-hour follow-up	N=97 Mean age 83.7 years Unknown dysfunction	Captopril 6.25 mg	Hypotensive effect of first dose 6.25 mg Captopril	54% had a SBP fall of at least 15% BP fall generally fell within 60 mins Greatest BP drop took place within 150 mins	N/A	Transient agitation and dizziness
Haffner et al. (1995)	Double-blind parallel group comparison, multicentre 3-and 6-month follow-up	N=80 Captopril mean age 77 years Enalapril mean age 75 years Unknown dysfunction	Captopril 12.5 mg BID Enalapril 2.5 mg BID	Hemodynamics: BP, HR Renal Function: GFR	No differences on GFR, although more patients given Captopril had improvement in GFR at 3 and 6 months	N/A	Enalapril: symptomatic hypotension, gastrointestinal symptoms Captopril
Gambassi et al. (2000)	Retrospective Study SAGE database 1-year follow-up	N=19,492 Mean age ACEI 83.9 years Mean age Digoxin 85.4 years	ACEI vs. Digoxin	1-year mortality, morbidity and physical function	N/A	Overall mortality rate ACEI was more than 10% less than Digoxin users Trend towards reduced hospitalizations Rate of functional decline was 25%–30% reduced among ACEI users (RR0.74; 95% CI 0.69–0.80)		Used 5-item 6-level activities of daily living (ADL) Scale
Ahmed et al. (2003)	Retrospective Study Medicare beneficiaries	N=1090 Mean age 79 years Unknown Dysfunction	ACEI	Association of LVEF evaluation and ACEI with 3-year survival	N/A	Both left ventricular function evaluation (HR 0.83; 95% CI 0.71–0.98) and ACE inhibitor use (HR 0.77; 95% CI 0.66–0.91) were associated with a lower 3-year mortality rate	N/A
Zi et al. (2003)	Double-blind randomized study, single center 6-month follow-up	N=74 Mean age 78 years Diastolic Dysfunction	Quinapril	Functional status	Significant mean 6-minute walk distance increased in Quinapril group, but not significant between groups No difference in quality of life scores	N/A	Worsening heart failure, chest infection, hypotension, cough, dizziness, tiredness, rehospitalization, cough
Ahmed et al. (2005)	Case Control Study 11 Alabama hospitals 4-year follow-up	N=295 Mean age 78.5 years Systolic dysfunction	ACEI	4-year survival using propensity score methods	N/A	Significant 2-fold increase in the risk of 4-year mortality (HR 2.33) if not on ACEI Non significant 23% higher risk of 4-year mortality if on ACEI	N/A
Trewet et al. (2007)	Retrospective Cohort Study Kansas Medicaid beneficiaries	N=470 Mean age 81	ACEI	All Cause Hospitalization	N/A	N/A	N/A	Hospitalizations were not decreased by ACEI use
Spironolactone
Butler et al. (2002)	Observational Study 28-day follow-up	N=18 Mean age 80.6 years Unknown dysfunction	Spironolactone 25 mg/day	Hyperkalemia (K>5 mmol/l)	6/9 RI vs. 1/9 no RI developed hyperkalemia	N/A	Compared between those with renal impairment (RI) Cr >150 mmol/l vs. no RI
Juurlink et al. (2004)	Population-based, Time Series Study Health care databases	N=12,422 Mean age 78.6 years Unknown dysfunction	Spironolactone 25 mg/day	Hyperkalemia requiring hospitalization	2.4 ⇢11 per 1000 rate of hospitalization for hyperkalemia 0.3 ⇢2.0 per 1000 mortality from hyperkalemia	N/A
Dinsdale et al. (2005)	Retrospective Study	N=66 Mean age 85 years Systolic and Diastolic Dysfunction	Spironolactone 25 mg/day	Hyperkalemia >6 mmol/l Renal Failure >354 mmol/l	30/64 Hyperkalemia 11% Renal Failure	N/A	Hypotension/postural hypotension	Predictors of adverse drug events included intercurrent illness
Furosemide
Van Kraaig et al. (1999)	Prospective Observational	N=20 Mean Age 75 Diastolic Heart Failure	Withdrawl of Furosemide	Post Prandial Hypotension, Stroke Volume	11/20 Patients safely discontinued Furosemide Decreased in postprandial SBP by 14 mmHg	N/A	Orthostatic postprandial hypotension
Digoxin
Carosella et al. (1996) GIFA	Observational Study, multicenter 3 annual surveys Hospitalized	N=20,047 Mean age 75 years Unknown dysfunction	Digoxin Mean dose 0.17 mg/day	Adverse Drug Reactions	2.1% of patients experienced ADRs to Digoxin 4 events mild ADRs 24 events severe ADRs	N/A	Cardiac arrhythmias more common than gastrointestinal symptoms	Predictors of ADR include advance age (>80 years), dose >0.25 mg, Cr >120 mmol/l, >6 drugs taken prior to admission, other medications (Amiodarone, Propafenone, Quinidine, Verapamil)
Misiaszek et al. (2005)	Cross-sectional	Long-term Care Mean age 85	Digoxin	Prevalence of Digoxin Use Risk For Adverse Events	1/3 of LTC Residents with HF were on Digoxin 26% of those people were at increased risk of toxicity	N/A	Not measured
Combination of Medications
Heckman et al. (2004)	Cross-sectional	N=1223	ACE Inhibitors	Prevalence of HF Medications used to treat HF	HF prevalence was 20% ACEI were prescribed in 55% of residents Beta Blockers prescribed in 25% of residents	N/A	N/A	N/A
Jensen et al. (2008)	Cohort Specialzed HF Clinics	N=150	Beta Blockers, ACE Inhibitors, and Spironolactone	Adverse Event Predictors, Target Doses, Appropriate Prescription	N/A	N/A	N/A	Age, COPD, Renal Dysfunction, Diabetes, and Pulse Pressure had Negative prognosis