Evidence-based

medicine: The CHF

trials
Moises Auron MD
Department of Hospital Medicine
Cleveland Clinic Foundation

September 21, 2007.

 Objectives
 Recognize the evidence supporting
the current approach to Chronic
Heart Failure (CHF) treatment as an
important factor to decrease
mortality and improve survival.
 Review each of the most important
trials for pharmacologic therapy of
CHF.
 Review the current alternatives for
treatment of CHF in children.
 Epidemiology
 Prevalence ≈ 5 million Americans with chronic
heart failure; at age 40, lifetime risk of
developing HF is 20%

 Incidence 550,000 new cases/year

 Morbidity 1,099,000 hospital discharges (2004) –

rose from 399,000 (1979); Most frequent
cause of hospitalization in elderly

 Mortality Causes or contributes to 286,000

deaths/year

 Cost $33.2 billion (2007); $5,912 per

Medicare discharge (2001)
- AHA: Heart Disease and Stroke Statistics - 2007 Update.
Circulation. 2007; 115.
- Circulation 2004;109:2685–2691.
Cardiorenal Model of HF
(1940-1960)

Amer. J Cardiol 1993; 71: 3C-11C

 Cardiorenal Model of HF
(1940-1960)
 Diuretic
s
 Digitalis

Amer. J. Cardiol. 1993;71:3C-11C

Cardiocirculatory Model
of HF
(1960 – 1990)

Amer. J Cardiol 1993; 71: 3C-11C

 Cardiocirculatory Model
of HF
(1960 – 1990)
 Vasodilators
 V-HeFT 1 (Hydralazine + Nitrate)
 Inotropic agents

Amer. J. Cardiol. 1993;71:3C-11C

 Initial insights:
Vasodilators in Heart
Failure
 Rationale for use of organic nitrates
and hydralazine in combination:
complementary "nitroprusside-like"
hemodynamic effect
 Predominant venodilatory action of
organic nitrates
 Arterial-dilatory effect of hydralazine.

 This combination leads to a significant

improvement in cardiac function, with a
concomitant reduction in right
Am J Cardiol. and left
2005 Oct
ventricular filling10;96(7B):37i-43i.
pressures and
 VHeFT-I (Vasodilator-Heart Failure
Trial)
African-american White
patients patients

Hydralazine (300 mg) + Isosorbide dinitrate (160 mg)

vs. Prazosin (20 mg)
vs. Placebo

N = 642 (male) – on Digoxin and diuretics

NEJM. 1986 Jun 12;314(24):1547-52
J Card Fail. 1999; 5(3):178-87
VHeFT-II (Vasodilator-Heart Failure
Trial)
 804 men
 Hydralazine (300 mg) + Isosorbide
dinitrate (160 mg) (ISDN-H) vs.
Enalapril (20 mg).
 Decrease in mortality after 2 years
 Enalapril group (18%) vs. ISDN-H group
(25%)
 28% reduction in mortality. (P=0.016)
 African-American population benefit more
N Engl J Med. 1991;325:303-
from ISDN-H 310.
VHeFT-II (Vasodilator-Heart Failure
Trial)

J Card Fail. 1999; 5(3):178-87

 Vasodilators in Heart
Failure
 V-HeFT I showed improvements in LVEF, exercise
tolerance, and survival in patients treated with
isosorbide dinitrate and hydralzaine compared
with placebo.
 Retrospective analysis of V-HeFT I and V-HeFT II
showed that the benefit of this combination was
seen mainly in African Americans.
 This observation led to the African American
Heart Failure Trial (A-HeFT).
 Concomitant use of hydralazine with a nitrate,
both in an animal model and in patients with CHF,
has been shown to prevent the development of
nitrate tolerance and Am maintain the Oct
J Cardiol. 2005 favorable
hemodynamic effect of nitrates.
10;96(7B):37i-43i.
Vasodilators in Heart Failure:
Hydralazine and Isosorbide

NEJM. 2004; 351(20): 2112-

AHeF-T (African-American
Heart Failure Trial)

NEJM 2004; 351 (20): 2049-57

-Am J Cardiol 2005; 96 (suppl): 44i– 48i
 AHeF-T (African-American
Heart Failure Trial)
 Compared with V-HeFT
 H+Iadded to conventional CHF
treatment.
 Post-Hoc analysis
 Beta-blocker increases survival in
AA.
Congest H Fail. 2004;
10(1):34-7
Neurohormonal Model of
HF
(1980 – present)
 Heart failure developed and
progressed:
 Endogenous neurohormonal
systems activated by the initial
injury to the heart
 Deleterious effects on the heart and
circulation
 Independent of the hemodynamic
Amer J Cardiol 1993; 71: 3C-11C
status of the patient.
Neurohumoral modification
in HF
 Renin-angiotensin-  Natriuretic

aldosterone system peptides

Sympathetic nervous Cytokines


 Endothelin
system
 Tumor necrosis
 Norepinephrine factor
 Vasodilators  Interleukins
 Bradykinin  Vasopressin
 Nitric oxide  Matrix
 Prostaglandins metalloproteinases
NEJM. 2003; 348 (20): 2007-
18.
NEJM. 1999; 341(8): 577-585.
From: Shrier, R. U. Colorado.
Neurohormonal Model of Heart Failure

Shah M et al. Rev Cardiovasc Med. 2001; 2 (suppl 2): S2–S6

Renin – Angiotensin –
Aldosterone System

Modified from Swedberg K. ESC –Heart Failure

Lisbon 2005.
Catecholamines in Heart
Failure

Am J Cardiol. 1984; 54:

783-6
 Relationship between
plasma NE and survival in
Heart Failure

NEJM. 1984: 311: 819-

823.
 Cathecolamines
 Stimulation of RAAS  further increase
in sympathetic activation.
 Enhanced sodium and water
retention, potassium loss, peripheral
vasoconstriction, and oxidative tissue
stress.

NEJM. 1999; 341(8): 577-585.

Congest Heart Fail. 2002 Sep-
Oct;8(5):262-9;
 Cathecolamines
 Circulating catecholamines adversely
affect cardiac structure and function.
 Desensitization (via G-protein
uncoupling) and down-regulation of β 1-
adrenergic receptors
 Myocardial ischemia  Enhanced
cardiomyocyte necrosis
 Apoptosis.
 Induce and potentiate cardiac
arrhythmias mediated predominantly
through β2-adrenergic receptor
stimulation.
 Cardiac remodeling
 Angiotensin II, aldosterone, and
catecholamines also function as growth
factors in paracrine fashion.
 Fibroblast activation and the induction
of myocyte hypertrophy.
 Increase in overall ventricular muscle
mass and fibrous tissue.
 Consequences of Neurohormonal
Activation
 Maladaptive hypertrophy  energy
starvation  necrosis
 Apoptosis
 Increased interstitial fibrosis
 Myocyte elongation  progressive
dilatation of the ventricle

CARDIAC REMODELING

Katz, AM. Heart Failure. Lippincott Williams &

Wilkins, 2000
Alterations in Myocyte Morphology with
Ventricular Dysfunction

Katz, AM. Heart Failure. Lippincott Williams &

Wilkins, 2000
NEJM. 2003; 348: 2007-18.
Cardiac hypertrophy

From: Tornoci L. Semmelweis U.

 CONSENSUS: Cooperative North
Scandinavian Enalapril Survival
Study

N = 253

Probability of death
NYHA IV on
diuretics and
digoxin
Enalapril 20 mg
BID vs Placebo

NEJM 1987; 316: 1429–35.

ACEI Trials

Adapted from Yan AT, et al. Ann Intern Med. 2005;

142: 132-145
 ACEI Trials
 CONSENSUS = Cooperative North Scandinavian
Enalapril Survival Study
 SOLV-D = Studies of Left Ventricular Dysfunction
 ATLAS = Assessment of Treatment with Lisinopril And
Survival Trial
 SAVE = Survival and Ventricular Enlargement
 AIRE = Acute Infarction Ramipril Efficacy
 TRACE = Trandolapril Cardiac Evaluation
- NEJM 1987; 316: 1429-35.
- Eur Heart J. 1999; 20(2):136-9.
- NEJM. 1991; 325: 293-302.
- NEJM. 1992; 327: 685-91.
- Circulation 1999 Dec 7; 100(23):2312-8.
- Eur Heart J 2000 Dec; 21(23):1967-78.
- NEJM. 1992;327:669-77.
- NEJM. 1995; 333: 1670-6.
- Lancet. 1993; 342: 821-8.
 ACE Inhibitors in HF
 Mortality ↓ 20%–25% (P< 0.001)
 Death plus hospitalization ↓ 30%–35%

HOWEVER…..

 ~ 50% will still die within 5 years

 30% may be rehospitalized for CHF
within three months
- JAMA. 1995;273:1450–1456
- AHA. 2001 Heart and Stroke Statistical Update. 20
- Am J Cardiol. 1999;83(Suppl 2A):1A–39A.
Sir James Black
 Nobel Prize 1988
 Discovery of Beta-
blockers
(Propranolol)
 Potential effects of β-
blockers in cardiac
remodeling
 ↓ Heart rate  Improvement in
 ↓ VO2 synthesis of
 Modulation of β- myocardial
receptors proteins
 Peripheral
 Protection from
vasodilation
catecholamine
 Decrease of heart
toxicity
 ↓ RAAS work
 Antioxidant action
 Anti-ischemic and
 Anti-inflammatory
anti-arrhythmic Eur Rev Med Pharmacol Sci. 2002; 6:
effect action
115-126.
 MERIT-HF (Metoprolol CR/XL
Randomized Intervention Trial in
CHF).
N = 3991
NYHA II-IV
34%
P=0.00
62

Lancet 1999; 353

(9169):2001-7.
 MERIT-HF (Metoprolol CR/XL
Randomized Intervention Trial
in CHF).
 Post-hoc analysis in NYHA IV (n=795)

Number of hospital days:

15 vs. 26

J Am Coll Cardiol. 2001;

38:932.
 COPERNICUS (Carvedilol
Prospective Randomized
Cumulative Survival)
N = 2289
NYHA III-IV

35% (P =
0.0014)

Carvedilol 25 mg BID vs. Placebo

NEJM 2001; 344(22): 1651-8.
 COMET (Carvedilol or
Metoprolol European
Trial)
Carvedilol 25 6%
mg BID vs. P=
Metoprolol 0.017
tartrate 50
mg BID

N = 3029
NYHA II-IV

Lancet 2003;
362(9377):7-13.
 Beta-Blockers: Trials
MERIT Metoprolol succinate 200 mg Qday All-cause Overall ↓ in
(12 mos) vs. placebo mortality mortality 34% (P =
0.0062)

CIBIS II Bisoprolol 10 mg/d vs. placebo All-cause Early termination; ↓

(16 mos) mortality in mortality 32%
(P< 0.001)

COPERNICUS Carvedilol 25 mg BID vs. placebo All-cause ↓ in overall

(10.4 mos) mortality mortality 35% (P =
0.0014). Not
worsening HF when
initiating Rx.
COMET Carvedilol 25 mg BID vs. Metoprolol All-cause Absolute risk ↓ 6%
(58 mos) tartrate 50 mg BID mortality favor carvedilol (P=
0.0017)

US Carvedilol 25 – 50 mg BID vs. placebo All cause Early termination. ↓

Carvedilol mortality, in mortality rate
(6 mos) exercise 38% (P < 0.001)
tolerance, QOL.
BEST Bucindolol 50 – 100 mg BID vs. All cause No difference (P=
(24 mos) placebo mortality 0.16)
Benefit in non-black
patients
Adapted from Yan AT, et al. Ann Intern Med. 2005;
142: 132-145
 Beta-Blockers: Trials
 MERIT-HF: Metoprolol CR/XL Randomized Intervention Trial in CHF
 CIBIS: Cardiac Insufficiency Bisoprolol Study
 COPERNICUS: Carvedilol Prospective Randomized Cumulative Survival
 COMET: Carvedilol or Metoprolol European Trial
 United States Carvedilol Heart Failure Study Group
 BEST: Beta-blocker Evaluation of Survival Trial (Bucindolol)
 CAPRICORN: Carvedilol Post-Infarct Survival Control in Left Ventricular
Dysfunction

Lancet 1999; 353 (9169):2001-7.

J Am Coll Cardiol. 2001; 38:932.
Lancet 1999 Jan 2;353(9146):9-13.
Am Heart J 2002 Feb;143(2):301-7.
Eur Heart J 2001 Jun; 22(12):1021-
31.
NEJM 2001; 344(22): 1651-8.
Circulation 2002; 106(17):2194-9.
Lancet 2003; 362(9377):7-13.
Circulation 1996; 94:2793-9.
Circulation 1996; 94:2800-6.
Circulation 1996; 94:2807-16.
NEJM 1996; 334:1349-55.
Lancet. 2001;357:1385-90.
NEJM 2001; 344(22):1659-67
 Not all Beta Blocker are the
Same!!!
 BEST Trial (Bucindolol)
 COMET Trial (Metoprolol Tartrate vs
Carvedilol)
 Atenolol - not proven in heart failure
 Labetalol – not proven in heart failure
 Metoprolol Tartrate – no trials showing
increased survival compared to
placebo
Treatment Strategies

Amer. J. Cardiol. 1993;71:3C-11C

Neurohormones in HF:
Aldosterone
 ↑ 20-fold in CHF
 Aldosterone
escape
phenomenon
 As well secretion
can be
independent of
[AT II]
 Extraadrenal
production
 Endothelial cells
NEJM. 1999; 341(8): 577-585.
 Vascular smooth
Int J Clin Pract. 2006
muscle in the heart
Jul;60(7):835-46.
NEJM. 2001
and Dec;
blood 345(23):
vessels
Neurohormones in HF:
Aldosterone

NEJM. 1999; 341(8): 577-585.

Int J Clin Pract. 2006
Jul;60(7):835-46.
NEJM. 2001 Dec; 345(23):
RALES (Randomized Aldactone®
Evaluation Study)
N = 1664
Class IV or
class III (EF <
35%) with hx.
< 6 mos of
class IV CHF

Spironolacton
e 25 mg/d vs.
placebo

34% (P =
0.001)

- Am J Cardiol 1996 Oct 15;

78(8):902-7.
- NEJM 1999; Sep 2;
341(10):709-17.
- NEJM 2003; Apr 3;
EPHESUS (Eplerenone In Heart
Failure Post Acute Myocardial
N= 6642
Infarction)
MI < 2 wk; EF < 40% with evidence of HF
and/or DM.
Eplerenone 50 mg/d vs. placebo

NEJM 2003; Apr 3;

348(14):1309-21.
Spironolactone in Heart Failure
 ACC/AHA guidelines - Spironolactone 25-
50 mg-day in:
 NYHA IV
 Creatinine < 2.5 mg/dL
 Serum potassium < 5 mEq/L.
 Endocrine side effects: gynecomastia,
breast pain, menstrual irregularities,
impotence, and decreased libido
 Non-selective binding to androgen and
progesterone receptors.

- Am J Cardiol 1996 Oct 15;

78(8):902-7.
- NEJM 1999; Sep 2;
 Neurohormones in HF:
Angiotensin II
 High mortality in CHF patients despite being on
ACEI and BB
 Potent vasoconstrictor and growth-stimulating
hormone
 May contribute to the impairment of left
ventricular function and the progression of heart
failure:
 increased impedance of left ventricular emptying
 adverse long-term structural effects on the heart and
vasculature
 activation of other neurohormones (NE, ET1,
aldosterone)
 Physiologically active levels in patient on ACEI
NEJM. 1999; 341(8): 577-585.
NEJM. 1999; 341(8): 577-585.
 Incomplete supression of ATII production
ACC/AHA Heart Failure Guidelines
 Intolerance to ACEI (cough due to increase in
2005.
 Angiotensin II Receptor
Blockage: Trials
ELITE II N = 3152 Losartan 50 mg/d All-cause mortality No superiority of
(18.5 Age > 60 vs. Captopril 50 one agent vs. other
mos) y/o mg TID. (P = 0.16)
NYHA II-IV
Val-HeFT EF
N =<5010
40% Valsartan 160 mg All-cause mortality; Similar mortality (P >
(23 mos) NYHA II-IV BID vs. Placebo mortality or cardiac 0.2)
EF < 40%; arrest or Absolute risk ↓3.3%
hospitalization for HF (P<0.002) in
LV
composite end-point.
dilatation
(Decreased
CHARM- N = 2548 Candesartan 32 CV death or Absolute
admissions)risk ↓ 4%
Added NYHA II-IV mg/d vs. placebo hospitalization for (P=0.011)
heart failure ↑ LVID ↓EF  ↑
(41 mos) EF < 40% Trend
Benefittoward lower all-
cause mortality (P=
On ACEI
0.086)
CHARM – N = 2028 Candesartan 32 CV death or Absolute risk ↓ 7%
Alternativ NYHA II-IV mg/d vs. placebo hospitalization for (P<0.001)
e EF < 40% heart failure Trend toward lower all-
(33.7 cause mortality (P=
Intolerance
mos) 0.11)
to ACEI

Adapted from Yan AT, et al. Ann Intern Med. 2005;

142: 132-145
 Angiotensin II Receptor
Blockage: Trials
 ELITE: Evaluation of Losartan in the
Elderly
 Val-HeFT: Valsartan heart failure trial
 CHARM: Candesartan in Heart Failure
Assessment of Reduction in Mortality
and Morbidity Lancet. 1997;349: 747-52.
Lancet. 2000;355: 1582-7.
NEJM 2001 Dec 6; 345(23):1667-75.
Circulation 2002 Nov 5; 106(19):2454-8.
J Am Coll Cardiol 2004 Jun 2;
43(11):2022-7.
Lancet 2003; Sep 6; 362(9386):759-66.
Lancet 2003; Sep 6; 362(9386):767-71.
Circulation 2004 Oct 12; 110(15):2180-3.
Summary of Major Therapeutic Options
for Systolic Heart Failure

2005 ACC/AHA
Guidelines.
Electrical consequences of
heart failure

www.HRSonline.org/professional_education/learning_cate
gories/articles
 Electrical therapy of
COMPANION CHF: Trials
N = 1520 1:2:2 ratio All-cause
mortality of
↓ composite
end-point 20%
(35 mo) NYHA III-IV -Medical Rx

EF < 35%, stable -Medical Rx + PM hospitalization (P= 0.015 and

0.011)
QRS=120 msec -Medical Rx +
Improvement in
PR>150 msec PM/ICD NYHA, 6 min.
walk distance,
CARE – HF N = 813 Medical Rx vs. BiV Time to death ↓ composite
and SBP. 29%
(29.4 mo) NYHA III-IV pacing (all-cause) or end-point
EF< 35% hospitalization (P< 0.001)
(CV) 33% ↓ mortality
Cardiac
(P <0.002)
dysynchrony
MADIT N = 156 Medical Rx vs. ICD All-cause ↑
↓ LVEF 7% at 18
overall
mortality mo
mortality 61%
(27 mo) NYHA I-III; prior MI
EF < 35%; (P= 0.009)
Documented VT;
MADIT II inducible
N = 1232 VT 3:2 ratio ICD vs. All-cause ↓ in overall
(20 mo) EF < 30%; Prior MI Medical Rx mortality mortality 28% (P
= 0.016)
SCD-HeFT N = 2521 1:1:1 Medical Rx + All-cause Amiodarone=pla
(45 mo) NYHA II-III placebo; Medical Rx mortality cebo
EF < 35% + amiodarone; ICD ↓ absolute
Medical Rx + ICD risk 7.2% in
mortality (P=
0.007)
Electrical therapy in CHF:
Trials
 COMPANION: Comparison of Medical Therapy,
Pacing, and Defibrillation in Heart Failure
 CARE-HF: Cardiac resynchronization in Heart
Failure
 SCD-HeFT: Sudden Cardiac Death in Heart Failure
Trial
 MADIT: Multicenter Automatic Defibrillator
Implantation Trial

NEJM 2004 May 20; 350(21):2140-50.

NEJM. 2005 Apr 14; 352(15):1539-49.
NEJM 2005 Jan 20; 352(3):225-37.
NEJM. 1996 Dec 26; 335 (26): 1933-40.
NEJM. 2002 Mar 21; 346(12):877-83.
JACC. 2004; 43(8): 1459-65
Stages of Heart Failure and Treatment
options

NEJM 2003; 348 (20):

2007-18.
 Other research
endeavors in CHF
 Stem cell transplantation
 Ultrafiltration (UNLOAD) - Completed
 Vasopressin antagonists
 Acute and Chronic Therapeutic Impact of Vasopressin 2
Antagonist in Congestive Heart Failure (ACTIV in CHF)
 SALT (Study of Ascending Levels of Tolvaptan in
Hyponatremia 1 and 2) - Completed
 EVEREST
 Thyroid hormone analog
 (3,5- diiodothyropropionic acid [DITPA])
 Endothelin receptors antagonists
 Neutral endopeptidase inhibitors
 Metalloproteinases inhibitors
Pediatr Cardiol. 2006 Sep-Oct; 27(5):
533-51.
 Vasopressin stimulation
Low cardiac output

Activation of the carotid sinus and aortic arch baroreceptor

↑ADH
V2 receptor (coll.tubule
1A receptor (vascular smooth muscle)

Thirst.

rease in systemic vascular resistance

crease Water retention

↓Na
Hyponatremia in HF

N = 203
Na > 137 = 373 d
Na < 137 = 164 d

Lee WH, Packer M. Circulation. 1986;

73(2): 257-267.
Vasopressin antagonists
 V1A receptor blockage  reduction
in SVR  afterload reduction 
improve myocardial fx
 V2 receptor blockage  increased
free water excretion  correction of
hyponatremia and volume overload

J Am Coll Cardiol 2005 Nov

Tolvaptan investigators

Circulation. 2003;107:2690-2696.
Tolvaptan investigators

Circulation. 2003;107:2690-2696.
 ACTIV Trial
N = 319
LVEF < 40% NYHA III-IV

- 1.6

- 2.8

JAMA. 2004;291:1963-1971
 EVEREST
 N= 4133 patients
 LVEF < 40 %
 Randomly assigned to tolvaptan (30 mg/day) vs.
placebo
 Minimum of 60 days.
 The primary end point was a composite score of
changes from baseline in patient-assessed global
clinical status
 and body weight at day 7 or discharge
 Secondary end points included patient-assessed
changes in dyspnea at day 1, global clinical
status at day 7 or discharge, body weight at days
1 and 7 or discharge, and peripheral edema at
day 7 or discharge for patients manifesting
 EVEREST
 EVEREST Clinical Status
 Weight loss -day 1- (1.7 - 1.8 vs. 1.0 kg
placebo) - P <0.001.
 Weight loss -day 7 or D/C- (3.3-3.8 vs. 2.7-2.8
kg placebo) - P <0.001.
 Dyspnea - improvement at day one (72-77% vs. 65-
71%placebo) – P <0.001.
 EVEREST Outcome
 Median follow up - 10 months - no difference in all
cause mortality or in a combined endpoint of
cardiovascular death or HF hospitalization.
 Baseline Na < 134 mEq/L  Tolvaptan ↑ Na at seven
days or D/C (5.5 vs. 1.9 mEq/L placebo)

JAMA. 2007 Mar 28;297(12):1319-31.

JAMA. 2007 Mar 28;297(12):1332-43.
 Nesiritide
 Decreases PCWP -6 to -10 mmHg vs 2 mmHg
placebo.
 Improved clinical status (60 and 67 % vs. 14 %
placebo).
 No difference when compared to intravenous
nitroglycerin.
 Pooled analysis 3 RCT (N = 862) comparing
nesiritide with noninotropic vasodilator therapy 
increase in 30-day mortality among patients
receiving nesiritide (7.2 vs. 4 %, P = 0.059).
 Less likely to provoke ventricular arrhythmias (vs.
dobutamine) N Engl J Med 2000 Jul 27;343(4):246-53
 Does not reduce the length JAMAof2002
stayMarcompared to
27;287(12):1531-40
dobutamine, but…. lowerAm readmission rate for
Heart J. 2006 Dec;152(6):1084-90
 Nesiritide
 Initial iv bolus of 2 mcg/kg, followed by a continuous
infusion of 0.01 mcg/kg/min
 Dose is increased if, after 3 to 24 hours, to target the
desired therapeutic response:
 increase in urine output
 symptomatic improvement
 reduction in cardiac filling pressures
 Infusion is usually increased by 0.005 mcg/kg/min,
preceded by a bolus of 1 mcg/kg, up to a maximum of 0.03
mcg/kg/min.
 If hypotension occurs, the infusion should be discontinued
and restarted when the blood pressure has stabilized, at a
30% lower dose without bolus.
 Continue iv diuretics
 ACE inhibitors can be given in combination with nesiritide –
if hypotension use ACEI rather
Clev than nesiritide
Clin J Med 2002
Mar;69(3):252-6
 Caveats
 Age
 Most trials include people 10 years
younger than in general population
 EF
 Little evidence for efficacy in patients
with near-normal EF
 Gender
 Few women have been included in trials

Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept

2006: 242-245
 Caveats
 Devices:
 Inclusion criteria
 EF < 35%
 QRS width > 120 ms.

 Actual EF in the population studied is <

25%
 Actual mean QRS is 150 ms.

Semin Cardiothorac Vasc Anesthesia. 10 (3); Sept

2006: 242-245
 Caveats
 Redefinition of the primary variable after
unblinding is considered unacceptable
 Post-hoc analysis does not have protection
against type I error
 Additional data-derived analyses on
endpoints other than the one defined
prospectively as the primary one, might be
useful in suggesting hypotheses for further
studies.
 the conclusions should not be considered in the
same manner as the principal hypothesis of
the study design.
Zanolla L. Eur J Heart Failure. 5 (2003): 717–
723.
 Thank you
 Dr. Shanti Gunawardena.
 Dr. Mark E. Dunlap.
 Dr. James C. Pile.
 Dr. David J. Mansour.
 Dr. Holly B. Perzy.