Statins and Heart FailureStatins and Heart Failure
Benjamin M. Scirica MD MPHBenjamin M. Scirica MD MPH
TIMI Study GroupTIMI Study Group
Brigham and Women’s HospitalBrigham and Women’s Hospital
Harvard Medical SchoolHarvard Medical School
Boston, MABoston, MA
TIMI Study Group: TIMI Study Group: Research grant support (significant) via BWH from Accumetrics, Amgen, Astra-Zeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly and Co, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck and Company, Merck-Schering Plough Joint Venture, Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, sanofi-aventis, Sanofi-Synthelabo, and Schering-Plough.
Dr. Scirica:Dr. Scirica: Honoraria for presentations (modest): sanofi-aventis and Pfizer
DisclosuresDisclosures
Statins in CVDStatins in CVD
Well proven benefit of statins in reducing CV Well proven benefit of statins in reducing CV eventsevents Primary Prevention – WOSCOPS, Primary Prevention – WOSCOPS,
AFCAPS/TexCAPs, ALLHATAFCAPS/TexCAPs, ALLHAT Secondary Prevention – 4S, CARESecondary Prevention – 4S, CARE
Intensive statin therapy may be superior to Intensive statin therapy may be superior to moderate statin therapymoderate statin therapy PROVE IT-TIMI 22, TNT, IDEAL, A2ZPROVE IT-TIMI 22, TNT, IDEAL, A2Z
Statins and heart failureStatins and heart failureUnanswered questionsUnanswered questions
Is low cholesterol associated with poor Is low cholesterol associated with poor outcomes in HF? outcomes in HF?
Could statins actually be detrimental?Could statins actually be detrimental?
Dose the dose of statins matter? (no Dose the dose of statins matter? (no effect in HF benefit in CARE, PROSPER, effect in HF benefit in CARE, PROSPER, ALLHAT, ASCOT)ALLHAT, ASCOT)
Statins and heart failureStatins and heart failureUnanswered questionsUnanswered questions
If statins are beneficial, is it due to If statins are beneficial, is it due to lipid lowering or “pleiotrophic” lipid lowering or “pleiotrophic” effects?effects?
Is the benefit similar in ischemic vs. Is the benefit similar in ischemic vs. non-ischmemic heart failure?non-ischmemic heart failure?
Who should be treated and is there a Who should be treated and is there a a “goal”?a “goal”?
Potential mechanisms of benefit and Potential mechanisms of benefit and harm in heart failureharm in heart failure
van der Harst et al, Card Research 2006
Statins and HFStatins and HFState of current evidenceState of current evidence
Several observational studies have shown Several observational studies have shown benefit with statin therapy benefit with statin therapy
Statin therapy improves LV EF compared to Statin therapy improves LV EF compared to placebo in pts with CHFplacebo in pts with CHF
Large randomized trials in ACS / CAD Large randomized trials in ACS / CAD suggest that intensive statin therapy may suggest that intensive statin therapy may improve HF, but few details are knownimprove HF, but few details are known ((TNT, TNT, IDEAL, A2ZIDEAL, A2Z))
Death and HF according to statin therapy – Death and HF according to statin therapy – Observational Study in 24,598 ptsObservational Study in 24,598 pts
0
5
10
15
20
25
30
35
Overall BaselineCHD
No BaselineCHD
Overall BaselineCHD
No BaselineCHD
Rat
e p
er 1
00 p
erso
n-y
ears
No Statin Statin
P<.001 for all comparisons
DEATH Hosp for HF
(24,598) (19,705) (4893) (24,598) (19,705) (4893)
Go et al, JAMA 2006Age and sex-adjusted
Death and HF according to statin therapy – Death and HF according to statin therapy – Observational Study in 24,598 ptsObservational Study in 24,598 pts
Go et al, JAMA 2006
Adjusted HR* (95% CI)Adjusted HR* (95% CI)
Intention-to-treatIntention-to-treat Time-varying-useTime-varying-use
All Cause All Cause MortalityMortality 0.760.76 (0.72-0.80)(0.72-0.80) 0.640.64 (0.60-0.68)(0.60-0.68)
Hosp for Hosp for HFHF 0.790.79 (0.74-0.85)(0.74-0.85) 0.750.75 (0.70-0.79(0.70-0.79
* Adjusted for age, sex, HTN, prior CVD, DM, non-CVD co-morbidities, concomitant meds, intensity of medical care, GFR and more…
Divergent results of statins in small Divergent results of statins in small prospective studies of pts with HFprospective studies of pts with HF
StudyStudy EndpointEndpoint
NodeNode
(n=63)(n=63)
%EF, TNF, %EF, TNF, BNPBNP
LaufsLaufs
(n=15)(n=15)TNF, PAI, cTnTNF, PAI, cTn
MozaffarianMozaffarian
(n=22)(n=22)
TNF-RI, CRP, TNF-RI, CRP, ET-1ET-1
SolaSola
(n=105)(n=105)
%EF, CRP, IL-%EF, CRP, IL-6, THN-RI6, THN-RI
StudyStudy EndpointEndpoint
Bleske Bleske
(n=15)(n=15)
Inflammatory Inflammatory markersmarkers
KrumKrum
(n=87)(n=87)
Inflammatory Inflammatory markers, %EFmarkers, %EF
Favor StatinFavor Statin
Kush, et al. J Card Fail 2006
No DifferenceNo Difference
Effect of 1-year of statin therapy on Effect of 1-year of statin therapy on LV dimension and functionLV dimension and function
0.37
0.31
0.33
0.25
0.27
0.29
0.31
0.33
0.35
0.37
0.39
0.41
0.43
Baseline 6 mon 12 mon
Atorva 20mg Placebo
30
40
50
60
70
1st Qtr 2nd Qtr
LV
ED
D (
mm
)
Atorva Placebo
Sola, et al. JACC 2006
Eje
ctio
n F
ract
ion
P=0.004
P=NSP=01
4,162 patients with an ACS < 10 days 4,162 patients with an ACS < 10 days
ASA + Standard Medical Therapy
Standard TherapyStandard Therapy(Pravastatin 40 mg)(Pravastatin 40 mg)
Duration: Mean 2 year follow-up
Primary Endpoint: Death, MI, UA, or StrokeSecondary Endpoint: Re-hospitalization for heart Failure
Primary Endpoint: Death, MI, UA, or StrokeSecondary Endpoint: Re-hospitalization for heart Failure
PROVE IT - TIMI 22: PROVE IT - TIMI 22: Study DesignStudy Design
2x2 Factorial: Gatifloxacin vs. placebo
Double-blindDouble-blind
Intensive TherapyIntensive Therapy(Atorvastatin 80 mg)(Atorvastatin 80 mg)
Cannon et al, AHJ 2004
Methods for HF analysisMethods for HF analysis
EndpointEndpoint – Hospitalization for new or – Hospitalization for new or worsening heart failure that occurred 30 days worsening heart failure that occurred 30 days after randomizationafter randomization
Mean follow-upMean follow-up 24 months 24 months
BNP BNP measured at baselinemeasured at baseline
Statistical AnalysisStatistical Analysis – – Kaplan-Meier estimates with HR comparing Kaplan-Meier estimates with HR comparing
pravastatin and atorvastatin pravastatin and atorvastatin
Scirica et al, JACC 2006;47:2326-31
Baseline CharacteristicsBaseline Characteristics
CharacteristicCharacteristic AtorvaAtorva PravaPrava P-valueP-value
AgeAge 58.158.1 58.358.3 NSNS
MaleMale 77.877.8 78.478.4 NSNS
DMDM 17.817.8 17.517.5 NSNS
Prior CHFPrior CHF 3.23.2 3.53.5 NSNS
Prior MIPrior MI 17.817.8 19.119.1 NSNS
STEMISTEMI 33.433.4 35.635.6 NSNS
RevascRevasc 69.169.1 68.768.7 NSNS
BNP (pg/ml)BNP (pg/ml) 3131 3232 NSNS
Scirica et al, JACC 2006;47:2326-31
0
1
2
3
4
30 180 365 540 720 900Days from Randomization
Atorvastatin 80mg
Pravastatin 40mg
No. at RiskPrava 2063 1930 1846 1785 866 342 Atorva 2099 1959 1869 1826 869 339
HR 0.55(0.35, 0.85)P=0.008
Ho
sp f
or
hea
rt f
ailu
re (
%)
Risk of heart failure and statin Risk of heart failure and statin therapytherapy
• Controlling for prior heart failure
HR 0.55 (0.35, 0.86) p=0.008 • Excluding all pts with MI/RI prior to heart failure
HR 0.47 (0.26, 0.86) p=0.015
• Including the first 30 days after randomization
HR 0.53 (0.35, 0.80) p=0.002
• Controlling for prior heart failure
HR 0.55 (0.35, 0.86) p=0.008 • Excluding all pts with MI/RI prior to heart failure
HR 0.47 (0.26, 0.86) p=0.015
• Including the first 30 days after randomization
HR 0.53 (0.35, 0.80) p=0.002
Scirica et al, JACC 06
Odds ratio
0.5 1 3.0
Study (n) Treatment Achieved LDL (mg/dl)
Odds ratio (95% CI)
TNT (10,001) Atorvastatin 8077
A to Z (4497) Simvastatin 8063
PROVE IT (4162) Atorvastatin 8062
IDEAL (8888) Atorvastatin 8081
Intensive statintherapy better
Moderate statintherapy better
Atorvastatin 10101
Simvastatin 2077
Pravastatin 4095
Simvastatin 20104
Intensive Moderate
0.74 (0.58,0.94)
0.72 (0.52,0.98)
0.54 (0.34,0.85)
0.80 (0.61,1.05)
0.73 (0.63,0.84), p<0.001 Overall (95% CI)
Meta-analysis of benefit of intensive Meta-analysis of benefit of intensive statin therapy trials on heart failurestatin therapy trials on heart failure
Scirica et al, JACC 2006;47:2326-31
Time (days)0 50 100 150 200 250 300
0
2
4
6
8
10
Mo
rtal
ity
(%)
Quartile 4
Quartile 2
Quartile 3
Quartile 1
B-type Natriuretic Peptide (BNP) and Mortality
deLemos et al. NEJM 2001; 345:1014-1021
Independent of age, Killip class,HR, BP, DM, anterior MIP < 0.001
Baseline BNP in patients with heart Baseline BNP in patients with heart failurefailure
58
31
0
10
20
30
40
50
60
70
CHF No CHF
BN
P (
pg/m
l)
41.2%
23.2%
0%
10%
20%
30%
40%
50%
CHF No CHF
P<0.001 P<0.001
Scirica et al, JACC 2006;47:2326-31
Baseline BNP (pg/ml) Pts Baseline BNP > 80
Baseline BNP and risk of heart Baseline BNP and risk of heart failurefailure
1.0 1.11.2
2.6
0
0.5
1
1.5
2
2.5
3
Q 1 Q 2 Q 3 Q 4
Adj
uste
d H
R
<15 pg/ml 16-32 pg/ml 33-65 pg/ml >65 pg/ml adjusted for age, sex, DM, HTN, BMI, Cr, index dx, and PCI during the index eventadjusted for age, sex, DM, HTN, BMI, Cr, index dx, and PCI during the index event
p=0.016
Scirica et al, JACC 2006;47:2326-31
0
2
4
6
8
30 200 400 600 800 900
Days from Randomization
Ho
spit
aliz
atio
n f
or
hea
rt f
ail
ure
(%
)
Risk of heart failure according to Risk of heart failure according to BNP and intensity of statin therapyBNP and intensity of statin therapy
4.7% Abs risk reduction
BNP <80 / Atorva(n=1482)
BNP <80 / Prava(n=1490)
BNP <80 / Atorva(n=1482)
BNP <80 / Prava(n=1490)
HR 0.59 (0.29, 1.1) p=0.099
BNP >80 / Prava(n=217)
BNP >80 / Atorva(n=215)
BNP >80 / Prava(n=217)
BNP >80 / Atorva(n=215)
BNP >80 / Prava(n=217)
BNP >80 / Atorva(n=215)
HR 0.32 (0.13, 0.8) p=0.014
Scirica et al, JACC 2006;47:2326-31
~7000 patients with diagnosis of HF (NYHA II-IV)~7000 patients with diagnosis of HF (NYHA II-IV)
Standard Medical Therapy
Duration: 3 year follow-up
Endpoints:•All cause mortality (1252 events)•All cause mortality and hosp for cardiac cause
Endpoints:•All cause mortality (1252 events)•All cause mortality and hosp for cardiac cause
GISSI – HF Study DesignGISSI – HF Study Design
Double-blindDouble-blind
n-3 PUFA Placebo
Rosuvastatin RosuvastatinPlacebo Placebo
~75% in R2
Tavazzi et al, Eur J Heart Fail. 2004
CORONA StudyCORONA Study
~5016 pts ~5016 pts >> 60yo with 60yo with •EF <40%(NYHA III-IV) or,EF <40%(NYHA III-IV) or,•EF <35% (NYHA II)EF <35% (NYHA II)
Duration: 52 months year follow-up
Endpoints:• 1° CV Death, non-fatal MI, stroke
• 2° All cause mortality
Endpoints:• 1° CV Death, non-fatal MI, stroke
• 2° All cause mortality
Rosuvastatin 10mg Placebo
Kjekshus et al, Eur J Heart Fail. 2005
Baseline CharacteristicsMean Age 73yoNYHA II 37%NYHA III 62%Mean EF 31%Prior MI 60%HTN 63%DM 30%
Double-blindDouble-blind
ConclusionConclusion
Statins indicated according to current Statins indicated according to current guidelines in pts with CADguidelines in pts with CAD Goal of < 70 mg/dlGoal of < 70 mg/dl Regardless of HF or no HFRegardless of HF or no HF
In non-ischemic HF, promising early In non-ischemic HF, promising early data but need results of RTCdata but need results of RTC
Potential for identification of pts who Potential for identification of pts who will benefit most from intensive statin will benefit most from intensive statin therapytherapy