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