1. Statins and Heart Failure
Benjamin M. Scirica MD MPH
TIMI Study Group
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA

2. Disclosures
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: Honoraria for presentations (modest): sanofi-aventis and Pfizer

3. Statins in CVD Well proven benefit of statins in reducing CV events
Primary Prevention – WOSCOPS, AFCAPS/TexCAPs, ALLHAT
Secondary Prevention – 4S, CARE
Intensive statin therapy may be superior to moderate statin therapy
PROVE IT-TIMI 22, TNT, IDEAL, A2Z

4. Statins and heart failure Unanswered questions
Is low cholesterol associated with poor outcomes in HF?
Could statins actually be detrimental?
Dose the dose of statins matter? (no effect in HF benefit in CARE, PROSPER, ALLHAT, ASCOT)

5. Statins and heart failure Unanswered questions
If statins are beneficial, is it due to lipid lowering or “pleiotrophic” effects?
Is the benefit similar in ischemic vs. non-ischmemic heart failure?
Who should be treated and is there a a “goal”?

6. Potential mechanisms of benefit and harm in heart failure
van der Harst et al, Card Research 2006

7. Statins and HF State of current evidence
Several observational studies have shown benefit with statin therapy
Statin therapy improves LV EF compared to placebo in pts with CHF
Large randomized trials in ACS / CAD suggest that intensive statin therapy may improve HF, but few details are known (TNT, IDEAL, A2Z)

8. Death and HF according to statin therapy – Observational Study in 24,598 pts
P<.001 for all comparisons
(24,598)
(19,705)
(4893)
(24,598)
(19,705)
(4893)
DEATH
Hosp for HF
Age and sex-adjusted
Go et al, JAMA 2006

9. Death and HF according to statin therapy – Observational Study in 24,598 pts
Adjusted HR* (95% CI)
Intention-to-treat
Time-varying-use
All Cause Mortality
0.76
( )
0.64
( )
Hosp for HF
0.79
( )
0.75 (
* Adjusted for age, sex, HTN, prior CVD, DM, non-CVD co-morbidities, concomitant meds, intensity of medical care, GFR and more…
Go et al, JAMA 2006

10. Divergent results of statins in small prospective studies of pts with HF
Favor Statin
No Difference
Study
Endpoint
Node
(n=63)
%EF, TNF, BNP
Laufs
(n=15)
TNF, PAI, cTn
Mozaffarian
(n=22)
TNF-RI, CRP, ET-1
Sola
(n=105)
%EF, CRP, IL-6, THN-RI
Study
Endpoint
Bleske
(n=15)
Inflammatory markers
Krum
(n=87)
Inflammatory markers, %EF
Kush, et al. J Card Fail 2006

11. Effect of 1-year of statin therapy on LV dimension and function
P=NS
P=0.004
Ejection Fraction
Sola, et al. JACC 2006

12. PROVE IT - TIMI 22: Study Design
4,162 patients with an ACS < 10 days
ASA + Standard Medical Therapy
Double-blind
Standard Therapy
(Pravastatin 40 mg)
Intensive Therapy
(Atorvastatin 80 mg)
PROVE IT is a double-blind, randomized trial that has enrolled 4,160 patients, who experienced an acute coronary syndrome (Q wave and non-Q-wave MI or unstable angina) within the previous 10 days. Patients received either 40 mg of pravastatin or 80 mg of atorvastatin within 10 days of their event and were followed for a mean follow-up period of 2 years.
To study the role of infection in ACS, one half of the patients in the trial also received gatifloxacin 400 mg in addition to either pravastatin or atorvastatin. Gatifloxacin was started on day 15 after the initial episode of ACS for a treatment period of 14 days. Gatifloxacin was subsequently given as a pulsed dose of 400mg per day for 10 days each month for a mean of 2 years. The other half of the patient population received an antibiotic placebo.
2x2 Factorial: Gatifloxacin vs. placebo
Duration: Mean 2 year follow-up
Primary Endpoint: Death, MI, UA, or Stroke
Secondary Endpoint: Re-hospitalization for heart Failure
Cannon et al, AHJ 2004

13. Methods for HF analysis
Endpoint – Hospitalization for new or worsening heart failure that occurred 30 days after randomization
Mean follow-up 24 months
BNP measured at baseline
Statistical Analysis –
Kaplan-Meier estimates with HR comparing pravastatin and atorvastatin
Scirica et al, JACC 2006;47:

14. Baseline Characteristics
Atorva
Prava
P-value
Age
58.1
58.3 NS
Male
77.8
78.4 DM
17.8
17.5
Prior CHF
3.2
3.5
Prior MI
19.1
STEMI
33.4
35.6
Revasc
69.1
68.7
BNP (pg/ml) 31 32
Scirica et al, JACC 2006;47:

15. Risk of heart failure and statin therapy4
Pravastatin 40mg
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 3
HR 0.55
(0.35, 0.85)
P=0.008
Hosp for heart failure (%) 2
Atorvastatin 80mg 1 30
180
365
540
720
900
Days from Randomization
No. at Risk
Prava
Atorva
Scirica et al, JACC 06

16. Meta-analysis of benefit of intensive statin therapy trials on heart failure
Odds ratio
Treatment
Achieved LDL (mg/dl)
Study (n)
(95% CI)
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)
TNT (10,001)
Atorvastatin 80 77
Atorvastatin 10
101
A to Z (4497)
Simvastatin 80 63
Simvastatin 20 77
PROVE IT (4162)
Atorvastatin 80 62
Pravastatin 40 95
IDEAL (8888)
Atorvastatin 80 81
Simvastatin 20
104
0.5 1
3.0
Intensive statin
therapy better
Moderate statin
therapy better
Odds ratio
Scirica et al, JACC 2006;47:

17. B-type Natriuretic Peptide (BNP) and Mortality10
Quartile 4
Independent of age, Killip class,
HR, BP, DM, anterior MI
P < 0.001 8 6
Quartile 3
Mortality (%) 4
Quartile 2 2
Quartile 1 50
100
150
200
250
300
Time (days)
deLemos et al. NEJM 2001; 345:

18. Baseline BNP in patients with heart failure
Baseline BNP (pg/ml)
Pts Baseline BNP > 80
P<0.001
P<0.001
BNP (pg/ml)
Scirica et al, JACC 2006;47:

19. Baseline BNP and risk of heart failure
Adjusted HR
<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 event
Scirica et al, JACC 2006;47:

20. Risk of heart failure according to BNP and intensity of statin therapy8
HR 0.32 (0.13, 0.8) p=0.014 6
4.7%
Abs risk reduction
Hospitalization for heart failure (%) 4 2
HR 0.59 (0.29, 1.1) p=0.099 30
200
400
600
800
900
Days from Randomization
Scirica et al, JACC 2006;47:

21. GISSI – HF Study Design Rosuvastatin Placebo Rosuvastatin Placebo
~7000 patients with diagnosis of HF (NYHA II-IV)
Standard Medical Therapy
Double-blind
n-3 PUFA
Placebo
~75% in R2
Rosuvastatin
Placebo
Rosuvastatin
Placebo
PROVE IT is a double-blind, randomized trial that has enrolled 4,160 patients, at approximately 400 sites in the US, Europe, Canada, and Australia, who have experienced an acute coronary syndrome (Q wave and non-Q-wave MI or unstable angina) within the previous 10 days. Patients received either 40 mg of pravastatin or 80 mg of atorvastatin within 10 days of their event and were followed for a mean follow-up period of 2 years.
To study the role of infection in ACS, one half of the patients in the trial also received gatifloxacin 400 mg in addition to either pravastatin or atorvastatin. Gatifloxacin was started on day 15 after the initial episode of ACS for a treatment period of 14 days. Gatifloxacin was subsequently given as a pulsed dose of 400mg per day for 10 days each month for a mean of 2 years. The other half of the patient population received an antibiotic placebo.
Duration: 3 year follow-up
Endpoints:
All cause mortality (1252 events)
All cause mortality and hosp for cardiac cause
Tavazzi et al, Eur J Heart Fail. 2004

22. Duration: 52 months year follow-up 1° CV Death, non-fatal MI, stroke
CORONA Study
~5016 pts > 60yo with
EF <40%(NYHA III-IV) or,
EF <35% (NYHA II)
Baseline Characteristics
Mean Age 73yo
NYHA II 37%
NYHA III 62%
Mean EF 31%
Prior MI 60%
HTN 63%
DM 30%
Double-blind
Rosuvastatin 10mg
Placebo
Duration: 52 months year follow-up
Endpoints:
1° CV Death, non-fatal MI, stroke
2° All cause mortality
Kjekshus et al, Eur J Heart Fail. 2005

23. Conclusion
Statins indicated according to current guidelines in pts with CAD
Goal of < 70 mg/dl
Regardless of HF or no HF
In non-ischemic HF, promising early data but need results of RTC
Potential for identification of pts who will benefit most from intensive statin therapy