Transcript To continue or not to continue use of statins in patients with

To continue or Not to
Continue statin therapy in
patients with diagnosed
CHF?
Erin Woodard
Mercer University
October 2011
Chronic Heart Failure (CHF)


Complex clinical syndrome resulting from any structural or
functional cardiac disorder that impairs ability of ventricle to
fill with or eject blood
Pericardium, myocardium, endocardium

Systolic dysfunction




Diastolic dysfunction




EF < 40%
Impaired LV contractility
Dilated LV
Normal EF
Impaired LV filling
Contractility preserved
In most patients, abnormalities of systolic and diastolic
dysfunction coexist, regardless of EF.
CHF Overview

Clinical Presentation




Epidemiology




Dyspnea
Fatigue
Lead to limiting exercise tolerance & excess fluid retention 
pulmonary congestion and peripheral edema
CAD
HTN
Dilated cardiomyopathy
There is no single diagnostic test for HF because it is largely a
clinical diagnosis that is based on a careful history and
physical examination.
CHF Overview Cont.

Symptomatic disorder


NYHA Functional assessment
Progressive disorder
NYHA Classification

Class I (asymptomatic): Patients with no limitation of
activities due to their HF; they suffer no symptoms from
ordinary activities.

Class II (mild): Slight limitation of physical activity.
Comfortable at rest, but ordinary physical activity results in
fatigue, palpitation, or dyspnea.

Class III (moderate): Patients with marked limitation of
activity due to their HF; they are comfortable only at rest.

Class IV (severe): Patients who have to be at complete rest,
confined to bed or chair due to their HF; any physical activity
brings on discomfort and symptoms occur at rest.
CHF Treatment
Jessup M et al. N Engl J Med 2003;348:2007-18.
Statins – Friend vs Foe

Known benefit and part of first-line
treatment for patients with CAD

HMG-coA reductase inhibitors
Increase presentation of LDL receptors

Total Cholesterol


Desirable
<200 mg/dL

Borderline high
200 – 239 mg/dL

High
>240 mg/dL
Treat CAD and prevent events 
decrease new onset HF
Lipoprotein – Endotoxin Hypothesis




Hypothesize optimum lipoprotein concentration
Serum lipoproteins to modulate the inflammatory immune
function
CHF patients have increased serum cytokine  increased
endotoxins
Circulating cholesterol – and triglyceride rick lipoproteins are
natural nonspecific buffers of endotoxins



Bind and detox bacterial LPS
Patients with CHF, a non-lipid-lowering statin (with
immunomodulatory and anti-inflammatory actions) could be
as effective or even more beneficial than a lipid-lowering
statin
Patients with CAD should be treated differently from patients
with ischemic CHF
Ubiquinone hypothesis






Inhibition of mevalonate synthesis 
decreases ubiquinone
Ubiquinone most abundant in heart
Essential component of mitochondrial
respiratory chain  ATP
Deleterious effects on cardiac muscles
CHF patients found to have depleted
ubiquinone levels
Addition of CoQ helpful?
Selenoprotein hypothesis


Reduction of mevalonate  reduction of
isopentenyl-pyrophosphate
Interfere with enzyme isopentenylation of SectRNA preventing maturation
Literature Support
1998
Vrederoe et al. Skin test anergy in advanced heart failure
Observational
secondary to either ischemic or idiopathic dilated cardiomyopathy
2000
Rauchhaus et al. Inflammatory cytokines and the possible
immunological role for lipoproteins in CHF
Observational
Small sample
2002
Horwich et al. Low serum total cholesterol is associated with
marked increase in mortality in advanced heart failure
Observational
Large sample
2003
Rauchhaus et al. Relationship between cholesterol and survival in
patients with chronic heart failure
Cohort
2006
Review: Statins in the treatment of chronic heart failure:
Biological and clinical considerations
2007
CORONA
Randomized, doubleblind placebo controlled
2008
GISSI-HF
Randomized, doubleblind placebo controlled
Vredevoe DL et al. Skin test anergy in advanced
heart failure secondary to either ischemic or
idiopathic dilated cardiomyopathy. Am J Cardiol
1998:82:323-8.
Vrederoe - 1998




Skin test anergy in advanced HF secondary to
either ischemic or idopathic dilated
cardiomyopathy
222 patients enrolled followed for 1 year
Skin testing in NYHA functional class III,IV
and assess mortality
Primary endpoints


Skin test anergy
Mortality
Vrederoe - 1998

Results

Skin test anergy occurred in 45% of HF patients



Mortality


Increased with lack of ACEi, dec CO, dec lipids
Significant differences in lipid values for TC, LDL,
and TG (all lower in anergy)




More with NYHA class IV
HF patients significantly less reactive for 3 antigens
Lower levels of lipids were predictors of higher mortality
Idiopathic: no significance
Ischemic: decreased lipids and increased mortality
Only 1 year follow – up
Rauchhaus M, Koloczek V et al. Inflammatory
cytokines and the possible immunological role for
lipoproteins in chronic heart failure. Int J
Cardiology 2000; 76:125-33
Rauchhaus - 2000



Goal: Observe fasting cholesterol, LDL, HDL, & TG
in patient with CHF in relation to concentrations of
tumor necrosis factor-alpha (TNFa), soluble TNF
receptor-1 and -2 and a ratio potentially indicating
recent endotoxin bioactivity (sCD14/TC)
58 CHF patients and 19 controls
Hypothesis – lipoprotein bind endotoxin as natural
buffer
Rauchhaus - 2000

Results




sTNF-R1 and sCD14 were higher in CHF patients
than controls where as TNFalpha and sTNF-R2
were not.
Increase cholesterol  decreased TNFalpha
TC <200  poor outcome
Limited small sample size, short term F/U
Horwich TB et al. Low serum total
cholesterol is associated with marked
increase in mortality in advanced heart
failure. J Card Failure 2002; 8:216-24
Horwich - 2002


1134 patients with advanced HF regardless of
etiology (NYHA class III, IV)
Purpose




Describe correlation between cholesterol and baseline
patient characteristics important in prognosis
Investigate relationship between lipids, lipoproteins, and
HF mortality
Excluded patients LVEF <40%
Primary endpoint

Death or urgent heart transplant
Horwich - 2002

Results


Patients divided into quintiles based on baseline lipids
1 and 5 year survival rates (death or urgent heart transplant)


Decreased TC  worse outcomes HF


More severe symptoms CHF
Increased LDL, HDL, TG  longer survival



Lowest death/urgent heart transplant at TC 190-205
< 25% with TC <129 survived >5yr
> 50% with TC>190 survived >5yr
Confirmed findings of small sample trial
Mortality based on Quintile of total cholesterol
Total
Cholesterol
<129
(n= 222)
129-160
(n= 225)
161-189
(n=227)
190-223
(n=232)
>223
(n=228)
1 year
Death/UT
Mortality
98
46.5%
62
29.6%
73
36%
45
21.4%
51
25.9%
2 year
Death/UT
Mortality
114
56.3%
77
38.6%
91
47.8%
63
32.8%
60
31.8%
5 year
Death/UT
Mortality
137
76.2%
108
64.9%
103
62.8%
77
48.4%
72
44.8%
Similar lipid lowering therapy
•14% in each group
•Drug unspecified
1yr
Survivors
(n=805)
Nonsurvivors
(n=329)
TC
185
165
LDL
120
106
TG
155
124
Horwich TB et al. Low serum total cholesterol is associated with marked increase in mortality in
advanced heart failure. J Card Failure 2002; 8:216-24
Rauchhaus et al. Relationship between
cholesterol and survival in patients
with chronic heart failure. JACC
2003; 42: 11
Rauchhaus - 2003

Report on 2 cohort studies



114 patients with CHF recruited to metabolic study
and followed for minimum 12 months (derivation
study)
303 unselected patients with CHF (validation
study)
Purpose

Relationship between endogenous lipoproteins and
survival was explored
Rauchhaus - 2003

Results


“reciever operator curve analysis” showed
201mg/dL
Decreased serum cholesterol = increased sTNF
receptor-1 levels
Theoretical Harm







Lower total cholesterol (<190mg/dl) indicative of
poor prognosis for CHF patients in NYHA class III
and IV
CAD lead to CHF
Statin is proven outcomes to treat CAD and prevent
coronary event
Statin has been shown to prevent new onset CHF
Statin decreasing levels of TC lead to poor prognosis?
Statin used after diagnosis NYHA class III, IV?
Studies and evaluation needed to describe risk/benefit
in pharmacologically induced low TC (statin) vs
naturally low TC
Kjeckshus, J. et al. Rosuvastatin in Older
Patients with Systolic Heart Failure. New
Engl J Med 2007; 357:2248-61.
“CORONA”
Controlled Rosuvastatin Multinational Trial in
Heart Failure
*supported by AstraZeneca*
CORONA - 2007

Large randomized placebo controlled study





Hypothesized beneficial effects of rosuvastatin would outweigh
any theoretical hazards


improve survival, reduce morbidity, increase well-being
Study drug:


Total of 5011 patients, >60yo
NYHA class II,III, or IV ischemic, systolic heart failure
EF of no more than 40%
Investigator thought no need for cholesterol-lowering drug
10mg of rosuvastatin vs placebo, 35 month follow up
Primary Outcome

Death from composite of cardiovascular causes, nonfatal MI, nonfatal
stroke
CORONA - 2007

Results:






Primary Outcome
Y
N
Rosuvastatin
(n = 2514)
692
1822
Placebo
(n=2497)
732
1765
NNT = 55
Baseline TC 5.35mmol/L
Baseline LDL 3.54mmol/L (137)  1.96mmol/L (76) at 3 months
Baseline HDL 1.24mmol/L (48)  1.29mmol/L (50) at 3 months
Baseline TG 2.01mmol/L (178)  1.56mmol/L (138) at 3 months
Baseline hsCRP 3.1mg/L  2.1mg/L
Conclusion


No significant reduction in primary outcome of deaths from any cause
Significantly fewer hospitalizations of any type in rosuvastatin group than
placebo group (for cardiovascular causes and heart failure)
GISSI-HF Investigators. Effect of
rosuvastatin in patietns with chronic heart
failure: a randomised, double-blind,
placebo-controlled trial. The Lancet; 372:
1231- 1239.
“GISSI/HF”
Gruppo Italiano per lo Studio della
Sopravvivenza nell’Infarto miocardico trial
*Funded by Societa Prodotti Antibiotici (SPA;Italy), Pfizer,
Sigma Tau, and AstraZeneca
GISSI/HF – 2008





Randomized, double-blind placebo controlled trial
Italy.
CHF class II-IV irrespective of LVEF
Intervention: rosuvastatin 10mg vs placebo
Followed for 3 – 9 year
Primary endpoint



Time to death
Time to death + time to admission to hospital for
cardiovascular reasons
Intent- to-treat
GISSI/HF – 2008


Results
Death
Death or hospital
R
657 (29%)
1305 (57%)
P
644 (28%)
1283 (56%)
P=0.943
P=0.903
Conclusion

Rosuvastatin 10mg daily did not affect clinical outcoems
in patients with chronic heart failure of any cause, in
whom drug was safe
Low TC a Cause or Consequence?

Association between Total Cholesterol (TC)
and all-cause mortality





Positive at 40 yo
Negligible at 50 – 70 yo
Negative at age 80 +
Incidence/prevalence of CHF increasing
steeply with age
CHF patient untreated with statin naturally
have cholesterol levels decrease?
Discussion Points

Most individuals on statin d/t CAD treatment



Those individuals not already on a statin with
prior need



Take them off?
Titrate down? Decrease aggressive tx?
Start statin?
Goal of increasing TC?
Leave it alone? Benefit vs. risk?
Other References
Hunt SA, Abraham WT, Chin MH, et al. 2009 focused
update incorporated into the ACC/AHA 2005
guidelines for the diagnosis and management of
chronic heart failure in the adult. JACC
2009;53(15):e1-90.