Algoritma Statin for Chf

10/2/2011

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Prof. AHMAD ABD ELLATIF

M.D.,F.A.C.C.

STATINS IN CHRONIC HEART FAILURE One of the great success stories in cardiology is the One of the great success stories in cardiology is the ability of statins to improve prognosis in patients at risk of primary or secondary cardiovasculat events. This fact has been challanged only in :

‐patients on dialysis

‐patients with chronic heart failure

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‐IN OUR AGING POPULATION WITH GROWING NUMBERS OF CASES OF HEART FAILURE SEVERAL QUESTIONS HAVE TO BEQUESTIONS HAVE TO BE ANSWERED TO IMPROVE OUTCOMES OF THESE CASES WHICH UP TO MOMENT REMAINSWHICH UP TO MOMENT REMAINS POOR

‐ IS IT BENEFICIAL TO CONTNUE STATIN TREATMENT IN END STAGE CAD THAT HAS RESULTEDSTAGE CAD THAT HAS RESULTED IN CHRONIC HEART FAILURE‐IS IT BENEFICIAL TO BEGIN STATIN THERAPY IN END STAGESTATIN THERAPY IN END STAGE CAD THAT HAS RESULTED IN CHRONIC HEART FAILURE

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BACK GROUND OF THIS CHALLENGE ‐ in Framingham study: dyslipidemia is a risk factor for the g y y pdeveloment of CHF

‐detailed analysis of the same Framingham database:totalcholesterol association with mortality has been:

‐positive at age 40

‐negligible at age 50‐70

‐negative at age 80 and up

In ischemic CHF higher cholesterol levels are associated with less mortality

Epidemiological studies:higher risk of adverse events with low levels of LDL in cases of CHF

BACKGROUND(contin.) ‐low cholesterol level can be a consequence of low cholesterol level can be a consequence of advanced CHF without a causal role

‐low chlesterol level may be only a marker of poor health

OR

STATINS MAY HAVE POTENTIALLY HARMFULL EFFECTS in CHF

‐

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Effect of pravastatin on coronary events in patients with coronary artery disease and a left ventricular ejection fraction (LVEF) of >0.40 enrolled in the Cholesterol And Recurrent

Events trial (2)

Copyright ©2002 American College of Cardiology Foundation. Restrictions may apply.

Krum, H. et al. J Am Coll Cardiol 2002;39:1567-1573

POTENTIALLY HARMFULL EFFECTS OF STATINS IN CHF ‐Endotoxin Lipoprotein Hypothesis:Endotoxin Lipoprotein Hypothesis:

‐ serum lipoproteins act as natural non‐specific buffers of endotoxins

‐diminished lipoproteins leeds to increased endotoxins

‐CHF patients have high level of cytokines p g ywhich may be due to increased endotoxin

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POTENTIALLY HARMFULL EFFECTS OF STATINS(continu.) UBIQUINONE HYPOTHESISUBIQUINONE HYPOTHESIS

statins inhhibit mevalonate synthesis, this decreases production of UBIQUINONE(CO ENZYME Q 10)

COENZYME Q 10:lipid soluble quinone , electron trasporter, essential for mitochondrial oxidative phosphorelation and production of ATP, also lipophilicantioaxidant protecting cell membranes and lipoproteins. Half is ingested, half is synthesized through mevalonate pathway:inhibited by statins

COENZYM Q10 ‐COENZYM Q10 DEFICIENCY IS ASSOCIATED COENZYM Q10 DEFICIENCY IS ASSOCIATED WITH MYOPATHY, THERE ARE CONCERNS ABOUT CARDIAC MUSCLE DYSFUNTION:MUSCLE ENERGY STARVATION, OXIDATIVE DAMAGE TO MYOCYTES

‐LOW CHOLESTEROL IS ASSOCIATED WITH WORSE PROGNOSIS IN CHFWORSE PROGNOSIS IN CHF

‐RECENT STUDY:LOW PLASMA COENZYME Q 10 IS AN INDEPENDENT PREDICTOR OF MORTALITY IN CHF

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The mevalonate-isoprene pathway



The hypothetical effects of statins on Chronic Heart Failure through the intermediates of the mevalonate pathway.

van der Harst P et al. Cardiovasc Res 2006;71:443-454

Copyright © 2006, European Society of Cardiology

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Effect of simvastatin on mortality among patients developing chronic heart failure (CHF) compared with those without clinical evidence of CHF in the Scandinavian Simvastatin

Survival Study trial(1)



POTENTIALLY HARMFUL EFFECTS(continu) Selenoprotein Hypothesis:statins interfere with Selenoprotein Hypothesis:statins interfere with mevalonate pathway, and so prevent maturation of functional tRNAmolecule:may be harmfull in CHF

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POTENTIALLY BENEFICIAL EFFECTS OF STATINS IN CHF ‐cholesterol lowering can improve coronary blood flowcholesterol lowering can improve coronary blood flow

‐statins can modify neurohormonal systems involved in pathophysiology of heart failure

‐LVH :statins can inhibit angiotensin 11 induced,andnoradrenalin induced hypertrophy

‐retard progression of atherosclerosisp g

‐anti‐inflammatory effect

‐metalloproteinases

Simplified schematic overview of the known processes involved in atherosclerosis and the established effects of statin treatment.



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(A) Adapted with permission from Kureishi et al. [75].



One-year hazard ratios (HRs) and 95% confidence intervals (CIs) for death or urgent transplantation, death from any cause, progressive heart failure death, and sudden death

for patients receiving statins compared with those not receiving statins


Horwich, T. B. et al. J Am Coll Cardiol 2004;43:642-648

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TNF-{alpha} and MMP-2


Zaca, V. et al. J Am Coll Cardiol 2007;50:551-557

Two-year rates of death or urgent transplantation in statin versus no-statin cohorts


Horwich, T. B. et al. J Am Coll Cardiol 2004;43:642-648

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Effect of myocardial infarction and unstable angina on risk of death and of hospitalization for chronic heart failure (CHF) in the Studies Of Left Ventricular Dysfunction (5)



Figure. Age- and Sex-Adjusted Rates of Death From Any Cause and Hospitalization for Heart Failure by Incident Statin Exposure Rates are during follow-up among cohort members with

dyslipidemia eligible for lipid-lowering treatment as defined by National Cholesterol Education Panel Adult Treatment Panel III risk-based criteria who had no known prior statin

use, overall, and stratified by the presence or absence of known coronary heart disease (CHD) at study entry.

Go, A. S. et al. JAMA 2006;296:2105-2111

Copyright restrictions may apply.

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Three-dimensional bar graph showing hypothetical relation of decreased coronary blood flow reserve (vertical axis) in relation to increasing levels of cholesterol (horizontal axis) and

decreasing Left Ventricular Ejection Fraction (LVEF; diagonal axis).



CLINICAL TRIALS ‐CORONA trial(controlled rosuvastatin multinational CORONA trial(controlled rosuvastatin multinational in heart failure):

‐5011 patient, 60years or more,NYHA class 11 or more ischemic heart failure

‐10 mg rosuvastatin or placebo

‐2.7 years7 y

‐no significant benefit

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CLINICAL TRIALS(continu.) ‐GISSI‐HF(groppo itaiano per lo studio dellaGISSI HF(groppo itaiano per lo studio dellasopravivenza nell insuuficienza cardiaca heart failure):

‐4574 CHF patients, for 3.9 years

‐same findings as CORONA

?AT SOME POINT WITH ADVANCED IHD, HEART FAILURE, AND OLD AGE PATIENTS REACH A POINT WHERE THEIR CARDIOVASCULAR DISEASE IS TOO ADVANCED TO MODIFY WITH STATINS

Figure. Age- and Sex-Adjusted Rates of Death From Any Cause and Hospitalization for Heart Failure by Incident Statin Exposure Rates are during follow-up among cohort members with

dyslipidemia eligible for lipid-lowering treatment as defined by National Cholesterol Education Panel Adult Treatment Panel III risk-based criteria who had no known prior statin

use, overall, and stratified by the presence or absence of known coronary heart disease (CHD) at study entry.

Go, A. S. et al. JAMA 2006;296:2105-2111

Copyright restrictions may apply.

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Figure 3. Kaplan-Meier survival and survival without cardiovascular (CV) hospitalization in propensity-matched patients grouped by statin therapy.

Fukuta H et al. Circulation 2005;112:357-363

Copyright © American Heart Association

Can naturetic peptides help identify heart failure patients for whom statins are benficial

‐CLELAND et al post hoc analysis of 3664 patients from the CORONA study:patients with the lowest level of N‐terminal pro‐B‐type naturetic peptide did benefit from statin therapy:?lower risk heart failure patients may still benefit from statin therapy

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CONCLUSION ‐THEORETICAL DOWNSIDES TO STATIN THERAPY IN CHF INCLUDE: REDUCTIONS IN COENZYME Q 10,SELENOPROTEIN LEVEL, AND DECREASED ABLLITY OF LIPOPROREINS TO BIND ENDOTOXINS.

‐SMALL SCALE STUDIES AND POST HOC ANALYSIS SUGGEST BENEFICIAL EFFECT OF STATINS IN CHF

‐NATURETIC PEPTIDES MAY HELP IDENTIFY CASES NATURETIC PEPTIDES MAY HELP IDENTIFY CASES OF HF THAT BENEFIT FROM STATIN THERAPY

‐DEFINITIVE PROSPECTIVE LARGE SCALE TRIAL IS REQUIRED TO ANSWER VARIOUS QUESTION IN THIS IMPORTANT SUBJECT

THANK YOU

Algoritma Statin for Chf

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