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To continue or Not to Continue statin therapy in patients with diagnosed CHF?

To continue or Not to Continue statin therapy in patients with diagnosed CHF?. Erin Woodard Mercer University October 2011. Chronic Heart Failure (CHF).

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To continue or Not to Continue statin therapy in patients with diagnosed CHF?

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  1. To continue or Not to Continue statin therapy in patients with diagnosed CHF? Erin Woodard Mercer University October 2011

  2. 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 • EF < 40% • Impaired LV contractility • Dilated LV • Diastolic dysfunction • Normal EF • Impaired LV filling • Contractility preserved • In most patients, abnormalities of systolic and diastolic dysfunction coexist, regardless of EF. 

  3. CHF Overview • Clinical Presentation • Dyspnea • Fatigue • Lead to limiting exercise tolerance & excess fluid retention  pulmonary congestion and peripheral edema • Epidemiology • 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.

  4. CHF Overview Cont. • Symptomatic disorder • NYHA Functional assessment • Progressive disorder

  5. 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.

  6. CHF Treatment Jessup M et al. N Engl J Med 2003;348:2007-18.

  7. 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 Statins – Friend vs Foe

  8. 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

  9. 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?

  10. Selenoprotein hypothesis • Reduction of mevalonate  reduction of isopentenyl-pyrophosphate • Interfere with enzyme isopentenylation of Sec-tRNA preventing maturation

  11. Literature Support

  12. 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.

  13. 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

  14. Vrederoe - 1998 • Results • Skin test anergy occurred in 45% of HF patients • More with NYHA class IV • HF patients significantly less reactive for 3 antigens • Mortality • Increased with lack of ACEi, dec CO, dec lipids • Significant differences in lipid values for TC, LDL, and TG (all lower in anergy) • Lower levels of lipids were predictors of higher mortality • Idiopathic: no significance • Ischemic: decreased lipids and increased mortality • Only 1 year follow – up

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. Horwich - 2002 • Results • Patients divided into quintiles based on baseline lipids • 1 and 5 year survival rates (death or urgent heart transplant) • Lowest death/urgent heart transplant at TC 190-205 • Decreased TC  worse outcomes HF • More severe symptoms CHF • Increased LDL, HDL, TG  longer survival • < 25% with TC <129 survived >5yr • > 50% with TC>190 survived >5yr • Confirmed findings of small sample trial

  21. Mortality based on Quintile of total cholesterol • Similar lipidlowering therapy • 14% in each group • Drug unspecified 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

  22. Rauchhaus et al. Relationship between cholesterol and survival in patients with chronic heart failure. JACC 2003; 42: 11

  23. 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

  24. Rauchhaus - 2003 • Results • “reciever operator curve analysis” showed 201mg/dL • Decreased serum cholesterol = increased sTNF receptor-1 levels

  25. 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

  26. 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*

  27. CORONA - 2007 • Large randomized placebo controlled study • 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 • Hypothesized beneficial effects of rosuvastatin would outweigh any theoretical hazards • improve survival, reduce morbidity, increase well-being • Study drug: • 10mg of rosuvastatin vs placebo, 35 month follow up • Primary Outcome • Death from composite of cardiovascular causes, nonfatal MI, nonfatal stroke

  28. CORONA - 2007 • Results: • 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) NNT = 55

  29. 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

  30. 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

  31. GISSI/HF – 2008 • Results • Conclusion • Rosuvastatin 10mg daily did not affect clinical outcoems in patients with chronic heart failure of any cause, in whom drug was safe

  32. 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?

  33. Discussion Points • Most individuals on statin d/t CAD treatment • Take them off? • Titrate down? Decrease aggressive tx? • Those individuals not already on a statin with prior need • Start statin? • Goal of increasing TC? • Leave it alone? Benefit vs. risk?

  34. 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.

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