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Prevention of Coronary Heart Disease

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Prevention of Coronary Heart Disease PREVENTION OF CORONARY PATIENT WITH CHD HEART DISEASE • Obese male patient with previous angina, cardiac catheterization with placement of two stents and now stable. • Notable clinical characteristics: Thomas F . Wh ayne, J r, MD , PhD, FACC Triglycerides 354 mg/dl. Professor of Medicine (Cardiology) HDL 28 mg/dl in men. Gill Heart Institute BP 140/90 mm/Hg. University of Kentucky Fasting glucose 120 mg/dl. November, 2009 • Specific management? Characteristics of Plaques Prone to HIGH SENSENSITIVITY Rupture From Inflammation and LDL CREACTIVE PROTEIN (hs-CRP) Fibrous cap Media • A MARKER OF INFLAMMATION: CRP AND Lumen Lipid hsCRP ARE SAME PROTEIN Core • MAY BE ANOTHER RISK FACTOR AND PLAY A ROLE IN PLAQUE FORMATION “Vulnerable” plaque • MAY PREDICT HIGH RISK ACUTE CORONARY SYNDROME • MAY INDICATE PATIENTS MOST LIKELY TO Lumen RESPOND TO STATINS T lymphocyte Lipid • STATINS SHOWN TO REDUCE CRP Core Macrophage foam cell (tissue factor) “Activated” Intimal SMC (HLA-DR+) – EZETIMIBE ACCENTUATES THIS EFFECT* “Stable” plaque Normal medial SMC • NEED STATIN DOSE RESPONSE CURVE Libby P. Circulation. 1999; 91:284491:2844--2850.2850. *Sager PT, et al. Am J Cardiol. 2003;92:1414-1418. Resultados Estudio VYTAL sobre PCR: Ezetimiba/Simvastatina vs. Atorvastatina en pts con DM II e Hipercolesterolemia (n=1229) CURRENT CLINICALLY USEFUL MARKERS OF INFLAMMATION Atorvastatina E/Simvas Atorvas E/S 10 mg 20 mg 10/20 40 mg 10/40 0 • LIPOPROTEIN-ASSOCIATED Ezetimiba/ --55 Simvastatina PHOSPHOLIPASE A2*. Atorvastatina ® asales --1010 a Sensibilidad – PLAC TEST. t b --1515 --13.713.7 de Al --13.813.8 • HIGH SENSITIVITY C-REACTIVE --2020 # PCR PROTEIN (hsCRP) . --2525 --23.323.3 desde niveles --3030 --28.628.6 • NEVERTHELESS, LDL REMAINS THE % Cambio PCR --3535 --33.333.3 STANDARD MAJOR RISK FACTOR. *Brilakis ES. Eur Heart J. 2005;26:137-144. Goldberg RB. Mayo Clin Proc 2006;81:15792006;81:1579--8888 #Willcox BJ. CVR&R. 2004;25:66-69. 1 Key Statin Pleiotropic Effects* JUPITER Trial design: Apparently healthy patients with LDL cholesterol <130 mg/dl and hs- CRP ≥2 mg/dl were randomized to rosuvastatin 20 mg daily or placebo. Clinical • Improved endothelial motor dysfunction. outcomes were compared at a median of 1.9 years. • Increased fibrinolysis (via PAI-1). Results (p < 0.00001) (p = 0.02) • Rosuvastatin associated with a significant ↓ in the • Favorable modulation of immune function. primary outcome of MI, stroke, unstable angina, revascularization, or cardiovascular death (HR 2 2 0.56, 95% CI 0.46-0.69, p < 0.00001) • Antithrombotic properties-decreased platelet Yrs Yrs - - • All-cause mortality ↓ with rosuvastatin (p = 0.02) aggregation. 1.36 • Serious adverse effects were similar (p = 0.60) 1.25 1 1.0 Conclusions • Decreased metalloproteinase activity with 0.77 1 decreased macrophage activity • Rosuvastatin was associated with a significant reduction in major cardiovascular events, including Events/100 Person Events/100 Person Events/100 death, in patients with LDL <130 mg/dl, but high hs- • Anti-inflammatory effects. 0 0 CRP (≥2.0 mg/dl) • May require revision of current guidelines • Increased nitric oxide. Primary outcome All-cause mortality Rosuvastatin Placebo Ridker PM, et al. NEJM 2008;359:2195-207 (n = 8,901) (n = 8,901) Presented by Dr. Paul Ridker at AHA 2008 *Davignon J. Curr Ath Reports. 2004;6:27-35 ASTEROID Atheroma Area OTHER IMPORTANT STUDY, 2006 10.16 mm2 POINTS WITH STATINS Baseline IVUS SUDDEN STATIN WITHDRAWAL MAY Exam INCREASE EVENT RATES IN ACUTE Lumen Area CORONARY SYNDROME (ACS) (Spencer FA. 6.16 mm2 Arch Intern Med. 2004; 164:2162-2168) Atheroma Area EARLY STATIN USE MAY EVENT RATES 5.81 mm2 IN ACS (BENEFIT QUESTIONED AT LOW Follow-up CHOLESTEROL LEVELS) IVUS ADHERENCE IMPROVED BY STARTING 24 months STATINS DURING HOSPITALIZATION AND rosuvastatin Lumen Area MAY HELP STABILIZE PLAQUES (Fonarow G. 5.96 mm2 Am J Cardiol. 2001;87:819-822) CHD Risk Is Increased With Sites of Action of ACEIs and AT1-Receptor Very High TG Levels# (500 mg/dL) Blockade Angiotensinogen TGs are independently associated with Renin premature familial CHD* 12 ACEI Angiotensin I Bradykinin 10 10.7 Chymase ACEACE--KininaseKininase II 8 Trypsin X X X Peptidase ds Ratio 6 BK IIII-- d AitiIIAngiotensin II ItiInactive receptor degradation 4 AT1 --receptorreceptor blocker products CHD O 2 2.8 1.7 1.0 1.2 1.1 X 0 Statins: AT --receptorreceptor NO <100 100-149 150-199 200-299 300-499 500+ AT 1 --receptorreceptor 2 reg. Serum Triglycerides (mg/dL) Vasoconstriction AntiAnti--proliferationproliferation Vasodilation *Triglyceride odds ratio adjusted for HDL-C; n=653 (FHx early CHD), n=1029 (control) Salt/water retention Cell differentiation NatriuNatriu--/diuresis/diuresis Remodeling Tissue repair AntiAnti--remodelingremodeling #Hopkins PN et al. J Am Coll Cardiol. 2005;45:1003-1012. European Heart Journal 1999;20:9971999;20:997--1008.1008. 2 LDL LOWER THAN 70 mg/dl (TNT†) Log-Linear Relationship Between LDL-C FOR THE HIGH RISK CV PATIENT Levels and Relative Risk for CHD • Stable CAD patients • This relationship is consistent 3.7 with a large body of • Atorvastatin 80 mg/dl [Mean lowest LDL = 77] epidemiologic data and data 2.9 available from clinical trials of (REVERSAL: mean lowest LDL = 79, Relative Risk LDL-C–lowering therapy. for CHD, 2.2 PROVE-IT: mean lowest LDL = 62 and Log Scale • These data suggest that for 1.7 every 30-mg/dL change in ASTEROID: mean lowest LDL = 61) 1.3 LDL-C, the relative risk for 1.0 CHD is changed in proportion by about 30%. • Significant clinical benefit over 10 mg/dl • The relative risk is set at 1.0 for 40 70 100 130 160 190 LDL-C = 40 mg/dL. • No overall mortality advantage for 80 mg/dl LDL-C, mg/dL • More elevated aminotransferase for 80 mg/dl LDL-C = low-density lipoprotein cholesterol; CHD = coronary heart disease. Reprinted with permission from Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent †LaRosa JC, et al. New Engl J Med. 2005;352:1425-1435. clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239; http://lww.com. FURTHER SUPPORT OF HIGH DOSE STATINS IN ACS LOWER IS BETTER PROVE-IT STUDY (2004)+: Decreased ACS problems with Atorvastatin (A) 80 mg vs Pravastatin (P) 40 mg; hsCRP almost SUBSTUDY OF PROVE-IT SHOWED the same: from 12.3 to 1.3 (A) vs. 2.1(P). THAT SUBGROUPS OF LDL < 40 [Mean lowes t LDL 62]. MG/DL AND LDL 40-60 MG/DL HAD MIRACL STUDY (ACS)*: FEWER MAJOR CARDIAC EVENTS†. Atorvastatin 80 mg/d ischemic events and rehospitalizations in the first 16wks †Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411-1416. +Cannon et al. N Engl J Med. 2004;350:1495-1504. *Schwartz et al. JAMA. 2001;285:1711-1718. ADVERSE EVENTS WITH HIGH Statins and Fatal Rhabdomyolysis* DOSE STATINS STATIN FATALITIES No./MILLION Rx • No increase reported in REVERSAL and Cerivastatin 31 3.16 PROVE-IT with Atorvastatin 80 mg/d. Lovastatin 19 0.19 • Evaluations prior to release of any statin have Simvastatin 14 0.12 shown more myos itis an d liver infl ammati on with higher doses. Atorvastatin 6 0.04 • IDEAL Study* (previous MI): Primary endpoint Pravastatin 3 0.04 of major coronary events failed and there were Fluvastatin 0 0.00 more myalgias with Atorvastatin 80 mg/d vs. *NEJM 2002;346:539-40. Simvastatin 20 mg/d. Occasionally, can see histopathologic changes of myopathy with *Pedersen TR et al. JAMA. 2005;294:2437-2445. statins despite normal CPK (Ann Intern Med. 2002;137:581-585). 3 AORTIC STENOSIS (AS) STROKE ALSO REDUCED BY STATINS • Heart Protection Study (HPS) showed decreased EXACERBATION BY LDL. strokes with simvastatin 40 mg, except with pre- EXACERBATION BY Lp(a). existing cerebrovascular disease.* STATINS (2002) MAY DEVEL.* OF AS. • CARDS Study showed decreased strokes with A SMALL RANDOMIZED 2005 STUDY SHOWED # FAILURE OF ATORVASTATIN TO DECREASE atorvastatin 10 mg in Type 2 Diabetes patients. PROGRESSION# OF AS. • SPARCL Study showed decreased strokes with A 2005 STUDY WITH ROSUVASTATIN+ atorvastatin 80 mg in patients with recent stroke MARKEDLY SLOWED PROGRESSION OF AS. or TIA and no known CHD. There was a slight NO IN AS IN SEAS TRIAL WITH increase in hemorrhagic stroke.+ EZETIMIBE/SIMVASTATIN^. *Clin. Cardiol 2002;25:201-202. +J Am Coll Cardiol 2007;49:554-561. *The Lancet 2004;363:757-767. # #N Engl J Med 2005;352:2389-2397. ^SEAS Trial, Medpage Today 2008, July 21. The Lancet 2004;364:685-696. +N Engl J Med 2006;355:549-559. THE ENHANCE STUDY: RESULTS* Residual Cardiovascular Risk Despite LDL-C Lowering • Group-1 (eze/sim): Significant decrease in LDL (58% vs. Therapies based on LDL-C lowering reduce the risks of CAD 41% in Group-2 (sim); p < 0.01). 4S CARE WOSCOPS LIPID AFCAPS HPS PROSPER CARDS ASCOT • Group-1: Slightly more progression in carotid intima- 0 media thickness but very insignificant. 10 20 15% • Group-1 vs. Group-2: No significant differences in CV 30 24% 24% 24% tion (%) 29% outcomes (the study was designed as an imaging only). c 40 34% 36% 37% 37% + 50 • Next step: an outcomes study: Improve-It . 60 • Lipid Research Clinics#: Men with upper 5% CV risk 70 80 using cholestyramine required 7.4 years with only LDL Relative risk Relative redu 90 lowering to show decreased cardiovascular events and 100 Despite the benefits of LDL lowering, this can be expected to apply to ezetimibe alone. 60-70% residual risk remains *Kastelein JJP, et al. N Engl J Med 2008;358:1431-1443. 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; WOSCOPS=West of Scotland Coronary Prevention Study; +The Wall Street Journal Jan.
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