Cholesterol Treatment Update

Transcription

1 Cholesterol Treatment Update Patrick E. McBride, M.D., M.P.H. Professor of Medicine, Cardiovascular Medicine Associate Director, Preventive Cardiology Program UW School of Medicine and Public Health

2 Disclosure: I have no financial interests to disclose.

3 ATP IV Expected 2013 Evidence-based only RCTs / MAs Critical questions Will be an update rather than comprehensive lipid management Still in development and confidential

4 NHLBI CVD Prevention Guidelines Project Map Blood Pressure Panel Evidence Review on BP Tx Cholesterol Panel Evidence Review on Cholesterol Tx Obesity Panel Evidence Review on Obesity Tx Risk Assessment WG Evidence Review & Risk Prediction Model Lifestyle WG Evidence Review on Diet & Physical Activity Implementation WG Implementability Guidance (e.g., GLIA) + CVD Risk Factor List* Risk Assessment Approach for BP + Heart Healthy Diet & Physical Activity* Modifications for BP + Approach to writing recommendations + CVD Risk Factor List* Risk Assessment Approach for Cholesterol + Heart Healthy Diet & Physical Activity* Modifications for Chol. + Approach to writing recommendations + CVD Risk Factors List* Risk Assessment Approach for Obesity + Heart Healthy Diet & Physical Activity* Modifications for Obesity + Approach to writing recommendations JNC Report Evidence-based recommendations on blood pressure ATP Report Evidence-based recommendations on cholesterol Obesity Report Evidence-based recommendations on obesity Risk Assessment WG Addnl Evidence Reviews Lifestyle WG Addnl Evidence Reviews Implementation WG Evidence Review on 4 implementation approaches Integrated Risk Reduction Report Evidence-based recommendations on Risk Assessment, Lifestyle, BP, Cholesterol, Obesity, Multiple RFs, Other Risk Reduction Topics, Implementation Integrated Panel Evidence Review on other topics &multiple RFs

5 ATP IV Critical Questions / Charge 1. Should we use LDL or non-hdl targets for initiation and monitoring of therapy? 2. Is there evidence for LDL targets? 3. Is there evidence that we should use risk assessment to guide treatment decisions? Diabetes? 4. Which medications have evidence to support benefit or harm in treatment of dyslipidemias? 5. Is there evidence for support in special populations women, racial / ethnic groups, age > 75, FH, high TG

6 % Patients with CHD Event Effect of Lowering LDL-C on CHD Events POSCH-PL 4S-PL Primary prevention trials POSCH-Rx 4S-Rx CARE-PL Secondary prevention trials HPS LIPID-PL TNT-10A CARE-Rx HPS-PL LIPID-Rx TNT-80A WOSCOPS-Rx HPS-Rx ASCOT-Rx ASCOT-PL AFCAPS-Rx LDL-C achieved mg/dl WOSCOPS-PL LRC-Rx AFCAPS-PL LRC-PL Statin trials Non statin trials Ballantyne CM. Am J Cardiol. 1998;82: O Keefe JH et al, J Am Coll Cardiol. 2004;43:

7 Key Lessons From Statin Trials (>90,000 pts) LOWERING LDL REDUCES CV EVENTS Endpoint Treatment Events (%) Control Events (%) Relative Risk (CI) Non-fatal MI 2001 (4 4) 2769 (6 2) 0 74 ( ) CHD death 1548 (3 4) 1960 (4 4) 0 81 ( ) Any major coronary event 3337 (7 4) 4420 (9 8) 0 77 ( ) Any coronary revascularisation 2620 (5 8) 3434 (7 6) 0 76 ( ) Haemorrhagic stroke 105 (0 2) 99 (0 2) 1 05 ( ) Presumed ischemic stroke 1235 (2 8) 1518 (3 4) 0 81 ( ) Any stroke 1340 (3 0) 1617 (3 7) 0 83 ( ) Any major vascular event 6354 (14 1) 7994 (17 8) 0 79 ( ) Baigent C et al. Lancet. 2005;366: Treatment Control better better p <

8 Primary Prevention NNT CTT (MA) 5 yr yr. 29 AFCAPS 5 yr yr 27 JUPITER 5 yr yr. 21 WOSCOPS 5 yr yr. 20 PROSPER 5 yr yr. 67 HHS (gemfibrozil) 5 yr. 7, 10 yr. 7

9 MRC/BHF Heart Protection Study - Lipids Baseline Simvastatin Vitamins Total cholesterol LDL-C HDL-C Triglycerides Apo B All vitamin lipid effects statistically significant except HDL-C Vitamins did not reduce the occurrence of any adverse events Simvastatin effect not appreciably modified by vitamins Lancet 2002;360:7

10 MRC/BHF Heart Protection Study Effects on 1 Endpoint by Baseline Feature Baseline feature STATIN (N=10,269) PLACEBO (N=10,267) RR and 95% CI Previous MI or CHD 1459 (21.8%) 1841 (27.5%) No prior CHD CVD 172 (18.7%) 212 (23.6%) PVD 327 (24.7%) 427 (30.5%) Diabetes 279 (13.8%) 367 (18.6%) ALL PATIENTS (19.9%) (25.2%) 24% decrease NNT = 19 (p<0.0001) STATIN better STATIN worse Lancet 2002;360:7

11 Diabetes Trials* CARDS (trial of only diabetics) AFCAPS / TexCAPS JUPITER MEGA * Note: primary prevention, mostly ages years, moderate to high intensity statin used (little to no data available for <40, > 75)

12 Diabetes Risk and Statins 1 per treated Based on post-hoc evaluation of trials Vital to recognize that those with GINT and DM have very significant benefits from statins and those with DM in trials on statins have no extra risk Mechanism for this possibility not clear Possible that it is due to the type of patient selected for the study (older / GINT)

13 Audience Response The risk of diabetes mellitus in the treatment groups in RCTs of statin therapy has been reported to be: % % 3. 1% 4. 10% 5. 20%

14 PROVE IT: Study Design 4,162 patients with an Acute Coronary Syndrome <10 days TC <240 mg/dl (<200 if on LLT; stabilized) Double-blind ASA + Standard Medical Therapy Standard Therapy (Pravastatin 40 mg) Intensive Therapy (Atorvastatin 80 mg) Duration: Mean 2 year follow-up (>925 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (>30 days after randomization), or Stroke Cannon CP, et al. N Engl J Med 2004;350

15 PROVE-IT: Primary Endpoint 30 Pravastatin (26.3%) % with Event Atorvastatin (22.4%) Cannon CP, et al. N Engl J Med 2004;350 Relative risk reduction = 16% Absolute risk reduction = 3.9% P = Months of Follow-up

16 Treating to New Targets (TNT) N = 10,001 stable CHD Mean age 60.3 years, 81% men 8 week open-label run-in Atorvastatin 10 mg daily LDL-C 35% Randomized to continue atorvastatin 10 mg vs. 80 mg daily LaRosa JC, et al. NEJM 2005; 352

17 TNT: Major Cardiac Events Cardiac Death, MI, Resusc. Arrest, Stroke LaRosa JC, et al. NEJM 2005; 352

18 TNT: Cardiovascular Outcomes Outcome Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) RRR p Total major CV % <0.001 events (%) CHD Death (%) % 0.09 Nonfatal MI (%) % Resuscitated cardiac arrest (%) % 0.89 Stroke (%) % 0.02 LaRosa JC, et al. NEJM 2005; 352

19 TNT: Safety 10% All p< % 7.2% 5% 5.8% 5.3% 0% 1.2% 0.2% AST/ALT Adverse Events Drug discontinuation High-dose Low-Dose 5 cases of rhabdomyolysis, 2 on high dose, 3 on low dose Rate ~0.01%/year LaRosa JC, et al. NEJM 2005; 352

20 JUPITER RCT of 17,802 healthy individuals Men >50, women >60 years with LDL-C <130 mg/dl hscrp >2.0 mg/l Rosuvastatin 20 mg daily vs. placebo Stopped early after 1.9 years Baseline characteristics (medians) Age 66 yrs, LDL-C 108 mg/dl, BP 134/80 mmhg BMI 28.3 kg/m2, 41% Metabolic Syndrome hscrp 4.3 mg/l 12 months: LDL-C 55 mg/dl, hscrp 2.2 mg/l Ridker PM et al. N Engl J Med 2008;359

21 JUPITER Cumulative Incidence Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death HR 0.56, 95% CI P < Number Needed to Treat (NNT 5 ) = Placebo 251 / Fewer Events Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

22 JUPITER NNT per year (over 1.9 years) Composite CVD events = 170 (83) MI/stroke/death = 250 (120) Death = 400 (167) Applies to about 7 million Americans (4% of adults); would prevent 28,000 hard events and 17,000 deaths/year Cost-effectiveness depends on statin price $116/month - $557,000 to save a life/year $5/month - $24,000 to save a life/year Ridker PM et al. N Engl J Med 2008;359

23 Considerations with Clinical Use of hscrp Strong associations with obesity, overweight, and diabetes mellitus do not do if ill High hscrp is rare in absence of high or borderline RF (4.4% men, 10.5% women) Yield for possible change of therapy based on screening all of U.S. 3-5% Limit to intermediate risk patients, borderline treatment cases, or to determine residual risk Measure at least twice, take lower value Miller M, et al. Arch Intern Med 2005;165:2063 Guttormsen B, et al. Am J Cardiol 2007;100:1130

24 Pharmacologic Therapy: Statins Safety: Myopathy Creatine kinase (CK) Elevation >10x ULN is observed in 0.1% of patients Monitor symptoms Risk of these events increases with dose escalation or in combination with fibrates or niacin Rhabdomyolysis (incidence = 1 in 10,000 patients) or renal failure may occur if drug is continued Reversed after discontinuation Maron et al. Circulation. 2000;101:207.

25 Audience Response While myalgias are commonly reported by patients, approximately 10-20% (though only 3-5% in clinical trials), the rate of the serious condition of rhabdomyolysis with statin use is reported at the rate of: % % % 4. 1% 5. 2%

26 ENHANCE* 720 patients with familial hypercholesterolemia Simvastatin 80 mg with / without ezetimibe 2 yrs Primary outcome: CIMT of carotids LDL-C: Baseline = mg/dl LDL-C 141 on combination therapy, 192 on simvastatin alone No significant difference in CIMT / events Not powered for event reduction NEJM 2008;358:1431

27 FIELD Fenofibrate Intervention and Event Lowering in Diabetes Average age 62 years, 37% female (n=9795) Mean DM 5 years, 57% HTN Prior known CVD: 22% Statin use 0% on entry, 17% placebo and 8% fenofibrate group during trial Fenofibrate 200 mg vs. placebo TG - 30%, LDL - 12%, HDL up 5% on fenofibrate Lancet Nov. 14, 2005 (

28 FIELD Fenofibrate Intervention and Event Lowering in Diabetes Primary Endpoint: Nonfatal MI & CHD: decreased 11% (5.9 vs 5.2%), NS p= % decreased in non-fatal MI, increased CHD death and SCD in fenofibrate group Total mortality 6.6% placebo, 7.3% fenofibrate (NS) Total CVD events (CVD mortality, MI, CVA, revascularization) decreased 11% (13.9 vs 12.5%), p = ( ) NNT = 70 No benefit if prior CVD Total CVD decreased 19% w/o prior CVD (p = 0.004) Adjusted for statin use: CHD decreased 19% (p = 0.01) Other serious Lancet Nov. 14, 2005 (

29 AIM-HIGH Trial of high dose simvastatin (+ ezetimibe if needed) to get LDL mg/dl 3414 Patients then randomized to addition of highdose extended release niacin or placebo (+ low dose niacin to cause flushing) Trial stopped prematurely (32 months) due to more strokes in combined treatment group: 28 strokes (1.6%) of the treatment group and 12 strokes (0.7%) - 9 / 28 strokes in niacin group occurred 2 months 4 years after discontinuation of niacin. Not seen in previous niacin studies Study not published

30 AIM-HIGH: Kaplan Meier Curve for the Primary End Point The AIM-HIGH Investigators. N Engl J Med 2011;365:

31 HPS-2 THRIVE 4 year study - 25,673 patients at risk for CVD Randomized to receive ER niacin 2 grams /laropiprant 40mg or a placebo - all received simvastatin (with or without ezetimibe). Primary endpoint: major vascular event (non-fatal MI or MI death, stroke, or angioplasty or CABG). Patients receiving ER niacin / laropiprant had a similar number of major vascular events as patients receiving placebo (13.2 vs. 13.7%, p=0.29). Significant excesses: bleeding (2.5 vs. 1.9 %) and infections (8.0 vs. 6.6%) among the ER niacin / laropiprant patients and significantly higher new onset diabetes (9.1 vs. 7.3%), diabetic complications (11.1 vs. 7.5%), GI problems (indigestion and diarrhea (4.8 vs. 3.8%), and itching and rashes (0.7 vs. 0.4 %).

32 Statin & Niacin Combination Therapy HDL Atherosclerosis Treatment Study (HATS) Sponsored by NIH - NHLBI N=160, CAD (1 vessel 50% or 3v 30%) HDL-C 35, LDL-C 145 mg/dl Niacin (x = 3.2 g) + simvastatin (x = 12 mg) Vit. E (800 IU) + vitamin C (1 g) + b- carotene (25 mg) Randomized all placebo antioxidants + placebo Niacin/simvastatin + placebo Niacin/simvastatin + antioxidants

33 Percent % HDL Atherosclerosis Treatment Study (HATS) Clinical Events %* 60%* * p< No Antioxidants Includes Antioxidants Placebo Placebo vits Niacin / statin Niacin / statin vitamins Brown BG, et al. N Engl J Med. 2001;345:

34 Niacin Improves Clinical Outcomes Study CDP Regimen Niacin alone Key Outcomes 2 nd infarct over 6 yr; total mortality at 15 yr IHD CLAS I and II Niacin, clofibrate Niacin, colestipol total and cardiac mortality over 5 yr CHD events and progression coronary atherosclerosis CAD regression in 16% CDP = Coronary Drug Project; IHD = Stockholm Ischaemic Heart Disease Secondary Prevention Study; CLAS I and II = Cholesterol-Lowering Atherosclerosis Study. Guyton JR. Am J Cardiol. 1998;82:18U-23U.

35 Niacin Pharmacology Vitamin B3 Niacin immediate - release or Niaspan Niaspan safest of all (4% GI side effects) Flushing - mostly blocked by ASA or NSAID, most develop tolerance in 1-2 weeks, use gradually increasing dose Start low and go slow know how to use 80+% success rate if used properly Niacin + food + Aspirin + water at HS

36 ACCORD: Lipids Study Overview RCT, 5518 patients with type 2 diabetes mellitus who were at high risk for cardiovascular events were all treated with simvastatin and assigned to receive either fenofibrate or placebo Mean follow-up of 4.7 years study of rates of the primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death)

37 The ACCORD Study Group. N Engl J Med 2010;362: Lipid Values

38 Kaplan-Meier Analyses of the Primary Outcome, Expanded Macrovascular Outcome, and Death The ACCORD Study Group. N Engl J Med 2010;362:

39 Conclusion The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes

40 Treating TG and HDL Lowers Risk Patients with Vascular Events at 5 Years (%) of Vascular Events* VA-HIT Diabetic Patients % Risk Reduction 28.0 Non-diabetic Patients % Risk Reduction 18.0 Placebo Gemfibrozil Placebo Gemfibrozil N = 627 P = 0.05 N = 1,904 P = * Vascular events represent coronary heart disease, nonfatal MI, and confirmed stroke. Rubins HB, et al. N Engl J Med. 1999;341(6):

41 TG & HDL : Lifestyle Change Weight Loss Daily Exercise Nutritional Changes: Decrease calories Decrease fats and simple carbohydrates Decrease alcohol to reduce TGs Fish oil: 3 4 grams divided BID

42 Omega 3 Fatty Acids Fish oil supplements and food Lifestyle paper will discuss food Myocardial infarction trials (GISSI / JELIS) trials had limitations use 1 gram of omega 3 s for post - MI Triglyceride lowering (20-40% at 4 grams of omega 3 s) DHA + EPA

43 Audience Response The dose of Omega 3's (DHA + EPA) needed to lower triglyceride levels for adult patients with hypertriglyceridemia is: mg daily mg twice daily 3. 1 gram twice daily 4. 2 grams twice daily

44

45 Mediterranean Diet Estruch R et al. N Engl J Med 2013;368: Hu, FB. N Engl J Med 2003;348:2595 Kris-Etherton P, et al. Circulation 2001;103:1823 Increased physical activity Bread and cereal Nuts and legumes Daily fruit and vegetables Fish Less red meat (use poultry) Replace butter and cream with olive oil

46 Kaplan Meier Estimates of the Incidence of Outcome Events in the Total Study Population. Estruch R et al. N Engl J Med 2013;368:

47 Deaths per 1000 patients/year Lyon Diet Heart Study Death Rates 200 Mediterranean Diet Western Diet Cardiac Death RR 0.35, p = 0.01 All-Cause RR 0.44 p = 0.03 de Lorgeril M, et al. Circulation 1999;99:779

48 Intestinal-Acting Cholesterol-Lowering Agents Inhibition of bile acid reabsorption BAS Cholestyramine (Questran ) Colestipol (Colestid ) Colesevelam (WelChol ) Inhibition of cholesterol absorption Plant stanol esters (Benecol ) and sterol esters (Take Control ) Selective cholesterol absorption inhibitors Ezetimibe (Zetia )

49 Plant Sterol and Stanol Esters Low absorption Chemically similar to cholesterol Reduce LDL-C by 10%-15% Plant stanol esters Saturated derivatives of plant sterol esters (Benecol and Take Control ) Very low absorption No outcomes data Nguyen. J Nutr. 1999;129:2109.

50 Easy Lipid Therapy LDL Statins Ezetimibe Resins Sterols TG / HDL Fibrates Niacin Fish Oil

51 Summary ATP IV should be released in 2013, and is limited to critical questions / evidence from trials Data from clinical trials strongly supports statin therapy for moderate to high risk patients Lifestyle is vital to achieve risk reduction in all patients at risk Risk assessment is vital to determine patients to treat Limitations exist related to many areas of lipid management, limiting recommendations