Decline in CV-Mortality

Transcription

1 Lipids id 2013 What s Changed? Christopher Granger, MD

2 Disclosure Research contracts: AstraZeneca, GSK, Merck, Sanofi- Aventis, BMS, Pfizer, The Medicines Company, Medtronic Foundation, and Boehringer Ingelheim Consulting/Honoraria: AstraZeneca, GSK, BMS, Pfizer, Lilly, Novartis, Roche, Boehringer Ingelheim, Johnson and Johnson, The Medicines Company, and Sanofi- Aventis For full listing see ww.dcri.duke.edu/research/coi.jspcoi.jsp

3 60 y/o smoker with history of MI 15 years ago,, chronic HF with LV EF 35%, on furosemide, aspirin, ACE-I, BB, and ICD. LDL cholesterol 105, HDL 35, BNP Should you start a statin? 1. Yes 2. No 3. I would even though I know the data do not support it 4. I would if the BNP was low

4 Decline in CV-Mortality Attribution ti of Treatment t / RF-Modification Treatment Decrease in Deaths by Initial (acute) treatment of MI / UAP 10% Secondary prevention after MI / UAP 11% Treatment of heart failure 9% Revasc for chronic angina 5% Other therapies 12% Reduction in cholesterol 24% Reduction in BP 20% Reduction in smoking 12% Reduction in physical inactivity it 5% Therapy 47% RF-Mod. 44% Ford et al, NEJM 2007;356:

5 7 Med Therapies Proven to Death in CV Disease Therapy Indication # pts Reduction in deaths* Relative Absolute Aspirin MI 19,077 30% 3.8% Thrombolysis MI 58,000 18% 1.8% Beta-blocker MI 28,970 13% 1.3% ACEI/ARB MI (late) 15,100 17% 2.8% Statins 2 prev 20,536 13% 1.8% ACEI 2 nd prev 9,297 17% 19% 1.9% Ticagrelor 2 prev 18,624 22% 1.4% ACEI/ARB Post-MI CHF 5,966 26% 5.7% Eplerenone Post-MI CHF 6, % 23% 2.3% Beta-blocker CHF 10,480 37% 4.8% Spiro/eplerenone CHF 4, % 3-11% ACEI/ARB CHF 2,569 16% 45% 4.5% Adapted from Granger, McMurray, JACC 2006

6 INTERHEART: Apolipoprotein B/A-1 1andMI 8 4 OR (99% CI) 2 1 Deciles: Cont Cases Median

7 Potential Impact of Risk Factor ModificationonMI on MI Risk Reduction Smoking (Life long vs none) By 2/3 20 mm diff in SBP (diur + ACE-I) By 1/2 LDL by 40 mg/dl (statin) By 1/3 Cumulative Theoretical Benefits 5/6 THEREFORE IF WE HAD PRACTICABLE WAYS OF MODIFYING 3 THEREFORE, IF WE HAD PRACTICABLE WAYS OF MODIFYING 3 CLASSICAL RISK FACTORS, MOST MI WOULD BE PREVENTED IN HIGH RISK INDIVIDUALS IN NORTH AMERICA Yusuf 2006

8 N Engl J Med 2013;368:341-50

9 Years Gained by Quitting Smoking 12 years Gained by quitting 4 years 6 years 9 years 10 years N Engl J Med 2013;368:341-50

10 Where have we been?

11 ATP 2004 Update: LDL-C Therapy by Risk Categories Based on Recent Clinical Trial Evidence Risk Category LDL-C Goal Initiate Therapeutic Lifestyle Changes (TLC) High risk: CHD or CHD risk equivalents (10-year risk >20%) Very high risk Moderately high risk: 2 risk factors (10-year risk 10% 20%) Moderate risk: 2 risk factors (10-year risk <10%) Consider Drug Therapy <100 mg/dl 100 mg/dl 100 mg/dl Optional goal of <70 mg/dl <130 mg/dl 130 mg/dl 130 mg/dl (consider (optional goal drug options if LDL-C <100 mg/dl) mg/dl) <130 mg/dl 130 mg/dl >160 mg/dl Low risk: 1 risk factor <160 mg/dl 160 mg/dl 190 mg/dl (consider drug options if LDL-C mg/dl) Adapted from Grundy SM et al. Circulation. 2004;110: ; 9

12 What has changed? More focus on benefits of statins for patients at risk of vascular disease events Data showing niacin, for the typical patient, is of limited value Continued challenge in management of the statin- intolerant patient Excitement about promise of experimental agents Anaceptrapib (REVEAL), evacetrapib (ACCELERATE) PCSK-9 inhibitors

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14 Niacin 1. Niacin (nicotinic acid) is vitamin B3, but for lipid treatment 20x to 80x vitamin dose is used. 2. Best clinically available HDL-raising drug, ~25% HDLC increase at 2000 mg/day. 3. Favorable effects on all lipoprotein p classes, including lipoprotein(a). 4. Niacin raises fasting gg glucose levels ~5% and has been associated with insulin resistance.

15 Niaspan vs. Gemfibrozil in Patients with Isolated Low HDL (VA-HIT HIT-like population) 1200 mg Gemfibrozil 2000 mg Niaspan * * * * HDL LDL TG Lp(a) Fibrinogen * *p<0.03 vs. comparator drug Arch Intern Med. 2000;160:

16 Coronary Drug Project 3,908 men aged <65 yrs with history of MI. Cum mulative MIs + CV Dea aths (%) % decrease in 20 nonfatal MI in niacin group. 15 Follow-up 9 years after end of trial: 11% lower total mortality in niacin group. 10 Placebo Niacin Years JAMA 1975; 231:360; JACC 1986; 8:1245

17 AIM-HIGH Trial Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes

18 Entry Criteria Patients Age 45 Years with Coronary Heart Disease (CHD), or Cerebrovascular Disease (CVD), or Peripheral Arterial Disease (PAD) And Dyslipidemia id i Low Levels of Baseline HDL-C <40 mg/dl for men; < 50 mg/dl for women; Triglycerides gy mg/dl; LDL-C < 180 mg/dl

19 Study Design Open-Label Run-In: Up-Titrate Niacin from 500mg to 2,000mg/day 4-8 weeks Adjust simva to LDL mg/dl ER Niacin mg/day simvastatin R Placebo mg/day simvastatin Follow to end of study Months Relative to Randomization

20 HDL-C at Baseline & Follow-up Combination Therapy Monotherapy 45 P < * * * mg g/dl Baseline Year 1 Year 2 Year 3

21 Triglycerides at Baseline and Follow-up 195 Combination therapy 175 Monotherapy mg/dl * * * Baseline Year 1 Year 2 Year 3

22 Primary Outcome tcome with Prim mary Ou Cumul lative % 50 Combination Therapy 40 Monotherapy Monotherapy Combination Therapy 1718 HR 1.02, 95% CI 0.87, 1,21 Log-rank P value= % 16.2% Natrisk Time (years)

23 Primary and Secondary Endpoints Primary Endpoint CHD Death Non-fatal MI Ischemic Stroke Hospitalization for ACS Symptom-Driven Coronary or Cerebral Revascularization Original Primary Endpoint (CHD death, non-fatal MI, ischemic i stroke, hospitalization for high-risk ACS) Composite of CHD Death, non-fatal MI or ischemic stroke All Cardiovascular Death P=0.11 Niacin better Niacin worse

24 But underpowered, placebo group got low dose niacin, not definitive, etc

25 Combination of statin and niacin and laropiprant, an anti-flushing agent, vs statin therapy alone in 25,673 patients at high risk. Median 3.9 years, the combination of niacin and laropiprant did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy, according to Merck. Even more troubling, the company reported that there was a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. December 20, 2012 Merck press release

26 Statins: When Are They Effective? Patients with or at risk of vascular disease Hyperlipidemia being one risk factor Patients at risk of CHD with normal cholesterol and elevated hscrp

27 Cholesterol Lowering Meta-Analysis No change in benefit according to presence of CHD or common risk factors Lancet 2005;366:

28 Intensive vs Moderate Statin Therapy: Relative Risk Reduction Trial CHD Death/MI Stroke PROVE-IT 17% -16% A-to-Z 15% 21% TNT 21% 25% IDEAL 12% 13% Total 16% (9-23%) 18% (4-29%) Cannon CP JACC 2006;48:

29 Myths regarding statin therapy 1. Statins are more effective for patients with high LDL cholesterol 2. Statins should be adjusted to target LDL cholesterol

30 Cholesterol Lowering Meta-Analysis No impact on benefit according to high or low initial lipid levels (135) Lancet 2005;366:

31 JUPITER Outcomes according to baseline LDL Hsia J. J Am Coll Cardiol. 2011;57:

32 Statins: When Are They Not Effective? Chronic heart failure ESRD

33 Primary endpoint CV death or non-fatal MI or non-fatal stroke 35 Placebo n = 732 (29.3%) 30 Rosuvastatin n = 692 (27.5%) Per ce ent Hazard ratio = % CI 0.83 to 1.02 p = No. at risk Placebo Rosuvastatin Months of follow-up Kjekshus J et al. N Engl J Med 2007;

34 Total mortality 35 Placebo n = 759 (30.3%) 30 Rosuvastatin n = 728 (28.9%) Per cen nt Hazard ratio = % CI 0.86 to 1.05 p = Months of follow-up No. at risk Placebo Rosuvastatin Kjekshus J et al. N Engl J Med 2007;

35 Could this 5,000 patient trial have been negative due to play of chance?

36 GISSI-HF: rosuvastatin vs placebo 4574 patients with NYHA class II-IV IV HF (HF hospitalisation within 12 months if LVEF >0.40); followed for a median of 3.9 years Primary endpoint: Death or CV hospitalization Proportion having an event (%) Placebo Rosuvastatin Adjusted HR* 1.01 (99% CI ) p=0.903 Unadjusted HR 1.02 (99%CI ) p=0.594 Log-rank test p= Time since randomisation (months) Lancet 2008; on line 31 August

37 Why Aren t Statins Effective in Heart Failure? Deaths are from heart failure progression Statins have a harmful effect that counter- balances benefits

38 End Stage Renal Disease

39 4D (n=1255) Cardiac Death, MI, Stroke P=0.37 Wanner, C. et al. N Engl J Med 2005;353:

40 AURORA: Primary Endpoint death from CV causes, MI, or stroke Fellstrom BC et al. N Engl J Med 2009;360:

41 What do the new guidelines say?

42 AHA 2012: Lipid Management for Stable Ischemic Heart Disease Class I 1. Lifestyle modifications are strongly recommended for all patients with SIHD. (Level of Evidence: B) 2. Dietary therapy for all patients should include reduced intake of saturated fats (to <7% of total calories), trans fatty acids (to <1% of total calories), and cholesterol (to <200 mg/d). (Level of Evidence: B) 3. In addition to therapeutic lifestyle changes, a moderate or high dose of a statin therapy should be prescribed, in the absence of contraindications or documented adverse effects. (Level of Evidence: A) Class IIa 1. For patients who do not tolerate statins, LDL cholesterol lowering lowering therapy with bile acid sequestrants,* niacin, or both is reasonable. (Level of Evidence: B) Circulation. 2012;126:e354-e471

43 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction Developed in Collaboration with American College of Emergency Physicians and Society for Cardiovascular Angiography and Interventions American College of Cardiology Foundation and American Heart Association, Inc.

44 Lipid Management I IIa IIb III I IIa IIb III High-intensity statin therapy should be initiated or continued in all patients with STEMI and no contraindications to its use. It is reasonable to obtain a fasting lipid profile in patients with STEMI, preferably within 24 hours of presentation. Circulation. 2013: published online before print December 17, 2012

45 Standards of Medical Care in Diabetes: 2013 American Diabetes Association Diabetes Care January 2013