Statins: The Most Important Drugs in Cardiology? Charles R. Caldwell, MD, FACC BHHI Primary Care Symposium February 28, 2014

Transcription

1 Statins: The Most Important Drugs in Cardiology? Charles R. Caldwell, MD, FACC BHHI Primary Care Symposium February 28, 2014

2 Financial Disclosures iheartdoc, LLC

3 What does my cholesterol have to do with heart attacks or strokes? Vascular Inflammation Endothelial Dysfunction Platelet Aggregation Plaque Stabilization LDL Oxidation Reduction

4 Lipoprotein Classes Chylomicrons, VLDL, and their catabolic remnants LDL HDL > 30 nm nm Potentially pro-inflammatory 9 15 nm Potentially anti-inflammatory Doi H et al. Circulation 2000;102: Colome C et al. Atherosclerosis 2000;149: Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:

5 The Role of Lipoproteins in Atherogenesis HDL High plasma LDL Endothelial injury LDL + VLDL Liver Cholesterol excreted LCAT APO-A1 LDL infiltration into intima Oxidative modification of LDL + Macrophages Foam cells Fatty streak Other growth factors Adherence of platelets Release of PDGF Advanced fibrocalcific lesion APO-A1=Apolipoprotein A1, HDL=High density lipoprotein, LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein, PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein

6 CHD Risk According to LDL-C Level Relative Risk for Coronary Heart Disease (Log Scale) LDL-Cholesterol (mg/dl) CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol Grundy S et al. Circulation 2004;110:227-39

7 I don t like taking a statin. It makes my muscles hurt. Myositis incidence is very low. Muscle pain is fairly common Does Co Q 10 help? Risk of liver damage is very low

8 HMG-CoA Reductase Inhibitor: Mechanism of Action Inhibition of the Cholesterol Biosynthetic Pathway HMG-CoA Reductase Squalene synthase Dolichol Acetyl CoA HMG- CoA Mevalonate Farnesyl pyrophosphate Squalene Cholesterol Farnesylated proteins Farnesyltransferase E,E,E- Geranylgeranyl pyrophosphate Geranylgeranylated proteins Ubiquinones

9 HMG-CoA Reductase Inhibitor: Mechanism of Action Cholesterol synthesis VLDL LDL receptor (B E receptor) synthesis VLDL R Apo B Apo E LDL-R mediated hepatic uptake of LDL and VLDL remnants Intracellular Cholesterol LDL Apo B Serum LDL-C Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-hdl particles from the systemic circulation

10 HMG-CoA Reductase Inhibitor: Adverse Effects 74,102 subjects in 35 randomized clinical trials with statins 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm) Dose-dependent phenomenon that is usually reversible 15.4% incidence of myalgias* (18.7% incidence in control arm) 0.9% incidence of myositis (0.4% incidence in control arm) 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm) Hepatocyte Skeletal myocyte *The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively. Kashani A et al. Circulation 2006;114:

11 Dealing with Statin-Induced Muscle Pain Take a good history before starting a statin. What already hurts? If the patient complains of severe muscle pain, check CK and stop the statin. Although rare, it may be myositis. Consider a trial of CoQ10. If the pain is mild to moderate, stop the statin and try to restart the same drug at a lower dose in 2-4 weeks. If the pain recurs, stop the statin and try another statin at low dose in 2-4 weeks.

12 HMG-CoA Reductase Inhibitor: Adverse Effects Risk Factors for the Development of Myopathy* Concomitant Use of Meds Fibrate Nicotinic acid (Rarely) Cyclosporine Antifungal azoles** Macrolide antibiotics HIV protease inhibitors Nefazadone Verapamil, Amiodarone Other Conditions Advanced age (especially >80 years) Women > Men especially at older age Small body frame, frailty Multisystem disease Multiple medications Perioperative period Alcohol abuse Grapefruit juice (>1 quart/day) *General term to describe diseases of muscles **Itraconazole, Ketoconazole Erythromycin, Clarithromycin Chronic renal insufficiency, especially from diabetes mellitus Pasternak RC et al. Circulation 2002;106:

13 HMG-CoA Reductase Inhibitor: Dose-Dependent Effect The Rule of 6 s Each doubling of the statin dose produces an additional 6% (approximate) reduction in the LDL-C level Illingworth DR. Med Clin North Am 2000;84:23-42

14 HMG-CoA Reductase Inhibitor: Reduction in LDL-C A Meta-analysis of 164 Trials* Statin 10 mg/d 20 mg/d 40 mg/d 80 mg/d Atorvastatin 69 (37) 80 (43) 91 (49) 102 (55) Fluvastatin 29 (15) 39 (21) 50 (27) 61 (33) Lovastatin 39 (21) 54 (29) 68 (37) 83 (45) Pravastatin 37 (20) 45 (24) 53 (29) 62 (33) Rosuvastatin 80 (43) 90 (48) 99 (53) 108 (58) Simvastatin 51 (27) 60 (32) 69 (37) 78 (42) Data presented as absolute reductions in LDL-C* (mg/dl) and percent reductions in LDL-C (in parentheses) *Standardized to LDL-C 186 mg/dl (mean concentration in trials) before Rx. Independent of pre-rx LDL-C Maximum dose of 80 mg/d administered as two 40-mg tablets Not FDA approved at 80 mg/d FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment Law MR et al. BMJ 2003;326:

15 I have a family history of heart disease and I want to prevent a heart attack. What can I do to lower my risk? Primary Prevention: Preventing disease in a population before it occurs.

16 HMG-CoA Reductase Inhibitor Trials: Chronology Study Population: Primary prevention Acute coronary syndromes Chronic Coronary heart disease

17 HMG-CoA Reductase Inhibitor: Primary Prevention Relationship between LDL-C Levels and Event Rates in Primary Prevention Statin Trials CHD event rate (%) Statin Placebo WOSCOPS WOSCOPS AFCAPS AFCAPS ASCOT ASCOT P= LDL cholesterol (mg/dl) AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm, WOSCOPS= West of Scotland Coronary Prevention Study O Keefe JH Jr et al. JACC 2004;43:2142-6

18 HMG-CoA Reductase Inhibitor: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) 6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years 31% RRR Rate of MI or CHD death (%) Placebo 5.3 Pravastatin P<0.001 Statins provide significant benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Shepherd J et al. NEJM 1995;333:

19 HMG-CoA Reductase Inhibitor: Primary Prevention Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) 6,605 patients with average LDL-C levels randomized to lovastatin (20-40 mg) or placebo for 5 years 37% RRR Rate of MI, unstable angina, or SCD (%) Placebo 3.5 Lovastatin P<0.001 Statins provide benefit in those with average LDL-C levels MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death Downs JR et al. JAMA 1998;279:

20 HMG-CoA Reductase Inhibitor: Primary Prevention Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Lipid Lowering Arm (ALLHAT-LLA) 10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin (40 mg) or usual care for 5 years Cumulative rate % % cross-over among patients with CHD CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk ALLHAT Collaborative Research Group. JAMA 2002;288: Pravastatin Usual care RR, 0.99; P= Years There is no significant difference between the two treatment arms, but a high rate of cross-over

21 HMG-CoA Reductase Inhibitor: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA) 10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years Cumulative incidence of MI and fatal CHD (%) Atorvastatin 90 mg/dl* Placebo 126 mg/dl* P= Follow-up (yr) 36% RRR Statins provide significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals CHD=Coronary heart disease, RR=Relative risk *Post-treatment LDL-C level Sever PS et al. Lancet. 2003;361:

22 I had a previous heart attack/stroke/ peripheral blockage/carotid blockage and I want to do everything I can to prevent another event. Secondary Prevention: Preventing a recurrence of disease.

23 HMG-CoA Reductase Inhibitor: Secondary Prevention Relationship between LDL-C Levels and Event Rates in Secondary Prevention Statin Trials of Patients with Stable CHD Event (%) Statin Placebo 4S LIPID LIPID CARE CARE HPS HPS TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) 4S LDL-C (mg/dl) CARE=Cholesterol and Recurrent Events Trial, HPS=Heart Protection Study, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study, TNT=Treating to New Targets LDL-C=Low density lipoprotein cholesterol LaRosa JC et al. NEJM 2005;352:

24 HMG-CoA Reductase Inhibitor: Secondary Prevention Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial 3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks Combined cardiovascular event rate (%)* Atorvastatin Placebo *Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Schwartz GG et al. JAMA 2001;285: RR=0.84, P= Weeks 17.4% 14.8% Acute intensive treatment significantly reduces event rates

25 HMG-CoA Reductase Inhibitor: Secondary Prevention Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) TIMI 22 Study 4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months Recurrent MI, cardiac death, UA, revascularization, or stroke Atorvastatin Pravastatin ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, UA=Unstable angina Cannon CP et al. NEJM 2004;350: Follow-up (months) P = % RRR Acute intensive treatment significantly reduces event rates

26 HMG-CoA Reductase Inhibitor: Secondary Prevention Cumulative event rate (%)* Aggrastat to Zocor (A to Z) Trial 4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months Time from randomization (months) *Includes CV death, MI, readmission for an ACS, and CVA de Lemos JA et al. JAMA 2004;292: Placebo + Simvastatin 20 mg/day Simvastatin 40/80 mg/day HR=0.89, P=0.14 Acute intensive treatment produces a trend towards reduced cardiovascular events

27 HMG-CoA Reductase Inhibitor: Secondary Prevention Scandinavian Simvastatin Survival Study (4S) 4,444 patients with angina pectoris or previous MI randomized to simvastatin (20-40 mg) or placebo for 5.4 years 30% RRR Mortality (%) Placebo Simvastatin P<0.001 Statins provide significant benefit in those with average LDL- C levels MI=Myocardial infarction, RRR=Relative risk reduction 4S Group. Lancet 1994;344:

28 HMG-CoA Reductase Inhibitor: Secondary Prevention Cholesterol and Recurrent Events (CARE) Study 4,159 patients with a history of MI randomized to pravastatin (40 mg) or placebo for 5 years 24% RRR Rate of MI or CHD death (%) Placebo 10.2 Pravastatin P=0.003 Statins provide significant benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Sacks FM et al. NEJM 1996;335:

29 HMG-CoA Reductase Inhibitor: Secondary Prevention Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study 9,014 patients with a history of MI or hospitalization for unstable angina randomized to pravastatin (40 mg) or placebo for 6.1 years 24% RRR CHD Death (%) Placebo 6.4 Pravastatin P<0.001 Statins provide significant benefit across a broad range of cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction LIPID Study Group. NEJM 1998;339:

30 HMG-CoA Reductase Inhibitor: Secondary Prevention Major CV Event* (%) Treating to New Targets (TNT) Trial 10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years Atorvastatin (10 mg) Atorvastatin (80 mg) 0.00 P< Years CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction *Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke LaRosa JC et al. NEJM 2005;352: % RRR High-dose statins provide benefit in chronic CHD

31 HMG-CoA Reductase Inhibitor: Secondary Prevention Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial 8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years Cumulative Hazard (%) 12 Simvastatin (20 mg) Atorvastatin (80 mg) 8 4 HR=0.89, P= HR=Hazard ratio, MI=Myocardial infarction *Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation Pedersen et al. JAMA 2005;294: Years Since Randomization High-dose statins provide a strong trend towards benefit after an MI

32 HMG-CoA Reductase Inhibitor: Secondary Prevention Baseline LDL-C (mg/dl) Statin (n = 10,269) Heart Protection Study (HPS) 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 years Placebo (n = 10,267) < (16.4%) 358 (21.0%) (18.9%) 871 (24.7%) Event Rate Ratio (95% CI) Statin Better Statin Worse ε (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) 0.76 ( ) P< CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus, HPS Collaborative Group. Lancet 2002;360: Statins provide significant benefit across a broad range of LDL-C levels

33 HMG-CoA Reductase Inhibitor: Intensive Therapy Trial Population Duration (years) LDL-C Reduction (mg/dl) RR in Primary End Point (%) RR in MI or CHD Death (%) PROVE IT- TIMI 22 ACS (N = 4162) A to Z ACS (N = 4497) TNT Stable CAD (N =10,001) IDEAL Stable CAD (N = 8888) SI conversion factor: To convert LDL-C to mmol/l, multiply by ACS=Acute coronary syndrome, CAD=Coronary artery disease, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RR=Relative reduction Cannon CP et al. JAMA 2005;294:

34 I don t really want to take a statin. I d rather just watch my diet or take instead. Diet Bile Acid Sequestrant Ezetimibe Niacin Fibrates

35 Dietary Adjuncts: Efficacy at Reducing LDL-C Therapy Dose (g/day) Effect Dietary soluble fiber 2-8 LDL-C 5-10% Soy protein LDL-C 5-7% Stanol esters LDL-C 10-15% Jones PJ. Curr Atheroscler Rep 1999;1: Lichtenstein AH. Curr Atheroscler Rep 1999;1: Rambjor GS et al. Lipids 1996;31:S45-S49 Ripsin CM et al. JAMA 1992;267:

36 Diet Evidence: Effect on Lipid Parameters and CRP Change from Baseline (%) 46 dyslipidemic patients randomized to a low fat diet, a low fat diet and lovastatin (20 mg), or a dietary portfolio* for 4 weeks LDL-C LDL-C:HDL-C CRP Weeks Weeks Weeks Low fat diet Statin Dietary portfolio* A diversified diet improves lipid parameters and CRP levels *Enriched in plant sterols, soy protein, viscous fiber, and almonds Jenkins DJ et al. JAMA 2003;290:502-10

37 Bile Acid Sequestrant: Efficacy at Reducing LDL-C LDL-C HDL-C TG % Change from baseline at week 24 * Placebo Colesevelam 3.8 grams/day *P<0.001 vs placebo P=0.04 vs placebo Insull W et al. Mayo Clin Proc 2001;76:971-82

38 Bile Acid Sequestrant: Primary Prevention Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) 3,806 men with primary hypercholesterolemia randomized to cholestyramine (24 grams) or placebo for 7.4 years 19% RRR Rate of MI or CHD death (%) Placebo 7.0 Cholestyramine P<0.05 Bile acid sequestrants provide benefit in those with high cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction The LRC-CPPT Investigators. JAMA 1984;251:351-64

39 Ezetimibe: Efficacy at Reducing LDL-C Pooled Phase III Study Results +5 LDL-C HDL-C Triglycerides* Mean % change from baseline to week Placebo Ezetimibe 10 mg *Median % change Knopp RH. Int J Clin Pract 2003;57:363-8

40 Nicotinic Acid: Efficacy at Raising HDL-C Change from Baseline 10% 5% 15% 9% 11% 22% 14% 28% 26% 17% 30% 30% 22% 21% HDL-C LDL-C 35% 39% 44% Dose (mg) TG Goldberg A et al. Am J Cardiol 2000;85:

41 Survival (%) Nicotinic Acid: Secondary Prevention Coronary Drug Project (CDP) 8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years Nicotinic acid stopped P= Nicotinic Acid Placebo Years of follow-up Nicotinic acid provides long-term benefit following a MI MI=Myocardial infarction Canner PL et al. JACC 1986;8:

42 Fibrate: Efficacy at Reducing Triglyceride 147 patients with type IV/V hyperlipoproteinemia randomized to fenofibrate (100 mg three times daily) or placebo for 8 weeks Mean % change from baseline TG = mg/dl 15 LDL 20 HDL TG LDL TG = mg/dl 23 HDL TG -55 TG=Triglyceride level Goldberg AC et al. Clin Ther 1989;11:69 83

43 Fibrate: Secondary Prevention Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) 9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 yrs 9 11% RRR CHD Death or Nonfatal MI (%) Placebo 5.2 Fenofibrate P=0.16 Fenofibrate fails to provide significant additional benefit* CHD=Coronary heart disease, MI=Myocardial infarction *Unadjusted for concomitant statin use Keech A et al. Lancet 2005;366:

44 Cholesterol Management Pharmacotherapy Therapy TC LDL-C HDL-C TG Patient tolerability Statins* 19-37% 25-50% 4-12% 14-29% Good Ezetimibe 13% 18% 1% 9% Good Bile acid sequestrants 7-10% 10-18% 3% Neutral or Poor Nicotinic acid 10-20% 10-20% 14-35% 30-70% Reasonable to Poor Fibrates 19% 4-21% 11-13% 30% Good HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin

45 The New Guidelines Are Here!

46 2013 ACC/AHA Lipid Guidelines 4 Groups That Benefit From Lipid Therapy Individuals with clinical ASCVD without New York Heart Association (NYHA) class II-IV heart failure or receiving hemodialysis. Individuals with primary elevations of low-density lipoprotein cholesterol (LDL-C) 190 mg/dl. Individuals years of age with diabetes, and LDL-C mg/dl without clinical ASCVD. Individuals without clinical ASCVD or diabetes, who are years of age with LDL-C mg/dl, and have an estimated 10-year ASCVD risk of 7.5% or higher.

47 The Omnibus Risk Estimator Age: A very powerful risk factor. Sex Race: AA vs White or Other Total Cholesterol HDL Cholesterol Systolic BP Treatment for Hypertension Diabetes Tobacco Use

48 LDL Targets? Non-Statin Drugs? There is no evidence to support continued use of specific LDL-C and/or non high-density lipoprotein cholesterol (non HDL-C) treatment targets. The appropriate intensity of statin therapy should be used to reduce risk in those most likely to benefit. Non-statin therapies, whether alone or in addition to statins, do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD.

49 Statin Intensity High-Intensity Statin Therapy Lowers LDL-C by 50% (Atorvastatin, Rosuvastatin) Patients with ASCVD age < 75. All patients age 75. LDL-C > 190 Diabetics with 10 year ASCVD risk 7.5%. Consider for age with 10 year ASCVD risk 7.5% (High or Moderate intensity statin).

50 Statin Intensity Moderate-Intensity Statin Therapy Lowers LDL-C by 30 to 50% (Simvastatin, Pravastatin) Patients intolerance to High-Intensity Statin. Diabetics with 10 year ASCVD risk < 7.5%. Consider for age with 10 year ASCVD risk 7.5% (High or Moderate intensity statin).

51 No Longer Appropriate Strategies for Lipid Treatment Treat To Target: No longer a goal LDL of 120, 100, or 70. Lower Is Best: The goal is to lower LDL by 50% in high risk populations. Multiple Lipid Medications: Non-Statin medications raise side effects without substantially lowering ASCVD risk.

52 2013 ACC/AHA Cholesterol Guidelines: Take Home Messages The focus is on reduction of CV events, not reduction of an LDL number. Statins, Statins, Statins. Treat patients with an even lower CVD 10 year risk. 7.5% vs the old 10%. Use of an online risk estimate tool. Check LFTs at start of statin therapy and if stable on 2 checks there is no need to continue checking. Check Cholesterol once or twice a year.

53 2013 ACC/AHA Cholesterol Guidelines: Unanswered Questions Statins for Primary Prevention in age>75: The data is unclear. Titration to Goal vs Fixed Dose Statin: Titration has been used in practice but fixed dosages in trials. Sub-maximal Statin doses with non-statin therapies in statin intolerant patients New onset diabetes with statin therapy: A new concern. Not enough data yet. Newer lipid agents added to statin therapy

54 Are Statins the Most Important Drugs in Cardiology?

55 Questions?