New ACC/AHA Guidelines on Lipids: Are PCSK9 Inhibitors Poised for a Breakthrough?

Transcription

1 New ACC/AHA Guidelines on Lipids: Are PCSK9 Inhibitors Poised for a Breakthrough? Sidney C. Smith, Jr. MD, FACC, FAHA Professor of Medicine/Cardiology University of North Carolina at Chapel Hill Immediate Past President World Heart Federation Nothing to Disclose ]

2 Institute of Medicine Report: Quality Chasm In its current form, habits, and environment, American health care is incapable of providing the public with the quality health care it expects and deserves. Design Rule 5: Current: Decision making is based on training and experience. New: Decision making is based on evidence. Patients should receive care based on the best available scientific knowledge. Care should not vary illogically form clinician to clinician or from place to place. Institute of Medicine, Crossing the Quality Chasm: A New Health System for the Twenty-first Century. Washington: National Academy Press, 2001

3 Development of clinical practice guidelines was a key role for NHLBI in those years Joint National Committee on Prevention, Detection, Evaluation, & Treatment of High Blood Pressure (JNC) JNC 7: 2003 JNC 6: 1997 JNC 5: 1992 JNC 4: 1988 JNC 3: 1984 JNC 2: 1980 JNC 1: 1976 Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP, Adult Treatment Panel) ATP III Update: 2004 ATP III: 2002 ATP II: 1993 ATP I: 1988 Clinical Guidelines on the Identification, Evaluation, & Treatment of Overweight and Obesity in Adults Obesity 1:

4 CHD event (%) Correlation Between CHD Events and LDL-C Levels 25 4S-P ? CARE-S 4S-S LIPID-P CARE-P LIPID-S LDL-C (mg/dl) S = Statin treated; P = Placebo treated

5 Statin Trials and Goals of Cholesterol-Lowering Therapy The quantitative relation between the magnitude of cholesterol lowering and CHD reduction has not been precisely defined 3 models a) Linear b) Threshold c) Curvilinear

6 Correlation Between CHD Events, LDL-C Levels, and Risk 210 Opie et al.,lancet 2006; 367: 69 78

7 Heart Protection Study (HPS) Risk ratio and 95% CI LDL Statin (10,269) Placebo (10,267) Simva 40 better Placebo better < 100 ATP III - No RX > 100 < 130 ATPIII - Diet or Rx > 130 ATP III - Rx c2 Het 2 = 0.8 All patients 2042 (19.9%) 2606 (25.4%) 24% SE 2.6 reduction (2P< ) Patients years old; CAD, CVD, PVD, diabetes or HTN; TC >135. Heart Protection Study Collaborative Group. Lancet 2002;360: American Heart Association

8 Death or major CV event (%) PROVE IT TIMI 22: Primary Endpoint* Pravastatin 40 mg LDL-C = 95 mg/dl (26.3%) Atorvastatin 80 mg LDL-C = 62 mg/dl (22.4%) 16% RRR P = No. at risk Months of follow-up Pravastatin 2,063 1,688 1,536 1, Atorvastatin 2,099 1,736 1,591 1, * Total mortality, NFMI, rehosp with UA, revasc-pci, CABG 30 d, stroke Cannon CP, et al. N Engl J Med. 2004;350:

9 CTT Meta-analysis 26 Trials

10 MORE VS LESS STATIN Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction ( 1 mmol/l = ~ 39 mg/dl) No. of events (% pa) More statin Less statin Relative risk (CI) per mmol/l LDL-C reduction Nonfatal MI 1175 (1.3%) 1380 (1.5%) 0.71 ( ) CHD death Any major coronary event 645 (0.7%) 1725 (1.9%) 694 (0.7%) 1973 (2.2%) 0.85 ( ) 0.74 ( ) CABG 637 (0.7%) 731 (0.9%) 0.72 ( ) PTCA Unspecified 1166 (1.3%) 447 (0.5%) 1508 (1.8%) 502 (0.6%) 0.60 ( ) 0.78 ( ) Any coronary revascularisation 2250 (2.6%) 2741 (3.2%) 0.66 ( ) Ischaemic stroke Haemorrhagic stroke 440 (0.5%) 69 (0.1%) 526 (0.6%) 57 (0.1%) 0.69 ( ) 1.39 ( ) Unknown stroke Any stroke 63 (0.1%) 572 (0.6%) 80 (0.1%) 663 (0.7%) 0.63 ( ) 0.74 ( ) Any major vascular event 3837 (4.5%) 4416 (5.3%) 0.72 ( ) 99% or 95% CI CTT Collaborators Lancet 2010: 376: More statin better Less statin better 10

11 Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction, by baseline LDL-C No. of events (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction More vs less statin <2.0 2,< ,<3.0 3,< Total 704 (17.9%) 1189 (18.4%) 1065 (20.1%) 517 (20.4%) 303 (23.9%) 3837 (19.4%) 795 (20.2%) 1317 (20.8%) 1203 (22.2%) 633 (25.8%) 398 (31.2%) 4416 (22.3%) 0.71 ( ) 0.77 ( ) 0.81 ( ) 0.61 ( ) 0.64 ( ) 0.72 ( ) Statin vs control <2.0 2,< ,<3.0 3,< Total 206 (9.0%) 339 (7.7%) 801 (8.2%) 1490 (10.8%) 4205 (12.6%) 7136 (11.0%) 217 (9.7%) 412 (9.1%) 1022 (10.5%) 1821 (13.3%) 5338 (15.9%) 8934 (13.8%) 0.87 ( ) 0.77 ( ) 0.76 ( ) 0.77 ( ) 0.80 ( ) 0.79 ( ) All trials <2.0 2,< ,<3.0 3,< Total 910 (14.7%) 1528 (14.0%) 1866 (12.4%) 2007 (12.3%) 4508 (13.0%) (13.0%) 1012 (16.4%) 1729 (15.9%) 2225 (14.7%) 2454 (15.2%) 5736 (16.5%) (15.8%) 0.78 ( ) 0.77 ( ) 0.77 ( ) 0.76 ( ) 0.80 ( ) 0.78 ( ) 99% or 95% CI CTT Collaborators Lancet 2010: 376: Statin/more better Control/less better 11

12 Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL-C reduction, by baseline prognostic factors No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Previous coronary disease: CHD Non-CHD vascular None 8395 (4.5%) 674 (3.1%) 1904 (1.4%) (5.6%) 802 (3.7%) 2425 (1.8%) 0.79 ( ) 0.81 ( ) 0.75 ( ) Diabetes: Type 1 diabetes Type 2 diabetes No diabetes 145 (4.5%) 2494 (4.2%) 8272 (3.2%) 192 (6.0%) 2920 (5.1%) (4.0%) 0.77 ( ) 0.80 ( ) 0.78 ( ) Sex: Male Female 8712 (3.5%) 2261 (2.5%) (4.4%) 2625 (2.9%) 0.77 ( ) 0.83 ( ) Age (years) 65 >65, 75 > (2.9%) 4032 (3.7%) 885 (4.8%) 7455 (3.6%) 4908 (4.6%) 987 (5.4%) 0.78 ( ) 0.78 ( ) 0.84 ( ) Body mass index (kg/m 2 ): <25 25,< (3.0%) 5033 (3.3%) 2732 (3.3%) 3688 (3.7%) 6125 (4.1%) 3331 (4.1%) 0.79 ( ) 0.78 ( ) 0.78 ( ) Smoking status: Current smokers Non-smokers 2268 (3.6%) 8703 (3.1%) 2896 (4.7%) (3.9%) 0.78 ( ) 0.78 ( ) Total (13.0%) (15.8%) 0.78 ( ) 99% or 95% CI CTT Collaborators Lancet 2010: 376: Statin/more better Control/less better 12

13 New Onset DM and MACE in Patients treated with Statins for ACS or CHD Preiss et al, JAMA. 2011;305(24):

14 Drug Interactions with Simvastatin Simvastatin: Key components of label change 1. Restrict 80 mg to >12 mos users 2. Switch 80 mg users to alternate drug for drug drug interaction 3. If LDL-C goal not achieved with 40 mg use another more potent statin i.e. atorvastatin or rosuvastatin. Egan, A & Colman,E NEJM 2011

15 CTT 2012 Meta-analysis of statins in those at lower risk of major CVD* * Major CVD = first nonfatal MI, coronary death, stroke, or coronary revascularization (27 trials, >134,000 participants) CTT Collaborators. Lancet 2012; 380:

16 Primary prevention 5 to <10% 5-year major CVD risk Per 1 mmol reduction LDL-C with a statin* Significantly greater 34% reduction in relative risk of major CVD than higher risk groups 17% reduction in total mortality *1 mmol/l (39 mg/dl) LDL-C reduction was the average in the primary prevention RCTs excluding JUPITER CTT Collaborators. Lancet 2012; 380:

17 *1 mmol/l LDL-C reduction was the average in the primary prevention RCTs CTT Collaborators. Lancet 2012; 380: Primary prevention <5% 5-year major CVD risk Per 1 mmol reduction LDL-C with a statin* 39% reduction in relative risk of major CVD No reduction in total mortality 88% of MEGA, 63% of JUPITER, 45% of AFCAPS/TexCAPS participants (92% of n=23,034)

18 CTT 2012 Meta-analysis of statins in those at lower risk of major CVD* * Major CVD = first nonfatal MI, coronary death, stroke, or coronary revascularization (27 trials, >134,000 participants) CTT Collaborators. Lancet 2012; 380: CTT Collaborators. Lancet 2012; 380:

19 Critical Question 1

20 Critical Question 2

21 New Perspective on LDL C & Non-HDL C Goals Lack of RCT evidence to support titration of drug therapy to specific LDL C and/or non-hdl C goals Strong evidence that appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit Quantitative comparison of statin benefits with statin risk Nonstatin therapies did not provide ASCVD risk reduction benefits or safety profiles comparable to statin therapy

22 2013 ACC/AHA Guidelines for Treating Hypercholesterolemia ( Summary)

23 Primary Prevention Global Risk Assessment To estimate 10-year ASCVD risk New Pooled Cohort Risk Equations White and black men and women More accurately identifies higher risk individuals for statin therapy Focuses statin therapy on those most likely to benefit You may wish to avoid initiating statin therapy in highrisk groups found not to benefit (higher grades of heart failure and hemodialysis)

24 ACC/AHA Risk Calculator

25 Lifetime risk estimator For age years, it provides lifetime risk estimate This is intended to drive discussions of greater adherence to heart-healthy lifestyle

26 10-Year ASCVD Risk (%) ASCVD Risk Calculator 55 yo AA and White Women African American Women 7.7 Your 10-Year ASCVD Risk (%) 1.8 Optimal (%) 3.6 White Women Your 10-Year ASCVD Risk (%) 1.4 Optimal (%)

27 Individuals Not in a Statin Benefit Group In those not clearly in a statin benefit group, additional factors may inform treatment decisionmaking: Family history of premature ASCVD Elevated lifetime risk of ASCVD LDL C 160 mg/dl hs-crp 2.0 mg/l Subclinical atherosclerosis CAC score 300 or ABI<0.9 Discussion of potential for ASCVD risk reduction benefit, potential for adverse effects, drug-drug interactions, and patient preferences

28 Primary Prevention Statin Therapy Thresholds for initiating statin therapy derived from RCTs Before initiating statin therapy, clinicians and patients engage in a discussion of the potential for ASCVD risk reduction benefits, potential for adverse effects, drugdrug interactions, and patient preferences

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30 Primary Prevention- Risk Discussion Must Precede Statin Prescription Best Scientific Evidence Patient preference Clinical Judgment Computers do not practice Medicine Shared Decision Making is Essential

31 PCSK9 Inhibition (Proprotein Convertase Subtilisin/Kexin type 9) A. PCSK9 binds LDL receptor leads to LDL receptor degradation B. PCSK9 Inhibition restores LDL receptor to hepatocyte wall causing increased uptake of LDL - C

32 Population Studies: PCSK9 Loss of Function Mutations Patients with loss-of-function mutations in PCSK9 or total lack of PCSK9 Have naturally low levels of LDL-C and reduced Coronary Heart Disease ( efficacy) Are not associated with other detectable abnormalities ( safety) PCSK9 Mutation LDL-C Reduction CHD Reduction Population Benn et al, JACC 2010 R46L 12% 46% 1) Copenhagen City Heart Study 2) Copenhagen General Population Study 3) Copenhagen Ischemic Heart Disease Study (DK) Cohen et al, NEJM 2006 R46L Y142X or C679X 14% 28% 47% 88% Atherosclerosis Risk Community Study (US) Benn, M. et al. J Am Coll Cardiol. 2010;55(25): ; Cohen, JC. et al. N Engl J Med. 2006;354(12):

33 PCSK9 Inhibitors Under Development

34 PCSK9 Inhibition (Proprotein Convertase Subtilisin/Kexin type 9) PCSK9 enhances degradation of hepatic LDL receptors. Its Inhibition increases LDL receptors and decreases LDL-C Recent Phase 2 trials GAUSS Statin intolerant pts due to muscle side effects AMG 145 sc q 4 wk, -63% AMG+E vs. 15 % E alone Rutherford Heterozygous FH pts AMG mg sc 55%, 65% < 70mg LDL-C RN316 - primary hypercholesterolemia not goal on statin RN 316 iv added to R/A/or S further LDLC & + HDLC Phase 3 trial ODYSSEY OUTCOMES - 18,000 patients with ACS compare statins to statins plus REGN

35 Ongoing PCSK9 inhibitor CVD outcomes trials (8 Reports on PCSK9 at ACC 2013) All performed on background of high intensity or maximally tolerated statin therapy with > 50% further reduction LDL-C LAPLACE-2 Evolocumab for 12 weeks 1117 pts Statin intolerant pts 63-75% LDLC vs. 20% with Ezetimibe RUTHERFORD-2 Evolocumab 12 weeks with He FH 331 pts 80% Rx had LDL-C < 70 mg/dl vs. 2% control group ODYSSEY OUTCOMES Alirocumab NCT Acute coronary syndromes (N=18,000) FOURIER Evolocumab NCT Very high risk CVD (n=22,500) SPIRE 1 & 2 Bococizumab NCT & NCT High CVD risk (LDL-C >70 - <100 mg/dl n=>12,000; LDL-C >100 mg/dl n=6300)

36 IMPROVE-IT A large scale (18,144 participants), multi-center RCT of high risk post Acute Coronary Syndrome (ACS) patients Intervention: ezetimibe 10 mg added to simvastatin 40* Comparator: simvastatin 40* Both groups achieved a mean LDL-C < 70 mg/dl Study took 9 years; f/u was 7 years No increase in side effects with the intervention *some uptitration allowed.

37 LDL-C and Lipid Changes in IMPROVE-IT 1 Yr Mean LDL-C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl IMPROVE-IT slide set with permission

38 Individual Cardiovascular Endpoints and CVD/MI/Stroke HR Simva* EZ/Simva* p-value All-cause death CVD CHD MI Stroke Ischemic stroke Cor revasc 30d UA CVD/MI/stroke Ezetimibe/Simva Better Simva Better *7-year event rates (%) IMPROVE-IT slide set with permission

39 View from 35,000 Feet: 1) Study reaffirms the central role of intensive LDL reduction in the prevention of recurrent cardiac events (heart attack and stroke) 2) Results expand the options for additional proven * lipid lowering therapies *Shown to add incremental benefit and are safe when taken as directed

40 Does This Change the Guidelines? 2013 ACC-AHA Guidelines recommended high-intensity statin therapy for those with ACS, but expressly stated: Clinicians treating high risk patients who have a less than anticipated response to statins, who are unable to tolerate a less than recommended intensity of a statin or who are completely statin intolerant, may consider the addition of non-statin cholesterol lowering therapy

41 New ACC/AHA Guidelines on Lipids: Are PCSK9 Inhibitors Poised for a Breakthrough? Sidney C. Smith, Jr. MD, FACC, FAHA Professor of Medicine/Cardiology University of North Carolina at Chapel Hill Immediate Past President World Heart Federation YES! Nothing to Disclose ] If justified by outcomes and safety

42 World Heart Federation Circulation June 29, 2004

43 World Heart Federation Strategic Principles for Development of National Clinical Guidelines Whereas the causes of CVD are common to all parts of the world, the approaches to its prevention at a societal or individual level will differ between countries for cultural, social, medical, and economic reasons. Smith et al., Circulation June 29, 2004