Medical Management of Coronary Artery Disease Focus on Residual Risk - - PowerPoint PPT Presentation
Medical Management of Coronary Artery Disease Focus on Residual Risk Duane Pinto, M.D., M.P.H. Interventional Cardiologist Chief, Interventional Section, Beth Israel Deaconess CV Division Associate Professor of Medicine Harvard Medical School
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Interventional Cardiologist Chief, Interventional Section, Beth Israel Deaconess CV Division Associate Professor of Medicine Harvard Medical School
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0.5 1.0 1.5 2.0
Antiplatelet Better Antiplatelet Worse
P<.0001
Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86
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Study Drug HF Severity Patients (n) Follow-up (years) Mean Dosage Effects on Outcomes CIBIS Bisoprolol* Moderate- Severe 641 1.9 3.8 mg/day All cause mortality 22% (p=NS) CIBIS-II Bisoprolol* Moderate- Severe 2,647 1.3 7.5 mg/day All cause mortality 34% (P<0.0001) BEST Bucindolol* Moderate- Severe 2,708 2.0 152 mg/day All cause mortality 10% (p=NS) MERIT-HF Metoprolol succinate# Mild- Moderate 3,991 1.0 159 mg/day All cause mortality 34% (P=0.0062) MDC Metprolol tartrate* Mild- Moderate 383 1.0 108 mg/day Death or Need for Tx 30% (P=NS) CAPRICORN Carvedilol Mild 1,989 1.3 40 mg/day All cause mortality 23% (P =0.03) US Carvedilol Carvedilol Mild- Moderate 1,094 0.5 45 mg/day All-cause mortality† 65% (P=.0001) COPERNICUS Carvedilol Severe 2,289 0.9 37 mg/day All-cause mortality 35% (P =0.0014)
*Not an approved indication
†Not a planned end point. #Not approved for severe HF or mortality reduction alone
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Yes >100 >160 Stage 2 Hypertension Yes 90–99 140–159 Stage 1 Hypertension Yes 80–89 120–139 Pre- hypertension Encourage <80 <120 Normal With compelling indications Initial drug therapy Lifestyle modification DBP* mmHg SBP* mmHg BP classification
ACEI=Angiotensin converting enzyme inhibitor, ARB=Angiotensin receptor blocker, BB=b-blocker, BP=Blood pressure, CCB=Calcium channel blocker, DBP=Diastolic blood pressure, SBP=Systolic blood pressure Chobanian AV et al. JAMA. 2003;289:2560-2572 *Treatment determined by highest blood pressure category. †Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. ‡Treat patients with chronic kidney disease or diabetes mellitus to blood pressure goal of <130/80 mmHg.
Drug(s) for the compelling indications.‡ Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Drug(s) for compelling
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Goal: Complete Cessation and No Exposure to Environmental Tobacco Smoke
quitting.
replacement and bupropion.
tobacco smoke at work and home.
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I I I I I a I I a I I a I I b I I b I I b I I I I I I I I I I I I I I a I I a I I a I I b I I b I I b I I I I I I I I I I I I I I a I I a I I a I I b I I b I I b I I I I I I I I I I I a I I a I I a I I b I I b I I b I I I I I I I I I
*Non-HDL-C = total cholesterol minus HDL-C
I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III I I I IIa IIa IIa IIb IIb IIb III III III IIa IIa IIa IIb IIb IIb III III III
If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*
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LaRosa JC et al. NEJM. 2005;352:1425-1435 LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study.
Statin Placebo Relationship between LDL Levels and Event Rates in Secondary Prevention Trials
TNT (atorvastatin 80 mg/d) TNT (atorvastatin 10 mg/d) HPS CARE LIPID LIPID CARE HPS
4S 4S
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Sever P & Mackay J. Br J Cardiol 2014;21:91- 3 Giugliano RP, et al. Lancet 2012;380:2007-17 Sabatine MS, et al. NEJM 2015;372:1500-9
– Chaperones LDL-R to destruction circulating LDL-C – Loss-of-fxn genetic variants LDL-R LDL-C & risk of MI
– Fully human anti- PCSK9 mAb – ~60% LDL-C – Safe & well-tolerated in Ph 2 & 3 studies – Exploratory data suggested CV events
evolocumab
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Evolocumab SC
140 mg Q2W or 420 mg QM
Placebo SC
Q2W or QM
LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL
Follow-up Q 12 weeks
Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)
RANDOMIZED DOUBLE BLIND
Sabatine MS et al. Am Heart J 2016;173:94-101
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An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
10 20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120 LDL Cholesterol (mg/dl) Weeks
Cohort of 11,077 patients who
Evolocumab Placebo Similar data out to 4 years in OSLER-1 (JAMA Cardiology online)
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Endpoint Evolocumab (N=13,784) Placebo (N=13,780) HR (95% CI)
3-yr Kaplan-Meier rate
CV death, MI, or stroke 7.9 9.9 0.80 (0.73-0.88) Cardiovascular death 2.5 2.4 1.05 (0.88-1.25) Death due to acute MI 0.26 0.32 0.84 (0.49-1.42) Death due to stroke 0.29 0.30 0.94 (0.58-1.54) Other CV death 1.9 1.8 1.10 (0.90-1.35) MI 4.4 6.3 0.73 (0.65-0.82) Stroke 2.2 2.6 0.79 (0.66-0.95)
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AC C .18
11
Post-ACS patients (1 to 12months) Run-in period of 2−16 weeks on high-intensity
rosuvastatin At least one lipid entry criterion met
R andomization Schwartz GG, et al. Am Heart J2014;168:682-689.e1.
Patient and investigators remained blinded to treatment and lipid levels for the entire duration of the study
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AC C .18
32
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Stable CAD (post MI) Residual Inflammatory Risk (hsCRP > 2 mg/L)
Randomized Canakinumab 150 mg SC q 3 months Randomized Placebo SC q 3 months Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Randomized Canakinumab 300 mg SC q 3 months Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+) Randomized Canakinumab 50 mg SC q 3 months
Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events
Ridker PM et al. N Engl J Med. 2017;377:1119-31
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Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months
HR 0.85 95%CI 0.76-0.96 P = 0.007
Ridker PM et al. N Engl J Med. 2017;377:1119-31
Cumulative Incidence (%) Follow-up Years
HR 0.83 95%CI 0.74-0.92 P = 0.0006
Follow-up Years
35 - 40% reductions in hsCRP and IL-6 No change in LDLC
1 2 3 4 5
Cumulative Incidence (%)
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Slide by C. Michael Gibson, M.S., M.D.
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Months from Randomization
Ticagrelor 60 mg HR 0.84 (95% CI 0.74 – 0.95) P=0.004 CV Death, MI, or Stroke (%)
3 6 9 12 15 18 21 24 27 30 33 36
Ticagrelor 90 mg HR 0.85 (95% CI 0.75 – 0.96) P=0.008
Placebo (9.0%) Ticagrelor 90 (7.8%) Ticagrelor 60 (7.8%)
6 5 4 3 10 9 8 7 2 1
Bonaca MP et al. and Sabatine MS. NEJM 2015;372:1791-800
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Slide by C. Michael Gibson, M.S., M.D.
Thrombin Made
Surface Thrombin Most Potent Activator
ADP Secreted by Platelet ADP Activates Platelet Antithrombins Thienopyridines “Amplification” “Burst” “Activation” “Growth of Thrombus”
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following ACS
models as triple therapy and is associated with less bleeding
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Christina Yip1*, Aruni Seneviratna2*, Sock Hwee Tan2, Sock Cheng Poh2, Zhen Long Teo3, Joshua Loh2, Eng Soo Yap1,4 , E. Magnus Ohman5, C. Michael Gibson6, Mark Richards2,3 and Mark Chan2,3
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Placebo
24
Rivaroxaban 2.5 mg BID
All Cause Death
24
Cardiovascular Death
Months
CV Death / MI / Stroke
Estimated Cumulative incidence (%)
24
Months Months HR 0.85 mITT p=0.039 ITT p=0.011 HR 0.62 mITT p<0.001 ITT p<0.001
2.7% 4.5% 4.2% 2.5% 10.4% 9.0%
Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Placebo Placebo
HR 0.64 mITT p<0.001 ITT p<0.001
NNT = 56 NNT = 71 NNT = 59
12 12 12
12% 5% 5%
Patients Treated with ASA + Thienopyridine
N Engl J Med 2012; 366:9-19. Gibson CM, TIMI 51 AHA 2011
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30-day run- in, ASA 100 mg Rivaroxaban 5.0 mg bid ± pantoprazole 40 mg od ASA 100 mg od ± pantoprazole 40 mg od Rivaroxaban 2.5 mg bid + ASA 100 mg od ± pantoprazole 40 mg od Final follow-up visit#
R
30-day washout period* Final washout period visit 1:1:1 N~27,000
Population: Documented CAD or PAD Objective: efficacy and safety of rivaroxaban, low-dose rivaroxaban plus ASA or ASA alone for reducing risk of MI, stroke or CV death in CAD or PAD
*Patients treated according to local standard of care
#≤30 days of the required pre-specified number of events having
www.clinicaltrials.gov/show/NCT01776424
Start: Q1-13 End: ~Q1-18
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Eikelboom et al. August 27, 2017DOI: 10.1056/NEJMoa1709118
Xaretlo 2.5mg is indicated for the prevention of stroke, myocardial infarction and cardiovascular death, and for the prevention of acute limb ischemia and mortality in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) in combination with ASA 100M. Use of Rivaroxaban is approved as well as for AF, DVT and PE at present.
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Outcome R + A N=9,152 A N=9,126 Rivaroxaban + Aspirin
N (%) N (%) HR (95% CI) p CV death 160 (1.7%) 203 (2.2%) 0.78 (0.64-0.96) 0.02 Stroke 83 (0.9%) 142 (1.6%) 0.58 (0.44-0.76) <0.0001 MI 178 (1.9%) 205 (2.2%) 0.86 (0.70-1.05) 0.14
Eikelboom et al. August 27, 2017DOI: 10.1056/NEJMoa1709118
Rivaroxaban is not FDA approved in the ACS setting or in patients with atrial fibrillation undergoing stent placement. It is in many other countries. Check your local label. The use of Rivaroxaban in chronic CAD is under regulatory review and is off label at present.
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Pooled Analysis of ATLAS ACS 2–TIMI 51 and COMPASS All-Cause Death CV Death
N Engl J Med 2012; 366:9-19. Eikelboom et al. August 27, 2017DOI: 10.1056/NEJMoa1709118
Data on file PERFUSE Study Group
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Rate Difference / 10,000 Patient-years
Benefit = Non-hemorrhage CV death, MI + ischemic stroke Harm = Fatal Bleeding + ICH
Benefit Harm
50
14
23
23
Gibson CM et al, JACC 2018 in press
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