Cardiology 2015: Status On Pharmacology News, Debates & Novelties George D. Dangas, MD, FESC, FACC Professor of Medicine (Cardiovascular Disease) Icahn School of Medicine at Mount Sinai Zena & Michael A. Weiner Cardiovascular Institute New York, USA
TAVR 2015: Current Status On Pharmacology
TAVR complications TAVR has produced similar result to surgery and superior to conservative management of severe AS Yet, it possesses its own range of complications, dominated by bleeding and vascular events Limiting peri-procedure anticoagulation might appear as an option if there was no fear of thrombosis
The Problem DWI (MRI) Following AVR Showing Silent Stroke 4
Thromboembolism from the valve site Thromboemboli from the bioprosthesis before endothelialization completes. Aggregation of platelet and fibrin has been known to occur on valve leaflet within a few hours after implantation. Tay et al, JACC Cardiovasc Interv 2011
Expression of Tissue Factor in aortic valve leaflets of varying status normal sclerotic stenotic Maréchaux et al. Cardiovasc Pathol 2009
Tissue Factor and Thrombin co-localize with calcification in patients with Aortic Stenosis (n=52) Breyne et al. Atherosclerosis 2010
Endothelization of the Valve Stent Long-term data from bioprosthetic valve studies indicate that neointimal tissue growth and endothelization of the valve stent occur about 3 months after implantation, when the risk of stroke shows a corresponding reduction 1. Histopathological studies of the CoreValve apparatus show a similar timeline for the endothelization of the transcatheter device 2. Thus, the critical period for devicerelated thromboembolic events is likely between 24 h and 3 months after TAVR. 1. Merie et al JAMA 2012 2. Noble et al EuroIntervention 2009
Reduced leaflet motion was observed in all valve types including surgical bioprostheses Corevalve Portico Sapien Perimount surgical valve Diastole Systole
Risk of ischaemic and bleeding complications after TAVR Nijenhuis VJ et al. Thromb Haemost 2015
Standard antithrombotic therapy during TAVR Anticoagulant therapy: UFH +/- protamine at the end of the procedure Coumadin+/-ASA or DAPT for afib+tavr Antiplatelet therapy: aspirin and/or clopidogrel pre-procedure at operators discretion (PARTNER Design) Nothing standardized
Dual Versus Single Antiplatelet Therapy in Patients Undergoing TAVR: A Systematic Review and Meta-Analysis No differences in stroke between DAPT and SAPT at 30 days Higher risk of bleeding with DAPT at 30 days No differences in mortality between DAPT and SAPT at 30 days Heart, Lung and Circulation (2014) xx, 1 8
Lefevre T, et al LBCT abstract Dangas GD et al, BRAVO3 Investigators paper submitted The Randomized Multicenter BRAVO-3 trial August 2015 Update: Complete - LBCT at TCT-2015 on October 15 802 patients undergoing transfemoral TAVR standard dosing of bivalirudin R Heparin Possible reversal with Protamine is allowed CO- PRIMARY EP MAJOR BLEEDING at 48hrs & NACE at 30-days
GALILEO Global study comparing a rivaroxaban-based antithrombotic strategy to an antiplatelet-based strategy after transcatheter aortic valve replacement to Optimize clinical outcomes George D. Dangas, MD, FACC, FESC & Stephan Windecker, MD, FESC
Rivaroxaban Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa. Factor Xa initiates the final common pathway of the coagulation cascade and results in the formation of thrombin, which catalyzes additional coagulation-related reactions and promotes platelet activation. Rivaroxaban In the ATLAS-ACS 2-TIMI 51 Trial, 2.5 mg Bid and 5 mg Bid Rivaroxaban decreased the risk of death, MI or stroke in patients with a recent acute coronary syndrome 1. The risk of fatal bleeding was increased only in the 5 mg arm. In the ROCKET-AF Trial, 20 mg Qd was noninferior to Warfarin in reducing the risk of stroke or systemic embolism and was associated with a reduction in risk of intracranial or fatal bleeding 2. 1. Patel et al - N engl j med 365;10 2. Mega et al - N engl j med 366;1
GALILEO Study Flow Diagram
Summary The balance between ischemic and bleeding events in TAVR patients is challenging With a more standardized antithrombotic protocols, a more meaningful assessment of CVE prevention can be made The optimal antithrombotic regimen (antiplatelet and/or anticoagulant) during and after TAVI has to be established Anticoagulation plus a oral antiplatelet appears appealing but still not assessed. Randomized, prospective trials of Embolic Protection Devices to commence soon with a multi-center, multi-country design
Longer DAPT is associated with lower risk of Stent Thrombosis and Myocardial Infarction Giustino,.. Dangas; JACC 2015
32,135 patients 10 trials Mean weighted follow-up time among all 10 RCTs was 19.6 months. Mean weighted exposure time to antiplatelet therapy within the S-DAPT and L-DAPT groups was 8.5 and 23.2 months, respectively. Giustino,.. Dangas; JACC 2015
Shorter DAPT is associated with lower risk of Clinically Significant Bleeding and All-Cause Mortality *CSB defined as a BARC 3 or 5, TIMI major or minor, GUSTO moderate or severe or STEEPLE major Giustino, Dangas; JACC 2015
Trade-Off Between Stent Thrombosis and Bleeding Over Time Incidence rates and standardized incidence risk difference for Stent Thrombosis and Clinically Significant Bleeding per 100 person/year between S-DAPT and L-DAPT For every ST event averted with L-DAPT, approximately 2.1 extra CSB events are estimated to occur (- 0.45 ST / 0.21 CSB per 100 person / year). *CSB defined as a BARC 3 or 5, TIMI major or minor, GUSTO moderate or severe or STEEPLE major Giustino,.. Dangas; JACC 2015
First- Versus Second-Generation DES and risk for Stent Thrombosis.. Where is the difference? 1 st -generation DES 2 nd -generation DES SES 13 months PES 11 months ZES 3 months EES 6 months Representative Images of 2 nd - vs. 1 st -generation DES in Human Coronary Arteries
Risk of ST with 1 st - and 2 nd -Generation Drug-Eluting Stents According to Duration of Dual Antiplatelet Therapy Giustino, Dangas; JACC 2015
Novelties 2015PCSK9: Proprotein Convertase Subtilisin-Kexin Type 9 PCSK9 plays a pivotal role in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor (LDL-R) promotes the degradation of the LDL-R prevents it from recycling to the membrane controls whether internalized LDL-R is recycled or catabolized may also influence Apo B synthesis and triglyceride secretion Serine protease predominantly expressed by the liver and intestine In PCSK9 human population studies: Gain-of-function mutations result in hypercholesterolemia Loss-of-function mutations associated with low LDL-C and low prevalence of CHD events Lambert et al Atherosclerosis 2009;203:1 7 Lambert et al J Lipid Res 2012;53:2515-24
The Role of PCSK9 in the Regulation of LDL Receptor Expression For illustration purposes only 25
Impact of an PCSK9 synthesis inhibition on LDL Receptor Expression For illustration purposes only 26
LDL-C values achieved vs. study time-points (ITT analysis). Percentages above Weeks 12 and 24 data points indicate LS mean (SE) percent change from baseline. Values above Weeks 24 and 52 indicate achieved LDL-C. In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile. European Heart Journal doi:10.1093/eurheartj/ehv028
Randomization 2:2:1:1 End of Study GAUSS-2 Study Design Screening and placebo run-in period Fasting LDL-C 5 10 days before randomization Subcutaneous injection of placebo Evolocumab 140 mg SC Q2W + Placebo PO QD N = 103 Evolocumab 420 mg SC QM + Placebo PO QD N = 102 Placebo SC Q2W + Ezetimibe 10 mg PO QD N = 51 Placebo SC QM + Ezetimibe 10 mg PO QD N = 51 Maximum 6 weeks Time point Evolocumab or Placebo SC Q2W Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 Evolocumab or Placebo SC QM Prior intolerance to 2 statins: LDL-C above NCEP ATP III risk category goal : Weekly dose 7 times the smallest available tablet strength or less Stroes et al J Am Coll Cardiol. 2014;63(23):2541-2548 QM EOS Q2W EOS*
Mean Percent Change in LDL-C from Baseline GAUSS-2: Evolocumab 140 mg Q2W LDL-C Response 0-20 -18% -40-60 -56% Study drug administration Biweekly SC -80 1 2 Number of subjects: 51 51 48 49 49 103 100 99 98 98 BL Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Week 1: Ezetimibe (N = 51) 2: Evolocumab 140 mg Q2W (N = 103) BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted. Stroes et al J Am Coll Cardiol. 2014;63(23):2541-2548
Mean Percent Change in LDL-C from Baseline GAUSS-2: Evolocumab 420 mg Q4W LDL-C Response 0-20 -15% -40-60 -80 1 2 Number of subjects: 51 50 51 44 45 102 100 100 91 96-53% Study drug administration Monthly SC BL Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Week 1: Ezetimibe (N = 51) 2: Evolocumab 420 mg QM (N = 102) BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted. Stroes et al J Am Coll Cardiol. 2014;63(23):2541-2548
Randomization 2:2:1:1 End of Study GAUSS-2 Study Design Screening and placebo run-in period Fasting LDL-C 5 10 days before randomization Subcutaneous injection of placebo Evolocumab 140 mg SC Q2W + Placebo PO QD N = 103 Evolocumab 420 mg SC QM + Placebo PO QD N = 102 Placebo SC Q2W + Ezetimibe 10 mg PO QD N = 51 Placebo SC QM + Ezetimibe 10 mg PO QD N = 51 Maximum 6 weeks Time point Evolocumab or Placebo SC Q2W Evolocumab or Placebo SC QM Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 Prior intolerance to 2 statins: LDL-C above NCEP ATP III risk category goal : Weekly dose 7 times the smallest available tablet strength or less Stroes et al J Am Coll Cardiol. 2014;63(23):2541-2548 QM EOS Q2W EOS*
Mean Percent Change in LDL-C from Baseline GAUSS-2: Evolocumab 140 mg Q2W LDL-C Response 0-20 -18% -40-60 -56% -80 1 2 Number of subjects: 51 51 48 49 49 103 100 99 98 98 Study drug administration Biweekly SC BL Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Week 1: Ezetimibe (N = 51) 2: Evolocumab 140 mg Q2W (N = 103) BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted Ṡtroes et al J Am Coll Cardiol. 2014;63(23):2541-2548
Mean Percent Change in LDL-C from Baseline GAUSS-2: Evolocumab 420 mg Q4W LDL-C Response 0-20 -15% -40-60 -80 1 2 Number of subjects: 51 50 51 44 45 102 100 100 91 96-53% Study drug administration Monthly SC BL Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Week 1: Ezetimibe (N = 51) 2: Evolocumab 420 mg QM (N = 102) BL, baseline. Vertical lines represent the standard error around the mean. Plot is based on observed data with no imputation for missing values. P values are multiplicity adjusted. Stroes et al J Am Coll Cardiol. 2014;63(23):2541-2548
Proportion of Patients Achieving LDL-C Target Goal at Week 12, n (%) GAUSS-2: LDL-C Goal Achievement 100.0 90.0 80.0 70.0 60.0 50.0 40.0 12 (92%) 7 (70%) at Week 12 28 (80%) 29 (91%) 36 (77%) 40 (76%) 30.0 20.0 10.0 0.0 0 (0%) 0 (0%) Lower Risk* < 160 mg/dl 1 (8%) 3 (20%) Moderately High Risk < 130 mg/dl 2 (7%) 1 (4%) High Risk < 100 mg/dl Ezetimibe QD + PBO Q2W Ezetimibe QD + PBO QM Evolocumab 140 mg Q2W + PBO QD Evolocumab 420 mg QM + PBO QD *Combination of NCEP ATP IIII moderate and low risk categories. Rate based on subjects with observed values at Week 12 and LDL-C above target goal at baseline Stroes et al J Am Coll Cardiol. 2014;63(23):2541-2548
Post-hoc Adjudicated Cardiovascular TEAEs (Same as primary endpoint of ongoing ODYSSEY OUTCOMES trial ) Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) % (n) of patients All patients on background of max tolerated statin ± other lipid-lowering therapy Alirocumab (n=1550) Placebo (n=788) CV events confirmed by adjudication 1.4% (22) 3.0% (24) CHD death 0.2% (3) 0.8% (6) Non-fatal MI 0.7% (11) 2.2% (17) Fatal + non-fatal ischaemic stroke 0.5% (8) 0.3% (2) Unstable angina requiring hospitalisation 0 0.1% (1) Patients are censored at the end of TEAE period (last injection of study treatment + 70 days). Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. Unstable angina requiring hospitalisation is limited to the UA events with definite evidence of progression of the ischemic condition (strict criteria). Robinson J et al ESC hotline session Barcelona Aug 31, 2014
Cumulative probability of event Post-hoc Adjudicated Cardiovascular TEAEs Safety Analysis (at least 52 weeks for all patients in ongoing study) Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment, including 607 patients who completed W78 visit) 0.06 0.05 0.04 0.03 Placebo + max-tolerated statin ± other LLT Alirocumab + max-tolerated statin ± other LLT Cox model analysis: HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01 Mean treatment duration: 65 weeks 0.02 0.01 No. at Risk Placebo Alirocumab 0.00 0 788 1550 12 776 1534 24 731 1446 36 703 1393 Weeks Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy Robinson J et al ESC hotline session Barcelona Aug 31, 2014 48 682 1352 60 667 1335 72 321 642 84 127 252
Evolocumab (AMG 145) Alirocumab (SAR236553 /REGN727) Bococizumab (RN 316) Sponsor Amgen Sanofi / Regeneron Pfizer Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II Sample size 22,500 18,000 12,000 6,300 Patients MI, stroke or PAD 4-52 wks post-acs High risk of CV event Statin Atorva 20 mg or equiv Evid-based med Rx Lipid-lowering Rx LDL-C mg/dl(mmol/l) PCSK9 Inhibitor Cardiovascular Outcomes Trials 70 ( 1.8) 70 ( 1.8) 70-99 (1.8-2.6) 100 ( 2.6) PCSK9i Dosing Q2W or Q4W Q2W Q2W Endpoint 1 : CV death, MI, stroke, revasc or hosp for UA, Key 2 : CV death, MI, or stroke CHD death, MI, ischemic stroke, or hosp for UA CV death, MI, stroke, or urgent revasc Completion 12/2017 1/2018 8/2017
INTERVENTIONAL PHARMACOLOGY 2015 Conclusions TAVR is expanding Dedicated pharmacological studies underway DAPT debate will continue as the academic rivalry (and stent type) drives the 2 different opinion PCSK-9 inhibitors will be a game changer for all vascular beds