State of the Art Cardiology and Advanced Limb Preservation Techniques

Transcription

1 NCVH Baton Rouge: State of the Art Cardiology and Advanced Limb Preservation Techniques

2 Faculty Craig M. Walker, MD, FACC, FACA, FACP, FSCAI, FASCI, FCCP, FICA (Chair) Founder, President and Medical Director, Cardiovascular Institute of the South Clinical Professor of Medicine Tulane University School of Medicine LSU School of Medicine New Orleans, Louisiana Deepak Thekkoott, MD (Faculty) Medical Director, Division of Cardiology Interventional Cardiology, Cath Lab Services, and Chest Pain Center Lane Regional Medical Center Cardiovascular Institute of the South Zachary, Louisiana

3 Activity Description Target Audience This educational activity is designed for cardiologists, interventional cardiologists, vascular medicine specialists, cardiothoracic, endovascular, vascular and general surgeons, interventional radiologists and other healthcare professionals involved in the care and treatment of patients with peripheral arterial disease. Statement of Need Peripheral arterial disease (PAD), an independent predictor of cardiovascular disease (CVD) morbidity and mortality, is associated with increased hospitalization costs, recurrent hospitalizations, and repeat revascularizations. Overall, patients with PAD have higher 1-year and 3-year hospitalization rates for vascular causes than those with other CVD. Adherence to guideline-recommended approaches, including antiplatelet therapy, significantly reduces the rates of major adverse limb events, major adverse cardiac events, and all-cause mortality. Select patient populations may require alternative and aggressive antiplatelet strategies to reduce recurrent events and rehospitalizations. This interactive activity will address selection of approaches to platelet inhibition for secondary prevention of CVD events in the PAD patient. Support This activity is supported by an educational grant from Merck & Company

4 Accreditation & Credit Designation The Academy for Continued Healthcare Learning is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Academy for Continued Healthcare Learning designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Staff and Reviewer Disclosures ACHL staff members and others involved with the planning, development, and review of the content for this activity have no relevant affiliations or financial relationships to disclose.

5 Disclosures Faculty Disclosures The Academy for Continued Healthcare Learning (ACHL) requires that the faculty participating in a CME/CE activity disclose all affiliations or other financial relationships (1) with the manufacturers of any commercial product(s) and/or provider(s) of commercial services discussed in an educational presentation and (2) with any commercial supporters of the activity. All conflicts of interest have been resolved prior to this CME/CE activity. ACHL also requires participating faculty to disclose when unapproved/unlabeled uses of a product are discussed in a CME/CE activity. Craig M. Walker, MD, FACC, FACA, FACP, FSCAI, FASCI, FCCP, FICA (Chair) Advisory Board: Abbott, CR Bard, Boston Scientific, and Spectranetics Consulting Agreements: Abbott, Boston Scientific, Cardiva Medical, Cook Medical, Lake Regional, Medtronic, and Spectranetics Stockholder: Cardiva Medical, Cardioprolific, Spectranetics, and Vasamed Honoraria Agreements: Abbott, Bard, Boston Scientific, Spectranetics, and Trireme Medical Speakers Bureau: Abbott, Arbor, Bard, Boehringer-Ingelheim, Bristol-Myers Squibb/Sanofi Pharmaceuticals, Cardiva Medical, Cordis, DSI/Lilly, Merck & Company, Pfizer, and Spectranetics Deepak Thekkoott, MD (Faculty) Types of financial relationships: None Discussion of Off-Label, Investigational, or Experimental Drug/Device Use: None

6 Learning Objectives Upon completion of this activity, participants will be able to: Outline the burden and risks of atherothrombotic events in patients with PAD Review the mechanisms of action of antiplatelet therapies for optimal postsurgical/interventional management of PAD Compare and contrast strategies for secondary prevention via platelet inhibition to reduce risks of PAD and CVD

7 Pre Assessment Please utilize the provided ARS keypad to submit your responses

8 73 y/o woman, type 2 diabetes and hypertension presents with symptomatic peripheral arterial disease. According to 2013 ACC/AHA guidelines, what antiplatelet regimens should she receive to reduce her risk of MI, stroke, and vascular death? A. Dual antiplatelet therapy B. Warfarin in combination with another antiplatelet agent C. She is not a candidate for antiplatelet therapy due to her comorbid conditions D. Monotherapy with either aspirin or clopidogrel Dual antiplatelet therapy 33% Warfarin in combination... 10% She is not a candidate fo... 0% Monotherapy with eithe... 56%

9 Which of the following best describes the mechanism of action of vorapaxar? A. Thromboxane synthase inhibitor B. Protease activated receptor (PAR)-1, PAR-2, and PAR-4 antagonist C. PAR-1 antagonist D. Glycoprotein IIb/IIIa inhibitor Thromboxane synthase i... 14% Protease activated recep... 29% PAR-1 antagonist 24% Glycoprotein IIb/IIIa inhi... 33%

10 Which of the following outcomes was significantly reduced in PAD patients who participated in the TRA 2 P TIMI 50 trial and received vorapaxar? A. Moderate to severe bleeding B. Hospitalizations for acute limb ischemia C. Limb amputations D. Stent thrombosis 10% 32% 26% 32% Moderate to severe ble... Hospitalizations for acut... Limb amputations Stent thrombosis

11 Treating PAD With Intervention Craig M. Walker, MD, FACC, FACA, FACP, FSCAI, FASCI, FCCP, FICA (Chair) Founder, President and Medical Director, Cardiovascular Institute of the South Clinical Professor of Medicine Tulane University School of Medicine LSU School of Medicine New Orleans, Louisiana

12 Prevalence of PAD in High-Risk Patients (PARTNER Trial) Age >70 or >50 if DM or Smoking Hx 29% of patients were diagnosed with PAD defined as ankle-brachial index <0.9 N= 6,979 Age > 70 years or years + diabetes or smoking 29% 44% 56% PAD only PAD and CAD Hirsch AT et al. JAMA. 2001;286:

13 Symptomatic And Asymptomatic PAD (PARTNER Trial) Prior Diagnosed PAD (n=366) 12.5% 61.7% 25.8% Newly Diagnosed PAD (n=457) 5.5% 46.3% 48.3% No Symptoms Nonspecific Symptoms Claudication Hirsch AT et al. JAMA. 2001;286:

14 Results of Coronary Angiograms in 634 Patients with PAD NORMAL MILD / MODERATE ADVANCED CABG CANDIDATE INOPERABLE Hertzer et al. Ann Surg.1984;199:

15 Patient Survival by Ankle-Brachial Index in Cardiovascular Health Study ABI>1.0 ABI: ABI: ABI< Newman et al. ATVB. 1999;19:

16 Five -year Mortality Rates : PVD Versus Cancer Five Year Mortality Rates Lung Cancer Colon/Rectal PAD Breast Cancer 0% 20% 40% 60% 80% 100% *Criqui M. Presentation: Vascular Medicine of the Lower Extremities at the American Diabetes Association s Scientific Sessions June 1999

17 Prognosis in Patients with Intermittent Claudication Population >55 yr Intermittent Claudication Peripheral Vascular Outcomes Other Cardiovascular Morbidity/Total Mortality Worsening Claudication 16% Lower Extremity Bypass Surgery 7% Major Amputation 4% 4% vs Nonfatal Cardiovascular Event (MI/Stroke, 5-year Rate) 20% 42.5% 5-yr Mortality 30% Cardiovascular Cause 75% Adapted from Weitz JI et al. Circulation. 1996;94:

18 PAD Patients are Hypercoaguable

19 Age & Gender Adjusted Odds Ratio Hemostatic Risk Factors for Coronary and Cerebrovascular Events in PAD Fibrinogen D-Dimer. tpa Antigen Viscosity N = 607 CAD Events Stroke Smith et al. Br J Hematol. 1998;100:

20 D-Dimer (ng/ml) Ongoing Fibrin Formation and Degradation as a Function of ABI Trend for both: p< CAD (+) CAD (-) > <0.5 Ankle-Brachial Index McDermott et al. Am J Cardiol. 2003;92:194-9.

21 Platelet Aggregation (%) Spontaneous Platelet Aggregation in Non-Coronary Vascular Disease p< CONTROL CEA AAA PAD Hertzer et al. Ann Surg. 1984;199:

22 CV Events (%) Effect of Antithrombotic Agents on Cardiovascular Events in PAD Patients p=0.004 Claudication Bypass-graft Angioplasty TOTAL Placebo Antithrombotic Agents 4,939 patients; 42 trials Antithrombotic Trialists. BMJ. 2002:324:71-80.

23 PAD/ CAD Management in DM Risk factor modification Smoking cessation Goal: complete cessation Lipid management Initiate therapy at LDL >100 mg/dl Raise HDL-C Lower triglycerides Blood pressure control Goal <140/90 mm Hg Blood sugar control (diabetic patients) Goal: HbA1c<7%3 Antiplatelet therapies Goal: reduction in risk of MI stroke, and vascular death ASA, clopidogrel Achieving ideal body weight Exercise

24 Why does endovascular therapy make sense? Angiography and flow restoration at same time No need for vein Less trauma Less risk of infection Quicker ambulation Leg veins spared Less risk of neuropathy Less pain Can be repeated Can treat very distal disease/open multiple IP vessels Can open occluded grafts Less cost

25 Cause of Interventional Failure Poor initial result Incomplete expansion Flow limiting dissection Elastic recoil Acute thrombosis Restenosis Negative remodeling Intimal hyperplasia Thrombus

26 Antiplatelet Therapies in Peripheral Arterial Disease Deepak Thekkoott, MD (Faculty) Medical Director, Division of Cardiology Interventional Cardiology, Cath Lab Services, and Chest Pain Center Lane Regional Medical Center Cardiovascular Institute of the South Zachary, Louisiana

27 Antiplatelet Agents: Mechanisms of Action Vorapaxar Thrombin ADP Clopidogrel Prasugrel Ticagrelor Cangrelor TXA 2 GP IIb/IIIa Platelet Aspirin Zhang C et al. Nature. 2012;492:387-92; Wallentin L. Eur Heart J. 2009;30:

28 Vorapaxar: PAR-1 Antagonist Terminal half-life: 126 to 269 h Metabolism: Hepatic, mainly via CYP3A4 (90% in bile as inactive) Route of administration: oral Vorapaxar does not impact: Platelet aggregation mediated by ADP, collagen or a thromboxane mimetic Coagulation parameters Bleeding time (as monotherapy) Cho J et al. Vasc Health Risk Manag. 2014;10:

29 Review of Clinical Data of Antiplatelet Therapies in PAD Aspirin monotherapy Clopidogrel vs. aspirin Dual antiplatelet therapy Vorapaxar in combination therapy

30 Meta-analysis of Aspirin Monotherapy for Cardiovascular Events In PAD Patients Endpoint RR (95%CI) P-value Reduction in CVD events not statistically significant CVD, MI, Stroke 0.75 ( ) 0.21 MI 0.88 ( ) 0.78 Significant reduction in nonfatal stroke Stroke 0.64 ( ) 0.04 CV Death 1.15 ( ) 0.48 Any Death 0.96 ( ) 0.74 Major Bleeding 1.04 ( ) JAMA. 2009;301(18): Aspirin Better Placebo Better

31 Clopidogrel Vs. Aspirin in Patients with Symptomatic Atherosclerosis (MI, Stroke, PAD): The CAPRIE Trial P for heterogeneity=0.042 Stroke MI Clopidogrel more effective than aspirin in reducing ischemic risks PAD All patients Aspirin Better Clopidogrel Better Relative-risk reduction and 95% CI by disease subgroup MI=myocardial infarction; PAD=peripheral arterial disease Ischemic stroke, myocardial infarction, or vascular death. CAPRIE Steering Committee. Lancet. 1996;348(9038):

32 Clopidogrel Plus Aspirin Following Peripheral Arterial Bypass Surgery (CASPAR) Study 851 patients: clopidogrel plus ASA vs. ASA for 6-24 month Proportion Event-free (%) Proportion Event-free (%) Clopidogrel Placebo Hazard Ratio=0.98 [95% CI ], P=NS Time to Event (days) Venous grafts: Hazard Ratio=1.25 [95% CI ], P=NS Prosthetic grafts: Hazard Ratio=0.65 [95% CI ], P= Treatment by type of graft interaction P= Venous-Clopidogrel Prosthetic-Clopidogrel Venous-Placebo Prosthetic-Placebo Adapted from Belch JJ et al. J Vasc Surg. 2010;52: Time to Event (days) Clopidogrel plus aspirin did not improve limb or systemic outcomes

33 Ticagrelor vs. Clopidogrel in Patients with ACS by PAD status Results from the PLATO trial (1,144 patients) Event CV Death/MI/Stroke Death From Any Cause CV Death Death from Vascular Causes or MI MI Stroke Severe Recurrent Ischemia Recurrent Ischemia Definite Stent Thrombosis PAD No PAD Total Events Favors Ticagrelor Favors Clopidogrel Adapted from Patel MR et al. Eur J Prevent Cardiol. 2015;22: Kaplan- Meier % T C HR (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Treatment by PAD Interaction P Value Reduction in CVD events with ticagrelor nonsignificant

34 TRA 2P-TIMI 50 Trial Design Prior MI, CVA, or PAD N=26,449 Standard care including oral antiplt rx RANDOMIZE 1:1 DOUBLE BLIND Vorapaxar 2.5 mg/d Placebo Morrow et al. N Engl J Med ClinicalTrials.gov NCT Follow up Visits (Median F/U 30 Months) Primary Efficacy Analysis: 1. CVD/MI/Stroke 2. CVD/MI/Stroke/Urgent Coronary Revasc Principal Safety EP: GUSTO Mod/Sev bleeding

35 Event Rate (%) Background 1 Efficacy Evaluation Overall Population CV Death, MI, or Stroke 12% 10% 8% 6% 4% N = Mean f/u: 2.5 years Hazard Ratio 0.87 p < Placebo Vorapaxar 10.5% 9.3% Vorapaxar reduced the risk of CVD events with increased risk for moderate to severe bleeding 2% 0% Adapted from Morrow DA et al. N Engl J Med. 2012;366(15): ClinicalTrials.gov NCT c GUSTO Mod/Sev at 3 yrs 4.2 v. 2.5%, HR 1.66, p< Days s inc e randomiza tion

36 Events/1000 Pts Efficacy vs. Bleeding in the Vorapaxar FDA-label Population*: Outcomes for every 1000 patients treated for 3 years CV Death, MI, Stroke MI CV Death Stroke GUSTO Severe P<0.001 P=0.002 P=0.11 P=0.002 P=0.16 P<0.001 * post-mi and PAD patients with no stroke or TIA history Adapted from Giulia Magnani et al. J Am Heart Assoc. 2015;4:e GUSTO Moderate/ Severe Vorapaxar is contraindicated in patients with history of stroke, transient ischemic attack, or intracranial hemorrhage (ICH), or active pathological bleeding.

37 Event Rate (%) TRA2P-TIMI PAD Cohort: CV Outcomes 14.0% 12.0% CVD/MI/Stroke Placebo Vorapaxar 10.0% 8.0% 6.0% 4.0% 2.0% 0.0% Days Since Randomization Vorapaxar did not reduce the risk of CV events 11.3% vs. 11.9% HR 0.94 ( ) P=0.53 Adapted from Bonaca MP et al. Circulation. 2013;127:

38 Event Rate (%) TRA2P-TIMI PAD Cohort: Bleeding 12.0% GUSTO Moderate/Severe Bleeding Placebo Vorapaxar 10.0% 8.0% Vorapaxar increased the risk of bleeding 6.0% 4.0% 2.0% 0.0% 7.4% vs. 4.5% HR 1.62 ( ) P= Days Since Randomization Adapted from Bonaca MP et al. Circulation. 2013;127:

39 Event Rate (%) Event Rate (%) TRA2P-TIMI PAD Cohort: Peripheral Outcomes Vorapaxar significantly reduced peripheral revascularization and hospitalization for acute limb ischemia 4.5% Hospitalization for Acute Limb Ischemia 25.0% Peripheral Revascularization 4.0% 3.5% Placebo Vorapaxar 20.0% Placebo Vorapaxar 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 2.3% vs. 3.9% HR 0.58 ( ) P= % Days Since Randomization 15.0% 10.0% 5.0% 0.0% Days Since Randomization 18.4% vs. 22.2% HR 0.84 ( ) P= Adapted from Bonaca MP et al. Circulation. 2013;127:

40 Summary of ACC/AHA 2013 Guideline Recommendations In patients with symptomatic PAD Antiplatelet therapy is indicated to reduce the risk of MI, stroke, and vascular death Aspirin (75 to 325 mg) is recommended Clopidogrel (75 mg) is recommended as alternative antiplatelet to aspirin The combination of aspirin and clopidogrel may be considered if low risk of bleeding and high cardiovascular risk Warfarin in addition to antiplatelet is not recommended In patients with asymptomatic PAD Antiplatelet therapy can be useful to reduce risks in individuals with an ABI 0.90

41 Summary: Antiplatelet Therapy in PAD Antiplatelet therapy plays a central role in secondary prevention in PAD patients Several antiplatelet agents with different mechanism of action are available and can be used as monotherapy or in combination Current guidelines favor monotherapy Clinical trials data on optimal antiplatelet therapy regimens in PAD and after intervention are rather scant Novel antiplatelet drugs (ticagrelor, vorapaxar) show some promise, future clinical trials are needed to establish the role of these agents in PAD

42 Case Discussion Craig M. Walker, MD, FACC, FACA, FACP, FSCAI, FASCI, FCCP, FICA (Chair) Founder, President and Medical Director, Cardiovascular Institute of the South Clinical Professor of Medicine Tulane University School of Medicine LSU School of Medicine New Orleans, Louisiana

43 54 yo male Post bilateral BTK synthetic fem-pop bypass Multiple left leg graft occlusions with rest pain Post aortic stent graft for AAA Clopidogrel resistance- On prasugrel /ASA Lytic therapy required each time with bleeding Apixaban added Nine episodes of acute graft occlusion (monthly)

44 ARS: What would be your next step in the management of this patient? A. Refer for interventional procedure B. Change to a different anticoagulant C. Change to a different antiplatelet regimen Refer for interventional... 23% Change to a different ant... 8% 70% Change to a different ant...

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54 54 yo male (cont) Atherectomy followed by drug-eluting balloon Vorapaxar 2.08 mg/day added with no further ischemic events in 9 months

55 ARS: One year later, he continues to do well. What antiplatelet therapy would you continue for him? A. Triple therapy with aspirin, prasugrel, and vorapaxar B. Dual antiplatelet therapy with aspirin and prasugrel C. Dual antiplatelet therapy with aspirin and vorapaxar D. Monotherapy with aspirin E. Monotherapy with prasugrel F. Monotherapy with vorapaxar Triple therapy with aspiri.. 18% Dual antiplatelet therap... Dual antiplatelet therapy... 2% 42% Monotherapy with aspirin 2% Monotherapy with vora... Monotherapy with prasu... 0% 36%

56 Post Assessment Please utilize the provided ARS keypad to submit your responses

57 73 y/o woman, type 2 diabetes and hypertension presents with symptomatic peripheral arterial disease. According to 2013 ACC/AHA guidelines, what antiplatelet regimens should she receive to reduce her risk of MI, stroke, and vascular death? A. Dual antiplatelet therapy B. Warfarin in combination with another antiplatelet agent C. She is not a candidate for antiplatelet therapy due to her comorbid conditions D. Monotherapy with either aspirin or clopidogrel Dual antiplatelet therapy 51% Warfarin in combination... 4% She is not a candidate fo... 0% Monotherapy with eithe... 45%

58 73 y/o woman, type 2 diabetes and hypertension presents with symptomatic peripheral arterial disease. According to 2013 ACC/AHA guidelines, what antiplatelet regimens should she receive to reduce her risk of MI, stroke, and vascular death? Dual antiplatelet therapy 33% 51% Warfarin in combination with another antiplatelet agent 4% 10% She is not a candidate for antiplatelet therapy due to her comorbid conditions 0% 0% Monotherapy with either aspirin or clopidogrel 45% 56% First Slide Second Slide

59 Which of the following best describes the mechanism of action of vorapaxar? A. Thromboxane synthase inhibitor B. Protease activated receptor (PAR)-1, PAR-2, and PAR-4 antagonist C. PAR-1 antagonist D. Glycoprotein IIb/IIIa inhibitor Thromboxane synthase i... 5% 7% 2% Protease activated recep... PAR-1 antagonist 86% Glycoprotein IIb/IIIa inhi...

60 Which of the following best describes the mechanism of action of vorapaxar? Thromboxane synthase inhibitor 5% 14% Protease activated receptor (PAR)-1, PAR-2, and PAR-4 antagonist 7% 29% PAR-1 antagonist 24% 86% Glycoprotein IIb/IIIa inhibitor 2% 33% First Slide Second Slide

61 Which of the following outcomes was significantly reduced in PAD patients who participated in the TRA 2 P TIMI 50 trial and received vorapaxar? A. Moderate to severe bleeding B. Hospitalizations for acute limb ischemia C. Limb amputations D. Stent thrombosis 4% 47% 36% 13% Moderate to severe ble... Hospitalizations for acut... Limb amputations Stent thrombosis

62 Which of the following outcomes was significantly reduced in PAD patients who participated in the TRA 2 P TIMI 50 trial and received vorapaxar? Moderate to severe bleeding 4% 10% Hospitalizations for acute limb ischemia 32% 47% Limb amputations 26% 36% Stent thrombosis 13% 32% First Slide Second Slide

63 Thank you for your participation To obtain CME, please complete and return your program evaluation to the meeting host before you leave