Αντιθρομβωτική αγωγή σε ασθενείς με περιφερική αρτηριακή νόσο των κάτω άκρων

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1 Αντιθρομβωτική αγωγή σε ασθενείς με περιφερική αρτηριακή νόσο των κάτω άκρων Μ. Ματσάγκας, MD, PhD, FEBVS Καθηγητής Αγγειοχειρουργικής Πανεπιστήμιο Θεσσαλίας

2 Prevalence (millions) PAD Affects Millions of Patients Worldwide Global burden of disease study million 120 million CAD PAD Non-classical symptoms 30% ~5% of patients with PAD have classical symptoms of intermittent claudication 2 Asymptomatic 65% 1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators, Lancet 2017;390: ; 2. McDermott MM et al, J Am Heart Assoc 2013;2:e000257

3 CAD and PAD are overlapping conditions The REACH registry showed 3 out of 5 patients with PAD also have CAD and/or CVD: 8322 patients had PAD 39% had PAD only 38% had PAD and CAD 10% had PAD and CVD 13% PAD, CAD and CVD Cacoub PP et al, Atherosclerosis 2009

4 2017 ESC/ESVS guidelines for the management of PAD Reported rate ranges of other localizations of atherosclerosis in patients with a specific arterial disease European Heart Journal 2018; 39,

5 Prevention of MACE in PAD Requires a Combination of Risk Factor Management and Antithrombotic Therapy Vascular protection Control of CV risk factors to limit atherosclerosis progression and stabilize existing plaques Prevention of blood clot formation over ruptured/eroded atherosclerotic plaques Lifestyle changes Smoking cessation Regular exercise Healthy diet Weight management Psychosocial support Medical therapies Lipid control statins Hypertension control ACE inhibitors/arbs Diabetes control insulin/anti-glycaemic drugs Antithrombotic therapy Single antiplatelet therapy with aspirin or clopidogrel Montalescot G et al, Eur Heart J 2013;34: ; Aboyans V et al, Eur Heart J 2018;39: ; Cortés-Beringola A et al, Eur J Prevent Cardiol 2017;24:22 28

6 Pharmacological therapy in PAD

7 Current Management of PAD Is Based on Control of Modifiable Risk Factors and Prevention of Thrombotic Events 2017 ESC/ESVS guidelines for the management of PAD Recommendation Class Level Smoking cessation is recommended in all patients with PAD I B Healthy diet and physical activity are recommended for all patients with PAD I C Statins are recommended for all patients with PAD I A In patients with PADs, it is recommended to reduce LDL-C to <1.8 mmol/l or decrease it by 50% if baseline values are mmol/l I C In diabetic patients with PADs, strict glycaemic control is recommended I C Antiplatelet therapy is recommended in patients with symptomatic PADs I C In patients requiring antiplatelet therapy, clopidogrel may be preferred over aspirin IIb B In patients with PADs and hypertension, it is recommended to control BP at <140/90 mmhg I A ACEIs or ARBs should be considered as first-line therapy in patients with PADs and hypertension IIa B Aboyans V et al, Eur Heart J 2018;39:

8 Antithrombotic Options for PAD are so far Limited Current guidelines for the use of antithrombotics in patients with PAD Recommendation Class Level 2017 ESC/ESVS guidelines 1 Long-term single antiplatelet therapy is recommended in symptomatic patients I A In patients requiring antiplatelet therapy, clopidogrel may be preferred over aspirin IIb B 2016 AHA/ACC guidelines 2 Antiplatelet therapy with aspirin alone ( mg per day) or clopidogrel (75 mg per day) is recommended to reduce MI, stroke and vascular death in patients with symptomatic PAD The effectiveness of DAPT (aspirin and clopidogrel) to reduce the risk of CV ischaemic events in patients with symptomatic PAD is not well established The overall clinical benefit of vorapaxar added to existing antiplatelet therapy in patients with symptomatic PAD is uncertain Anticoagulation should not be used to reduce the risk of CV ischaemic events in patients with PAD I IIb IIb III (Harm) A B-R B-R A 1. Aboyans V et al, Eur Heart J 2018;39: ; 2. Gerhard-Herman MD et al, J Am Coll Cardiol 2017;69:e71 e126

9 Antiplatelet therapy in PAD Antithrombotic Trialists Collaboration PAD patients 42 Clinical Trials 23% reduction in CV events (p = 0.004) Antithrombotic Trialists' Collaboration BMJ 2002;324;71-86

10 CAPRIE: Subgroup analysis Relative Risk Reduction RRR (%) Cerebral ishemia (p/ys=12.033) p=0,26 CAD (p/ys ) p=0,66 PAD (p/ys ) p=0,0028 TOTAL (p/ys=35.155) p=0, ASA better Clopidogrel better CAPRIE Steering Committee. Lancet 1996

11 Cumulative event rate (%) Dual antiplatelet therapy CHARISMA trial 8 6 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% 4 2 RRR: 7.1% [95% CI: -4.5%, 17.5%] p= Months since randomization Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006

12 Tigagrelor vs clopidogrel Primary endpoint: a composite of cardiovascular death, AMI, or stroke Hiatt et al, NEJM 2017

13 Antiplatelet therapy + Oral anticoagulants in PAD patients WAVE trial: Antiplatelet Coumadin vs Antipatelet alone Efficacy (MI, Stroke, CV death) Safety (major bleeding) >3x Warfarin Antiplatelet Vascular Evaluation Trial Investigators N Engl J Med 2007

14 Selection of antiplatelet therapy 49 RCTs PAD pts Katsanos et al, PloS one 2015

15 Aspirin Is the Most Commonly Prescribed Antiplatelet Agent in Patients with PAD Antiplatelet use in US patients with PAD enrolled in the REACH registry Cannon CP et al, Am J Card 2010;105:

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18 Since then.. Two major issues changed the landscape The 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS) European Heart Journal 2018; 39, The COMPASS-PAD study Anand SS et al. Lancet 2018; 391:

19 2017 ESC/ESVS PAD Guidelines What s new Terminology PAD: Peripheral Arterial Disease (any kind!!) LEAD: Lower Extremity Arterial Disease

20 2017 ESC/ESVS PAD Guidelines What s new

21 2017 ESC/ESVS PAD Guidelines What s new

22 2017 ESC/ESVS PAD Guidelines Carotid artery disease

23 2017 ESC/ESVS PAD Guidelines

24 2017 ESC/ESVS PAD Guidelines What s new Lower Extremity Arterial Disease (LEAD)

25 2017 ESC/ESVS PAD Guidelines What s new

26 2017 ESC/ESVS PAD Guidelines What s new Antithrombotic therapy in PAD patients focused mainly in lower extremity artery disease (LEAD) requiring long-term oral anticoagulant

27 2017 ESC/ESVS PAD Guidelines What s new Antithrombotic therapy in PAD patients requiring long-term oral anticoagulant

28 2017 ESC/ESVS PAD Guidelines What s new

29 Publication in New England Journal of Medicine COMPASS trial

30 2-year Kaplan Meier estimate (%) ATLAS ACS 2 TIMI 51: Rivaroxaban Vascular Dose Reduced CV Events and Death in Patients with ACS Patients with elevated cardiac biomarkers and no prior stroke/transient ischaemic attack CAD CV death, MI or stroke CV death All-cause death HR=0.80 (95% CI ); p=0.007 Placebo HR=0.55 (95% CI ); p<0.001 NNT=50 Placebo HR=0.58 (95% CI ); p<0.001 NNT=49 Placebo Rivaroxaban 2.5 mg bid 2 1 Rivaroxaban 2.5 mg bid 2 1 Rivaroxaban 2.5 mg bid Days Days Days 720 Mega JL et al, Eur Heart J 2014;35(Suppl.):992.

31 A Dual Pathway Approach Targeting Chronic Patients with CAD or PAD was Investigated in COMPASS Objective: To determine the efficacy and safety of rivaroxaban, vascular dose of rivaroxaban plus aspirin or aspirin alone for reducing the risk of MI, stroke and cardiovascular death in CAD or PAD Population: Chronic CAD (91%) PAD (27%) N=27,395 1:1:1 R 30-day run-in, aspirin 100 mg Rivaroxaban 2.5 mg bid + Aspirin 100 mg od Rivaroxaban 5.0 mg bid Aspirin 100 mg od 30-day washout period Factorial design ± pantoprazole* Average follow-up: 23 months at early termination of study Final follow-up visit Final washout period visit Antithrombotic investigations* were stopped 1 year ahead of expectations in Feb 2017 due to overwhelming efficacy in the rivaroxaban 2.5 mg bid + aspirin arm *Patients who were not receiving a proton pump inhibitor (PPI) were randomized to pantoprazole or placebo (partial factorial design); the PPI pantoprazole component of the study is continuing; data will be communicated once complete 1. Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa ; 2. Bosch J et al. Can J Cardiol 2017;33(8):

32 Inclusion and Exclusion Criteria Ensure That Patients Are Chronic CAD and PAD Patients Key inclusion criteria* PAD CAD with 1 of: Age 65 years Age <65 years plus atherosclerosis in 2 vascular beds or 2 additional risk factors Current smoker Diabetes mellitus Renal dysfunction (egfr<60 ml/min) Heart failure Non-lacunar ischemic stroke 1 month ago Key exclusion criteria Stroke 1 month or any haemorrhagic or lacunar stroke Severe HF with known ejection fraction <30% or NYHA class III or IV symptoms Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy egfr <15 ml/min # Including but not limited to; any other exclusion criteria in conjunction with the local Product Information and any other contraindication listed in the local labelling for rivaroxaban or the comparator have to be considered [accessed 21 Mar 2017]; Bosch J et al, Can J Cardiol 2017;33:

33 Main Study Outcomes Primary efficacy outcome Composite of MI, stroke or CV death Secondary efficacy outcomes Composite of major thrombotic events Coronary heart disease death, MI, ischaemic stroke, acute limb ischaemia Cardiovascular death, MI, ischaemic stroke, acute limb ischaemia Mortality (all cause) Primary safety outcome Modified ISTH major bleeding Fatal bleeding, and/or Symptomatic bleeding in a critical area or organ, such as intracranial, or Bleeding into the surgical site requiring re-operation, and/or Bleeding leading to hospitalization Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa

34 Modified ISTH Major Bleeding Definition Applied at Regulators Request with the Intent of Capturing all Bleeding that Required Medical Attention ISTH major bleeding 1 Modified ISTH major bleeding (COMPASS) Fatal bleeding, and/or Symptomatic bleeding in a critical area or organ (such as intracranial), and/or Bleeding causing a drop in haemoglobin level of 20 g/l, or leading to transfusion of 2 units of whole blood or red cells Fatal bleeding, and/or Symptomatic bleeding in a critical area or organ (such as intracranial), or Bleeding into the surgical site requiring re-operation, and/or Bleeding leading to hospitalization Unlike the standard ISTH criteria, all bleeding that led to presentation to an acute care facility or hospitalization were considered as major compared with the standard ISTH major bleeding definition 1. Schulman S et al, J Thromb Haemost 2005;3:

35 Cumulative incidence (%) Dual Pathway Inhibition with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Reduced CV Death, Stroke and MI CAD PAD 10 8 Aspirin 100mg od Rivaroxaban 5mg bid Rivaroxaban 2.5mg bid + Aspirin 100mg od MACE* % HR (95% CI) p-value Aspirin 100mg OD Rivaroxaban 5mg BID ( ) 0.12 Rivaroxaban 2.5mg BID + Aspirin 100 mg OD ( ) < Year Number at risk Aspirin 100mg od Riva 5mg bid Riva 2.5mg bid + Aspirin 100mg od *Rates as at mean follow up of 23 months Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa

36 CAD PAD Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin: Significantly Reduced CV Events by 24% Versus Aspirin Outcomes, n (%) CV death, stroke, or MI Rivaroxaban 2.5 mg bid + aspirin 100 mg N=9152 Aspirin 100 mg N=9126 Rivaroxaban 2.5 mg bid + aspirin 100 mg vs aspirin 100 mg HR (95% CI) p-value 379 (4.1) 496 (5.4) 0.76 ( ) <0.001 CV death 160 (1.7) 203 (2.2) 0.78 ( ) 0.02 Stroke 83 (0.9) 142 (1.6) 0.58 ( ) <0.001 MI 178 (1.9) 205 (2.2) 0.86 ( ) 0.14 Outcomes, n (%) CV death, stroke, or MI Rivaroxaban 5 mg bid N=9117 HR (95% CI) Rivaroxaban 5 mg bid vs aspirin 100 mg p-value 448 (4.9) 0.90 ( ) 0.12 CV death 195 (2.1) 0.96 ( ) 0.69 Stroke 117 (1.3) 0.82 ( ) 0.12 MI 182 (2.0) 0.89 ( ) 0.24 Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa

37 Bleeding Rates Increased, but Low with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin Alone, with No Differences Seen in Fatal and Intracranial Bleeding Rates at mean follow-up of 23 months Rivaroxaban 2.5 mg bid + aspirin 100 mg N=9152 Rivaroxaban 5 mg bid N=9117 CAD Aspirin 100 mg N=9126 Modified major ISTH bleeding 288 (3.1%) 255 (2.8%) 170 (1.9%) Fatal 15 (0.2%) 14 (0.2%) 10 (0.1%) Non-fatal ICH* 21 (0.2%) 32 (0.4%) 19 (0.2%) Non-fatal other critical organ* 42 (0.5%) 45 (0.5%) 29 (0.3%) Rates at mean follow-up of 23 months Rivaroxaban 2.5 mg bid + aspirin 100 mg vs aspirin 100 mg Rivaroxaban 5 mg bid vs aspirin 100 mg HR (95% CI) p-value HR (95% CI) p-value Modified ISTH major bleeding 1.70 ( ) < ( ) <0.001 Fatal 1.49 ( ) ( ) 0.41 Non-fatal ICH* 1.10 ( ) ( ) 0.07 Non-fatal other critical organ* 1.43 ( ) ( ) 0.06 The use of the standard ISTH major bleeding definition would have led to approximately one third fewer major bleeding events than with the use of the modified ISTH definition Each event is counted in the most severe hierarchical category (fatal; critical organ bleeding; bleeding into surgical site requiring re-operation; bleeding leading to hospitalization) only. For each outcome, the first event experienced per patient is considered. Subsequent events of the same type are not shown. Therefore subcategories do not necessarily sum up to overall category. *Symptomatic Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa PAD

38 CAD PAD Net Clinical Benefit: 20% RRR with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin Definition: composite of CV death, stroke, MI, fatal bleeding or symptomatic bleeding into a critical organ In other words, net clinical benefit represented the composite of fatal and non-fatal events of irreversible harm Outcome Net clinical benefit Rivaroxaban 2.5 mg bid + aspirin 100 mg N=9152 Aspirin 100 mg N=9126 Rivaroxaban 2.5 mg bid + aspirin 100 mg vs aspirin 100 mg HR (95% CI) p-value 431 (4.7%) 534 (5.9%) 0.80 ( ) <0.001 Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa

39 CAD PAD Rivaroxaban 2.5 mg bid + Aspirin Improved Overall Survival in Patients with CAD or PAD Study / Treatment arm Control %/year Intervention %/year HR HR (95% CI) p-value COMPASS 1 Rivaroxaban 2.5 mg bid CHARISMA 2 Clopidogrel 75 mg od PEGASUS 3 Ticagrelor 90 mg bid Ticagrelor 60 mg bid TRA2P-TIMI 50 4 Vorapaxar 2.5 mg od ,5 1 2 Favours Favours intervention control 1. Eikelboom JW et al. N Engl J Med 2017; DOI: /NEJMoa ; 2. Bhatt DL et al. J Am Coll Cardiol 2007;49: ; 3. Bonaca MP et al. N Engl J Med 2015;372: ; 4. Morrow DA et al. N Engl J Med 2012;366:

40 Antithrombotic secondary prevention strategies in stable vascular disease Fox KAA, et al. Eur Heart J 2018

41 COMPASS PAD Analysis

42 COMPASS PAD Analysis

43 Inclusion and Exclusion Criteria Ensure That Patients Are Chronic CAD and PAD Patients Key inclusion criteria* PAD Aortofemoral bypass surgery, limb bypass surgery, percutaneous transluminal angioplasty, revascularisation of the iliac, or infrainguinal arteries Limb or foot amputation for arterial vascular disease Intermittent claudication Ankle brachial index (ABI) of less than 0 90 Peripheral artery stenosis ( 50%) documented by angiography or duplex ultrasound Carotid revascularisation Asymptomatic carotid artery stenosis of at least 50% diagnosed by duplex ultrasound or angiography Key exclusion criteria Stroke 1 month or any haemorrhagic or lacunar stroke Severe HF with known ejection fraction <30% or NYHA class III or IV symptoms Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy egfr <15 ml/min # Including but not limited to; any other exclusion criteria in conjunction with the local Product Information and any other contraindication listed in the local labelling for rivaroxaban or the comparator have to be considered [accessed 21 Mar 2017]; Bosch J et al, Can J Cardiol 2017;33:

44 31% RRR in MACE or MALE Including Major Amputation with Rivaroxaban 2.5 mg bid + Aspirin Versus Aspirin in Patients with PAD PAD Rivaroxaban 2.5 mg bid + aspirin 100 mg vs aspirin 100 mg: HR 0.69 ( ), p= Rivaroxaban 5 mg bid vs aspirin 100 mg: HR 0.84 ( ), p=0.08 Number at risk Rivaroxaban + aspirin Rivaroxaban Aspirin Anand SS et al. ESC 2017, Abs 1157; Available at: Anand SS et al. Lancet 2017;In Press

45 Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Significantly Reduced Both MACE and MALE in Patients with PAD *Crude incidence over mean follow-up of 21 months Anand S et al, Lancet 2018;391: Rivaroxaban 2.5 mg bid + aspirin significantly reduced major amputation by 70% versus aspirin

46 Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Resulted in Low Increases in Major Bleeding in Patients with PAD *Modified ISTH definition: fatal bleeding, and/or symptomatic bleeding in a critical area or organ (such as intracranial), or bleeding into the surgical site requiring re-operation, and/or bleeding leading to hospitalization; symptomatic Anand S et al, Lancet 2018;391:

47 Compass PAD treatment Is Compass treatment for every PAD patient? If not Which patients should we treat most?

48 Indication to include prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischaemic events for Xarelto 2.5 mg co-administered with acetylsalicylic acid;

49 Identifying Patients with PAD at High Risk of MACE or MALE PAD is under-diagnosed and under-treated, and has an ominous prognosis Risk stratification is critical in identifying high-risk patients

50 Despite Standard Therapy, Patients with Intermittent Claudication Are at Risk of Adverse Events and Disease Progression Asymptomatic PAD (4 11%) 1 Intermittent (12 29%) 1 claudication CLI or worsening IC General prognosis (systemic) Limb prognosis (leg) All-cause mortality: 10 36% 1,2 CV mortality: 9 25% 1 Non-fatal MI/stroke: 20% 2 Stable: 70 80% 2 Further reduced walking distance: 10 20% 2 Amputation: 4 27% annually 1 1. Sigvant B et al, Eur J Vasc Endovasc Surg 2016;51: ; 2. Norgren L et al, J Vasc Surg 2007;45:S5 S67

51 There Is a High Residual Risk of MACE with Established Vascular Protection Therapies In patients with multiple CV risk factors, or established disease and well treated with secondary prevention therapies, contemporary studies indicate a 15-20% rate of CV death, myocardial infarction or stroke at 3-4 years * Risk reduction MACE All-cause death Lipid lowering (1 mmol/l) 1 21% 9% BP lowering (10 mmhg) 2 20% ACEI 22% (HOPE) 3 13% 16% * Fox KAA, et al. Eur Heart J ; O Donoghue ML, et al. JAMA 2014;312: ; Rapsomaniki E, et al. Eur Heart J Qual Care Clin Outcomes 2016;2: CTT Collaboration, Lancet 2015;385: ; 2. Ettehad D et al, Lancet 2016;387: ; 3. HOPE Investigators, N Engl J Med 2000;342:

52 Patients with PAD Are Likely to Have Polyvascular Disease Polyvascular disease at baseline in the REACH registry CAD: 24.8% (22.0% two locations; 2.8% three locations) CVD: 40.2% (34.3% two locations; 5.9% three locations) PAD: 61.5% (48.0% two locations; 13.5% three locations) Bhatt DL et al, JAMA 2006;295:

53 Patients with Chronic Atherosclerotic Disease Remain at High Risk of Events over the Long-Term, Especially if They Have Polyvascular Disease 4-year MACE rates (REACH registry) *All event rates adjusted for age and gender Bhatt DL et al, JAMA 2010;304:

54 1-year incidence rates (%) Patients With Both CAD and PAD Are at Increased Risk of MACE Compared with Patients with Either CAD or PAD 1-year outcomes in patients with CAD alone, PAD alone or CAD+PAD (REACH registry) 25 CAD alone (n=28,867) 23,1 20 PAD alone (n=3246) CAD+PAD (n=3264) 17, , ,4 2,4 4,6 All-cause mortality 3,2 1,6 1,4 1,4 1,0 1,5 0,9 0,8 1,2 CV death Non-fatal MI Non-fatal stroke 3,6 3,1 5,5 CV death, MI or stroke CV death, MI, stroke or hospitalization Steg PG et al, JAMA 2007;297:

55 Rivaroxaban 2.5 mg bid plus Aspirin Significantly Reduced the Risk of MACE in Patients with Polyvascular Disease Incidence of the primary efficacy and safety outcomes in patients with CAD plus PAD and in patients with CAD only in COMPASS Connolly SJ et al, Lancet 2018;391:

56 Patients with PAD at High Risk of MACE Patients with Polyvascular Disease Patients suffering from PAD + CAD

57 Patients with PAD

58 Rivaroxaban 2.5 mg bid plus Aspirin Significantly Improved Outcomes Versus Aspirin Alone in Patients with Symptomatic Lower-Extremity PAD Outcomes in patients with symptomatic lower-extremity PAD in the COMPASS trial ARR: 2.0% HR=0.55 (95% CI ) ARR: 1.6% HR=1.71 (95% CI ) ARI: 1.4% Anand SS et al, Lancet 2018;391: Anand SS et al, Lancet 2018

59 Patients with PAD at High Risk of MALE Symptomatic PAD Patients with Disease Progression and deterioration

60 2-year rates per 1000 patients Despite Current Therapy, Patients with a Prior Revascularization Remain at Risk of MACE and MALE 2-year outcomes in US patients with PAD enrolled in the REACH registry according to PAD status at baseline Asymptomatic (n=134) Claudication (n=539) Prior revascularization (n=692) Prior amputation (n=312) CV death/mi/ stroke CV death/mi/ stroke/cv hospitalization Worsening of claudication Lower-limb amputation Peripheral angioplasty/ stenting Peripheral bypass graft Mahoney EM et al, Circ Cardiovasc Qual Outcomes 2010;3:

61 Despite Guideline-Recommended Therapy, Outcomes Are Significantly Poorer After MALE than Before Outcomes before and after MALE in the COMPASS trial Anand SS et al, J Am Coll Cardiol 2018; doi: /j.jacc

62 Prognosis After MALE Is Improved with Rivaroxaban 2.5 mg bid plus Aspirin Versus Aspirin Alone *HR determined by time-dependent Cox model Anand SS et al, presented at ACC 2018, Orlando, USA

63 Patients with PAD at High Risk of MALE PAD Patients with a Prior Revascularization

64 What s next

65 Perspectives for the future.. A head-to-head comparison between the addition to aspirin of a second antiplatelet drug versus a very low dose of a factor Xa inhibitor could be of great interest (DAPT vs Compass) Perhaps substituting a P2Y12 inhibitor for aspirin, together with a very low dose of a factor Xa inhibitor, might lead to even greater efficacy (Riva+Clop vs Compass) In my opinion.. In PAD patients comparing clopidogrel instead of aspirin with combination therapies, could be of great importance (Clop vs Compass)

66 For the time being Compass-PAD sub analyses Ongoing trials

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68 In Conclusion ESC/ESVS PAD guidelines improved our understanding for antithrombotic treatment in those highrisk patients, making clear the so far indications For the first time there are guidelines for PAD patients requiring long-term anticoagulation for other reasons In general these patients do not need an additional antiplatelet drug on the top of the anticoagulant

69 In Conclusion.. PAD patients have quite often polyvascular disease and are difficult to treat After years of negative trials, there now may be an alternate treatment in this high risk population that improves ischemic events and also reduces mortality Identifying Patients with PAD at High Risk of MACE or MALE is of major importance, as they will benefit more from a Compass therapy, combining low-dose Rivaroxaban (2.5mg x 2) with lowdose aspirin (100mg x 1)

70 In Conclusion.. PAD patients at higher risk to benefit more from a Compass strategy Patients with Polyvascular Disease (mainly suffering from PAD + CAD) Symptomatic PAD Patients with Disease Progression PAD Patients with a Prior Revascularization Do not forget to exclude patients at high bleeding risk No guidelines recommendations for DOACs in PAD yet

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