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Evolving Management of Vascular Diseases through the Years

Evolving Management of Vascular Diseases through the Years . Jenny L. Beltran, MD, FPCP, FPCC, FSVM. 43 rd PHA Annual Convention May 23-25,2012. No disclosure. Venous Thromboembolism. ACCP Conference on Antithrombotic & Thrombolytic Therapy for Venous Thromboembolism. Objectively

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Evolving Management of Vascular Diseases through the Years

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  1. Evolving Management of Vascular Diseases through the Years Jenny L. Beltran, MD, FPCP, FPCC, FSVM 43rdPHA Annual Convention May 23-25,2012

  2. No disclosure

  3. Venous Thromboembolism

  4. ACCP Conference on Antithrombotic & Thrombolytic Therapy for Venous Thromboembolism Objectively Confirmed DVT/PE GRADE 1A Unprovoked proximal DVT or PE GRADE 1A GRADE 1A GRADE 1B

  5. ACCP Conference on Antithrombotic & Thrombolytic Therapy on Venous Thromboembolism VTE prophylaxis In HFS, THA, TKA GRADE 1B THA,TKA,HFS Decline or uncooperative with injections or IPC VTE prophylaxis GRADE 1B

  6. Traditionally, strict bed rest for several days in combination with IV heparin to avoid thrombi from breaking off and causing PE. • 2 randomized studies with limited sample sizes : bed rest plus anticoagulation was not shown to reduce the incidence of silent PE as detected by lung scanning Arch Int Med 1992, Ann Int Med 1993

  7. Year2001 : the rate of resolution of pain and swelling was significantly faster with early ambulation and leg compression garments • Cohort of 1289 patients with acute DVT treated with LMWH: low incidence of recurrent and fatal PE : mobile patients do not require bed rest VASA 2001 J VascSurg 2000

  8. Peripheral Arterial Disease

  9. Recommendations for Antiplatelet & Antithrombotic Drugs ACCF/AHA Task Force on Practice Guidelines

  10. 2011Focused Update of theGuidelinesonthe Management of PAD • Review of 5 RCTs & 1 meta-analysis • 2002 Antithrombotic Trialist’s Collaboration meta-analysis: • significant reduction in CV events among symptomatic PAD patients randomized to antiplateletvs placebo • significant heterogeneity of enrollment criteria and antiplatelet dosing regimens ACCF/AHA Task Force on Practice Guidelines

  11. 2011 Focused Update of the Guidelines on the Management of PAD • Review of 3 RCTs of aspirin use (100mg daily) vs placebo for CV risk reduction among PAD patients • 2 larger trials with longer duration of ff-up : no benefit of aspirin • 1) POPADAD (Prevention of Progression of Asymptomatic Diabetic Arterial Disease) : ABI < 0.99 • 2) Aspirin for Asymptomatic Atherosclerosis trial • ABI < 0.95, calculated the ABI using the lower pedal pressure • enrolled only asymptomatic patients derived from population screening based on very mild decrements in ABI (low risk patients) JAMA 2010 BMJ 2008

  12. 2011 Focused Update of the Guidelines on the Management of PAD • CLIPS (Critical Leg Ischemia Prevention Study) • enrolled patients with more advanced PAD (symptoms and/or ABI <0.85) • significant reduction in CV events randomized to aspirin • stopped early due to poor recruitment (366/2000 patients)

  13. 2011 Focused Update of the Guidelines on the Management of PAD • 2009 meta-analysis of aspirin therapy for PAD patients: • CLIPS and POPADAD trials only • 34% risk reduction for nonfatal stroke • no significant reduction in the overall CV events • Recommended dose range of aspirin : 75mg to 325mg /day JAMA 2009

  14. Recommendations for Antiplatelet & Antithrombotic Drugs ACCF/AHA Task Force on Practice Guidelines

  15. 2011 Focused Update of the Guidelines on the Management of PAD • After CAPRIE ( Clopidogrelvs Aspirin in Patients at Risk of Ischemic Events) : • no new clinical trials directly compared ASA monotherapy with clopidogrel • CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management & Avoidance) : • reasonable to combine ASA with clopidogrel for certain high risk patients with PAD who are not at increased risk of bleeding

  16. CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management & Avoidance) : • Patients with PAD in the CHARISMA trial: • Aim : to determine whether clopidogrel plus ASA provides greater protection against major CV events than ASA alone in patients with PAD • Inclusion criteria for PAD: • 1) symptomatic PAD :either current intermittent claudication together with ABI > 0.85 or history of intermittent claudication together with a previous related intervention (amputation, surgical or catheter based peripheral revascularization) • 2) asymptomatic PAD : ABI of 0.9 with multiple risk factors • Prospective, randomized, multicenter, double blind, placebo controlled : 3096 patients with symptomatic (2838) or asymptomatic PAD

  17. CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management & Avoidance) : • Primary endpoint : first occurrence of MI, stroke (of any cause), or death from CV causes (including hemorrhage) • Principal secondary endpoint : first occurrence of MI, stroke, death from CV causes, hospitalization for UA, TIA, or a revascularization procedure (coronary, cerebral, or peripheral) • Results : • Primary endpoint: 7.6% in clopidogrel plus ASA; • 8.9% in placebo plus ASA • Rate of MI : 2.3% in clopidogrel plus ASA • 3.7% in placebo plus ASA • Rate of hospitalization for ischemic events : 16.5% in clopidogrel plus ASA; 20.1% in placebo plus ASA • Severe, fatal, or moderate bleeding : did not differ between groups • Minor bleeding : 34.4% in clopidogrel plus ASA • 20.8 % in placebo plus ASA

  18. Recommendations for Antiplatelet & Antithrombotic Drugs ACCF/AHA Task Force on Practice Guidelines

  19. no clinical trials have examined the efficacy of the new antithrombotics such as prasugrel, and ticagrelor to reduce ischemic events in patients with PAD

  20. Recommendations for Critical Limb Ischemia : Endovascular & Open Surgical Treatment for Limb Salvage ACCF/AHA Task Force on Practice Guidelines

  21. Recommendations for Critical Limb Ischemia: Endovascular & Open Surgical Treatment for Limb Salvage ACCF/AHA Task Force on Practice Guidelines

  22. Recommendations for Critical Limb Ischemia : Endovascular & Open Surgical Treatment for limb Salvage ACCF/AHA Task Force on Practice Guidelines

  23. BASIL ( Bypass Versus Angioplasty in Severe Ischemia of the Leg) • Funded by the UK NIH Research & Health Technology Assessment Programme • 5 year period, 452 patients with CLI (rest/night pain, & tissue loss such as skin ulceration & gangrene) • randomized to either open surgery or balloon angioplasty • major clinical outcomes : • amputation-free survival & overall survival • Initial results in 2005, CLI with infrainguinal disease • similar short term clinical outcomes between bypass surgery-first & balloon angioplasty first • bypass surgery-first was one third more expensive • associated with higher morbidity

  24. BASIL (Bypass Versus Angioplasty In Severe Ischemia of the Leg) Mean follow-up of 3.1 yr (range :1 – 5.7 yrs) • bypass surgery-first : significant increase in overall survival of 7.3 months (95% CI:1.2 to 13.4 months; P= 0.02) & a trend toward improved amputation-free survival of 5.9 months(95%CI: 0.2 to 12 months; P=0.6) who survived for at least 2 years after randomization

  25. BASIL (Bypass Versus Angioplasty in Severe Ischemia of the Leg) • Reasonable for a bypass surgery first approach to be considered for these carefully selected patients to prolong amputation free survival & overall survival. • Confirmed that outcomes ff prosthetic bypass were extremely poor

  26. Personalized vascular medicine : Are we ready?

  27. Give different drugs to different patients, for the sweet ones do not benefit everyone, nor do the astringent ones, nor are all the patients able to drink the same things. • recognizing the “great natural diversities” between persons, he instructed his students to “give different drugs to different patients” to both maximize efficacy and minimize adverse effects Hippocrates, circa 400 BC

  28. Novel strategies designed to permit tailoring 3 major pharmacotherapeutic drug classes within vascular medicine: • antiplatelet therapy • lipid lowering therapy • antithrombotic therapy

  29. Antiplatelet therapy • Residual high platelet reactivity on antiplatelet therapy represent a significant proportion with atherosclerotic disease, & a markedly increased risk of future events • Emergence of novel potent antiplatelets and point-of-care platelet function assays and genetic testing : genotype & phenotype based individualized therapy

  30. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

  31. Loss of function CYP2C19 alleles CYP2C19*2 or *4 : 22% less platelet inhibition upon exposure to clopidogrel • patients with 2 loss of function CYP2C19 alleles and HPR : less responsive to dose escalation of clopidogrel

  32. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine Aspirin dose, clopidogrel dose, or need for combination therapy

  33. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

  34. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

  35. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

  36. Lipidlowering therapy Even in high risk patients, trials of fenofibrate as monotherapy or combination add-on therapy to statins have failed to show a reduction in macrovascular events. The Study of Heart & Renal Protection (SHARP) trial : 17% reduction in atherothrombotic events among patients with CKD randomized to simvastatin & ezetimibevs placebo. (not designed to compare ezetimibe plus statin to statinmonotherapy alone) Combination therapy, statin plus fibrates, niacin, & ezetimibe has yet to demonstrate an incremental clinical outcome benefit above & beyond statinmonotherapy in randomized controlled studies Journal of SVM Vol 16,no.5, 2011

  37. Incidence of CV events in secondary prevention cohorts : 20% after 4 – 5 years even with intensive treatment & vigilant monitoring It is not clear that evaluating SLCO1B1 status would confer an advantage over current precautions to minimize stain-related muscle side effects

  38. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

  39. Antithrombotic Therapy • CYP2C9 metabolizes S-warfarin : 3-5 times more potent than R-warfarin • warfarin : racemic mixture of S and R-enantiomers • CYP2C9*3 and CYP2C*2 alleles : significantly reduce CYP2C9 enzyme activity slower warfarin metabolism, carriers require lower maintenance and cumulative induction doses • susceptible to supratherapeutic INRs, increase the risk of serious or life threatening bleeding deGoma, et.al. J of Vasc med vol 16,no.5, 2011

  40. Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

  41. Antithrombotic Therapy • VKORC1: target enzyme of warfarin • recycles the oxidized form of vit K to its reduced form , cofactor for gamma-glutamyl carboxylation necessary for activation of factors 11, V11, 1X, and X • gene polymorphisms of VKORC1: significant impact on individual & interethnic daily warfarin dose requirements • higher frequencies of VKORC1 SNPs 1173TT & 1639AA among Asians : heightened sensitivity to warfarin deGoma, et.al. J of Vasc med vol 16,no.5, 2011

  42. Translation to routine clinical practice awaits the results of ongoing randomized clinical trials comparing personalized approaches with standard of care management

  43. Thank you Thank you

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