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 2004 evidence- based guidelines (7 th ed.) 2008 evidence- based guidelines (8 th ed.) 2012 evidence- based guidelines (9 th ed.) Comments therapy: LMWH or IV heparin LMWH or monitored IV or SQ heparin, unmonitored IV or SQ UFH or fondaparinux 2008 guidelines remain current in 2012 guidelines Objectively Confirmed DVT/PE GRADE 1A Treatment with VKA for 6-12 months Treatment with VKA for 3 months Treatment with VKA for 3 months 2008 guidelines remain current in 2012 guidelines Unprovok ed proximal DVT or PE GRADE 1BGRADE 1A

ACCP Conference on Antithrombotic & Thrombolytic Therapy on Venous Thromboembolism 2004 evidence- based guidelines (7 th ed.) 2008 evidence- based guidelines (8 th ed.) 2012 evidence- based guidelines (9 th ed.) Comments No recommendation LMWH, fondaparinux for days LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban. LDUH, adjusted- dose VKA, ASA for days New recommendation on apixaban, dabigatran, rivaroxaban and ASA in 2012 guidelines No recommen dation No recommenda- tion Apixaban or dabigatran (alterantively rivaroxaban or adjusted dose VKA) New recommendation In 2012 guidelines VTE prophylaxis In HFS, THA, TKA GRADE 1B THA,TKA,HFS Decline or uncooperative with injections or IPC VTE prophylaxis GRADE 1B

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

Year 2001 : 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 Vasc Surg 2000

Peripheral Arterial Disease

Recommendations for Antiplatelet & Antithrombotic Drugs 2005 recommendations2011 Focused Update Comments CLASS 1 ASA, mg OD safe & effective antiplatelet reduce the risk of MI, stroke or vascular death in atherosclerotic LE PAD (LOE : A) ASA, mg OD safe & effective antiplatelet reduce the risk of MI, stroke, or vascular death with symptomatic atherosclerotic LE PAD, including those with intermittent claudication or critical limb ischemia, prior LE revascularization (endovascular or surgical) or prior amputation for LE ischemia (LOE: B) Modified recommendation (wording clarified : LOE changed from A to B) ACCF/AHA Task Force on Practice Guidelines

2011 Focused Update of the Guidelines on the 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 antiplatelet vs placebo significant heterogeneity of enrollment criteria and antiplatelet dosing regimens ACCF/AHA Task Force on Practice Guidelines

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 < ) 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 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) 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

Recommendations for Antiplatelet & Antithrombotic Drugs 2005 Recommendations2011 Focused UpdateComments CLASS 1 Clopidogrel, 75 mg OD effective alternative antiplatelet to ASA to reduce the risk of MI, stroke or vascular death in atherosclerotic LE PAD (LOE: B) Clopidogrel, 75 mg OD safe & effective alternative to ASA to reduce the risk of MI, ischemic stroke, or vascular death in symptomatic atherosclerotic LE PAD, including intermittent claudication, or critical limb ischemia, prior LE revascularization (endovascular or surgical) or prior amputation for LE ischemia (LOE : B) Modiified recommendation (wording clarified) ACCF/AHA Task Force on Practice Guidelines

After CAPRIE ( Clopidogrel vs 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 2011 Focused Update of the Guidelines on the Management of PAD

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 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 CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management & Avoidance) :

Recommendations for Antiplatelet & Antithrombotic Drugs 2005 Recommendations 2011 Focused UpdateComments CLASS 11a CLASS 11b Antiplatelet therapy useful to reduce the risk of MI, stroke, or vascular death in asymptomatic patients with ABI < 0.9 (LOE: C) The usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in asymptomatic individuals with borderline abnormal ABI, 0.91 – 0.99 is not well established (LOE: B) NEW recommendation ACCF/AHA Task Force on Practice Guidelines

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

Recommendations for Critical Limb Ischemia : Endovascular & Open Surgical Treatment for Limb Salvage 2005 Recommendations2011 Focused UpdateComments CLASS 1 Combined inflow & outflow disease with critical limb ischemia, inflow lesions should be addressed first (LOE: C) Combined inflow & outflow disease with critical limb ischemia or infection persist after inflow revascularization, outflow revascularization should be performed(LOE: B) 2005 recommendation remains current in 2011 focused update ACCF/AHA Task Force on Practice Guidelines

Recommendations for Critical Limb Ischemia: Endovascular & Open Surgical Treatment for Limb Salvage 2005 Recommendations2011 Focused Update Comments CLASS 11a Limb-threatening LE ischemia & estimated life expectancy of < 2 years or an autogenous vein conduit is not available, balloon angioplasty is reasonable to perform when possible as the initial procedure to improve the distal blood flow (LOE:B) NEW recommendation ACCF/AHA Task Force on Practice Guidelines

Recommendations for Critical Limb Ischemia : Endovascular & Open Surgical Treatment for limb Salvage 2005 Recommendations2011 Focused Update comments CLASS 11a Limb threatening ischemia & an estimated life expectancy > 2 years, bypass surgery, when possible & when an autogenous vein conduit is available, is reasonable to perform as the initial treatment to improve the distal blood flow (LOE:B) NEW recommendation ACCF/AHA Task Force on Practice Guidelines

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

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 randomizat ion

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

PERSONALIZED VASCULAR MEDICINE : ARE WE READY?

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

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

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

Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine Pharmacotherap eutic Area Therapeutic Question Guiding TestsPotential Personalized intervention Antiplatelet therapy Aspirin dose, clopidogrel dose, or need for combination therapy Platelet aggregation assays (VerifyNow, PRA-100) Substantial platelet aggregation suggests residual high platelet reactivity Benefit from higher dose ASA, higher clopidogrel, prasugrel, or combination therapy including omega 3FA or cilostazol

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

Clopidogrel : pro-drug subject to enzymatic intestinal reflux, hydrolysis by serum esterases, & oxidation by cytochrome P450 enzymes, which render the approx. 85% of the pro- drug inactive. CYP2C19 gene encodes the protein responsible for the conversion of the clopidogrel pro-drug to the active form

Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine Pharmacotherap eutic Area Therapeutic Question Guiding TestsPotential Personalized intervention Antiplatelet therapy Cytochrome P450 2C19 (CYP2C19) genotype Carriers of CYP2C19 variants CYP2C19*2 or CYP2C19*4 : reduced conversion of the clopidogrel pro- drug to the active metabolite Benefit from higher dose clopidogrel or the alternative prasugrel Aspirin dose, clopidogrel dose, or need for combination therapy

Pharmacotherap eutic Area Therapeutic Question Guiding TestsPotential Personalized Intervention Antiplatelet therapy Aspirin dose, clopidogrel dose or need for combination antiplatelet therapy Paraoxonase 1 (PON 1) genotype Carriers of the PON1 allele QQ192 : reduced conversion of the clopidogrel pro- drug to the active metabolite Benefit from higher dose clopidogrel or the alternative prasugrel Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

Antihypertensive therapy Renin profiling : promising and mechanistically rational technique to individualize therapy Haplotype analysis : renin-angiotensin- aldosterone & kininogen-kallikrein- bradykinin axes – identify responders and non-responders to ACEI therapy Examination of 24 hr ambulatory BP patterns, pulse wave velocity, aortic pulse pressure

Pharmacotherap eutic Area Therapeutic Question Guiding Tests Potential Personalized Intervention Lipid-lowering therapy Statin drug or dose Solute carrier organic anion transporter family, member 1B1 (SLCO1B1) genotype Carriers of the SLCO1B1*5 variant : increased risk of statin myopathy, most consistently with simvastatin due to impaired hepatic influx & increased plasma concentrations of statins Benefit from alternative statin (e.g. Rosuvastatin) Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

Pharmacotherap eutic Area Therapeutic Question Guiding Tests Potential Personalized Intervention Lipid-lowering therapy Benefit of fenofibrate Apolipoprotein A5 (ApoA5) genotype carriers of the APOA5 SNP 56G : greater benefit from fenofibrate therapy : more pronounced increases in HDL & decreases in fasting & postprandial triglycerides Benefit of ezetimibe Niemann- Pick C1 Like (NPC1L1) Carriers of the NPC1L1 : greater benefit from ezetimibe : more pronounced reductions in LDL Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

Lipid lowering therapy The Study of Heart & Renal Protection (SHARP) trial : 17% reduction in atherothrombotic events among patients with CKD randomized to simvastatin & ezetimibe vs placebo. (not designed to compare ezetimibe plus statin to statin monotherapy alone) Combination therapy, statin plus fibrates, niacin, & ezetimibe has yet to demonstrate an incremental clinical outcome benefit above & beyond statin monotherapy in randomized controlled studies 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. Journal of SVM Vol 16,no.5, 2011

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

Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine Pharmacotherap eutic Area Therapeutic Question Guiding TestsPotential Personalized Intervention Antithrombotic Therapy Warfarin dosingCytochrome P450 2C9 (CYP2C9) genotype Carriers of CYP2C9 variants CYP2C9*3 and CYP2C9*2 : slower warfarin metabolism & require lower maintenance & cumulative induction doses of warfarin

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

Pharmacotherap eutic Are Therapeutic Question Guiding TestsPotential Personalized Intervention Antithrombotic Therapy Warfarin dosingVitamin K epoxide reductase complex (VKORC1) genotype Carriers of the A allele at position 1639 of the VKORC1 gene require lower maintenance & cumulative induction doses of warfarin. The VKORC1 gene encodes the target enzyme of warfarin’s anticoagulant effect Overview of Approaches to Personalize Pharmacotherapeutic Management in Vascular Medicine

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

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