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Vascular Medicine Update

Vascular Medicine Update. Suman Rathbun MD, MS Professor of Medicine Director, Vascular Medicine OUHSC. New Therapies. New anticoagulants VTE prevention in orthopedic surgery VTE treatment CVA prevention in atrial fibrillation Catheter directed thrombectomy / lysis for DVT.

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Vascular Medicine Update

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  1. Vascular Medicine Update

    Suman Rathbun MD, MS Professor of Medicine Director, Vascular Medicine OUHSC
  2. New Therapies New anticoagulants VTE prevention in orthopedic surgery VTE treatment CVA prevention in atrial fibrillation Catheter directed thrombectomy/lysis for DVT
  3. Limitations of warfarin Frequent monitoring with dosing adjustments Concomitant medications Coexisting illnesses Dietary variability Compliance Provider knowledge, experience, diligenceRates of discontinuation are high! 25% at 1-year despite ongoing indication Circulation 2007:115:2689
  4. VII XI IX X II Xa IIa Targets for Anticoagulant Drugs1 Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XIa Heparins andLMWH2 Vitamin K antagonists3 Direct thrombin inhibitors4 Factor Xa inhibitors5 IXa VIIa VIII VIIIa Xa V Va 1Adapted with permission from Petitou M et al. Nature. 1991;350 (6319 suppl):30. 2Hirsh J et al. Chest. 2001;119:64S. 3Hirsh J, Fuster V. Circulation. 1994;89:1449. 4Weitz JI, Hirsh J. Chest. 2001;119:95S. 5Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1. (Thrombin) IIa Fibrinogen Fibrin
  5. Targets of New Inhibitors X VIIIa IX IXa Xa Va Dabigatran Prothrombin Thrombin Fibrin Fibrinogen
  6. Why Target Thrombin X VIIIa Self-Amplification Xa Va Thrombin Prothrombin Platelet Fibrin Fibrinogen Factor XIII In contrast to heparin, DTIs have access to clot bound thrombin No local inhibitor of DTIs
  7. Targets of New Inhibitors X VIIIa IX IXa Rivaroxaban Apixaban Edoxaban Xa Va Prothrombin Thrombin Fibrin Fibrinogen
  8. Why Target Factor Xa IXa VIIa VIIIa TF X X Xa Va Intrinsic Extrinsic Prothrombin Thrombin Fibrin Fibrinogen Convergence enzyme of both pathways DXI inhibit factor Xa within prothrombinase complex
  9. New Anticoagulants Acute Coronary Syndrome VTE Treatment VTE Prevention Orthopedics Hip Knee DVT PE Extension VTE Prevention Medically Ill Cerebrovascular Accident Prevention Afib Warfarin Aspirin Outpatient Cancer Hospitalized
  10. New Anticoagulant Development The Clinical Trial Pathway DVT/VTE Prophylaxis Orthopedic Surgery DVT/VTE Treatment AFib/Stroke Prophylaxis Arterial Disease Other Potential Indications
  11. Studies to date
  12. Drug characteristics
  13. Properties of warfarin and oral inhibitors of thrombin and factor Xa inhibitors approved for use and in advanced stages of development Bauer. J ThrombHaemost 2011;9:S12-19
  14. VTE prevention in Orthopedic surgery Hip replacement Knee replacement
  15. Orthopedic surgery: Hip arthroplasty Lancet 2007;370:949 NEJM 2008;358:2765
  16. Orthopedic surgery: total knee J ThrombHaemost 2007;5:2178 NEJM 2008;358:2776
  17. Results from phase III clinical trial programs for most advanced novel anticoagulants. Dosages of novel anticoagulants are mentioned in the corresponding chapter. Van Es. J thombHaemost 2011;9:S265-74
  18. VTE Treatment RE-COVER (Dabigatran) EINSTEIN (Rivaroxaban)
  19. RE-COVER Trial Design: Double Blind Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism N Engl J Med Volume 361:2342-2352 December 10, 2009
  20. Risk of Recurrent VTE / Death (N = 2,539) NEJM 2009;361:2342-2352)
  21. Major or Any Bleeding NEJM 2009;361:2342-2352)
  22. Conclusions for VTE RX: Dabigatran Dabigatran has comparable efficacy to warfarin. Dabigatran has comparable major bleeding and lower total bleeding rates than warfarin. Dabigatran provides an oral, fixed-dose treatment for acute VTE as an alternative to warfarin.
  23. EINSTEIN DVT / PE Program: Rivaroxaban EINSTEIN-PE (Confirmed PE without DVT) EINSTEIN-DVT (Confirmed DVT without PE) R Enoxaparin BID > 5 days + VKA to target INR = 2.5 (range 2-3) Rivaroxaban 15 mg BID for 3 weeks; then 20 mg once daily Primary Outcome: Symptomatic Recurrent VTE
  24. EINSTEIN-DVT: Study Design Randomized, open-label, event-driven, noninferiority study Up to 48 hours heparin/fondaparinux treatment permitted before study entry. 88 primary efficacy outcomes needed. N = 3449 Treatment period: 3, 6, or 12 months Rivaroxaban Rivaroxaban Enoxaparin Confirmed symptomatic DVT without symptomatic PE 30-day observation period 15 mg twice daily 20 mg once daily 1.0 mg/kg twice daily ≥ 5 days, followed by VKA – INR range 2-3 Day 1 Day 21 ClinicalTrials.gov Identifier: NCT00440193
  25. Primary Efficacy Outcome Analysis 0.68 ITT population 0.44 1.04 0 1.00 2.00 Hazard ratio Rivaroxaban superior Rivaroxaban noninferior Rivaroxaban inferior P = .076 for superiority P < .0001 for noninferiority (two-sided) (one-sided) Büller HR, ESC; August 2010; Stockholm, Sweden
  26. Safety Outcomes
  27. Conclusions Rivaroxaban VTE RX Non-inferiority to LMWH/VKA for efficacy: HR = 0.68 (0.44 – 1.04); p < .0001 for non-inferiority Similar safety: HR = 0.97 (0.76 – 1.22); P = .77.
  28. EINSTEIN-EXTENSION HR: 0.18; 95% CI, 0.09 – 0.39 NNT = 15 NNH = 139
  29. Results from phase III clinical trial programs for most advanced novel anticoagulants. Dosages of novel anticoagulants are mentioned in the corresponding chapter. Van Es. J thombHaemost 2011;9:S265-74
  30. Atrial Fibrillation An Opportunity for Stroke Prevention Affects ~ 1% of the population, ~ 10% of elderly The number is rising. 5% / year stroke rate The risk may be falling. 12% / year for those with prior stroke An important opportunity for stroke prevention! AF-related strokes have worse outcomes Often horrible, always costly. $ billions annual cost for stroke care Prevention means savings.
  31. Atrial Fibrillation: Background 5 fold increased risk of stroke Warfarin reduces this risk ~ 70% Aspirin reduces this risk ~ 20%
  32. Stroke Risk in Atrial Fibrillation Untreated Control Groups of Randomized Trials Stroke Rate (% per year) Age (years) Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449.
  33. Risk Stratification in AF Stroke Risk Factors Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005;112:1687.
  34. Risk Assessment for Stroke In Atrial Fibrillation CHADS – 2 Score JAMA 2001;285:2864
  35. Stroke Prediction in AF: CHADS 2 JAMA 2001;285:2864
  36. RE-LY Trial Randomized Evaluation of Long-term Anticoagulant Therapy with DabigatranEtexilate n = 18,113 Open-label Blinded Primary objective: noninferiority vs. warfarin Observation period: minimum 1, mean 2, maximum 3 years Primary endpoint: all stroke + systemic embolism Safety measure: bleeding during treatment Connolly SJ et al. N Engl J Med 2009;361:1139.
  37. RE-LY Trial Primary Events All Strokes and Systemic Embolic Events P <0.001 (Superiority) P <0.001 (Noninferiority) Event Rate (%/year) Connolly SJ et al. N Engl J Med 2009;361:1139.
  38. RE-LY Trial All Major Bleeding Hgb ↓ ≥2 g/dl or Transfusion ≥2 units or Critical Site p = NS p = 0.04 p = 0.002 Event Rate (%/year) Connolly SJ et al. N Engl J Med 2009;361:1139.
  39. RE-LY Trial Hemorrhagic Stroke Events Intracerebral Hemorrhages p <0.001 p <0.001 Event Rate (%/year) Connolly SJ et al. N Engl J Med 2009;361:1139.
  40. RE-LY Trial Net Clinical Benefit Nonhemorrhagic Strokes + Life-threatening Bleeds + Deaths Life-threatening bleeding Nonhemorrhagic stroke All-cause mortality Net Benefit (Adverse Events Avoided) 110 mg bid 150 mg bid Dabigatran Compared to Warfarin Connolly SJ et al. N Engl J Med 2009;361:1139. Beasley BN, Unger EF, Temple R. N Engl J Med 2011;364:1788.
  41. Adherence and Discontinuation RE-LY Trial *p<0.05 N Engl J Med 2009;361:1139
  42. ROCKET-AF Trial Study Design Risk Factors CHF Hypertension At least Age ≥ 75 2 or 3 Diabetes required* or Stroke, TIA, or Systemic embolism Atrial Fibrillation Randomize Double Blind / Double Dummy (n ~ 14,000) Rivaroxaban Warfarin INR target – 2.5 (2.0-3.0 inclusive) 20 mg daily 15 mg for Cr CI 30-49 ml/min Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior stroke, TIA, or systemic embolism and only 2 factors limited to 10% ROCKET AF Study Investigators. Am Heart J 2010;159:340.
  43. ROCKET-AF Trial Stroke and Systemic Embolism 1 0.5 Rivaroxaban better Warfarin better * p values for superiority Mahaffey KF, Fox KAA. American Heart Association, Chicago, IL, November 15, 2010.
  44. ROCKET-AF Trial Hemorrhagic Events Hazard ratio And 95% CIs Event rates %/y based on on-treatment population * Statistically significant 2-sided p-value for superiority 0.2 0.5 1 2 5 Favors Rivaroxaban Favors Warfarin Hacke W. European Stroke Conference, Hamburg, Germany, May 25, 2011.
  45. Results from phase III clinical trial programs for most advanced novel anticoagulants. Dosages of novel anticoagulants are mentioned in the corresponding chapter. Van Es. J thombHaemost 2011;9:S265-74
  46. Major Bleeding! * Uncommon event!* *2,500,000 patients on warfarin
  47. Antithrombotic Therapy for Atrial Fibrillation ACC / AHA / ESC Guidelines 2006, Updated 2011 Fuster, V, et al. Eur Heart J 2006;27:1979. Wann S, et al. J Am CollCardiol2011;57:223.
  48. Antithrombotic Therapy for Atrial Fibrillation The Future of Risk-Stratified Treatment? Risk Category Possible Therapy
  49. Agents Used for Reversal of Anticoagulant and Antiplatelet Agents JTH 2011;9:1705
  50. Managing Bleeding Complications FEIBA (factor eight bypass activity)* 50 µg/kg rFactorVlla* 60 µg/kg Risk of arterial thrombosis Last resort Prothrombin complex concentrate * Use caution in patients with liver disease * Monitor for DIC in all patients post infusion J ThrombHaemost 2009;7(Suppl. 1):107-110 Circulation 2011;124
  51. Hemodialysis?? Small molecule~ 60% dialyzable Problems: Volume distribution ~ 50 liters Requires central venous catheter If reasonable renal function, dialysis may not greatly augment clearance Requires > 2 hours Plasmapheresis/hemofiltrationdon’t work J ThrombHaemost 2009;7(Suppl. 1):107-110
  52. Are there drug interactions? P-glycoproteins (PgP) Inducers Reduce circulating drug levels Example: Rifampin Inhibitors Increase circulating levels Example: quinidine amiodarone
  53. Potential advantages and disadvantages of oral direct thrombin and factor Xa inhibitors Bauer. J ThrombHaemost 2011;9:S12-19
  54. Emerging Anticoagulants Clinical Uncertainties Will a short half-life obviate the need for an antidote or escalate risk related to missed doses? How to assess the anticoagulant effect in acute situations? Starters or switchers: Balancing benefit and risk for warfarin-naïve patients vs. those stable on warfarin. Can better anticoagulants reduce or eliminate the need for risk- stratification? Is it ethical to withhold these newer agents? Will eliminating anticoagulation monitoring adversely impact other aspects of care?
  55. Endovascular treatment of Deep-Vein Thrombosis
  56. Epidemiology of Venous Thromboembolism annual incidence of 1 case per 1,000 population >300,000 patients per year in the U.S. Fourth leading cause of death in the western society More fatalities than breast cancer, AIDS and traffic accidents combined Risk factors include: age, obesity, smoking, cancer, pregnancy, trauma, hospitalization Preventable and treatable disease
  57. Annual Incidence of VTEBy Age and Gender Men Annual incidence/100,000 Women  Age group (yr)
  58. Consequences of DVT and PE $
  59. Post-thrombotic syndrome
  60. After Treated DVT… 20-40% of patients will develop Post-Thrombotic Syndrome 10% of patients have severe form of PTS To date, no reliable way to predict who will develop PTS No effective therapies to treat this condition PTS leads to chronic morbidity to patients (quality of life, mobility) PTS is costly to the health care system Preventing PTS should be a goal of treating acute VTE
  61. Post-Thrombotic Syndrome Prospective study of 355 patients with DVT All patients advised to wear 40 mmHg stockings Years since Cumulative DVT Incidence of PTS 1 17 % 2 23 % 5 28 % 8 29 %  PTS - recurrent, ipsilateral DVT NOT - extent of DVT Prandoni - Ann Intern Med (1996)
  62. Iliofemoral DVT Iliofemoral DVT has more serious long-term consequences than infra-inguinal DVT After 5 years: - 95% develop chronic venous insufficiency - nearly ½ have venous claudication - 15% develop venous ulcers - substantially reduced Quality of Life
  63. Iliofemoral DVT Potential Benefits of Clot Removal: More rapid relief of obstruction Preservation of valve function Reduction in clot recurrence Reduction in post-thrombotic morbidity
  64. Iliofemoral DVT Catheter-Directed Thrombus Reduction: Successful thrombolysis - more rapid return to function - reduced chronic post-thrombotic symptoms - improved quality of life Bleeding  - Major bleeding <5% - Intracranial bleeding <1% Clinical pulmonary embolism <1%
  65. Is DVT an important clinical problem? 1 Yes: What is the best treatment? AC treatment 2 RCT RCT RCT RCT Evidence-based Guidelines: Yes 3 4 Into routine patient care
  66. Clinical Utility Patients eligible to receive catheter-directed thrombolysis-% with isolated iliofemoral DVT vs. other proximal DVT-% who are not high risk for bleeding:In the only randomized trial, only 35/207 screened patients enrolled, most excluded due to high risk of bleeding (post-op) Elsharawy Eur J Vasc Endovasc Surg 2002;24:209
  67. Cogo, Arch Int Med 1993;153:2777
  68. Clinical validity Efficacy Outcomes-Recurrent DVT/PE/mortality-Post-thrombotic syndrome (PTS): Villalta, Ginsberg, valvular reflux-Quality of life (short and long-term) Safety Outcomes-Major bleeding
  69. The cumulative incidence of severe cases and all cases of the post-thrombotic syndrome (PTS) in patients with a first episode of symptomatic deep venous thrombosis. The dashed lines represent the 95% Cis.
  70. Cost Post-thrombotic syndrome -QOL: general (SF-36) and disease- specific (VEINES)-Economic cost: days lost from work Procedural cost without complications$6000-$10,000 Medication/Filters/StentsHospital/ICU stay
  71. Catheter-directed Thrombolysis: RCTs
  72. Management of Venous Thromboembolism: A Systematic Review for a Practice Guideline Annals of Internal Medicine; 146: 2007Feb 6: pg. 214
  73. Estimated Risk for Development of the Postthrombotic Syndrome (Univariate and Multivariate Analysis) *More than 50% time vs. < 50% spent beneath the target range. INR, International Normalized Ratio; OR, odds ratio. Recurrent VTE with standard care 5-8% (RR 2.4 ipsilateral, 1.2 popliteal, 0.8 occlusive) vs. 20% CDT
  74. Risk of Occurrence of PTS for Different Cut-Offs in Percentage of Time Spent in the Lowest INR Range PTS, postthrombotic syndrome; INR, International Normalized Ratio; OR, odds ratio. Bleeding risk: UFH/LMWH 1-2% CDT: Pooled data 8.5%-13%
  75. VEINES-QOL/Sym and EQ-5D Among Patients and Controls Ghanima. J ThrombHaemost 2011;9:1261
  76. Comparison of patient characteristics with good outcomes
  77. Patient Selection Consider… Young Low bleeding risk Risk factor induced DVT Iliofemoral DVT Lysis +/- thrombectomy Stent longevity Rethrombosis Antiplatelet agents Length anticoagulation Practice Guidelines needed
  78. Is PTS an important clinical problem? 1 YES : What is the best treatment? CDT 2 RCT: Elsharawy 35 pts RCT CaVenT RCT TORPEDO RCT ATTRACT Evidence-based Guidelines: NO 3 4 Into routine patient care: Not yet!
  79. Other therapies for prevention of PTS Compression hose(50% risk reduction)-SOX trial (Kahn et al. BMC Cardiovascular Disorders 2007;7:21) LMWH only therapy (Daskalapoulos et al, Eur J VascEndovascSurg 2005;29:638, Hull, Am J Medicine 2009) Exercise (Partsch et al. Immediate mobilisation in acute thrombosis reduces post-thrombotic syndrome. IntAngiol 2004;23:206-12)
  80. Summary Lack of randomized trials of CDT for outcomes of PTS and QOL; studies underway 70% of patients will not develop PTS (80+% will not with stocking use): Best predictor of PTS is Recurrent DVT PTS with new anticoagulants unknown Variable methods for CDT (lysis + mechanical thrombectomy), no standardized proven approach especially in the hands of the less experienced operator Guidelines needed for patient selection, veins treated and timing of lysis
  81. www.ThisIsSerious.org T H I S I S S E R I O U S L I S T E N T O M E K N O W Y O U R R I S K
  82. This Is Serious
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