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www.epccs.eu. Rapid Clinical updates since last EPCCS, Part 2 What’s new in AF and VTE guidelines? Prof David Fitzmaurice Birmingham, United Kingdom. Declarations. I have received honoraria from BI, Roche Diagnostics, Bayer, BMS-Pfizer I went to the same primary school as Matt Fay. VTE.

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  1. www.epccs.eu Rapid Clinical updates since last EPCCS, Part 2 What’s new in AF and VTE guidelines? Prof David Fitzmaurice Birmingham, United Kingdom

  2. Declarations I have received honoraria from BI, Roche Diagnostics, Bayer, BMS-Pfizer I went to the same primary school as Matt Fay

  3. VTE Comprises DVT and PE 3rd leading cause of cardiovascular mortality 1 million deaths per year in Europe At least 50% due to hospital admission VTE causes more deaths than MRSA, AIDS, Breast Cancer and RTAs combined 1/20 lifetime incidence

  4. Aims of treatment • To prevent extension • To prevent embolisation • To allow stabilisation and recanalisation • To prevent recurrence • To prevent long term effects (PTS, PH)

  5. Current Treatment • Initial treatment with UFH, LMWH, SP • No placebo controlled trials • Minimum 5 days (average 7) • LMWH drug of choice for cancer patients

  6. Current Treatment • Combined with warfarin (VKA) • Treatment phase 3-12 months • One placebo controlled trial (PE pts, Barritt and Jordan 1960) • Duration of therapy?

  7. Current Treatment – What’s the problem? • INR monitoring • Which LMWH – HIT?? • Bleeding versus recurrence • Duration of therapy

  8. Rivaroxaban EINSTEIN phase III: study designs EINSTEIN Extension1 (superiority study) Treatment period of 6 or 12 months Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA N=1,197 Rivaroxaban 20 mg od 30-day observation after treatment cessation R Placebo Day 1 EINSTEIN DVT1 and EINSTEIN PE2 (non-inferiority studies) Treatment period of 3, 6 or 12 months Confirmed acute symptomatic DVT without symptomatic PE Rivaroxaban Rivaroxaban N=3,449 15 mg bid 20 mg od 30-day observation after treatment cessation R Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start ≤48 hours, target INR range 2.0–3.0 Confirmed acute symptomatic PE with or without symptomatic DVT N=4,833 Day 1 Day 21 The EINSTEIN investigators, 1. N Eng J Med 2010;363:2499-2510 & 2. N Eng J Med 2012;366:1287-1297 L.GB.01.2013.1379 Jan 2013

  9. Einstein - Conclusion Rivaroxaban • Non-inferior acutely compared with standard therapy • Superior in terms of secondary prevention compared with placebo but some excess bleeding • Pre-specified joint analysis suggest superiority of rivaroxaban

  10. Einstein A new era?

  11. Length of Treatment • 1st episode of idiopathic VTE should be treated with warfarin at an INR of 2.0 to 3.0 at least three months • the optimal length of time and optimal degree of anticoagulation are not known • BaglinTet al. JTH 2012 Duration of anticoagulant therapy after a first episode of unprovoked pulmonary embolus or deep vein thrombosis: guidance from the scientific and standardization committee of the international society on thrombosis and haemostasis. • BoutitieFet al. BMJ 2011; 342:d3036 Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials.

  12. Length of Treatment – balance of risksThrombosis vs bleeding • Risk benefit analysis • Patients values and preferences in regard to such risks and benefits • The potential benefit of extending anticoagulation to six (or more) months may be offset by a higher risk of bleeding and the greater cost and inconvenience of the longer duration of treatment

  13. 2012 ACCP Guidelines Recommendations based upon the perceived balance between • the number of deaths from recurrent VTE prevented by continued anticoagulation versus • the number of fatal bleeding episodes associated with continued anticoagulation

  14. Risk of rVTE after discontinuation of anticoagulation

  15. Risk of major bleeding if anticoagulation is continued

  16. BLEEDING • Warfarin in top 10 drugs largest number of serious adverse event reports submitted to the United FDA • Anticoagulants also ranked first in 2003 and 2004 in the number of total mentions of death for drugs "causing adverse effects in therapeutic use" • a common cause of emergency department visits • "black box" warning re warfarin's bleeding risk • Related to the degree of anticoagulation as well as the presence in the patient of pre-existing risk factors for bleeding.

  17. ISTH guidance 2012 • 1st provoked episode VTE or unprovoked calf DVT – a/c no greater than 3 months • 1stunprovoked episode VTE – initial treatment 3-6 months • Continue provided perceived risk a/c related bleeding not so high to preclude continued treatment

  18. ISTH guidance 2012 – unprovoked VTE • In favour of long term a/c (>3-6 months) • Male • Moderate to severe PTS • Ongoing dyspnoea • Satisfactory a/c control • Elevated D-dimer 3-4 weeks after stopping (using study validated assay)

  19. ISTH guidance 2012 – unprovoked VTE • In favour of stopping a/c at 3-6 months • female • Absent or mild PTS • Unsatisfactory a/c control • Low D-dimer 3-4 weeks after stopping (using study validated assay)

  20. Issues to consider • Patient information and counselling • Estimated risk of recurrence • Bleeding risk • Patient values and preferences Age, comorbidities, quality of life issues

  21. Length of Treatment Who is truly low risk of recurrence? Who is truly high risk of bleeding?

  22. Aspirin • Warfasa and Aspire trials • 40% reduction compared to placebo following standard treatment

  23. VTE Conclusion • New agents now available • Optimal length of time of anticoagulation are not known (low risk of recurrence) • Cost? • New care pathways • Warfarin here for a while yet

  24. AF • Most common heart rhythm disorder • 25% risk of AF for those over 40 • 5-fold increase in risk of stroke with non-valvular AF • Worsens stroke outcomes • 15% of all strokes caused by AF

  25. AF • 3 new agents • All good • All reduce ICH • Headline data • Issues: cost, monitoring, reversal

  26. New anticoagulants (1) • Dabigatran RE-LY trial NEJM 2009; 361:1139 • 150mg v warfarin • stroke: 1.0% vs 1.6%, RR 0.64 (0.51-0.81) • death: 3.6% v 4.1%, RR 0.88 (0.77-1.00) • major bleed: 3.3% v 3.6%, RR 0.93 (0.81-1.07) • 110mg v warfarin • stroke: 1.4% vs 1.6%, RR 0.92 (0.74-1.13) • death: 3.7% v 4.1%, RR 0.91 (0.80-1.03) • major bleed: 2.9% vs 3.6%, RR 0.80 (0.70-0.93)

  27. New anticoagulants (2) • Rivaroxaban ROCKET-AF NEJM 2011 • stroke 2.1% vs 2.4%, RR 0.88 (0.75-1.03) • death 1.9% vs 2.2%, RR 0.85 (0.70-1.02) on treatment • major bleeding 3.6% vs 3.4%, RR 1.04 (0.9-1.2) on treatment

  28. New anticoagulants (3) • Apixaban: ARISTOTLE NEJM 2011 • stroke 1.3% vs 1.6%, RR 0.79 (0.66-0.95) • death 3.5% vs 3.9%, RR 0.89 (0.80-0.99) • major bleeding 2.1% vs 3.1%, RR 0.69 (0.6-0.8) on treatment

  29. Who to anticoagulate? • NICE dabigatran guidance (March 2012) • Previous stroke or TIA • Age 75 or over • Left ventricular ejection fraction < 40% • Age 65 or over with a risk factor (diabetes; CHD; hypertension) • Who not to anticoagulate? • Age under 65 (unless 2 risk factors) • Age 65-74? • Role of aspirin (ESC guidelines)

  30. Stroke risk stratification CHADS2 CHA2DS2VASc2 Low risk = 0 Moderate risk = 1 High risk ≥ 2

  31. Guidelines for antithrombotic therapy in AF NICE guidelines (2006) European Society of Cardiology (2010)

  32. HAS-BLED Score for bleeding risk on oral anticoagulation in AF Feature Score if present Hypertension (systolic > 160mmHg 1 Abnormal renal function 1 Abnormal liver function 1 Age > 65 years 1 Stroke in past 1 Bleeding 1 Labile INRs 1 Taking other drugs as well 1 Alcohol intake at same time 1 Increased 1-year bleed risk with score of 3 or more on anticoagulant. Is this sufficient to justify caution or more regular review?

  33. Conclusions • New agents • More emphasis on risk:benefit • Individual versus population • Warfarin?

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