What’s new in AF and VTE guidelines? 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 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

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

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

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

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

Rivaroxaban EINSTEIN phase III: study designs Methods of VTE treatment Rivaroxaban EINSTEIN phase III: study designs 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 Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA Rivaroxaban 20 mg od Placebo Day 1 N=1,197 EINSTEIN Extension1 (superiority study) Treatment period of 6 or 12 months R 30-day observation after treatment cessation Rivaroxaban EINSTEIN phase III: study designs The EINSTEIN phase III study programme consisted of three phase III clinical studies assessing the effect of rivaroxaban in the treatment of VTE. EINSTEIN DVT and EINSTEIN PE1,2 Randomised, open-label, active-controlled, parallel-group, non-inferiority, event-driven studies. EINSTEIN DVT has been completed. EINSTEIN PE is still on going. Patients had confirmed acute symptomatic DVT without symptomatic PE (EINSTEIN DVT), or confirmed acute symptomatic PE with or without symptomatic DVT (EINSTEIN PE) Patients were randomized to receive oral rivaroxaban 15 mg bid for 3 weeks then 20 mg od or subcutaneous enoxaparin (1 mg/kg bid for at least 5 days) then VKA (INR 2.0–3.0 started within 48 hours) for 3, 6 or 12 months1,2 Treatment duration (3, 6 or 12 months) was decided by the investigator prior to randomization according to the patient’s risk profile and local standards EINSTEIN Extension1 A randomised, double-blind, placebo-controlled, parallel-group, superiority study in patients with confirmed symptomatic DVT or PE. Patients with confirmed symptomatic DVT or PE were treated for 6 or 12 months with rivaroxaban or a VKA before the decision for continued treatment was made. At this point, where there was no clear decision for stopping or continuing anticoagulation therapy, patients were randomized to receive rivaroxaban 20 mg od or placebo for 6 or 12 months. References The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510 EINSTEIN PE. Available at: http://clinicaltrials.gov. Trial ID: NCT00439777. Accessed August 2011 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

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

Einstein A new era?

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 Baglin Tet 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. Boutitie Fet 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.

Length of Treatment – balance of risks Thrombosis 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

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

Risk of rVTE after discontinuation of anticoagulation Risk or rVTE 1st year Thereafter 1st VTE provoked by surgery 1% 0.5% 1st VTE provoked by a nonsurgical factor 5% 2.5% 1st unprovoked VTE 10% 2nd episode unprovoked VTE 15% 7.5%

Risk of major bleeding if anticoagulation is continued Risk factors Risk category During 1st 3 months Thereafter/yr None LOW 1.9% 0.9% 1 INTERMEDIATE 3.2% 1.6% 2 HIGH 12.8% > 6.5%

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.

Thrombotic recurrence risk group LOW bleeding risk group INTERMEDIATE bleeding risk group HIGH bleeding risk group 1st VTE provoked by surgery Discontinue (strong) 1st VTE provoked by a nonsurgical factor or 1st unprovoked distal DVT (weak) 1st unprovoked proximal DVT or PE Continue 2nd episode unprovoked VTE

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

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)

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)

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

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

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

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

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

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

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)

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

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

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)

Stroke risk stratification CHADS2 CHA2DS2VASc2 Risk factor Score CHF 1 Hypertension Age >75 Diabetes Stroke / TIA 2 Risk factor Score CHF OR LVEF ≤ 40 % 1 Hypertension Age ≥ 75 2 Diabetes Stroke / TIA Thromboembolism Vascular Disease Age 65 - 74 Female Low risk = 0 Moderate risk = 1 High risk ≥ 2

Guidelines for antithrombotic therapy in AF NICE guidelines (2006) Stroke risk Recommended antithrombotic therapy High risk Anticoagulation with warfarin Moderate risk Consider OAC or aspirin Low risk Aspirin 75-300mg if no contraindications European Society of Cardiology (2010) CHA2DS2VASc score Recommended antithrombotic therapy CHA2DS2VASc ≥ 2 Oral anticoagulant (OAC) CHA2DS2VASc = 1 Either OAC or aspirin 75–325 mg daily. Preferred: OAC rather than aspirin CHA2DS2VASc = 0 Either aspirin 75–325 mg daily or no antithrombotic therapy. Preferred: no antithrombotic therapy rather than aspirin

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?

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