BGS Autumn Conference 2014

Transcription

1 Management of VTE Dr Raj Patel King s Thrombosis Centre, London

2 Acute DVT Originate in the deep veins of the lower extremities >90% originate in the calves 1 Signs and symptoms are non-specific Only ~30% of symptomatic patients have confirmed acute DVT 2 Upper limb (10%) lines, malignancy,assisted conception Other sites Cerebral venous sinus Porto-spleno-mesenteric, Budd-Chiari 1. Stamatakis JD. Brit J Surg Kahn S. Thrombosis and Haemostasis. 1999

3 VTE: the burden of disease Acute VTE In-hospital mortality 6-15% after PE Recurrent VTE Post-thrombotic syndrome Pulmonary hypertension Risks of anticoagulation

4 Deep vein thrombosis Common femoral vein Thrombus Proximal Knee Distal

5 Presentation of deep vein thrombosis 75% patients presenting with DVT have other diagnoses Kind permission from Ola Dahl Cellulitis Congestive cardiac failure Gout Lymphangitis Post-thrombotic syndrome Ruptured Baker s cyst Superficial thrombophlebitis Varicose veins Trauma: Muscle strain/tear, haematoma Jowett 1999

6 NICE CG 144 Diagnosis Guidance Clinical history Physical examination Wells Score (2-level) Confirmatory tests Proximal leg vein ultrasound (US) ---whole leg? D-dimer test Autumn Conference 2014 BGS NICE Clinical Guidance 144. Venous thromboembolic diseases Last Accessed

7 NICE Clinical Guideline 144 Two-level DVT Wells score 1. NICE Clinical Guidance 144. Venous thromboembolic diseases: Appendix C Last Accessed Wells PS. New Eng J Med

8 NICE CG 144 Diagnosis of DVT Algorithm Autumn Conference 2014 NICE Clinical Guidance 144. Appendix C:Venous thromboembolic diseases Last Accessed BGS

9 NICE Clinical Guideline 144 Initial DVT treatment LMWH or Fondaparinux unless contraindicated: egfr under 30ml/min: UFH infusion with APTT monitoring Elevated bleeding risk: UFH infusion with APTT monitoring Rivaroxaban and Apixaban licensed Rivaroxaban NICE-approved

10 NICE Clinical Guideline 144 Ongoing DVT treatment LMWH / Fondaparinux / UFH : Continue for at least 5 days or until INR>2 for at least 24hrs (whichever longer) LMWH for 6 months in active cancer, reassess risk/benefit at 6 months VKA for 3 months in provoked proximal DVT VKA beyond 3 months in unprovoked proximal DVT if recurrence risk high and no additional bleeding risk. NOACs: all 3 now licensed Rivaroxaban NICE-approved

11 NICE s Incremental Costeffectiveness Ratios (ICER) Patient group ICER ( /QALY) Meaning 3 months anticoagulation RIV dominates RIV less costly, greater QALYs than LMWH/VKA 6 months anticoagulation 3200 RIV cost-effective 12 months anticoagulation 14,900 RIV cost-effective Cancer NA Long term 19,400 RIV cost-effective

12 Key features of rivaroxaban (1) o Oral o Once daily o Rapidly absorbed o Cmax 2-4 hours after taking tablet o Half-life 5-9hrs (young) 11-13hrs(elderly) o Anticoagulation effect for 24hrs o 1/3 is excreted unchanged by the kidneys o 2/3 is metabolized by the liver to inactive metabolites Xarelto SmPC June 2012 O O N N O H N O O Rivaroxaban S Cl

13 Key features of rivaroxaban (2) o Fixed dose (varies by indication) o No need for routine anticoagulation monitoring o 15 mg and 20mg tablets take with food Xarelto SmPC June 2012 O O N N O H N O O Rivaroxaban S Cl

14 Current dual-drug approach is effective but demanding NHS Choices. Treating deep vein thrombosis o Need for two drugs o Initial subcutaneous injections o Coagulation monitoring o Frequent dose adjustments o Many drug drug interactions o Dietary restrictions

15 Drug interactions with rivaroxaban o Rivaroxaban not recommended in combination with o Systemic azole-antimycotics (ketoconazole, itraconazole) o HIV protease inhibitors o Dronedarone (lack of information) o Use rivaroxaban with caution in combination with o Other anticoagulants o NSAIDS o Platelet inhibitors o Strong CYP3A4 inducers such as rifampicin or St John s Wort Xarelto SmPC June 2012 BGS Autumn Conference 2014

16 Rivaroxaban EINSTEIN phase III: study designs Confirmed acute symptomatic DVT without symptomatic PE N=3449 Confirmed acute symptomatic PE with or without symptomatic DVT Confirmed symptomatic DVT or PE completing 6 or 12 months of rivaroxaban or VKA R N=4833 EINSTEIN DVT 1 and EINSTEIN PE 2 (non-inferiority studies) Treatment period of 3, 6 or 12 months Rivaroxaban 15 mg bid Enoxaparin 1.0 mg/kg bid for at least 5 days, followed Day 1 Day 21 N=1197 R Day 1 Rivaroxaban 20 mg od by VKA to start 48 hours, target INR range EINSTEIN EXT 1 (superiority study) Treatment period of 6 or 12 months Rivaroxaban 20 mg od Placebo 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499; 2. The EINSTEIN PE Investigators. N Engl J Med 2012;366: day observation after treatment cessation 30-day observation after treatment cessation

17 EINSTEIN DVT and EINSTEIN PE pooled analysis: primary efficacy outcome* Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) n (%) n (%) First symptomatic recurrent VTE 86 (2.1) 95 (2.3) Recurrent DVT 32 (0.8) 45 (1.1) Recurrent DVT + PE 1 (<0.1) 2 (<0.1) Non-fatal PE 41 (1.0) 36 (0.9) Fatal PE/unexplained death where PE cannot be ruled out 15 (0.4) 13 (0.3) 0 Rivaroxaban superior p=0.41 for superiority (two-sided) ITT population Prins MH et al. Thromb J. 2013;11: HR Rivaroxaban non-inferior p<0.001 for non-inferiority (one-sided) 1.75 Rivaroxaban inferior

18 EINSTEIN DVT and EINSTEIN PE pooled analysis: major bleeding Cumulative event rate (%) Rivaroxaban n/n (%) 40/4130 (1.0) Enoxaparin/VKA n/n (%) 72/4116 (1.7) First major bleeding HR (95% CI) p-value 0.54 ( ) p=0.002 Enoxaparin/VKA N=4116 Rivaroxaban N= Time to event (days) Number of patients at risk Rivaroxaban Enoxaparin/VKA Safety population Prins MH et al. Thromb J. 2013;11:21

19 EINSTEIN DVT and EINSTEIN PE pooled analysis: types of major bleeding Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) n % n % Major bleeding* Fatal 3 < Retroperitoneal <0.1 Intracranial 2 <0.1 4 <0.1 Gastrointestinal/thorax 1 <0.1 3 <0.1 In a critical site Retroperitoneal 1 < Intracranial 3 < Intraocular 3 <0.1 3 <0.1 Pericardial <0.1 Intra-articular <0.1 Adrenal/pulmonary/abdominal 3 <0.1 2 <0.1 Fall in haemoglobin 2 g/dl and/or transfusions 2 units *Some patients had >1 event Prins MH et al. Thromb J. 2013;11:21 HR (95% CI) p-value 0.54 ( ) p=0.002

20 EINSTEIN DVT and EINSTEIN PE pooled analysis: outcomes in fragile patients* Outcome Recurrent VTE Rivaroxaban Enoxaparin/VKA HR (95% CI) n/n % n/n % Fragile 21/ / Non-fragile 65/ / Major bleeding Fragile 10/ / Non-fragile 30/ / *Age >75 years or CrCl <50 ml/min or body weight 50 kg Prins MH et al. Thromb J. 2013;11: ( ) 0.98 ( ) 0.27 ( ) 0.80 ( )

21 EINSTEIN DVT and EINSTEIN PE pooled analysis: clot size and recurrent VTE Limited ( 25% of vasculature of a single lobe, popliteal vein only) Rivaroxaban Enoxaparin/VKA n/n % n/n % 10/ / Intermediate 41/ / Extensive (multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein) Prins MH et al. Thromb J. 2013;11:21 35/ /

22 EINSTEIN DVT and EINSTEIN PE pooled analysis: outcomes in patients with cancer Outcome Recurrent VTE Rivaroxaban Enoxaparin/VKA HR (95% CI) n/n % n/n % Cancer 16/ / No cancer 70/ / Major bleeding Cancer 9/ / No cancer 31/ / Prins MH et al. Thromb J. 2013;11: ( ) 0.93 ( ) 0.53 ( ) 0.53 ( )

23 DVT or SVT? Superficial veins: upper limb thrombophlebitis Brachial, ulna, radial, cephalic, basilic veins Superficial veins: lower limb thrombophlebitis Short saphenous vein (SSV) Long saphenous vein (LSV) (Varicose vein phlebitis)

24 SVT: isolated lower limb (LSV/SSV) phlebitis <3 cm from saphenofemoral junction (SFJ) or saphenopopliteal junction (SPJ) Treat as DVT >3 cm from SFJ or SPJ <5 cm long Symptomatic management e.g. NSAID Consider rescan if no improvement at 1 week or progressive symptoms >5 cm long If one of: knee involvement, severe symptoms, LSV, previous DVT/SVT, active cancer, recent surgery then prophylactic LMWH 6/52 (if not then treat as for <5 cm long) Recurrent unexplained SVT: Vascular Surgeon

25 NICE Clinical Guideline 144: IVC filters Offer temporary IVC filter Proximal DVT or PE where anticoagulation contraindicated Remove filter when eligible for anticoagulation Consider IVC filter in recurrent proximal DVT or PE despite adequate anticoagulation only after: Increased INR target 3 4 Switch to LMWH Filter removal strategy (earliest opportunity) NICE Clinical Guideline 144,

26 NICE Clinical Guideline 144 thrombolysis for DVT Consider catheter-directed thrombolysis Symptomatic ilio-femoral DVT and Symptom duration less than 14 days and Good functional status, life expectancy over 1 year and Low bleeding risk NICE Clinical Guideline 144,

27 NICE Clinical Guideline 144 Investigations for cancer Offer all patients diagnosed with unprovoked VTE (who are not already known to have cancer): a physical examination a chest X-ray full blood count, serum calcium and liver function tests Urinalysis Consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women): all patients aged over 40 years with a first unprovoked VTE (who do not have signs or symptoms of cancer)

28 Clinic review Complications ECHO Massive PE or post-thrombolysis or RV strain at presentation Ongoing symptoms >6 weeks GCS post-dvt Daily wear of below-knee GCS on affected leg (daytime only) mmhg ankle pressure Renew 3 6 monthly (according to manufacturer) 2 years, extend duration if PTS Lower grade compression if not tolerated, assess barriers (e.g. application) Reassure: symptoms fluctuate, likely to stabilise/improve over time Emollient for dryness/itching (Doublebase, Epiderm ) Ulcers: tissue viability nurse review

29 Clinic review: PHT investigation Indications Massive PE, thrombolysis, RV strain at presentation Ongoing symptoms (SOB, syncope, chest pain) Tests ECHO, chest X-ray ECHO suggestive of PHT? Pulmonary arterial systolic pressure >40 mmhg Tricuspid regurgitation velocity m/s Lung function: spirometry, Sa0 2, CO transfer Refer to Chest Physician at KCH, then regional unit Long-term anticoagulation

30 Provoked and unprovoked VTE Transient/ reversible factors e.g. surgery or hospitalisation Provoked VTE Continuing/ irreversible factors e.g. cancer ACCP guidelines recommend at least 3 months anticoagulation therapy after provoked VTE or longer after unprovoked (idiopathic) VTE* *In the case of low to moderate bleeding risk Zhu T et al. Arterioscler Thromb Vasc Biol 2009;29;298; Gensini GF et al. Semin Thromb Hemost 1997;23:55; Kearon C et al. Chest. 2012;141:e419S No identifiable cause Unprovoked (idiopathic) VTE

31 Recurrence Risk C: unprovoked A: surgical D: non-surgical 1. Baglin et al. Lancet 2003; 362:523; 2. Prandoni et al. Haematologica 2007;92:199; 3. Kearon et al. Circulation 2004;110:I-10 Cambridge Cohort Study 1 (2-year cumulative recurrence rates) Unprovoked VTE 17% Surgical trigger 0% Non-surgical trigger 8% Highest recurrence risk 1st year after initial event 2 Recurrence risk at 8 years 46% Warfarin prevents 95% recurrences 3

32 Idiopathic VTE: duration 1st unprovoked VTE: 1000 patients, 5 years Warfarin: (low risk) 24 major bleeding events, 3 deaths (high risk) 98 major bleeding events, 11 deaths No warfarin : 264 VTE recurrences, 10 deaths Kearon C et al. Chest. 2012;141:e419S

33 Duration Duration: considerations Unprovoked PE more likely ( 3) to recur as PE than DVT 1 Risk of fatal PE more likely (>5-fold) in patients with symptomatic non-massive PE, compared with those with DVT without symptomatic PE 2 Unprovoked calf VTE has a lower risk of recurrence CTEPH more likely after recurrent PE Morbidity from PTS (common) vs ICH (rare) 1. Baglin T et al. J Thromb Haemost 2010;8:2436; 2. Laporte S et al. Circulation 2008;117:1177

34 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Residual vein occlusion Does not predict a likelihood of recurrent DVT to a degree that is clinically useful PTS A prospective cohort study showed PTS associated with 2.6-fold increased rate of recurrent DVT Male gender 1.8-fold higher risk of recurrence after unprovoked VTE Baglin T et al. J Thromb Haemost 2012;10:698

35 D-dimer Abnormal D-dimer level 1 month after discontinuation of anticoagulation (~40%) 1 Significant incidence of recurrent VTE compared with normal D-dimer level (15% vs 6.2% after 1.4 years; adjusted HR 2.27) Negative predictive value of D-dimer % in subjects with an unprovoked qualifying event 1. Palareti G et al. N Engl J Med 2006;355:1780; 2. Wang Y et al. J Thromb Thrombolysis. 2011;32(4):410

36 Duration of anticoagulation therapy after an unprovoked VTE: guidance from the SSC of the ISTH Other factors to predict risk of recurrence: 1. D-dimer 2. Residual vein occlusion 3. PTS 4. Thrombophilia 5. Male gender 6. Mode of presentation Baglin T et al. J Thromb Haemost 2012;10:698

37 Five Decades of VTE Treatment o From nothing to heparin o From intravenous to subcutaneous heparin o From heparin to low-molecular-weight heparins (LMWH) o From immobilization to early mobilization o From inpatient treatment to outpatient treatment o From LMWH to synthetic, specific anticoagulants

38 Dr Raj Patel King s Thrombosis Centre King s College Hospital rajpatel@nhs.net