Clinical Cases with Deep Venous Thrombosis - The position of Apixaban Stavros KAKKOS, MD, MSc, PhD, RVT Department of Vascular Surgery. University Hospital of Patras Chairman: Ioannis Tsolakis
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Deep Vein Thrombosis Venous Gangrene
Risk of recurrent VTE Initial 1 (0 έως ~7 days) Stages of VTE treatment Long-term (~7 days to ~3 months Extended/secondary prevention (after ~3 months) Parenteral* (VKA) or other factors Treatment Secondary prevention Time from initiation of treatment Initiation of treatment and secondary prevention End of teatment * Heparin, low molecular weight heparin (LMWH), fondaparinux. Includes LMWH and NOACs 1. Kearon C et al. Chest. 2012;141(2 Suppl):e419s-e494s. 2. Kearon C. J Thromb Haemost. 2012;10:507-511. 4
Thrombosis Bleeding Disadvantages of VKAs Narrow therapeutic window thrombosis bleeding Difficulty maintaining INR within this window Numerous food & drug interactions Require frequent monitoring of INR and narrow therapeutic window dose adjustments Slow onset and end of action Increased risk of bleeding Dose
Targets of DOACs Xll Xl lx TF VIIIa Va X VII Direct inhibitors of Xa Rivaroxaban, Apixaban II Direct inhibitors of thrombin Dabigatran I Fibrin clot Adopted from Ansell J. J Thromb Haemost. 2007;5(suppl 1):60-64. Turpie AGG. Arterioscler Thromb Vasc Biol. 2007;27:1238-1247.
Apixaban: a direct oral anticoagulant (DOAC) Apixaban (Eliquis/Pfizer και Bristol-Myers Squibb)
O Apixaban O N NH 2 N O N N O No prodrug Bioavailability: ~50% T max : 3 4 hours ~87% binding to plasma proteins T 1/2 : ~12 hours Apixaban SmPC 2012. Pinto et al. J Med Chem. 2007;50(22):5339-56.
Apixaban is equally effective with eno/warfarin RR 0.84 (95% confidence interval [CI], 0.60 to 1.18; P<0.001 for noninferiority). AMPLIFY, NEJM 2013
Practice change with DOACs No INR monitoring Reduced drug and no food interactions No ΗΙΤ Monotherapy (only apixaban and rivaroxaban) Forget bridge therapy Pay attention to renal function
Practice change with DOACs I forgot to tell you something No INR monitoring very important! Reduced drug and no food interactions No ΗΙΤ Monotherapy (only apixaban and rivaroxaban) Forget bridge therapy Pay attention to renal function
Practice change with DOACs Treatment: reduced frequency of major bleeding 1.08% 1.73% Kakkos, Kirkilesis, Tsolakis. EJVES 2014
Event rate (% /year) Event rate (% /year) Event rate (%/year) Event rate (% /year) Event rate (% /year) AMPLIFY 2.0 1.5 1.0 0.5 Primary Safety Outcome: Major Bleeding* Major Bleeding* 0.6 n=15 1.8 n=49 25.0 20.0 15.0 10.0 5.0 0.0 Major + CRNM Bleeding 4.3 n=115 Apixaban 9.7 n=261 Enoxaparin/Warfarin P<0.001 RR=0.44 (95% CI 0.36 0.55) 25.0 20.0 15.0 10.0 5.0 0.0 CRNM Bleeding 3.8 n=103 Apixaban 8.0 n=215 Enoxaparin/Warfarin P not reported RR=0.48 (95% CI 0.38-0.60) 0.0 Apixaban P<0.001 RR=0.31 (95% CI 0.17 0.55) Enoxaparin/warfarin blood, occurred into a critical site, or contributed to death. CI, confidence interval; CRNM, clinically relevant nonmajor; RR, relative risk. 25.0 20.0 15.0 10.0 5.0 0.0 Minor Bleeding 1 11.7 n=313 Apixaban 18.8 n=505 Enoxaparin/Warfarin P not reported RR=0.62 1 (95% CI 0.54-0.70) 25.0 20.0 15.0 10.0 5.0 0.0 All Bleeding 1 15.0 n=402 Apixaban 25.1 n=676 Enoxaparin/Warfarin P not reported RR=0.59 1 (95% CI 0.53-0.66) Clinically relevant nonmajor bleeding was defined as overt bleeding but associated with medical intervention, contact with a physician, interruption of the study drug, or discomfort or impairment in carrying out activities of daily life. Secondary safety outcome was the composite of major or clinically relevant nonmajor bleeding. * Bleeding was defined as major if it was overt and associated with a decrease in the hemoglobin level of 2 g/dl, required the transfusion of 2 units of 1 Apixaban SmPC http://www.medicines.org.uk/emc/medicine/27220/spc Created from Agnelli G et al. N Engl J Med. 2013;369:799-808. 17
AMPLIFY EXT, NEJM 2013
Practice change with DOACs Treatment: reduced frequency of deaths due to major bleeding 0.09% 0.18% Kakkos, Kirkilesis, Tsolakis. EJVES 2014
Practice change with DOACs Treatment: reduced frequency of clinically significant non-major bleeding 6.6% 8.5% Kakkos, Kirkilesis, Tsolakis. EJVES 2014
Practice change with DOACs Secondary prevention: reduced frequency of VTE 1.3% 7.2% Kakkos, Kirkilesis, Tsolakis. EJVES 2014
Practice change with DOACs Secondary prevention: reduced frequency of fatal PE Kakkos, Kirkilesis, Tsolakis. EJVES 2014
Practice change with DOACs Secondary prevention: reduced frequency of all cause death 0.41% 0.86% Kakkos, Kirkilesis, Tsolakis. EJVES 2014
Antidote for Apixaban Adnexanet alpha On May 4 th 2018
Presentations of clinical cases
Case No 1 57 year old Caucasian female with a past medical history of hypertension on treatment and surgery for breast cancer stage IIa some 10 years ago, disease free on her last follow-up, presented to the emergency room of an outside hospital with a two day history of massive swelling of the right leg.
Case No 1 Duplex scanning revealed extensive DVT Admitted to hospital Renal function: WNL Started on a LMWH Tumor recurrence was ruled out Discharged on LMWH after 3 days PET scan: WNL/no uptake
Case No 1 After 10 days on LMWH, our patient developed a large skin necrosis at the injection site in her abdomen
Case No 1 Referred by the Dermatology service asking for advice regarding anticoagulation options in this case of apparent heparin-induced skin necrosis Hematomas
Case No 1 Cessation of LMWH Was it necessary in the first instance? Well-informed patient, requested a DOAC Fear of bleeding! Apixaban was deemed appropriate.
Case No 1 Apixaban SPC Start treatment with apixaban 10mg BID for 7 days and then switch to 5mg BID
Case No 1 Apixaban SPC Start treatment with apixaban 10mg BID for 7 days and then switch to 5mg BID HOWEVER applicable only for the initial stage of treatment! Therefore in this case: start on apixaban 5mg BID
Case No 2 35 year old healthy motorbike driver had a low-speed accident and sustained a fibula fracture and also a grade 1 knee sprain on his L leg Cast and LMWH
Case No 2 Presented to the ER some 15 days later complaining of new-onset calf pain. Duplex: extensive calf vein thrombosis PLT count: WNL Thromboprophylaxis cannot be 100% effective!
Case No 2 Treatment options 1. Increase the dose of the LMWH: patient denied to continue on a failed treatment
Case No 2 Treatment options 1. Increase the dose of the LMWH: patient denied to continue on a failed treatment 2. Observation with repeat Duplex @ 6 weeks: not indicated due to the presence of Sx.
Case No 2 Treatment options 1. Increase the dose of the LMWH: patient denied to continue on a failed treatment 2. Observation with repeat Duplex @ 6 weeks: not indicated due to the presence of Sx. 3. Switch to apixaban: 5mg BID
Treatment options 1. Increase the dose of the LMWH: patient denied to continue on a failed treatment 2. Observation with repeat Duplex @ 6 weeks: not indicated due to the presence of Sx. 3. Switch to apixaban: 5mg BID 4. Switch to apixaban: 10 mg BID for 1/52 then 5mg BID Case No 2
Case No 2 Duration of treatment Fear of bleeding 6 weeks? 6 months? Indefinite?
VTE recurrence Frequency after Tx cessation Unprovoked Other risk factors* Baglin, Lancet 2003 Recent surgery * Except pregnancy and surgery
Duration of anticoagulation Tx: recurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 1.736 patients with a first episode of provoked DVT or PE Three months 6-12 months RR 0.99 95% CI 0.74 to 1.32 No recurrence Recurrence Pinede, Circulation, 2001 Agnelli, Ann Intern Med, 2003 Agnelli, NEJM, 2003 Campbell, BMJ, 2007 ICS, 2003
Duration of anticoagulation Tx: major bleeding 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% 3 months 6-12 months RR 2.5 95% CI 1.16 to 5.83 Absence of major bleeding Major bleeding Pinede, Circulation, 2001 Agnelli, Ann Intern Med, 2003 Agnelli, NEJM, 2003 Campbell, BMJ, 2007 ICS, 2003
Case No 2 The correct answer (not listed) is three months of apixaban monotherapy
Case No 3 86 year old female presents with acute onset L leg swelling and pain diagnosed as DVT on Duplex scanning Otherwise healthy, underweight (45Kg) Labs: creatinine 2mg%
Case No 3 86 year old female presents with acute onset L leg swelling and pain diagnosed as DVT on Duplex scanning Otherwise healthy, underweight (45Kg) Labs: creatinine 2mg% e-gfr: 14.3 ml/min
Case No 3 CAUTION ALL DOACS REQUIRE GFR CALCULATION CONTRAINDICATED IN SEVERE RENAL FAILURE TO AVOID BLEEDING AND PRESERVE THEIR REPUTATION!
Case No 4 54 year old male with a PMH of HT & NIDDM had an episode of unprovoked DVT of his R leg some 5 years ago, treated with LMWH - acenocoumarol for 6 months. Recurrence of DVT with nearly fatal PE a month after he stopped anticoagulation.
VTE recurrence Frequency after Tx cessation Unprovoked VTE n=1,626 Provoked VTE Prandoni, Haematologica 2007
Case No 4 Recurrence was treated with thrombolysis, LMWH - acenocoumarol. No stop date. Regular INR checks. Labile INR readings, often below 2. Increasing anxiety about potential of another recurrence. Psychiatry visit.
Case No 4 A year after recurrent DVT had occurred he presented to my outpatient clinic with painless swelling of his right leg started 6/12 ago. Gradual deterioration worse in PM, subsides after bed rest. Duplex: no recurrence.
Post thrombotic syndrome Risk factors Early symptoms Iliofemoral DVT Recurrence of DVT Elderly Obesity Females Subtherapeutic INR Kahn, Ann Intern Med. 2008 Van Dongen, J Thromb Haemost 2005
Case No 4 Reflux in the popliteal vein on additional testing What to do next?
Case No 4 Treat PTS with a class 2 elastic stocking. Optimum anticoagulation in patients with established PTS?
Case No 4 Apixaban will provide a stable anticoagulation level and was actually proposed to the patient. Patient is now very happy with the proposal. He understood well the need for prolonged treatment.
Case No 4 Any consideration missing??
Case No 4 Any consideration missing?? Dose!
Case No 4 5 mg BID? 2.5 mg BID?
AMPLIFY EXT, NEJM 2013
AMPLIFY EXT, NEJM 2013
Case No 5 45 year old female with an unremarkable PMH sustained a minor skiing accident with a left ankle sprain. Family history included father with unprovoked DVT at the age of 60. Cast and thromboprophylaxis.
Case No 5 Returned after 9 days with pain and swelling of the left leg, requiring cast removal, examination confirming edema with tenderness on OE. Duplex: CFV
Interpretation? Case No 5
VTE recurrence Frequency after Tx cessation Unprovoked Other risk factors* Baglin, Lancet 2003 Recent surgery * Except pregnancy and surgery
OPTIMAL DURATION STRATEGY Acute PE or DVT Provoked Gray Zone Unprovoked 3-6 Months Rx Individualize Rx Consider Lifelong Rx Consider past/family VTE history, gender, recanalization of leg veins on U/S, hypercoagulability, patient preference Courtesy of Samuel Goldhaber Circulation 2011
Case No 5 A clear case for apixaban monotherapy 10mg BID for 7 days 5mg BID for 3 months Dose reduction after 6 months: 2.5mg BID
Case No 6 29 year old female with longstanding varicose veins. Hereditary, related also to occupation (hair dresser). Conservatively managed (elastic compression stockings, venoactive drugs)
Case No 6 Superficial Vein Thrombosis (SVT) Kakkos et al, Thrombosis Research 2010
Clinical manifestations of SVT Rubor Pain Local edema Palpable firm thrombi Mostly a clinical diagnosis
Superficial Vein Thrombosis ` Duplex: Extensive thrombosis of the left great saphenous vein, measuring 30 cm in length GSV incompetence Incompressible great saphenous on US probe compression
Exclusion of deep-vein thrombosis in patients with SVT is necessary (level of evidence high)
Case No 6 SVT extending through perforators into gastrocnemius (deep) veins
Superficial Vein Thrombosis is not a Benign Disease A significant proportion (10-20%) of patients has already extension of thrombosis into the deep venous system, fact that necessitates a duplex scan to be performed to R/O DVT. A significant proportion of patients (10% in POST) will develop extension or recurrence during the first three months.
From January 1992 to January 1996, 263 patients were identified with superficial venous thrombosis isolated to the superficial veins with no evidence of deep venous involvement by duplex ultrasound examination. Thirty (11%) patients had documented progression to deep venous involvement within 2-10 days. J Vasc Surg 1996;24:745-9.)
Patterns of extension into the deep veins From the greater saphenous vein in the thigh into the common femoral vein (SFJ, n=21, 70%), with 18 of these extensions noted to be non occlusive and 12 having a free-floating component. From the above-knee saphenous vein through thigh perforators to occlude the femoral vein in the thigh (n=3). Below-knee saphenous disease into the popliteal vein (?SPJ, n=3) Below-knee thrombi into the tibioperoneal veins through calf perforators (n=3). Chengelis, J Vasc Surg 1996
Superficial Vein Thrombosis is not a Benign Disease Three-Month Incidence of Venous Thromboembolic Events in Isolated SVT Thromboembolic Event (n 586) Incidence [95% CI], n (%)* Any 58 (10.2 [7.7 12.7]) Symptomatic 46 (8.3 [6.0 10.6]) PE or DVT 18 (3.3 [1.8 4.8]) DVT 15 (2.8 [1.4 4.2]) Proximal 7 Distal 8 PE 3 (0.5 [0 1.2]) SVT Recurrence 10 (1.9 [0.7 3.0]) Extension 18 (3.3 [1.8 4.8]) Asymptomatic 12 (2.1 [0.9 3.2]) 8.3% symptomatic thromboembolic events @ 3 months *Percentages are probabilities computed by using survival curve analysis. Assessed by compression ultrasonography 8 14 days after presentation.
Case No 6 Because of extension into the deep veins, apixaban was prescribed for three months. Varicose vein surgery afterwards. Without recurrence three years later. No need for extended anticoagulation.
Three-year cumulative rates of deep-vte recurrence (DVT or pulmonary embolism [PE]) in patients with a first isolated SVT or a first isolated proximal DVT Galanaud JTH 2017
Case No 7 74 year old male with a PMH of HT and DLP presented to the ER department with a five day history of right leg pain and calf tenderness. Two-point Duplex WNL, d-dimers not measured. Returned two days later because of clear deterioration of his symptoms.
Case No 7 What went wrong?
Case No 7 Repeat Duplex scan revealed extensive calf vein thrombosis
Case No 7 Treatment options Observation with repeat scanning? Prophylactic anticoagulation? Therapeutic anticoagulation? Type? Duration?
Case No 7 ACCP 2016
Case No 7 ACCP 2016
Need for long-term anticoagulant treatment after a 1 st episode of symptomatic calf-vein thrombosis Three-month follow-up OPEN LABEL RCT P< 0.01 29% * proven by venography Lagerstedt, 1985, Lancet
Need for long-term anticoagulant treatment after a 1 st episode of symptomatic calf-vein thrombosis One-year follow-up P< 0.02 4.4% 32% * proven by venography Lagerstedt, 1985, Lancet
Need for long-term anticoagulant treatment after a 1 st episode of symptomatic calf-vein thrombosis Lagerstedt, 1985, Lancet
Case No 7 ACCP 2016
Case No 7 Apixaban 10mg BID for 7 days and then switch to 5mg BID for three months
Conclusions Apixaban has a wide range of indications in patients with DVT of the leg during the acute phase of the disease and in the long term. Extremely useful in extended treatment of DVT for the purposes of safe and also effective secondary prevention using a halved dose.
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