6/20/2019 Topic Outline VENOUS THROMBOEMBOLISM: So Many Questions…Oy! 1. Direct Oral Anti-Coagulants (DOACs): A Little Review 2. Obesity 47 th Annual UCSF Advances in Internal Medicine 3. Gastric Bypass 4. Coagulation Tests and Drug levels Andrew D. Leavitt, MD 5. Superficial Venous Thrombosis (SVT) 6. IVC Filters 7. Flight / Extended Travel June 20, 2019 8. Your Cases Case 1 . Doppler ultrasound demonstrates occlusive CASE 1: What Would You Do? thrombosis in the left femoral vein from the mid thigh distally into the popliteal vein. YOU WOULD?... A 32 year old man comes to your office with 5 days of progressive discomfort in his left leg, and 2 days of swelling A. Start him on LMWH with bridge to warfarin. 50% from the knee down. B. Start LMWH & 1 week later switch to oral Dabigatran (PRDAXA) 36% No significant PMH. He takes no Rx. He cannot recall any particular injury. He is afebrile. C. Start him on oral Rivaroxaban (XARELTO) D. Start him on oral Apixaban (ELIQUIS) History and exam lead you to suspect a DVT. You send him 7% 7% for a left leg ultrasound E. Start LMWH & 1 week later switch to oral 0% 0% 0% Edoxaban (SAVAYSA) r . e . . . . . . . . . . h . t . . . a t h a . b a t t l o a l i O i r p w k a x k e i e s v p o H e i A e h F. Admit him to the hospital for treatment w R w W l e 1 a l a 1 h M r & r o & t L o o n H n n H t o o W o W m m m m i M M h i h i L h i h L t G. Other i t t t t m t r r r r a r a a a a t d t t t t A S S S S S 1
6/20/2019 Coagulation Cascade in Patients Tissue Factor Tissue Factor Tissue Factor TF TF A LITTLE DOAC TF TF XI XIa AND VIIa IX VII IXa TF VIIIa Ca ++ /Pl TF/VIIa RivaroXaban ANTICOAGULATION ApiXaban X Xa EdoXaban Va = Warfarin BetriXaban Ca ++ /Pl REVIEW II IIa (Thrombin) DabigaTran Fibrinogen Fibrin XIIIa X-linked Fibrin Tissue Factor Tissue Factor Tissue Factor Anticoagulant Preference and Concerns among DOACs – A Few Summary Points Venous Thromboembolism Patients Lutsey et al. Thromb Haemost 2018:118:553-61 All have a black box warning with two key points: A Survey of 519 VTE Patients Premature discontinuation increases risk of thrombotic events EXTREMELY CONCERNED ABOUT THE FOLLOWING OUTCOMES: These findings are from the Atrial Fibrillation trials Recurrent VTE 33% Therefore: Parenteral bridging if DOAC to Warfarin Major bleeding 21% Spinal/Epidural Hematoma Moderate bleed 16% Need protocols for stopping/starting around procedures All-cause death 29% Decline in renal function leads to increased bleeding risk PREFERENCES FOR THEIR ANTICOAGULANT: Think E lderly, N SAIDs, D ehydration/nausea/vomiting ( END ) Reversible 53% Blood test to monitor 30% Be sure proceduralist is aware your patient is taking the medication AGREE WITH THESE STATEMENTS: Not for use with mechanical heart valves Regular blood tests are inconvenient 18% Comfortable using the newest Rx 15% Patients need follow up but you lack the INR clinic connection Difficult to change diet for for the Rx 17% 2
6/20/2019 DOACs and Obesity Anticoagulation Care Tips 1. Everyone wants to know ‘how long?’ But you cannot please CASE #2 everyone. 2. I do not say life-long. Extended….indefinite…let’s see…? A 32 year old man, 140 Kg (BMI 44 Kg/m 2 ), comes to your 3. What are the patient’s wants AND fears? office with 5 days of progressive discomfort in his left leg, and 4. Extended use REQUIRES ongoing risk/benefit assessment. 2 days of swelling from the knee down. 5. DOACs and renal function! No significant PMH. He takes no Rx. He cannot recall any particular injury. He is afebrile. 6. DOACs and anti-platelet agents 7. Much we do not know. Admit this and gain the patient’s History and exam lead you to suspect a DVT. You send him confidence and their participation for a left leg ultrasound 8. Have a visit before stopping anticoagulation – warn them about symptoms DOACs & Obesity Case 2 . Doppler ultrasound demonstrates occlusive thrombosis in the left femoral vein from the mid thigh distally into the popliteal vein. YOU WOULD?... Extreme obesity/morbid obesity = BMI > 40 Kg/m 2 7.7% of adult US population A. Start him on LMWH with bridge to warfarin. ~20 million people B. Start LMWH & 1 week later switch to oral 41% CDC VTE estimates: Dabigatran (PRDAXA) 900,000 people affected in the US/year ~70,000 extreme obese patients will need anticoagulation C. Start him on oral Rivaroxaban (XARELTO) 27% 18% D. Start him on oral Apixaban (ELIQUIS) -- International Society of Thrombosis and Hemostasis (ISTH) 2016: 9% E. Start LMWH & 1 week later switch to oral 5% “Use of the DOACs in Obese People" 0% 0% Edoxaban (SAVAYSA) Due to lack of data, suggest against us in patients r . e weighing >120Kg, or with BMI >40kg/m 2 . . . . . t . . . . a . h . . . . t h a . b a t O F. Admit him to the hospital for treatment t l o a l i i k r x k p w a e i e s e v p e o H i A h But, if you do, obtain a peak and trough level w R w W l l e 1 a a 1 h M r & r o & t L o o n n H n H t o G. Other o W o W m m m M m M i h i h i h i L h L t i t t t t m t r r r r r a a a d a a t t t t t A S S S S S 3
6/20/2019 DOACs & Obesity DOACs & Obesity Efficacy and Safety of Direct Oral Factor Xa Inhibitors in 795 Morbidly Obese Patients Kushnir et al. Am Soc Hem Annual Mtg Abstract Dec 2018 Piran S, et al. Res Pract Thromb Haemost. 2018;2:684-8 Montefiore Medical Center Institutional Database Adults with BMI > 40 kg/m 2 -- 366 VTE; 429 A Fib SUBJECTS: • 38 patients > 120 Kg Apixaban, Rivaroxaban, or Warfarin for AF or VTE: 3/1/2013 – 3/1/2017 • 7 Apixaban; 10 Dabigatran; 21 Rivaroxaban Reviewed charts for recurrent VTE and bleeding (366 VTE patients) • Age (mean) 64 +/- 11 years VTE confirmed by imaging • 30 of 38 Male • Median Weight 132.5 Kg Bleeding per standard/accepted ISTH criteria Time from first Rx to recurrent VTE and bleed for 366 VTE patients FINDINGS: Recurrent VTE: 2.1% apixaban; 2% rivaroxaban; 1.2% warfarin 1. 21% had a peak plasma concentration < the usual on-therapy range 2. All but 2 had a peak higher than the median trough 92 of 366 had BMI >50 (!). No recurrent VTE Bleeding (clinically relevant and major): equal across the 3 groups DOACs and Gastric Bypass Case 3 . Doppler ultrasound demonstrates occlusive thrombosis in the left femoral vein from the mid thigh CASE #3 distally into the popliteal vein. YOU WOULD?... A. Start him on LMWH with bridge to warfarin. The 32 year old 140 Kg (BMI 44 Kg/m 2 ) man from the prior 57% B. Start LMWH & 1 week later switch to oral question has gastric bypass and he drops his weight to 98 Kg Dabigatran (PRDAXA) (BMI 29 Kg/m2) and he comes to your office with 5 days of progressive discomfort in his left leg, and 2 days of swelling C. Start him on oral Rivaroxaban (XARELTO) 25% from the knee down. D. Start him on oral Apixaban (ELIQUIS) 11% 7% E. Start LMWH & 1 week later switch to oral No significant PMH. He takes no Rx. He cannot recall any 0% 0% 0% particular injury. He is afebrile. Edoxaban (SAVAYSA) r . . . e . . . . . . . h . t . . . . a h a . b a t l o l t O t a p i i k r x k w a i s e v p e o e e H w R i A w h W F. Admit him to the hospital for treatment l e 1 l a 1 M a h r r t History and exam lead you to suspect a DVT. You send him & o o & L o H n n H t n o W o o W m m m m M M h i i i i h h L h L t t i G. Other t t t r t m for a left leg ultrasound r r r a r a a a a d t t t t t S S S S A S 4
6/20/2019 Gastric Bypass DOACs: Coagulation Testing Rou-en-Y Sleeve Gastrectomy & Drug Level Testing Biliopancreatic Diversion Gastric Banding with duodenal switch Martin KA et al., Am J Med 2017(130)517-24 DOACs & Drug Level Testing DOACs & Laboratory Testing I have ordered DOAC drug level testing for: We Lack Data Correlating Drug Level and Efficacy/Hemorrhage aPTT and PT : too insensitive, too sensitive, no clear dose response 96% A. Dabigatran (PRDAXA) Direct Thrombin Inhibitor – Dabigatran: B. Rivaroxaban (XARELTO) aPTT more sensitive than PT -But, not standardized and prolongation not predictable C. Apixaban (ELIQUIS) -And, normal aPTT does not rule out ‘on therapy’ drug level D. Edoxaban (SAVAYSA) Thrombin Time is exquisitely sensitive E. None of the DOACs If normal, then essentially no clinically significant drug in system Xa Inhibitors – Rivaroxaban, Apixaban & Edoxaban: 4% 0% 0% 0% PT is more sensitive than is the aPTT -But a normal PT does not rule out ‘on therapy’ drug level Dabigatran (PRDAXA) Rivaroxaban (XARELTO) Apixaban (ELIQUIS) Edoxaban (SAVAYSA) None of the DOACs Need chromogenic Factor Xa activity assay standardized to the Rx No effect on Thrombin Time 5
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