Obesity, renal failure, HIT: which anticoagulant to use?

Obesity, renal failure, HIT: which anticoagulant to use? Mark Crowther with thanks to Dr David Garcia and others. This Photo by Unknown Author is licensed under CC BY-SA 1

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Drug choices The DOACs have changed the way that we deal with anticoagulants BUT the LMWHs, warfarin and other older anticoagulants still have an important role to play LMWHs remain the drugs of choice for VTE prophylaxis in many settings LMWHs at therapeutic doses provide flexibility in selected higher risk patients particularly at the extremes of weight The ability to monitor and adjust warfarin provide it with a great deal of flexibility Anticoagulation is a high-risk activity and thus we have to have a great deal of familiarity with agents before we use them 3

Obesity: Prophylaxis Prophylaxis with LMWH Soft evidence that as weight goes up, efficacy goes down, suggesting weight based adjustment may be required 4

198 patient RCT allocating patients to enoxaparin 40 mg BID or fondaparinux 5 mg OD Enoxaparin initiated pre-operatively Fondaparinux initiated post-operatively Clinical outcomes BMI 45.7 (Enox) vs 45.1 (Fonda) Screening detected DVT 2/2 MRV all clots in Left Iliac vein Symptomatic DVT 0/0 5

DOACs Limited data with clinically relevant outcomes 6

Conclusions For LMWH as weight rises dose increments should be considered Weight adjusted LMWH is particularly appealing For DOACs Limited data that available suggests that weight has limited impact on drug levels but at extremes may consider LMWH For warfarin weight should have no impact 7

Obesity: Therapeutic dosing LMWH Dose increment without capping is generally accepted Warfarin No influence of weight on effect DOACs Limited, but surprising, data 8

In conclusion in AF and VTE patients treated with DOACs or with warfarin patients with low body weight had a paradoxical increase in the risk of thromboembolism compared with non-low body weight patients. The subgroup of AF patients with a high bodyweight had a favorable thromboembolic outcome compared with AF patients with a non-high body weight. Limited data on the very large Analysis based on wide patient weight classes Obesity paradox is seen in other settings 9

Obesity summary Warfarin remains effective across the range of body weights For prophylaxis consider weight adjusting LWMH and use DOACs with care For therapy use uncapped LMWH and reasonable to use DOACs (where indicated) at weights up to (and perhaps beyond) 130 kg 10

Renal Failure 11

Why are we worried about renal insufficiency? Impaired renal clearance will lead to bioaccumulation and avoidable bleeding 12

Kidney dysfunction increases both risk for clotting and bleeding VTE + kidney dysfunction increases the incidence of both fatal PE and fatal bleeding Multivariate Analysis on the Risk of Developing Fatal PE Multivariate Analysis on the Risk of Developing Fatal Bleeding Variables Odds Ratio (95% CI) P-Value Symptomatic PE 17 (8.8-34) <0.001 Renal function <0.001 Variables Odds Ratio (95% CI) P-Value CrCl > 60 ml/min Reference - Immobility >4 d 3.3 (1.5-7.3) 0.003 CrCl 30-60 ml/min 2.0 (1.2-3.4) 0.008 Cancer 2.7 (1.2-6.0) 0.015 CrCl <30 ml/min 5.2 (3.4-7.8) <0.001 Renal function - Immobility >4 d 2.4 (1.7-3.4) <0.001 CrCl > 60 ml/min Reference - Cancer 2.0 (1.4-2.9) <0.001 CrCl 30-60 ml/min 1.4 (0.3-5.9) 0.677 Initial therapy, UFH 1.9 (1.2-3.0) <0.001 CrCl <30 ml/min 5.0 (2.0-12) <0.001 Inpatients 1.5 (1.0-2.1) 0.027 CrCl: creatinine clearance; CI: confidence interval; PE: pulmonary embolism; UFH: Unfractionated Heparin Monreal M, et al., Findings from the RIETE Registry. Am J Med. 2006;119:1073-1079.

Risk of Anticoagulant-associated Major Bleeding Increases with Lower GFR We have an assumption that heparin and warfarin are safe in patients with renal insufficiency We have learned the LMWH and DOACs are unsafe with renal failure BOTH OF THESE ASSUMPTIONS MAY BE INCORRECT ARISTOTLE

LMWH: Prophylaxis and therapy 15

PROTECT 3600 patient study comparing LMWH with UFH in critically ill patients Innovations: Large sample size High consent rate Head to head comparison Included patients with renal failure

Primary outcome: Proximal deep vein thrombosis

Prophylaxis Dalteparin Reduced clinical pulmonary embolism 24 vs 43 cases (p = 0.01) Was safely used in patients over the full range of renal function Including patients on dialysis Caused less HIT 5 vs 12 cases despite contamination Was administered once daily Did not increase bleeding Any bleeding: 244 vs 247 patients Renal failure and LMWH Dalteparin Does not bioaccumulate at prophylactic doses Enoxaparin Appears to bioaccumulate requiring dose reduction Both are effective for prevention of VTE across the full range of renal function

The CLOT Study post-hoc Analysis Methods 200 IU/kg dalteparin SC QD month 1, and 150 IU/kg SC QD months 2-6 200 IU/kg dalteparin SC QD days 1 5 and VKA QD, until INR was 2.0 3.0 CLOT patients divided by renal function at baseline. Renal impairment (CrCl <60 ml/min) was defined as moderate (CrCl 30 to <60 ml/ min) or severe (CRCL <30 ml/min). Primary efficacy outcome was the rate of VTE recurrence (ITT population) Primary safety outcomes included clinically overt bleeding (any and major) in the as-treated (AT) population

The CLOT Study post-hoc Analysis VTE and Bleeding Outcomes in Patients with RI (CrCl < 60 ml/min) Variable Treatment Events % p - value Hazard Ratio (ITT) VTE (n = 162) (AT) Any bleeding (n = 161) (AT) Major bleeding (n = 161) Dalteparin 2/74 2.7 OAC 15/88 17.0 Dalteparin 15/74 20.1 OAC 21/87 24.1 Dalteparin 7/74 9.5 OAC 6/87 6.9 0.0111 0.148 0.4658 0.781 0.6511 1.287 Results were consistent with the overall CLOT study, for dalteparin vs. OAC: VTE: 27/336 (9%) vs. 53/336 (17%) respectively, p = 0.002 Any bleeding: 47/338 (14%) and 64/335 (19%) respectively, p = 0.09 Major bleeding: 19/338 (6%) and 12/335 (4%) respectively, p = 0.27

Dalteparin compared with UFH in an unselected General Medical population Park et al. J Gen Intern Med. 2015 Jul 25. Compared clinically significant bleeding in patients with GFR < 60 ml/min receiving therapeutic dose dalteparin to patients receiving therapeutic doses UFH Non-randomized retrospective cohort study. Outcomes: Major bleeding within 10 days of anticoagulation

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LMWH: Renal failure Key results: Dalteparin treated patients were significantly less likely to experience a major bleed than patients treated with UFH (1.14% vs. 3.49%, p <0.001). Difference remained significant after adjustment In patients with CKD, treatment with therapeutic dose dalteparin was associated with lower rates of bleeding than treatment with UFH Limited data for enoxaparin but that that exists suggests safety with empiric dose reduction 24

DOACs 25

Special Populations in the Phase III Randomized Trials of DOACs Trial Name Study Year Dosing Total N ecrcl 30-50 Dabigatran RECOVER I/II RE-LY VTE AF 2009/14 2009 150 bid 150/110 bid 5107 18113 245 3505 Rivaroxaban EINSTEIN-DVT EINSTEIN-PE ROCKET-AF DVT PE AF 2010 2012 2011 20 qd 20 qd 20 qd 3449 4832 14262 235 398 2949 Apixaban AMPLIFY ARISTOTLE VTE AF 2013 2011 5 bid 5 bid 5395 18201 338 3017 Edoxaban HOKUSAI ENGAGE-AF VTE AF 2013 2013 60 qd 60/30 qd 8240 21105 541 4074 NB: Many of these trials included pre-specified dose adjustments for reduced renal function.

No evidence of difference in efficacy for Atrial Fibrillation or Venous Thrombosis Most studies excluded patients with ESRD 27

That is all well and good but what should we do We should do studies! 28

Apixaban with renal failure Canadian Package insert US Package insert http://www.pfizer.ca/sites/g/files/g10028126/f/201607/ ELIQUIS_PM_184464_16June2016_E_marketed.pdf Access 21 Sept 2016 https://packageinserts.bms.com/pi/pi_eliquis.pdf Accessed 21 Sept 2016 29

Rivaroxaban with renal failure 30

Renal Impairment, my opinion Moderate renal impairment (Cr Cl 30-50 ml/ min): All Xa inhibitors are at least as safe as warfarin Apixaban safer? Check package insert for dose adjustments! Severe renal impairment (Cr Cl < 30 ml/min): Avoid all DOACs pending more data If a DOAC is chosen, get informed consent and consider monitoring for bioaccumulation Do not assume that warfarin is a safer and more effective alternative it may just be we are inured to its problems!

HIT Rules of the game Confirm diagnosis using objective testing Avoid all heparin-like anticoagulants Reverse warfarin if platelets less than 150 Ensure patients are aware of need to avoid heparins in future 32

Drugs available and indications Argatroban Renal failure, requiring therapeutic anticoagulation Bivalirudin Hepatic disease, requiring therapeutic anticoagulation Fondaparinux Has become agent of choice in many circumstances DOACs Emerging evidence 33

National, multicenter registry HIT objectively diagnosed Treated with argatroban, lepirudin, danaparoid or fondaparinux Outcome measures: thromboembolic events, amputations, recurrent/ persistent thrombocytopenia, skin lesions and bleeding 34

Argatroban Danaparoid Fondaparinux Exposures 46 61 84 Arterial thromboembolism 2.2% 3.3% 0% Venous thromboembolism 6.5% 4.9% 0% Amputation 2.2% 1.6% 0% Skin necrosis 0% 3.3% 0% Bleeding 6.5% 6.6% 4.8% Deaths 10.9% 19.7% 0% Adapted from Schindewolf et al. 35

DOACs and HIT 36

22 adults with suspected or confirmed HIT rivaroxaban 15 mg bid until HIT assay available positive assay continued rivaroxaban 15 mg bid until platelet recovery then reduced to 20 mg daily until day 30. 1 HIT patient had new VTE 1 HIT patient required limb amputation despite platelet recovery Rivaroxaban appears to be effective for treating patients with confirmed HIT, although the small number of patients enrolled limits precision 37

HIT summary Fondaparinux is now, probably, the standard in those patients who are eligible for it Argatroban, Bivalirudin have important roles in subsets of patients DOACs will likely evolve into an important role, initially replacing warfarin s current role in HIT management 38

Three cases 36 year old woman attending for hip replacement surgery Weight 147 kg Recommend: Probably some for of weightadjusted LMWH If tinzaparin is available it has a weight adjusted dosing schedule If not suggest at least double the usual prophylaxis 39

A 72 year old male with a CrCl of 15 ml/min presents with new, objectively confirmed left leg DVT Treat with usual dose dalteparin for 5 to 7 days and transition to warfarin Admit for IV UFH transitioned to warfarin Probably the less safe of the two options Probably would not use a DOAC as very limited data for VTE in this setting 40

A 58 year old woman develops serologically proven HIT on POD6 CABG + mitral valve replacement Initial therapy Limited data, high risk of thrombosis with MVR IV argatroban, danaparoid, bivalirudin Would not transition to fondaparinux in setting of fresh MVR Long term Rx warfarin once platelets have normalized 41