Update in Standard of Care for Venous Thromboembolism from the June 2012 Supplement to CHEST and 2017 AC Forum

Update in Standard of Care for Venous Thromboembolism from the June 2012 supplement to CHEST and 2017 AC Forum

Sharyl Magnuson, MD Adjunct Faculty, Pacific University School for PA Studies former Associate Medical Director, Lovelace Clinical Thrombosis Center Member THSNA Disclosures

• Nothing to disclose from pharmaceutical sources of income. • I have been an Investigator on many Pharmaceutical sponsored Clinical trials, last more than 7 years ago. • I have been a promotional speaker in the past for Xarelto, last more than 2 years ago. Scope of the Problem • “On average, one American dies of a blood

clot every 6 minutes” 100,000/year. National Blood Clot Alliance • The precise number of people affected by DVT/PE is unknown, although as many as 900,000 people could be affected (1 to 2 per 1,000) each year in the United States. • Estimates suggest that 60,000-100,000 Americans die of DVT/PE (also called venous thromboembolism). • 10 to 30% of people will die within one month of Clot diagnosis. • Sudden death is the first symptom in about one-quarter (25%) of people who have a PE. • Among people who have had a DVT, one-half will have long-term complications (post-thrombotic syndrome) such as swelling, pain, discoloration, and scaling in the affected limb. • One-third (about 33%) of people with DVT/PE will have a recurrence within 10 years. • Cdc.gov Best Resource • MAQI2 version 1.7, the Michigan Anticoagulation Quality Improvement Initiative, a consortium of AC clinics and experts across MI, produced this 65pg Quick Reference using updated review literature. http://anticoagulationtoolkit.org/sites/default /files/toolkit_pdfs/toolkitfull.pdf • Free. Also, you should have a direct, downloadable link through this conference with my favorite Dental AC advice publications included as well. Available anti-coagulants

Heparins Unfractionated Heparin = UFH Low Molecular weight Heparins = LMWH Pentasaccharide (Fondaparinux) Vitamin K antagonists (VKA) Warfarin = Coumadin In Europe, Macumal and some others, all same effect on INR DOAC’s Dabigatran , Rivaroxaban, Apixaban, Edoxaban, with Betrixaban Investgational (targeting Fac XI & XII) Established Anticoagulants

XII XIIa I N WARF VIIIa T R XIa XI EXTRINSIC IX I N WARF IXa UFH S LMWH I C TF VIIa WARF

Xa II Va X

WARF IIa

FIBRINOGEN FIBRIN A. Spyropoulos Our old friend, Warfarin

• Wisconsin Alumni Research Foundation + the “arin” to relate it to coumarin. Why something + warfarin is needed to initiate VTE therapy.

Warfarin is a competative inhibitor of Vit K, inhibits carboxylation reactions required for synthesis of factor II, VII, IX, & X, all pro -thrombotic. Also inhibits production of anti-thrombotic proteins, Proteins C & S.

Kitchens, Alving, & Kessler; Consultative Hemostasis& Thrombosis; 2nd edition; pg 449 Approx 1/2-Life of Vit K-Dependent Factor/pro- & Anti-coagulants • Factor or Anticoagulant Half-Life • Factor VII (pro) 6 hours (INR) • Factor IX “ 24 hours • Factor X “ 36 hours • Factor II (Thrombin) “ 50 hours • Protein C (anti) 8 hours • Protein S “ 30 hours

Table Compiled from data from Goodman and Gillman’s The Pharmacological Basis of Therapeutics, 1996 Fall of Vit K Dependent Factors with the start of Warfarin

Fac VII, inversely impacts INR. Vitdep K factors

Prot C, hypercoagulable when low.

Thrombin, drop has most meaningful impact on anticoagulation.

[Danger Zone] days Warfarin induced skin. necrosis. Due to acquired Prot C deficiency with early Warfarin tx.

Early drop of Prot C, late fall of Fac II (Thrombin) in setting of thrombogenic milieu is cause of this adverse event of Warf initiation. Can also cause clot extension, embolism, infarction. In Afib patients with active atrial clots, can lead to clot growth with friable new clot and increased embolic risk, stroke and arterial emboli. It takes 5-10 days off Warfarin for the system to reset to Warfarin naive, requiring new initiation bridge. Initial Unbalanced Fall of Vit K dependent factors

PT is prolonged by decreases in factor VII, one of the earliest factors to fall, especially if warfarin is “loaded”. This may also cause an early profound drop in Protein C levels, producing an unfavorable balance of anti- vs pro- thrombotic effects. When in the setting of an active clot, the preponderance of pro-thrombotic influences is particularly dangerous. Kitchens, pg 449. Choosing A Safe Initial Bridging Agent Initial Bridge Choices LMWH: Can be monitored with Factor Xa levels. Must monitor Platelets 5-10 days into treatment (small risk of HIT compared w UFH). Partial reversal w Protamine. Dalteparin (Fragmin): 200 units/kg/day SC, max 18,000 units/dose. Dosing nomogram wt based in insert. QD dosing. Proph dosing, 5000 units SQ qd Metabolism, liver; CYP450. T1/2 3-5hrs, 6-7 in renal impairment. In severe renal impairment (CrCl < 30), test anti-Xa levels after 3-4 doses, target 0.5-1.5 IU/ml. Adjust accordingly. Half dose with platelet counts 50-100K. Don’t use if Plt < 50K. . Arch Intern Med. 2012;172(22):1713-1718. Published online November 5, 2012. doi 10.1001/2013.jamainternmed.369 LMWH cont.

Enoxaparin (Lovenox): 1mg/kg/bid SC (or 1.5mg/kg/qd, equally safe and effective). 40% renal excretion. T1/2 4.5-7 hrs Must adjust for CrCl less than 30 to 1mg/kg/day. Doesn’t remove well with Dialysis. Accumulates in renal impaired patients even at the 40mg SQ QD prophylactic dose. Choice of Initial Bridging Agent cont. Fondaparinux(Arixtra): 3 tiered daily dosing. 5mg SC if wt < 50kg, 7.5mg SC if wt 50-100 kg, and 10mg SC if wt > 100kg. Excreted mainly in urine. T1/2 17-21 hrs. No good reversal agents. Synthetic. Almost no HIT risk. UFH or Heparin: Mention only to discourage use in the treatment of outpatient VTE. Can be used easily IV. Less easily SQ weight based. No pre-prepared single use syringes other than the 5000 U Proph dose, must be drawn up by patient for treatment dosing. Direct-Acting Oral Anticoagulants DOACs • NOAC----”no anticoagulant” That’s a real problem. Happened several times in interpretation of hospital orders. • TSOAC----Thought to be a bit obscure. Target specific is correct, but TS is hard to say. • DOAC is easy and clear, D stands for Direct- Acting or Directed. Now the DOAC’s Directed Oral AntiCoagulants • Factor Xa inhibitors: – Share mixed clearance, renal and hepatic, to variable degrees. – All to be avoided in severe Hepatic failure. – All need to be used carefully in renal insufficiency. – Clarithromycin/Erythromycin, -azole antifungals, and HIV protease inhibitors---all lead to increased drug levels. – CYP3A4 inducers that cause measurable decreased levels: rifampicin, carbamazepine, phenobarbatol, St. John’s Wort. Fac Xa inhibitors • Rivaroxaban (Xarelto) and Apixaban (Eliquis) – Both can be started alone to treat VTE. – Both use larger starting dose in setting of active VTE. –Rivaroxaban: – Starter pack, 21 days of 15mg bid and 9 days of 20mg qd taken with the evening meal. – 36% excreted unchanged in urine. – 2/3 of dose is metabolized through various pathways: CYP450, P-gp transport. – Normal PT/INR means no sig Rivaroxaban levels. !!!Rivaroxaban is the only Fac Xa inhibitor that can use the INR this way to test residual drug presence!!!! Riva & Apixa –Apixaban: – Downloadable calendar to remind patients to take (2) 5mg tabs BID for 7d, then 5mg BID. – Cleared 25% total dose in feces & urine, CYP metabolism main pathway. – Biggest mistake is under-dosing. Patients have increased risk of VTE events or strokes if dose too low. Assess risk accurately. • 2.5 mg twice daily is recommended for patients with at least 2 of the following characteristics: • age ≥80 years • body weight ≤60 kg • serum creatinine ≥1.5 mg/dL More Xa inhibitors • Edoxaban (Savaysa): – requires a 7d pretreatment of LMWH or UFH before starting tx. – Less than 10% dose metabolized via any pathway, very few interactions. • P-gp inducers, rifampin, can lower drug level. • Some P-gp inhiitors can raise levels, requiring dose reduction from 60mg qd to 30mg qd. • 50% excreted unchanged in urine. • Reduce dose to 30mg qd for CrCl 15-50 ml/min. • Betrixaban just released for post hospitalization VTE prophylaxis. – Not yet approved for VTE tx. No reversal agents yet for Fac Xa Inhibitors Direct Thrombin inhibitor, Dabigatran (Pradaxa) • No overall improved safety over warfarin, but decreased Intra-Cranial Hemorrhage. (ICH) • Requires 5-10 days parenteral AC prior to starting. Then BID dosing. (A function of the study design) • Induces number and activity of Thrombin receptors on platelets. May be reason cessation leads to increased thrombosis. • GI upset common non-bleeding side effect. • Dronedarone and Ketakonazole co-use lead to sig increase in levels. Dabigatran Cont. • 80% renally cleared. • The rest, hepatic, so not advised in severe liver failure. (you will see this only in pkg insert fine print). • HemoDialysis removes 62% of circulating Dabigatran in 2hrs. • aPTT or TCT (Thrombin Clotting Time) testing measures residual Dabigatran effect. • Praxbind is available antidote. Safety & Monitoring of DOACs See MAQI pg 52

• Assess labs: – Just post initiation: H/H and ? in 1 month and 3 months – Q 6 months Renal function if CrCl 30-60 ml/min* or if on dabigatran and >75 years or fragile – Q 3 months Renal function if CrCl 15-30 ml/min* – As needed If clinically indicated for conditions that may impact renal or hepatic function. DOAC Safety and Monitoring cont.

• With each visit Assess: – Compliance: Educate, monitor adherence, Stress non- compliance concerns. Riva with food. Dabi in package, ect. – Thromboembolism: TIA, Stroke, VTE, art emb, PE. – Bleeding: Remember, increased GI. Investigate per normal screening stool, uterine, and urine bleeding protocols. If benign and minor, treat to mitigate and encourage continuation. – Side effects: Usually minor bleeding. GI upset on Dabi. – New Meds: May interact. P-gp inhib/inducers for Dabi & Edoxa, P-gp/CYP3A4 inhib for Riva & Apixa. Added anti-Plts will increase bleeding. Preliminaries At or prior to start of treatment with DOACs, LMWH, fondaparinux, and/or warfarin: (Any long term anticoagulant)

Obtain laboratory information including: CBC with platelets. Creat. PT/INR, PTT (baseline &coagulopathy). LFT’s are now advised with DOACs.

History: Previous VTE, Family hx, bleeding hx, arterial side clots, CA hx, good ROS especially metabolic, pulmonary and cardiac. Need COMPLETE Medication list (for interactions).

Physical: Weight, HR, RR, BP, cardiac, pulmonary, extremities (measure), derm. O2 sat very helpful.

? hypercoagulable testing ?, usually don’t do it. Pregnancy counseling and testing!!! Use Creat, age, and true weight to calculate Cockcroft-Gault eq. http://touchcalc.com/calculators/cg for LMWH, DOACs. Mrs Cho 54 yo Asian woman. She was playing football with her grandchildren and severely sprained her L ankle 2 weeks ago. Presents with 1 week of L lower extremity swelling and discomfort She has some SOB, and is scared. She is a healthy woman with no chronic conditions, no cancer, no allergies, no medications, no previous surgeries, no VTE history, and no significant family history. Her exam in your office shows her normal BP (120/60), P of 105, RR of 18, and she weighs 65kg.

RA O2 sat 95%. Needed Lab info

Labs show: Normal CrCl, Plt ct, & Hct.

RA O2 sat 95%. Get baseline PT/INR, PTT on anyone you even consider anticoagulating. These are in normal range for Mrs Cho, suggesting no severe liver dysfunction. New VTE. What to do? Warfarin treatment • You suspect a provoked LLE DVT and a PE. The PE is not hemodynamically significant. • Start pt on LMWH now while you order your diagnostic studies. –Lovenox 1.5mg/kg SQ qd = 100mg syringe (97.5), or –Fragmin 12.5K units (pre-filled syringe). What to do for provoked VTE cont.

• Obtain L LE doppler. – Most say that we should look at only the vessels above the knee. • If +, no need to get d-dimer or chest CT. • If -, be led by D-Dimer for CT (because of ? of PE). • If no ? of PE, would do 1 week f/u doppler of proximal LLE to see if DVT is visible now . With + Doppler • Add Warfarin to the LMWH. – Asians often slow metabolizers, requiring lower doses, so start with 5mg qd, expecting to move down on the recheck. • Recheck day 3. – Suspect INR will be close to 3, with our target 2-3. If INR is 5, we would hold Warfarin, but not LMWH, due to the Prot C/Thrombin suppression mismatch. • Recheck again day 5, and get Plt ct. – If INR over 2, able to stop LMWH if completed 5 d overlap. Now what? • As this is a provoked clot, duration of therapy is 3 months, then reassess. • Do a post treatment doppler at about 4-6 mo. Gives baseline for ? of recurrence or extension. • When off Warfarin, discuss ASA 81mg qd. Discuss procedural prophylaxis and travel proph. Compression stockings for comfort. Options for Secondary Prevention of VTE 8 Agent Risk Reduction Regimen

None 0% —

Full-dose Warfarin INR 2−3; maintenance anticoagulation1-3 ~80-90% dosing dabigatran, rivaroxaban, apixaban, edoxaban

Low–dose DOAC₂ ~80% Apixaban 2.5 mg BID Rivaroxaban 10mg QD Low-intensity warfarin3 75% Warfarin INR 1.5−1.9

ASA4 32% 100 mg po daily

1. Agnelli G et al. N Engl J Med. 2013;368:699-708. 2. EINSTEIN INVESTIGATORS N Engl J Med 363;26 3. Kearon C et al. N Engl J Med. 2003;349:631-639. 4. Brighton TA et al. N Engl J Med. 2012;367:1979-1987. CHEST 2016: In patients with an unprovoked proximal VTE who are stopping anticoagulant therapy and do not have a contraindication to ASA we suggest ASA ..to prevent recurrent VTE.

Taken from ‘17 AC Forum lecture of TRACY MINICHIELLO, MD Change it up.

Mrs. Cho has a drop in BP and lower O2 sat Significant PE • Mrs Cho has a significant drop in her BP and

in her O2 sat. – She would then meet criteria to consider hospital admission for PE. – You would put her on a Heparin drip in anticipation of possible systemic thrombolysis. – Assess for RV dysfunction, and watch for sys BP < 90 for 15 min. Or generalized deterioration. – Assess for bleeding risks, balance against clot severity. If very low bleeding risk, lysis threshold is lower. Thrombolysis • Contraindications/Cautions: Recent major surgery/trauma within 2wks, intracranial surgery within 3mo, LP within 1wk History of CVA, especially within previous 3 months Advanced age, > 65yo risk of intracranial hemorrhage is 2.71 Significant uncontrolled hypertension, >185/110 Concomitant anti-coagulation medication, GPIIB/IIIa inhibitor, platelet inhibitor use Active serious bleeding anywhere, internal bleeding within 3wks Active cancer

1Gurwitz et al, Risk for ICH after TPA, Annals of Int Bleeding diathesis, liver impairment Med, ‘98, 129:1879-85 PE treatment Modalities

Lysis of PE clot results in better Right Ventricular function, exercise capacity, wellness, & QOL at 3mo.

Kline JA et al. J Thromb Haemost 2014. Treatment recommendations: *Rapid risk assessment for hemodynamic compromise. *Recommend Systemic thrombolysis unless major bleeding contraindications in Massive PE. *Recommend treatment via peripheral vein. *Recommend administration of thrombolytics with short infusion times over prolonged. (Alteplase) Thrombolytic agents T-PA (Alteplase) • 10mg IV initially, then the rest of the 100mg over the remaining 2 hours. • Heparin not administered during Alteplase infusion. • Check PTT after infusion, then Q 4hrs • When PTT < 2X control, resume Heparin drip and adjust to target. • Monitor for Bleeding. • Usually this is all done in ICU level of care. Streptokinase

Only other FDA approved thrombolytic. T-PA is preferred agent Thrombolytics, cont. • Reteplase: nonapproved indications – catheter-directed intra-arterial or intravenous infusion for peripheral vessel occlusions – as 5-minute bolus doses (in 1U increments) for acute ischemic stroke – as a low-dose solution for occluded catheters or grafts – as an intravenous double bolus for massive pulmonary embolism. – Across studies, the incidence of bleeding complications associated with reteplase treatment appeared to be similar to that associated with other thrombolytic agents. PE treatment, not preferred • Catheter based Thrombolysis for PE is reserved for: – Failed systemic Thrombolysis in massive PE. – Contradiction to systemic Thrombolysis in Massive PE. – In low bleeding risk sub-massive PE patients where benefits outweigh risks. • Pharmacomechanical Thromectomy: AngioJet – Breaks up and aspirates the clot. – Infuses thrombolytic agent in conjunction with disruption of clot. What if Mrs Cho wanted a DOAC? • Mrs Cho preferred a DOAC. • You would try to add LFT’s to the preliminary labs, or you would get them very soon afterwards, on one of your early f/u’s. • Rivaroxaban 15mg BID (21d) or Apixaban 10mg BID (7d) to start. Then to standard dosing. • Same 3 mo duration. Same f/u doppler and ASA considerations, prophylactic considerations. Pointers on which DOAC to choose MAQI pgs 15-19 High risk of bleeding: HAS- Consider agent/dose with Dabigatran 110mg BID BLED score > 3 lowest risk of bleeding Apixaban

Previous GI Bleed or high risk Consider agent with lowest Apixaban for GI bleeding reported incidence GI bleed High ischemic stroke risk, low Consider agent/dose that best Dabigatran 150mg BID bleeding risk reduces ischemic stroke Previous stroke Agents best at reduction of Rivaroxaban (secondary prevention) 2nd stroke Apixaban CAD, Previous MI, or high risk Consider agent with a + effect Rivaroxaban for ACS/MI on ACS Renal Impairment Consider agent least Apixaban/Edoxaban dependent on renal function Rivaroxaban (lower dose)

GI upset/disorders Consider agent with no Apixaban reported GI effects Rivaroxaban, Edoxaban

Patient Preference Consider once daily dose Rivaroxaban, Edoxaban (post LMWH initiation) Extended DOAC instead of ASA

• RE-MODY & RE-SONATE w Dagibagran: risk higher than placebo due to MI. • EINSTIEN-CHOICE with Rivaroxaban vs 100mg ASA: – Overall, the 10mg QD dose showed better VTE protection with similar bleeding. • AMPLIFY-EXT with Apixaban vs 100mg ASA: -Overall, the 2.5mg BID dose showed benefit in VTE prevention with no significant increase in bleeding in patients with previous VTE. VTE and Cancer Mrs. Cho’s VTE was due to colon cancer, and she is in the middle of her treatment regimen.

LMWH, weight based, is still the recommended and preferred treatment of VTE related to cancer. 50% better outcomes than Warfarin. VTE in the Cancer Patient • DOACs are now being used, and support is building with comparable outcomes in clinical and the few research settings when compared to Warfarin. • Dec. ‘17, Hokusai VTE Cancer study was Published in the NEJM, comparing Savaysa vs Dalteparin (LMWH) in acute or recurrent VTE in Cancer patients: At least non-inferiority for Recurrent VTE endpoint. Increased major bleeding endpoint, but only GI major bleeding. Less bleeding in all other sites.

Hokusai VTE Cancer, Gary E. Raskob, Ph.D, et al.,December 12, 2017, NEJM.org. In Cancer • May want to use LMWH for 3mo, or longer. • May want to use LMWH during the active phase of chemo. – Injectable, so no issues with N&V. – No dietary or drug interactions. – Savaysa (Edoxaban) has almost no chemo interactions. May want to consider as alternative. • Transition to DOAC or Warfarin for the duration of the cancer. When the cancer is gone, the provoking factor is gone. Mrs. Cho has a very severe and symptomatic proximal DVT

Phegmasia Alba Dolens Extensive DVT and PTS • Mrs Cho presented with an extremely swollen and painful L LE. All else is the same, but the pain is unbearable in her leg. – Doppler shows extensive proximal DVT. Very little venous return from her left leg. Admit and start IV heparin in anticipation of Catheter Directed Thrombolysis of this Proximal DVT.

An NIH-sponsored trial, the ATTRACT study, hopes to determine if Thrombolysis in the setting of extensive DVT promotes early recanalization and decreases PTS. Post thrombitic syndrome

From www.dermatology.cdlib.org. PTS Clot around venous valves, despite anticoagulation, permanently damages or destroys valves, causing reflux and impaired venous return. Treatment of Severe DVT • Catheter Directed Thrombolysis (CDT) of Acute DVT: Extensive Proximal DVT (Ileo-femoral better outcome than fem-pop). Symptoms for less than 14 days Good functional status and life expectancy of ≥ 1yr. Low bleeding risk. Significant risk of major bleeding with thrombolysis. Thrombolysis significantly reduces risk of PTS.  CDT is preferred over systemic thrombolysis or Operative/Percutaneous Venous Thrombectomy.  Afterwards, anti-coagulate as if no thrombolysis occurred.

2012 ACCP Guidelines Compression Stockings: Oh Yay…

Your patients just love these. Compression stockings: SOX Trial • NOT proven to lower the chance of developing Post Thrombitic Syndrome. Kahn SR, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014 Mar 8;383(9920):880-888. • Graduated knee high compression stockings now recommended strength lower strength, to wear for symptomatic relief only. Easier to get on and off than the 30-40 mm Hg wt. • Knee high is as good as thigh high, even if the clot is in the saphenous or femoral veins. Compliance is better and cost is lower. Intracranial Hemorrhage, or other contraindications to anticoagulation

ICH is one of several contraindications to AC. In patients with significant VTE risk and with acute but stabilized ICH, starting (or restarting) anticoagulants after 7-14 days is appropriate.

Starting prophylactic UFH, LMWH, or possibly a DOAC, may be a choice prior to starting full treatment dosing.

Goldstein, Greenberg; Should AC be resumed after ICH?; Cleve Clin J Med. 2010 Nov; 77(11): 791–799 Mrs Cho has a brain bleed! • Mrs Cho suffers her L LE DVT in the setting of an Intracranial Hemorrhage. • This is a situation where full dose anticoagulation is contraindicated. • Consider IVC filter placement, to be removed when full AC can be started. • Consider using Apixaban or Rivaroxaban to avoid LMWH bridge with its’ high bleeding risk. • Start full AC in 7-14 days, and pull IVC filter.

Goldstein, Greenberg; Should AC be resumed after ICH?; Cleve Clin J Med, 2010Nov, 77(11): 791-799. Those Pesky “free floaters” • The imaging department says Mrs Cho has a large, proximal “free-floating” L femoral vein clot, and they are suggesting an IVC filter. • Multiple studies have reviewed “free- floating” clots, and other “unstable” clots and determined that the rate of clinically significant PE’s in these patients is no greater than in those with occlusive clots. • No justification for IVC filter.

Pacouret G et al. Arch Intern Med 1997 Feb 10. IVC Filters  Recommend against routine use in addition to anti-coagulants.  Remove retrievables by 6 weeks if possible.

Permanent filters are almost never placed anymore.

Decousus H et al. NEJM 1998; 338(7):409-415., PREPIC Study Group. Circulation 2005; 112:416-22. IVC Filters In the setting of acute PE or prox DVT; and with strong contraindications to anti-coagulation, place retrievable filter. * Start treatment dose AC when contraindication passes, and remove the filter. * Avoid stopping AC to remove filter if possible. * If filter not retrievable, AC if you can. Continue AC as Filter is an ongoing clot risk. Clot Cuisinarts? • Permanent IVC filters: – may possibly decrease PE’s, but – do increase DVT, and – have no mortality benefit. – Decousus et al. NEJM 1998. – PREPIC Invest. Circulation 2005. • Removable filters: – don’t decrease PE’s, – do decrease fatal PE’s but – don’t decrease death in high risk patients. Mismetti P et a. JAMA 2015. Mrs Cho is Pregnant! • Mrs Cho is now a 24yo pregnant female. – Weight based LMWH is your best choice. – Switch to UFH in the week before anticipated delivery for its’ shorter half-life. – Try to hold SQ UFH for 8hrs prior to delivery, treating delivery like a surgical procedure. – Resume LMWH post delivery. • Transition to warfarin with an initiation bridge if needed to complete a 3-6mo course. • Warfarin is not excreted in breast milk. • DOACs are not recommended in breastfeeding. – Will need DVT proph for 6 weeks post partum. How about she has renal failure? • Mrs Cho has end stage renal failure. – Warfarin would be your best choice. – Would need to use UFH, probably IV, to initiate the Warfarin therapy. Bleeding risk would be too high with LMWH SQ initiation with poor renal clearance. – If on dialysis, LMWH is still a problem as Enoxaparin (Lovenox) is not removed well by dialysis and will accumulate. The Prosthetic Cardiac Valve

• Mrs Cho has a prosthetic mitral or aortic valve. – Warfarin is the only choice for AC, and she should already be on it. – Patients who develop VTE while anti-coagulated should be carefully evaluated for acquired hypercoagulable disorders, such as cancers or APLAS. – May need higher INR. – May need addition of LMWH. Moving on to Duration of Therapy Does anti-coagulation need to go on and on and on? Duration of therapy MAQI pg 22 • Provoked Prox LE DVT or PE 3 mo • Provoked isolated distal LE DVT 3 mo • 1st Unprovoked LE DVT or PE at least 3 mo – In high bleed risk individual 3 mo – In low risk bleed individual Extended 2nd Unprovoked DVT or PE High risk bleeding 3+ mo Low risk bleeding Extended VTE in setting of Cancer Special Extended

Kearon C, Akl E, Ornelas J, etal. Antithrombotic Therapy For VTE Disease: Chest Guideline Published online January 07, 2016. doi:10.1016/j.chest.2015.11.026. Peri-Procedural AC Management Bridging, will continue to be needed

There will continue to be Warfarin patients requiring LMWH/UFH bridging. Prosth mitral valve, very high CHADS2 risk Afib pts, and hypercoagulable pts. Definition of Bridge (Chest) Vol 133, # 6, June 2008, pg. 299, ACCP supp. • Temporary interruption of warfarin before a procedure to normalize INR for the procedure. • Stop 5 days before procedure. • Resume warfarin 12-24hrs post procedure. • High risk patients, bridge with therapeutic dose LMWH SC or IV Heparin during interruption of VKA. LMWH for outpatient, Heparin if renal failure. Last dose of LMWH 24hrs before procedure. • Restart LMWH/UFH post procedure 24hrs (for high bleeding risk, 48-72hrs, or even later, or lower dose, or not at all, depending on patient and surgical risk parameters. Bridge Timeline

Drug levelDrug Warfarin INR

LMWH Op day Op Conflicting Study Results

Duration of Warfarin Hiatus in these episodes of peri- operative periods were not defined, but were a minimum of 5 days, and often much more due to waiting for hemostasis. hr With alternative AntiCoagulants? Recommendations used in MAQI2 • Doherty et al. 2017 Periprocedural Anticoagulation Pathway in Pts with NonValvular AFib, JACC in press 2017. http://www.onlinejacc.org/content/early/2017/01/05/j.jacc.2016.11.024 – Expert Consensus. Limited in that only addresses Afib, and uses only Cardiology viewpoint. • AC Spyropoulos et al, Periprocedural Management of patients receiving a VKA or DOAC requiring elective procedure or surgery, JTH 2016, DOI:10.111/jth.13305 14: 1-11. http://onlinelibrary.wiley.com/doi/10.1111/jth.13305/full – Comprehensive guidelines. Lacks easy flowcharts. Not Just AFib

• Spyropoulos article addresses the chronic VTE, the Prosthetic valve, as well as the Afib patient. High risk = Consider Bridge.

• Afib high risk: CHADS-VASC 7-9 (CHADS2 5 or more) • Prosthetic Mitral valve is high risk. Older Aortic prosthetic valves are high risk. • Hypercoagulable state (Prot C def, APLAS), hx of procedure related clots are VTE high risk. First case, Mrs O’Dell

• 67yo woman with HTN and Afib. • Has been on Warfarin 6mg daily (2 of the 3mg pills) with stable INR’s for 3 years and doesn’t want to change to DOAC because of cost. Only other med is Lisinopril. • Needs a cholecystectomy for cholelithiasis.

• CHADS2 score is 1. Stroke risk is moderate. • Bleeding risk for this procedure, done laparoscopically, is moderate. So? Bridge? • Most would say no. • She needs peri-procedural management of her Warfarin. Her INR needs to be below 1.5 for best procedural hemostasis. Some surgeons want INR closer to 1. • A written plan needs to be made with the patient and her surgeon on her anticoagulation management. No LMWH for Mrs O’Dell

• Low CHADS2 score, reasonable thrombotic risk. Our references reassure TE risk with no Bridge is low. • Moderate bleeding risk procedure, so able to restart warfarin on PM of procedure, or day post---keeping hold time short. (Garcia et al). – Keep the Warfarin hold less than 5 days, if possible, less than 7 days with no LMWH bridge is done often and safely. – If hemostasis is not obtained, and surgeon wants to wait on Warfarin re-initiation, will need to use re- initiation LMWH bridge when restarting Warfarin. • Balance patient specific thrombotic/bleeding risks in setting of procedure specific risks to craft a peri-procedural AC management plan, • WRITE IT OUT for patient and proceduralist. • Communicate. Make sure the patient and the surgeon are clear on the plan. Daisy O’Dell 78 kg

Afib, Cholelithiasis. Brown, Green 2-3

Warfarin dosing 6mg qd.

3/7/17 2.8 first day of hold 3/8/17 3/9/17 //////////////////////////// //////////////////////////// 3/10/17 //////////////////////////// 3/11/17 ///////////// 1.1 done in clinic

6-12mg 3/13/17 //////////////////////////// 6mg 3/14/17 //////////////////////////// 6mg 3/15/17 //////////////////////////// 2.3 6mg

6mg //////////// 6mg 6mg 6mg 3/20/17 2.6 “ Some Considerations • If INR was over 1.5 on pre-op day -1, using OTC Vit K preparations can allow patient to stay on schedule. – GNC stores carry a reliable 0.1mg Vit K (0.5mg) supplement. Other stores will carry these as well. – Rx oral vit K is $$$$. Can use parenteral preparation orally, mg/ml. Much cheaper. – Dietary Vit K is less predictable, but some of your patients will know their response. (10 spears asparagus = 0.5 INR drop; ½ cup sauerkraut = 0.3 INR drop; ect.) – Talk with surgeon, recheck INR prior to procedure in AM. Usually good. Mr. Jones aaaaaa 58yo Black Male with Afib, HTN, and DMII. Looking for AC management for upcoming R knee replacement for DJD and pain.

CHADS2 score is 2. Meds: Warfarin 12.5mg daily, goal INR 2.5, and he has been within range (TTR) > 90% during the last 6mo. Amlodipine 5mg po qd. Metformin 500mg AM, 1000mg PM no supplements or NSAIDs NC PMHx, FMHx, SocHx, and ROS. VS and PE are not concerning.

Labs done 3wks prior to the procedure are all OK. Creat Cl by Cockalt Gault is 62. High metabolizer, cont. • Mr. Jones is a high metabolizer. Like Mrs Cho, he probably doesn’t need a LMWH bridge, but does have some considerations. – He will need a shorter pre-op hold of Warfarin to get to a normal INR. Start his hold 3-4 days prior to procedure. – He will probably become Warfarin Naïve sooner than will Mrs. Cho. Closer to 5 days than to 10 days. Make sure his hold is no longer than 5 days, otherwise he needs a re-initiation LMWH bridge to his Warfarin. Second Case, Mr. Alvarez.

76yo male with hx of Afib for about 15yrs. He is on Warfarin 5mg PO QD with a target INR of 2.5. He is requiring a TURP for significant BPH with BOO causing repeat UTI’s and increasing Creat. He suffered a stroke 3 years ago during a Warfarin hold for a hip replacement.

Problem list: Medication list: 1. CHF 1. Lasix 20mg BID 2. DMII 2. Digoxin 0.125mg PO QD 3. HTN 3. Metformin 850mg BID 4. Afib w CVA hx 4. Warfarin 5mg QD + 0.1mg Vit K QD 5. BPH w BOO 5. Flomax 0.4mg QD 6. DJD multiple joints

CHADS2 score is 6, very high risk, and he has a history of a CVA with previous, un-bridged procedure. Pre-procedural labs---1 mo prior

• H/H 14/41, Plt 171K, PTT 31sec, INR 2.6, Cr 2.1 EKG, lytes, remainder of safety labs all OK. • Vitals: in normal range for pt, and CHF/HTN/DM all controlled. Weight, 74kg with tr edema. – Cockcroft-Gault calculated Creat Cl = 31.3 • Meds reviewed, and you discuss holding Metformin around surgery as well as AC management. Digoxin dosing will be decreased, too. Mr Alvarez is very different from Mrs O’Dell • Very high risk patient for TE events. He would be very uncomfortable with no LMWH bridge. • This is a high bleeding risk procedure, and the bleeding persists post-op for a considerable time. Consequences of bleeding are mainly cardiac and transfusion related. • Avoiding surgery is not a good option. He already is having UTI’s, renal insufficiency, and symptoms from his BOO. He is not getting younger or healthier. Frank Alvarez 74 kg

Afib, BOO, DM, CHF, HTN. Brown, Green 2-3

Sheduled for TURP 3/12. Warfarin dosing 5mg qd with 0.1mg po Vit K supp.

3/7/17 2.6 first day of hold 3/8/17 3/9/17 ///////////// ///////////// 75mg 3/10/17 ///////////// 75mg 3/11/17 ///////////// 1.2 done in clinic

5mg 3/13/17 //////////////////////////// 5mg 3/14/17 40mg /////////////// 5mg 3/15/17 40mg ////////////// 1.7 5mg Hct 40mg ////////////// 5mg & 40mg ///////////// 5mg 40mg ///////////// 2.6 5mg stop Lovenox 5mg 3/20/17 “ A standard LMWH Bridge

If there were no issues of impaired creat clearance. If the bleeding risk were moderate, and not prolonged post-op. Then, this high TE risk patient would have a standard bridge. Frank Alvarez 74 kg

Afib, BOO, DM, CHF, HTN. Brown, Green 2-3

Sheduled for Lap Chole 3/12. Warfarin dosing 5mg qd with 0.1mg po Vit K

3/7/17 2.6 first day of hold 3/8/17 3/9/17 75mg 75mg 3/10/17 75mg 75mg 3/11/17 ///////////// 1.2 done in clinic

5-10mg 3/13/17 ? ? 5mg 3/14/17 75mg 75mg 5mg 3/15/17 75m5 75mg 1.7 5mg Hct 75mg 75mg 5mg & 75mg 75mg 5mg 75mg xxx 2.6 5mg stop Lovenox 5mg 3/20/17 “ Alternatives • This might be a good time to discuss a change to a DOAC with Mr Alvarez. – Pre-op could be Warfarin with LMWH or could change to DOAC pre-op. – Good choices in this pt would be Apixaban or Edoxaban, due to renal issues. • Both would be easy to start just by waiting for INR to be close to 2, then starting. • Long term safety monitoring---initial quarterly H/H & creat, then check 2-4x yearly with liver checks occasionally. Frank Alvarez 74 kg

Afib, BOO, DM, CHF, HTN. Brown, Green 2-3

Sheduled for TURP 3/12. Warfarin dosing 5mg qd with 0.1mg po Vit K supp.

3/7/17 2.6 first day of hold 3/8/17 3/9/17 ///////////// ///////////// 75mg 3/10/17 ///////////// 75mg 3/11/17 ///////////// 1.2 done in clinic

3/13/17 3/14/17 Start Apixaban at proph dose, 2.5mg BID 3/15/17 //////////////// //////////////////////////“ ///////////////// /////////////////////// //////////////// ////////////////////

Bleeding in catheter bag is decreased, so increase Apixaban to full dose, 5mg BID. 3/20/17 Management of Peri-Proc DOACs General Principles MAQI pg 44 • Duration of pre procedural hold mostly depends on Creat Cl. Longer for Dabigatran. Longer for Neuranesthesia. Longer than in pkg insert for all DOACs. • Duration of post procedural hold depends on bleeding risk. Remember, unlike Warfarin, DOACs are fully active, patient fully anticoagulated, within hours of first dose. DOAC Subtleties • LMWH bridging is almost never needed. Exceptions may be the very high TE risk pt on long Neuranesthetic hold, pt NPO post op who needs parenteral/SQ AC, or pt changing to Warfarin from DOAC. • Proph dose of Apixaban (and ? Edoxaban) shown to be very low rate of bleeding compared to Rivaroxaban or LMWH---Good option post-op in high bleeding risk situations. DOAC Subtleties cont. • Utilize the short half-life of DOACs to avoid AC holds. – Arrange procedures to occur just prior to the next scheduled DOAC dose. – If low bleed risk, no need to miss dose. – If higher risk, may only need to miss one dose. • GI bleeding is higher with DOACs. Possibly due to local AC action in the GI tract. Consider this with polypectomy and other GI procedures. • Rivaroxaban, even in proph. doses, has higher post op bleeding rates than other DOACs (especially post orthopedic procedures). Jared: Case # 3 dd 39 yo obese male with hx of multiple bilateral LE DVT’s starting age 16. Has a Hx of poor compliance and unstable INR’s on Warfarin, so was transitioned to Rivaroxaban 20mg qd about a year ago. About 6 months ago, per the recommendations of a Hematologist, he was moved to the 10mg qd dosing for prolonged DVT prevention. He has done better, had fewer DVT’s, fewer bleeds on this regimen. Now requesting periprocedural management of AC for R hip replacement for severe DJD and pain. PMHx: DVT’s as above. Sleep apnea, non-compliant on C- PAP. Candida intertrigo. FMHx: Father died of a PE age 44. Mother has DMII. NKDA Meds: Rivaroxaban 10mg po qd Multivitamin Percocet PRN hip pain ASA 81mg qd – 650mg qid +/- Naproxen prn. (you just found this out on close questioning.) Habits: Smokes MJ at least 4 joints daily. 6 pack beer daily, Occasional hard liquor, pack of cigs weekly.

VS: BP 152/89, P 86, RR 15, O2 Sat 94%, Wt 148kg, ht 5’10”.

Exam is as you would expect. Out of shape, some minor cardio- pulmonary findings, skin issues, ect.

Labs are surprisingly good, with no significant abnormalities. Even the liver tests are good. Risks? • Patient’s VTE risk is pretty high. – Hx multiple LE DVT’s – Multiple risk factors, obesity, orthopedic surgery, lifestyle risks, smoking, ect. • Bleeding risk from a hip replacement is moderately high. – Boney disruption. – Multi-layer surgery. – Many patient specific bleeding risks, including NSAID’s, ASA, ETOH, obesity, smoking, ect. Orthopedic surgeon is NOT thrilled with Rivaroxaban post op. She has read about increased OP site bleeding with proph dosing. Write it out!

• Whatever the plan, write it out. • Send copies with patient and to the surgeon. • Double check on the anesthesia. If the plan is for spinal anesthesia, check with the anesthesiologist. – You may need to stop the Rivaroxaban 4 or more days prior to surgery. – Consideration on restarting AC depends on when spinal catheter removed. Wait minimum of 24hrs p removal. For Procedures with Neuraxial Procedures & Anesthesia. • Hold Dabigatran (Pradaxa) 4-5 days prior to procedure. • Hold Fac Xa Inhibitors (Rivaroxaban, Apixaban, Edoxaban) 3-5 days prior to procedure. – (For all DOACs, longer hold times for poorer kidney function, shorter for normal kidneys) – (For pt at very high thrombotic risk, consider shorter holds, or a LMWH bridge with the longer hold)

• Restart DOACs 24hrs post procedure, or later when hemostasis is achieved. Custom DOAC PeriProc Plan • Per both the ‘17 ACC and ‘16 JTH Spyropoulos Review articles: – Stop Rivaroxaban 2-3 days prior to mod/high risk bleeding procedures. (MAQI & Spyropoulos) – Stop ASA and NSAIDs 7-10 days prior to surgery. • Restart a DOAC post-op on day +2-3 for all Fac Xa inhibitors and Dabigatran. Hemostasis must be obtained first. – Rivaroxaban can be started at proph dosing, 10mg qd, but surgeon has concerns about post-op bleeding. – Apixaban can be started at full dose, 5mg BID, or proph dose, 2.5mg BID. – Edoxaban can be started at 60mg QD, full tx dosing. – Proph LMWH can be started post-op for several days before restarting full dose Rivaroxaban or starting a new DOAC. Mrs. Quinn 85yo lady with Afib. Other dx include: Hyperlipidemia Hx of MI x 2 Now having intermittent large bowel obstructions, determined to be due to adhesions from old surgery. Psurg Hx: Diverticulitis with peritonitis, s/p open partial bowel resection and extended IV antibiotic course. P2G2Ab0. Meds: Eliquis (Apixaban) 5mg po BID. ASA 81mg po qd (per her Cardiologist) Carvedilol 3.125mg po qd Hx’s, nothing to add. VS: Wt. 54kg ( from 62kg), Ht. 5’2”, HR 67, RR 12, O2 sat 95% PE, frail thin older lady with good cognition, irreg/irreg COR, clear resp, scaphoid sl tender abdomen. Mrs. Quinn, cont. • Labs show some pre-renal findings and a calculated CrCl of 34. Albumin is low, and some minor anemia is seen, otherwise OK. • She has lost weight, now meeting criteria to take 2.5mg BID dosing of Apixaban. (over 80yo, under 60kg) Her Creat is not > 1.5. • So… Lower dose to 2.5mg BID, write out plan. – Moderate risk pt, moderate risk procedure. Esther Quinn 54kg

Afib, Abd Adhesions/BO Apixaban 2.5 BID, adult FTT. CHADS2 1, but MI hx.

AM PM ……………………………………..

Eliquis 2.5mg po BID

2.5mg No Eliquis……………………………….. No Eliquis No Eliquis………………………………….. No Eliquis No Eliquis

0 0 0 2.5mg 2.5mg “ “ CBC, CMP “ “ “ “ “ Alternative for Mrs. Quinn May want to use LMWH post op instead of DOAC because this is an abdominal/GI procedure. * She may be NPO post op. * She would need to use a dose of 60mg of Lovenox SQ qd (Shaikh & Regal, Dosing of Enox in Renal Impair., P&T, Vol. 42 No. 4 • April 2017) or Fragmin 10,000 IU SQ qd. * If had underlying chronic renal dz, risk of stroke/systemic emboli and bleeding would be higher. Relative stroke risk increases 7% with every 10-mL/min/1.73 m2 decrease in eGFR*. * 60% of Afib pts have some degree of renal insufficiency.

*J Fanikos, A Burnett, C Mahan, P. Dobesh, Renal Func Considerations Stroke Prev in Afib, http://dx.doi.org/10.1016/j.amjmed.2017.04.015* PeriProcedural Considerations

Sometimes Less is more when balancing risks and benefits. WhoProcedures Doesn’t need that a Periprocedural don’t require Hold? holding Anticoagulation

Even Full mouth extraction now is “minor”.

Now includes most compressible Bx’s. Who should not have a peri-procedural anticoagulant hiatus?

(Or periprocedural hiatus) Don’t forget about controlling the Bleeding!! Tranexamic acid (TXA) • Antifibrinolytic: safe in pregnancy & nursing. Caution in renal disease. $100-$200/course. • Use has been proven to significantly reduce blood loss in trauma, vaginal bleeding, child birth, surgery, and dentistry. Is used in bleeding disorders. • Can be given topically, orally, or parenterally. – 5% mouthrinse for dental extractions. – Oral preparations useful to lessen menorrhagia. – IV in surgical, post partum, emergency situations. • Does not cause hypercoagulable problems. ProCoagulant Concentrates: $$$$ • PCC: ProCoagulant Concentrate. K-CENTRA – Good for the Fac Xa Inhibitor caused bleeding. – Thrombogenic • aPCC: Activated PCC. FEIBA – Good for use in treating Dabigatran associated bleeding. – Very thrombogenic. Both have multiple adverse events: allergies, vomiting, HA, MI, Death from VTE. Made from human plasma. Protamine

Protamine Sulphate works very well to reverse LMWH, as well as Heparin. Has all the same problems of immune rxns, blood pressure drops, and the problems of administration. Carefully Throw in the Kitchen sink (the expensive one) MAQI pg 61 *In severe, uncontrolled, AC related bleeds, start with support measures. *Rapidly advance through more aggressive treatments as they are available and make sense. *Have Tranexamic acid and other hemostatic agents available. *Time is on your side with the DOACs. Short half lives in patients with normal renal function. All in Perspective Perspective, Take home points • Get the right pre-treatment testing. • Pick the correct dose and treatment, overlap correctly. • Duration of treatment: 3 months for 1st provoked, open-ended otherwise, for VTE. • Recommend post tx imaging for LE DVT to have comparison. • IVC filters: Discouraged unless absolutely indicated. • Thrombolysis: Encouraged within parameters. • Customize the treatment to the patient. • Compression stockings: Now no longer needed acutely. • Implications of VTE: Cancer? May change treatment. • Bridging: No longer needed for most patients, but careful periprocedural AC management improves safety. • Use of DOACs around procedures usually eliminates need for Bridge. • Write out Peri-Procedural management plans. Take Home Points cont.

• DOAC Periprocedural holds are NOT per package inserts, and are very different for Neuranesthesia. • Treated Warfarin bleeds are equal to or worse than un-reversed DOAC related bleeds---so the lack of specific reversal agents is not a reason to avoid DOACs. • In DOAC bleeding, try mechanical and chemical hemostatic methods. • Time is your friend in DOAC bleeding. • After surgery, DOACs are not Warfarin which needs days to start having anticoagulation action, DOACs are fully effective within hours. This needs to be included in post op restart planning and dosing.