Venous Thromboembolism: Principles of Outpatient and Inpatient Management

Transcription

1 Venous Thromboembolism: Principles of Outpatient and Inpatient Management August 1, 2017 Seth Maliske, M.D. Internal Medicine Aspirus Wausau Hospital Disclosures/Conflicts of Interest I have no financial or non financial disclosures to report 1

2 Objectives 1. Describe the principles of venous thrombosis 2. Examine provoked vs unprovoked VTE and how it pertains to length of anticoagulation 3. Describe VTE prophylaxis and the new FDA approval of Betrixiban 4. Apply these objectives in a clinical context People learn 3 4 things from each lecture 1. Provoked VTE carries a low risk of recurrence (~0.5%), but only encompass a specific set of scenarios 2. Unprovoked VTE is a chronic disease and the interplay between risk for recurrent VTE vs bleeding never stops. 3. D dimer testing is an option to be considered in all patients w/ unprovoked clot w/ plans to stop AC 4. Thrombophilia testing is complex and should not be ordered in all patients 5. DOACs are effective medications and safe to use in most patient populations 6. Betrixiban has been FDA approved for outpatient VTE prophylaxis following hospitalization in high risk medical patients 2

3 FREQUENT ABBREVIATIONS VTE: Venous thromboembolism DVT: Deep vein thrombosis PE: Pulmonary embolism PSVT: Portal/splenic vein thrombosis NOAC: Non vitamin K oral anticoagulant DOAC: Direct acting oral anticoagulant VKA: Vitamin K antagonist AC: Anticoagulation 3

4 1. Risk of Recurrent VTE 2. Risk for Major Bleeding 3. Patient preference Why is it important? 4

5 STATISTICS U.S. Data 3 rd most common cardiovascular disease after MI and stroke Approximately 1 2/1000 adults affected each year 1/10,000 younger than 40yrs old vs. 1/200 adults >80yrs old Approximately 600,000 new diagnoses per year 2/3 DVT, 1/3 PE 60,000 deaths/year 10% die within first month Sudden death is presenting symptom in 25% of new PE Cost: $15.5 billion dollars/year Only accounting for breast and prostate cancer populations Clotting Cascade Eliquis, Xarelto, Betrixiban, Lovenox, Fondaparinux Dabigitran Warfarin= Factors II, VII, IX, X (Vit K dept factors) Heparin= Factors II, X, IX, XI, XII (AT dept factors) 5

6 Virchow s Triad Mr. Anderson 75yo male presents to ER CC: LLE swelling and pain LE Duplex US: common femoral vv clot Diagnosed with LE DVT Patient asks, Why did I get this blood clot? What do you tell him? What questions would you ask? 6

7 Risk Factors Acquired= Persistent/Reversible Surgery Inpatient Medical Cares Immobility, Travel Trauma, Fractures Medications OCPs/HRT Testosterone therapy Cancer agents/chemotherapy Steroids Obesity Central lines Tobacco Abuse Spinal Cord Injury (+/ ) Elderly Disease states Pregnancy/Post partum Antiphospholipid Syndrome Cancer, MPN, PNH SLE, Behcet s, IBD Nephrosis and Liver Failure Hereditary Irreversible Anticoagulant Deficiencies ** Protein C Protein S AT III Procoagulant Excess FVL, PGM 20210A Non O Blood type MTHFR /hyperhomocystenemia Height/Longer legs Gender Male > Female **Technically Prot C/S and ATIII defiencies can all be acquired too Risk Factors Major Provoking Risk Factors PROVOKED CLOT Minor Provoking Risk Factors UNPROVOKED CLOT Permanent Risk Factors Persistent Risk Factors Reversible Risk Factors 7

8 Major Provoking Risk Factors All Surgery Orthopedic Abdominal/Pelvic Neurosurgery Bariatric surgery Post splenectomy Post C/section Hospital stays Medical Moderate severe immobilization x 72hr ICU Major Trauma/Fractures Spinal Cord Injury Stroke with hemiplegia Other Cancer Red denotes potential irreversible risk factors Not all Risk factors created equal Major Factors Risk for initial VTE w/o prophylaxis clinical and subclinical Risk Factor Incidence (%) Relative Risk NNT Medical Patient 10 20% General, Major GYN, Major Urologic, and Neuro Surgery 15 40% Hip arthroplasty or 40 60% fracture Major Trauma 40 80% Spinal Cord Injury 60 80% Stroke 20 50% Critical Care 10 80% Assuming incidence of VTE in general population is 1/1000 Majority are subclinical. ~10% of subclinical lead to symptomatic VTE. 8

9 Minor Provoking Factors Surgery < 30min procedure No anesthesia Age <40 Medical Hospital stay <72hr Travel OCPs/HRT Pregnancy Minor Trauma Other Thrombophilia Disease states Red denotes potential irreversible risk factors Not all risk factors created equal Minor Factors INCIDENCE OF FIRST VTE Risk Factor Incidence Relative risk OCP use 3 9/10, Pregnancy 5 20/10, Post partum 40 65/10,000 ~20 HRT 34/10, Obesity N/A 2.3 BMI >40 N/A 2.7 IBD N/A 2.2 Airline Travel N/A Risk Factor Incidence Relative Risk Thrombophilia ~10% 2 10 FVL (hetero) 2 7% 3 5 FVL (homo) <0.1% 7 20 PGM (hetero) 1 2% 2 3 PGM (homo) Rare 2 21 Compound ~0.1% 1 5 hetero Protein C % 10 Protein S 0.1% 10 AT III <0.1% 10 APLS 2% 7 Thrombophilias can be found in 25 50% of unprovoked VTE. Risk + prevalence has led to widespread testing 9

10 Mr. Anderson Mr. Anderson reports: History of heart disease with prior MI and compensated HFpEF but no recent surgery or recent hospital stays. No prolonged travels No personal or family history of blood clot BMI is approximately ~35 40 No history of cancer No history of varicose veins Is this a provoked clot or unprovoked clot? Mr. Anderson Mr. Anderson s DVT has been deemed unprovoked. He does have risk factors but no major provoking risk factors Age, gender, obesity, and heart failure with relative inactivity each contributed to his DVT He was started on Eliquis He responds, Another medication! How long do I have to be on this one? 10

11 RISK OF RECURRENCE What is considered an unprovoked first VTE? No surgery in last 3 months No medical hospital or ICU stays No recent mjor trauma/fractures with casting No immobility >3 days No stroke No post partum after C section LENGTH OF THERAPY THROMBOPHILIA PARADOX Risk Factor Relative Risk for recurrence FVL (hetero) FVL (homo) 1.8 PGM (hetero) PGM (homo) Unknown Compound 2.7 hetero Protein C Protein S AT III APLS

12 LENGTH OF THERAPY THROMBOPHILIA Thrombophilia testing has been suggested as a means to identify those patients who merit extended anticoagulation. However, hereditary thrombophilia has very limited utility in predicting risk of recurrent unprovoked VTE Counterintuitively, the presence of a thrombophilia tends to be much less predictive of a recurrent VTE event than for an initial event, a phenomenon described as the thrombophilia paradox. A hypothetical benefit of screening for thrombophilia is to identify patients with a sufficiently high risk for recurrent VTE that extended anticoagulation should be offered. However, no outcome data support this supposition. As all patients with unprovoked VTE are at high risk for recurrence, detection of a thrombophilia may not provide any additional value to inform the decision to offer extended anticoagulation. The 10th ACCP guidelines, as well as others, recommend treating unprovoked VTE in presence of thrombophilia no different from any other unprovoked clot LENGTH OF THERAPY CALF VEIN CLOT (DISTAL CLOT) If all patients with suspected DVT have ultrasound examination of the calf veins (whole leg ultrasound), isolated distal DVT accounts for about 50% of all DVT diagnosed Natural history studies suggest that when left untreated, 15% of symptomatic distal DVT will extend into the proximal veins and that if extension does not occur within 2 weeks, it is unlikely to occur subsequently If isolated distal DVT is diagnosed, there are two management options: (1) treat patients with anticoagulant therapy, or Thrombosis that is extensive or close to the proximal veins (eg, > 5 cm in length, involves multiple veins, > 7 mm in maximum diameter), no reversible provoking factor for DVT, active cancer, history of VTE, and inpatient status (2) monitor with US and only treat patients with anticoagulant therapy if extension of the DVT is detected on a follow up US done after 1 and 2 weeks Thrombosis that is confined to the muscular veins has a lower risk of extension If AC is chosen, use for 3 months. Indefinite anticoagulation is discouraged unless unprovoked in setting of cancer or with multiple unprovoked distal DVT Isolated distal DVT is estimated to be associated with about one half of the risk of recurrence of proximal DVT and PE 12

13 Recurrence Triangle LENGTH OF AC 3 months Long term VTE due to major transient risk factor Woman with VTE on hormones Non-major transient risk factor Woman with unprovoked VTE DVT PE Man with unprovoked VTE DVT PE Cumulative VTE Recurrence Rate 1 year 5 years 1 % 3 % 5 % 15 % 10 % 30 % [Kearon C et al. Blood 2014;123: ] Unprovoked VTE encompasses >50% of all cases 2 CONTINUE ANTICOAGULATION Anticoagulation decreases risk of recurrence by ~90% 4 DISCONTINUE ANTICOAGULATION 1. Risk of VTE <1% after major provoking factor 1 ~10%/year if unprovoked and off anticoagulation and ~30% risk of recurrence after 5 years 3 Mortality risk with recurrent VTE: ~5 10% 5 3. Patient preference 2. Risk for Major Bleeding 2 3% is average risk 5 3 5% risk in elderly >75 years of age 5 A major bleed carries a 10 15% risk for mortality What is their anticoagulation hate factor Do they most desire to be off blood thinners? 13

14 LENGTH OF THERAPY RISK OF RECURRENCE D DIMER D Dimer D dimer is a product of lysis of stabilized fibrin clot that is considered an indirect marker of coagulation activation. Original studies: Thrombosis Heamostasis 2002, Palareti et al: Evaluated incidence of elevated D dimer elevation after stopping warfarin 15.5% of all patients had elevated D dimer the day warfarin stopped 40.3% of all patients had elevated D dimer 1mo after stopping warfarin Circulation 2003, Palareti, et al: Evaluated D dimer 1 month after discontinuing warfarin ad rates of recurrence. Altered D dimer results were associated with a significantly higher recurrence rate in patients with an unprovoked qualifying VTE event (HR = 2.43) and especially in those with thrombophilia (HR = 8.34). The higher relative risk for recurrence of altered D dimer was confirmed by multivariate analysis after adjustment for other risk factors. Prospective RCTs PROLONG I and PROLONG II laid groundwork for use of D dimer in evaluating length of therapy Systematic review Annals of Internal Medicine 2008, Douketis et al patients evaluated with unprovoked VTE. A negative D d result was associated with a 3.5% annual risk for recurrent disease, whereas a positive D d result was associated with an 8.9 % annual risk for recurrence LENGTH OF THERAPY PROLONG I Normal D dimer 385 Patients Total 608 Patients Abnormal D Dimer 223 Patients No deaths from recurrent VTE in 18 month follow up Recurrent VTE 6.2% (4%/yr) (HR 2.3) No anticoagulation 120 Patients Recurrent VTE 15% (11%/yr) (HR= 4.3) Resume anticoagulation 103 Patients 9 refused anticoagulation Recurrent VTE 2.9% (2%/yr) The number of study subjects was small enough that some clinically important interactions may not have been detectable. 14

15 LENGTH OF THERAPY PROLONG II Extended follow up from 1.4yr (mean) in PROLONG I to 2.6yr (mean) in PROLONG II Total 608 Patients Normal D dimer 385 Patients Abnormal D Dimer 223 Patients Recurrent VTE 13.2% (5%/yr) (HR= 2.7) No anticoagulation 120 Patients Recurrent VTE 23.1% (10%/yr) (HR= 3.8) Resume anticoagulation 103 Patients 9 refused anticoagulation Recurrent VTE 5% (2%/yr) Longer follow up confirmed increased risk in the randomized groups LENGTH OF THERAPY PREDICTION TOOLS Any prediction guide is anchored on what is considered an acceptable annual risk of recurrent VTE that would justify stopping anticoagulant therapy. Risk of bleeding is 2 5% depending on age What s acceptable risk of VTE 3% vs 5% The International Society on Thrombosis and Haemostasis (expert counsel) suggests that it is appropriate to stop anticoagulants in subgroups with a point estimate of recurrent VTE at one year below 5% Is 5% acceptable in Patient A vs Patient B?? A systematic review addressing case fatality rates of bleeding and recurrent VTE if patients with a first VTE continued or stopped anticoagulation has also suggested that an annual rate of recurrent VTE of 3% or lower would be required to justify stopping anticoagulation 15

16 Vienna Prediction Model Gender Male >Female Location Distal low risk Proximal higher risk PE higher risk D Dimer Elevated after d/c anticoagulation (checked once) Nomogram offers a cumulative recurrence rate (%) 12 months vs 60 months Example: Male, Distal DVT, normal D dimer: 2/7% Male, Proximal DVT, elevated D dimer: 3.6/13% Male, PE, elevated D dimer: 4.3/15.6% DASH Prediction Model Elevated Ddimer >500 (+2) Age < 50 (+1) Male gender (sex) (+1) Hormone use at time of VTE ( 2) Calculate annual VTE recurrence risk (%) 2 points: 1.8% 939/181 8= 1 point: 1% 51.6% 0 points: 2.4% 1 point: 3.9% Consider stopping 2 point: 6.3% Consider continuing 3 point: 10.8% 4 point: 20% 879/1818= 48.4% HER-DOO-2 Prediction Model For women ONLY (all men considered high risk (8.4%)) Hyperpigmentation, Edema, or Redness in either leg (1 point) D dimer level 250 μg/l (1 point) Obesity with body mass index 30 (1 point) Older age, 65 years (1 point) Each criteria was assessed after 5 12 month on AC (VK or NOAC) 700/ / men 600 women Consider stoppingrisk < 3% per patient year Consider continuing, risk 8.1% per patient year Recurrence Triangle LENGTH OF AC 3 months Long term VTE due to major transient risk factor Woman with VTE on hormones Non-major transient risk factor Woman with unprovoked VTE DVT PE Man with unprovoked VTE DVT PE D-dimer + Predictive Model + [Choosing Wisely ; Hicks LK, et al. Hematology Am Soc Hematol Educ Program. 2014;2014: ] Cancer + Isolated Distal DVT ACCP, AHA, ISTH, BJH 16

17 Mr. Anderson Mr. Anderson understands the risks and benefits of being on anticoagulation and has agreed to begin medication. Mr. Anderson will begin Eliquis 10mg BID x7 days, followed by 5mg BID thereafter. He asks, Doc, I ve seen those commercials on TV about these blood thinners. Are you sure, Eliquis is safe? What are my options? DOACs/NOACs The DOACs are rapidly replacing warfarin as the anticoagulant of choice for many indications, including stroke prevention in atrial fibrillation, treatment of VTE, and postoperative thromboprophylaxis in patients undergoing orthopedic surgery. In a pooled analysis of the 6 phase 3 trials: Similar efficacy Better safety profile Recurrent VTE and VTE related deaths occurred in 2.0% of patients receiving DOACs compared with 2.2% of those given VKAs (relative risk [RR] 0.90, 95% confidence interval [CI]: ). There was overall a 40% reduction in the risk of major bleeding in patients receiving DOACs with lower risks of intracranial bleeding (63% relative reduction), fatal bleeding (64% relative reduction), and clinically relevant non major bleeding (27% relative reduction) With similar efficacy, better safety and the convenience of fixed dosing, guidelines now recommend the DOACs over VKAs for VTE treatment 17

18 DOACs Who to be cautious with use? Kidney disease Liver disease Obesity Thrombocytopenia (Plt <100/mm3) Low body weight Active cancer Concommitant use of meds that affect p glycoprotein Pregnancy and breastfeeding Noncompliant patients **Dose reductions for weight <60kg, GFR <30, and age >80 only applies to dosing in Afib ** **A new reversal agent for factor Xa inhibitors, Adexenet Alfa, will hope to be FDA approved in the near future** Mr. Anderson Fast forward 5 years No longer on anticoagulation. He had another MI and needed to be on ASA and Plavix. He had a GI bleed while on triple therapy and the patient wanted to stop anti thrombotics He is now hospitalized for a heart failure exacerbation. What anticoagulation should be started? He asks, Doc, I m allergic to Eliquis. I bled because of it in the past. Are you sure I should be getting these shots? 18

19 Why is it important? 40% of all VTE are associated with hospitalization, occurring either in the hospital or shortly after discharge and 1/3 of k VTErelated deaths are perioperative VTE is one of nine hospital acquired conditions (HACs) targeted for a reduction in preventable harms by the Partnership for Patients, a collaborative national health care quality initiative led by CMS CMS considers VTE in hospitalized patients a never event, which is pegged to the pay for performance initiative. VTE prophylaxis VTE IS COMMON Million Women Study Population based, prospective cohort study 947,454 middle aged women in U.K. enrolled between Mean follow up 6.2 years 239,614 underwent surgery 5,419 (2.3%) readmitted for VTE within 12 weeks of inpatient surgery 270 deaths from fatal PE (5%) 19

20 ENDORSE Trial All medical inpatients 40+ years or over and all post surgical patients 18+ years in 358 hospitals across 32 countries These patients were assessed for risk of VTE on the basis of hospital chart review based on ACCP guidelines. 68,000 patients 31,000 surgical patients 20,000 deemed to be at high risk for VTE 37,000 (45%) medical (55%) patients 15,000 deemed to be at high risk for VTE IMPLEMENTATION OF PROPHYLAXIS IS POOR 12,000 received appropriate DVT prophylaxis (58.5%) 6,000 received appropriate DVT prophylaxis (38.5%) VTE prophylaxis IMPLEMENTATION OF PROPHYLAXIS IS POOR IMPROVE study A multinational observation study of 15,156 acutely ill medical patients 60% of patients judged to be at risk of VTE actually received ACCP guidelinebased prophylaxis CURVE study a chart audit in 29 Canadian hospitals 90% of acutely ill medical patients had an indication for thromboprophylaxis Only 16% received appropriate prophylaxis (defined as an ACCPrecommended type of prophylaxis administered at the approved Canadian dose). SHOULD WE JUST PLACE PROPHYLAXIS MEDS ON EVERYONE?? 20

21 VTE Prophylaxis VTE Prophylaxis The guideline includes a Policy Implication statement against hospital performance measures that promote universal VTE prevention regardless of a patient's individual risks for VTE and bleeding.performance measures encouraging routine prevention in all patients are inappropriate.. this is best left to physician judgment Universal use of anticoagulation leads to use in patients at low risk for VTE where bleed risk outweighs risk for VTE 21

22 VTE Prophylaxis 1. Risk of VTE 2. Risk for Bleeding Should this patient receive VTE prophylaxis or not? Are we confident that the benefits of reducing fatal and nonfatal VTE exceed the harms of increasing fatal and nonfatal major bleeding? VTE prophylaxis How to measure risk Caprini Risk Assessment: Non ortho, surgical patients ++ external validation of model Commonly extrapolated to medical patients but wasn t designed to study med patients Padua Risk Assessment Designed for medical inpatients. Easy to use. Not externally validated Rogers Risk Assessment Non ortho, surgical patients no external validation Not encouraged for clinical practice 22

23 VTE Prophylaxis CAPRINI RISK SCORE VTE prophylaxis 23

24 Non fatal VTE/ Non fatal bleed Scenario Moderate VTE/ Average Bleed Moderate VTE/ High bleed High VTE/ average bleed High VTE/ high bleed Baseline Risk of svte Baseline Risk of Major Bleeding (%) (%) RR VTE (UFH vs no Prophy) RR Bleed (UFH vs no Prophy) NNT Vs NNH 100/ / / / 50 Number of VTEs Prevented (per 1000) Number of Bleeds Caused (per 1000) Non fatal VTE/ Non fatal bleed Scenario Moderate VTE/ Average Bleed Moderate VTE/ High bleed High VTE/ average bleed High VTE/ high bleed Baseline Risk of svte Baseline Risk of Major Bleeding (%) (%) RR VTE (UFH vs no Prophy) RR Bleed (UFH vs no Prophy) NNT Vs NNH 93/ / / / 87.7 Number of VTEs Prevented (per 1000) Number of Bleeds Caused (per 1000)

25 VTE Prophylaxis MODALITIES Target Virchow s triad Stasis Hypercoagulability Heparin Lovenox (Enoxaparin) Arixtra (Fondaprinux) Eliquis (Apixiban) Xarelto (Rivaroxaban) Bevyxxa (Betrixiban) Aspirin?? VTE Prophylaxis Recommendation for mechanical prophylaxis from ACP 25

26 VTE Prophylaxis ACCP 9 th Ed. (2012) VTE Prophylaxis Recommendations for mechanical prophylaxis ACCP ACCP Recommendation: SCD use is a reasonable option if bleeding risk is high and pharmacologic prophylaxis is contraindicated but do not recommend use of GCS s (Grade 2Cstrong recommendation, moderate evidence) Evidence: Evidence: mechanical thromboprophylaxis Compared with anticoagulants and ASA, mechanical methods of thromboprophylaxis have the advantage of not increasing bleeding. These agents are effective in reducing thrombosis compared with no prophylaxis. However, there is no compelling data establishing the efficacy of these agents in prevention of fatal PE. Use is indicated in lowrisk surgical patients 26

27 VTE Prophylaxis STATEMENT RE: VTE MADISON VTE Prophylaxis 27

28 Lovenox UFH Fonda Excretion Renal Hepatic Renal Dose 40mg/day vs 30mg/day vs 30mg BID 5000 U TID vs 5000 U BID 2.5mg/day Cost $21.65 for 40mg $15.48 for 5000U $ for 2.5mg Risk for HIT 0.2% 2.6% 0% VTE and Obesity Thromboprophylaxis dosing at U Iowa 28

29 VTE Prophylaxis WHO TO OFFER EXTENDED PROPHYLAXIS? Orthopedic 1. THA, TKA, hip fracture 2. Lower extremity fracture in cast w/ risk factors Abdominal Surgery 3. In setting of Cancer 4. Following bariatric surgery 5. Gynecologic Surgery (not for cancer) Medical patients 6. Spinal cord injury 7. Cancer + Lenolidamide 8. High risk patients Betrixiban Betrixiban 29

30 Betrixiban Apex Trial Background: High risk medical patients carry increased risk of VTE for 4 6 weeks after a hospitalization. Lovenox (EXCLAIM), Apixiban (ADOPT), and Rivaroxaban (MAGELLAN) have no shown benefit for extended anticoagulation therapy (35 42 days). Design: randomized, double blind, double dummy, parallel group multicenter clinical trial APEX is the first thrombosis prevention trial to incorporate an enrichment strategy and statistical analysis plan derived from FDA and EMA guidance on enrichment strategies for clinical trials. 30

31 APEX Trial APEX Trial 24% risk reduction 31

32 APEX Trial By utilizing an enrichment strategy in hopes of streamlining recommendations for guidance on use of the medication and failing to find statistical significance in the first cohort of this intention to treat population, conclusions for cohort 2 and 3 can not be made. However, the FDA believed that the data in Cohort 1 were sufficiently strong to support a full assessment of Cohort 2 and the overall study population. They therefore approved this medication for adult patients hospitalized for an acute illness who are at risk for VTE due to moderate to severe restricted mobility and other risk factors for VTE as outlined in inclusion criteria. As the risk of bleeding is not increased and the greatest effect seemed to come from those >75, I will be inclined to use this medication in the outpatient setting in those of more advanced age. If younger than 75, I may order D dimer to guide consideration for Betrixiban for 35 days. Should be available this fall or early winter 32

33 Summary Provoked VTE carries a low risk of recurrence, but only encompass a small spectrum of scenarios Defined as: surgery in last 3 months, or medical hospital stays, or recent fractures, or no immobility >7 days, no ICU stays, no stroke, and/or no pregnancy and post partum VTE is a chronic disease and the interplay between risk for recurrent VTE vs risk for bleeding never stops. Risk for recurrence: 10%/year if unprovoked Risk for bleeding: 2 3% on average, 3 5% in elderly Acceptable risk for recurrence: <3 5% D dimer testing can be considered in all patients w/ unprovoked clot and plans to stop anticoagulation Would not use D dimer test results alone. Assessing Ddimer allows use of prediction models. Each prediction model has its flaws DOACs are effective medications and safe to use in most patient populations Caution use in low BMI (<60kg) and BMI >40, elderly, non compliant patients VTE prophylaxis in the hospital is a CMS quality control measure and deemed a never event. Pharmacologic prophylaxis is preferred method when risk of bleeding is not deemed high Consider days of out of hospital use of Betrixiban in high risk medical patients CONTINUE ANTICOAGULATION DISCONTINUE ANTICOAGULATION 1. Risk of VTE 2. Risk for Major Bleeding 3. Patient preference 0 10 What is their anticoagulation hate factor Do they most desire to be off blood thinners? 33

34 THANK YOU. QUESTIONS? 34