Anticoagulation Debbie L. Cardell, MD Asst. Clinical Prof of Medicine Medical Director UHC-D Anticoagulation Clinic Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Today’s Topics Diagnoses for which anticoagulation is necessary Duration of therapy INR goal Starting warfarin Sources of evidenced based medicine Drug/Drug interactions System wide protocol Work up of PE/DVT Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Diagnoses requiring warfarin Atrial fibrillation - sometimes Valvular Heart Disease Prosthetic heart valves DVT PE Hypercoagulable States - sometimes THR, TKA, hip fracture repair Pulmonary Hypertension Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Antithrombotic therapy for prevention of stroke (ischemic and hemorrhagic) in patients with nonvalvular AF: adjusted-dose warfarin compared with placebo Fuster, V. et al. Circulation 2001;104:2118-2150 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08 Copyright ©2001 American Heart Association

Case 1 46 y.o. male continuity patient with allergic rhinitis, found on exam to have irregular pulse. No other medical problems. Pulse irreg. 76 bpm, BP 132/76 EKG shows a-fib Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 1 Does the patient need anticoagulation? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Answer No Provide proof for your answer Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Atrial Fibrillation CHADS2 score is an easy to use clinical tool for determining who needs warfarin C – CHF- 1 point H – treated HTN - 1 point A – age >75 – 1 point D – diabetes – 1 point S – prior history of stroke or TIA-2 points Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

CHADS2 score and risk of stroke Risk of Stroke per 100 patient years 1.9 1 2.8 2 4.0 3 5.9 4 8.5 5 2.5 6 18.2 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Interpreting the CHADS2 score Risk Anticoagulation Therapy Considerations Low Aspirin 325 mg likely to offer most benefit 1-2 Moderate Aspirin or Warfarin INR goal 2-3 3 High Warfarin Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Exception to CHADS2 Although a patient with a prior stroke and no other risk factors would only have a score of 2 and calculates out as a moderate risk, they are truly high risk and should be treated with warfarin in the absence of contraindications. Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Case 2 54 y.o. man with HTN well controlled on HCTZ and metoprolol, found to have irregular pulse EKG shows a-fib Echo one year ago EF 60% Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 2 Does this patient need warfarin? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Interpreting the CHADS2 score Risk Anticoag-ulation Therapy Considera-tions Low Aspirin 325 mg likely to offer most benefit 1-2 Moderate Aspirin or Warfarin INR goal 2-3 3 High Warfarin Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Valid contraindications to warfarin Patient refusal Non-compliance with INR monitoring Alcohol consumption Bleeding diathesis History of major bleeding Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 3 56 y.o. woman with MVP admitted 4 mos ago for TIA Does she need warfarin? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Answer Only if she is an ASA failure MVP with h/o stroke or TIA –ASA dose of 50-160mg daily If fails ASA – then warfarin Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Valvular Disease MVP with h/o stroke or embolization – ASA 50-160 mg MVP with ASA failure – warfarin – long-term range 2-3 Rheumatic heart disease – mitral valve – with a-fib and/or prior history of stroke – lifetime use of warfarin with a goal of 2-3 Rheumatic Mitral Valve disease and NSR with Left Atrial size >5.5 cm – lifetime warfarin goal 2-3 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 4 60 y.o. man with prosthetic aortic valve, echo shows nl EF. He has never had a stroke or TIA. He has a bi-leaflet valve. What is his INR goal? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Prosthetic Heart Valves Goals Aortic position – NSR, NL LA size, bi-leaflet or tilting disc prosthesis - INR 2.0-3.0 Aortic position – other risk factors* INR 2.5-3.5 Mitral position – 2.5-3.5 Duration – lifetime if mechanical, 12 weeks post surgery if bio-prosthetic (porcine) Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

AVR + Other Risk Factors = INR 2.5-3.5 Atrial Fibrillation Myocardial infarction Left atrial enlargement > 5.5cm Endocardial damage Low ejection fraction Caged ball or caged disc valve Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 5 Patient with AVR tells you his brother just had an MI at 49y.o. He picked up a new habit, smoking, since you last saw him. Would you start ASA for primary prevention of CV disease? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Answer Yes Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Aspirin Plus Warfarin? When? Only proven benefit is in patients with Prosthetic Valves and increased CV risk or previous MI WARIS II ASPECT 2 Dose should be 81mg Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Next Case 28 y.o. woman presents to the ER on one of your call days with a unilateral swollen leg Doppler reveal a DVT History reveals she just had breast reduction surgery 2 weeks ago Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 6 What is her INR goal? How long would you treat her? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Deep Vein Thrombosis INR goal is 2.0-3.0 Duration depends on clinical scenario Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Classifying Patients First-episode DVT secondary to a transient risk factor First-episode DVT and concurrent cancer First-episode idiopathic DVT First-episode DVT associated with a prothrombotic genotype Recurrent DVT CHEST 2003 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

1st DVT, Transient Risk Factor Treat to INR 2-3 for 3 months Transient Risk factors include Surgery Pregnancy Hospitalization Trauma Fracture Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Next Case 67 y.o. male continuity patient seeing you after hospital discharge, comes to clinic for follow up. He was admitted for a UE DVT. During admission he was found to have widely metastatic liver cancer. What is your anticoagulant of choice? How long do you treat him? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

DVT in the setting of Cancer LMWH is recommended the in CHEST guidelines for the first 3-6 months of long term therapy LMWH is recommended for advanced and metastatic cancers LMWH is recommended during chemotherapy In select patients with localized disease, warfarin can be considered Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Next Case 37 y.o. man in your clinic comes in acutely complaining of leg pain and swelling. He denies, travel, recent surgery, hospitalization, prolonged immobilization. You are able to obtain dopplers. He has a DVT Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 7 What is his INR goal? How long do you treat him? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

First Idiopathic VTE At least 6 months (6-12 months) PREVENT trial – after 3 months of anticoagulation, 508 patients randomized to continuation of warfarin (INR 1.5-2.0) vs. placebo. Trial stopped after 4.3 years when there was a significantly lower rate of recurrent VTE in the warfarin group (2.6 versus 7.2 per 100 patient-years, hazard ratio [HR] 0.36, 95% CI 0.19-0.67) ELATE – after 3 months of INR 2.0-3.0, 738 patients randomized low dose warfarin INR 1.5-1.9 vs. 2.0-3.0. f/u 2.4 yrs. Recurrent VTE was significantly lower in the higher dose warfarin group (1.9 versus 0.7 per 100 patient-years, HR 2.8, 95% CI 1.1-7.0). Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

After six months Risks and benefits need to be reviewed with the patient Risk of minor bleeding with continued anticoagulation 12.8 per 100 pt years, major bleeding is 2.7 per 100 patient-years, with a case fatality rate of 9.1 percent (95% CI 2.5-22) Ann Intern Med 2003 Dec 2;139(11):893-900. Risk of recurrent VTE on no warfarin 7.2-8.4 per 100 pt years in PREVENT and THRIVE III trials, low dose warfarin 1.9-2.6 per 100 pt years (ELATE and PREVENT), and .7 episodes per 100 pt years on full dose warfarin (ELATE) Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Case Continued His 6 months of warfarin therapy are over You discuss the risks and benefits of treating him for a year vs. stopping now He opts to stop the warfarin Should you test him for acquired and hereditary thrombophilias? Are there any other tests to determine his individual risk? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

The risk-benefit of indefinite treatment with a VKA for a second episode of VTE has been evaluated in a randomized trial in which Schulman et al58 compared 6 months of treatment with indefinite treatment (average, 4 years) in 227 patients with a second episode of VTE. Conventional-intensity anticoagulant treatment (INR, 2.0 to 3.0) was used in both groups. After 4 years of follow-up, the cumulative incidence of recurrent VTE was 20.7% in patients who received 6 months of therapy, compared to 2.6% in patients who continued anticoagulant treatment (p < 0.001; absolute risk reduction, 18.1%; RRR, 87%). This benefit was offset partially by major bleeding. The cumulative incidence of major bleeding was 8.6% for the indefinite treatment group, compared with 2.7% in the 6-months group (p = 0.084; absolute risk increase, 5.9%). Thus, during extended treatment for an average of 4 years, the number needed to treat (NNT) to prevent one episode of recurrent VTE was 6, and the number needed to harm (NNH) for major bleeding was 17. CHEST Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Screening for Thrombophilias Controversial – there is no consensus Arguments against screening – excessive, not cost effective, does not impact treatment Arguments for screening – some patients (1-2%) have very high risk profiles, knowledge could help manage risky situations such as surgery and pregnancy Helps in screening of family members Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Inherited Thrombophilias Require life long anticoagulation only in the following cases: Two or more spontaneous thromboses or one spontaneous thrombosis in the case of antithrombin deficiency or the antiphospholipid syndrome One spontaneous life-threatening thrombosis (e.g., near-fatal pulmonary embolism; cerebral, mesenteric, or portal vein thrombosis) One spontaneous thrombosis at an unusual site (e.g., mesenteric or cerebral vein) One spontaneous thrombosis in the presence of more than a single genetic defect predisposing to a thromboembolic event UpToDate Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Consider screening In Strongly Thrombophilic patients – First idiopathic VTE prior to 50 y.o. History of recurrent thrombotic episodes First-degree relative with thrombotic episode prior to the age of 50 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

When not to screen Recent major surgery, trauma, or immobilization Active malignancy Systemic lupus erythematosus Inflammatory bowel disease Myeloproliferative disorders Heparin-induced thrombocytopenia with thrombosis Preeclampsia at term Retinal vein thrombosis Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Individual Risk Assessment D-dimer testing – 4 studies have shown an increased risk of recurrent VTE in patients with elevated D-dimers after 3 months of anticoagulation HR 2-2.5 One of the studies showed only 5 patients out of 186 with a normal D-dimer with a recurrent VTE, this give a negative predictive value of >96%. Thromb Haemost 2002 Jan;87(1):7-12. Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Recurrent VTE Trials are ongoing to determine the optimal duration of treatment, but for now recommendations say “indefinite” unless there is a reversible cause If reversible cause – then treat until the risk factor is no longer an issue Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Upper Extremity Thrombosis General consensus is that this represents a more thrombogenic patient No randomized controlled trials to determine the most appropriate length of therapy If a reversible cause – can treat for 3-6 months If not – long term anticoagulation Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Next Case You are called to the ER to see one of your clinic patients. She is 42 y.o. c/o SOB for 1 day, she is breathing rapidly and is tachycardic, her O2 sats are 88%. CXR is negative. WBCs are normal. She is not hypotensive. You order a PE protocol CT. It is positive. How long will this patient need to be treated for her PE? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Treatment for PE Treatment goals are the same as DVT Duration the same as DVT Exception is “massive PE” which is defined as “shock” or requiring pressors – this would constitute a reason for lifelong anticoagulation Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Other Considerations Compression Stockings should be prescribed at 30-40mm Hg at the ankle in all patients with DVT within a month after Dx and continued for 1-2 years. This has been proven to reduce the incidence of post-thrombotic syndrome by 50% Lancet 1997;349,759-762 Patients should be on “ambulation as tolerated” NSAIDs are not recommended during the acute treatment of DVT Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Total Hip Replacement Low Molecular Weight Heparin (LMWH) or Warfarin with a target INR of 2.0-3.0 Fondaparinux 2.5 mg daily Duration: 28-35 days Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Hip Fracture Surgery Same recommendations as Total Hip Replacement Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Total Knee Arthroplasty (TKA) LMWH at high risk doses or Warfarin with INR goal 2.0-3.0 Fondaparinux Duration: 10 days Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Next Case 62 y.o. female with Pulmonary Hypertension secondary to COPD She is in NSR Her last echo showed an EF of 50% Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 8 Does she need warfarin? Does your recommendation change if her EF was 20%? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Pulmonary Hypertension INR goal of 2.0 for Pulmonary Hypertension secondary to chronic thromboembolic disease PulmHTN with afib Idiopathic Pulmonary Hypertension Familial Pulmonary Hypertension Pulmonary Hypertension with severe left heart failure Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Starting Dose Start with 5mg of warfarin (CHEST) Consider a lower dose in very elderly Get a baseline INR Follow a nomogram Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Nomogram One can be found in the Annals Annals of Internal Medicine 2003;138:714 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

5-mg Warfarin Initiation Nomogram Kovacs, M. J. et. al. Ann Intern Med 2003;138:714-719 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Initiation Case Your previous DVT patient is started on 5mg warfarin (following CHEST guidelines) His baseline INR is 1.1 You start him on 1mg/kg of enoxaparin BID He comes back on day three with an INR of 1.4 Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Question 9 What dose do you tell him to take? When do you tell him to come back? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Follow up Arrange for appointments as per the nomogram INR check on days 3,4,5,6, Then twice weekly for two weeks Weekly for two more weeks If stable, then every 4 weeks Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Initiation of anticoagulation How many days of enoxaparin should you write for? What are the instructions for stopping the enoxaparin? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Answer Write for a minimum of five days of enoxaparin INR should be therapeutic for two days in a row before stopping enoxaparin Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Monitoring After the initial 2 weeks, INRs usually become more stable Maintenance nomograms may be utilized to help in decision making An experienced clinician is equivalent to a nomogram Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Maintenance Case 65 y.o. woman with A-fib, DM and hyperlipidemia had to switch her statin from atorvastatin to simvastatin for insurance coverage purposes. Her repeat INR after med change shows the INR is 3.6 What adjustment do you make? When should she follow up? Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

INR changes while on maintenance Worsening CHF New medication Stopped a medication Stopped or started smoking Increased or decreased physical activity Infection This is why an experienced clinician performs as well as a nomogram or calculator Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Anticoagulation Clinic vs. PCP Anticoagulation Clinic saves money Decreases hospitalizations (related to anticoagulation) Decreases INRs outside of range Decreases anticoagulation related complications Am J Hosp Pharm 985:42,304-308, Pharmacotherapy 10=995:15,732-739, Drug Intell Clin Pharm 1985;19,575-580, Arch Intern Med 1998:158,1641-1647, Chest 2005:127,1515-1522. Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Point of Care vs. Lab Point of care testing (POC) – utilizes the finger stick to obtain an INR Convenient Quick Less blood needed Reliable There are restrictions Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

When not to use POC While on enoxaparin Hct below 30 Patients with antiphospholipid antibodies Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Drug Interactions Safest to assume all drugs interact with warfarin Check all new medications in epocrates or a similar program Don’t forget about herbals and over the counter meds Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Common Bad Actors Acetataminophen Trimethoprim/sulfamethoxazole Fluoroquinolones Antibiotics in general Gemfibrozil Aspirin Clopidogrel Prednisone Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

When Forced If you must use one of these medications, recheck the INR in 3 days OR look on MicroMedex and see how strong the interaction is For Bactrim, decrease weekly warfarin dose by 30% and recheck in 3 days Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

System Based Protocol Goals Uniformity of treatment Encourage the use of evidence based guidelines Create a patient registry Uniformity of dose adjustment and follow up Provide seamless care Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Resources CHADS2 score Wells score for DVT and PE Warfarin initiation nomogram Warfarin maintenance calculator CHEST guidelines Patient information in English and Spanish Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Referring Patients From inpatient setting – use Consult upon discharge option Anticoagulation referral Tell patient to go to ExpressMed at the hospital in 2-3 days (follow protocol) Order INR in Sunrise Stat patient waiting Give paper to patient Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Referring Patients From Outpatient setting Use Outpatient Consult or Anticoagulation Consult In pull down menu, select anticoagulation Tell patient to go to ExpressMed clinic in 2-3 days (follow protocol) Order INR from within Sunrise Stat patient waiting Hand the paper to the patient Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08

Questions Debbie L. Cardell, MD Div Gen Med UTHSCSA 2/29/08