(3/19) Shapiro Lecture: Treatment and Prophylaxis of VTE Venous Thromboembolism (VTE)

- Anatomical Deep Vein Thrombosis (DVT): The deep veins include: o Inferior vena cava o Iliac vein o Popliteal vein o Anterior tibia vein o Femoral vein

- Anatomical Upper Extremity Deep Vein Thrombosis (UEDVT): Includes: o Brachial vein o Axillary vein o Subclavian vein o Internal jugular veins o Clinical Manifestations: Edema, dilated collateral circulation (see new veins), pain

- Risk Factors: Virchow’s 3 Sources – Blood stasis, vascular injury, hypercoagulability o Blood stasis: Such as hospitalization, extended surgeries, paralysis, immobility, obesity o Vascular injury: Potentially related to a foreign object, trauma, surgery, catheters o Hypercoagulability: Coagulation exacerbated by comorbid conditions (malignancy, IBD, pregnancy), a

deficiency (Protein S/C, Antithrombin), an excess (Factor VIII, Factor XI, or drug (estrogen OCP) General Categories of VTE Treatment

- Prophylaxis: Prophylactic treatment should be used when there are identifiable risk factors for VTE - Outpatient: Uncomplicated DVT or PE can be safely treated in the outpatient - Full treatment: Most patients with VTE should receive 3 months of anticoagulation therapy, which may involve

initial treatment with a rapid-acting anticoagulant and warfarin overlap (warfarin + injectables x5 days, INR >2) Prophylaxis of VTE

- Non-Pharmacological: Active or passive mobilization – moving is huge. Get that person walking around post-op day 1. Adequate hydration is crucial. Try to stabilize fractures early

o Mechanical Prophylaxis: In some patients, anticoagulation therapy is not safe à use non-drug measures § Graduated Compression Stockings (GCS): Provides

circumferential pressure that gradually decreases from the ankle to the thigh to promote venous blood flow and prevent pooling

§ Intermittent pneumatic compression (IPC): Leggings that repeatedly inflate and deflate to mimic calf muscle contractions. Downside, must be worn > 18h/day

- Pharmacologic: Inpatient or outpatient, prophylactic tx should be used when there are identifiable risk factors\ o In general, LMWH and Fondaparinux are preferred, particularly in high-risk surgical patients due to their

proven efficacy and extended experience o Medical Illness: Use Padua Prediction Scoring system to determine if a pt’s medical status requires tx

§ High risk of thrombosis (³ 4 points) à LMWH, LD-UFH, Fondaparinux, Betrixaban § Low Risk (£ 3pts) à Nothing or mechanical prophylaxis

o Outpatient: In general, pharmacologic prophylaxis is not recommended. Only in patients with extended periods of immobility (long-distance travel) should mechanical prophylaxis be employed

o Surgical Patients: Use Caprini score to estimate VTE risk following surgery. High score (³ 5) § Neuraxial Anesthesia/Spinal Puncture: Use ASRA guidelines to determine the risk of Hematoma.

Hematomas may result in long-term or permanent paralysis. So risk factors and the appropriateness of anticoagulation therapy pre- and post- procedure should be reviewed

o Orthopedic Surgery: CHEST 2012 suggests LMWH has the best level of evidence and history of safety § ASA, Adjusted-dose warfarin, LMWH, and UFH are all indicated for the surgeries listed below § Hip or knee replacement à 10-14 days of LMWH (preferred), Fondaparinux if HIT § Hip fracture surgery à 10-14 days of LMWH (preferred), Fondaparinux if HIT § Major Orthopedic surgery à Dual prophylaxis + antithrombotic. Suggested up to 35 days

• Start LMWH 12h or more pre-operatively, or 12 or more post-operatively - IVC (Inferior Vena Cava) Filters: Can provide short-term protection against PE in very high-risk patients by

blocking embolization of thrombus formed below the filter o “Retrievable” filters are often inserted and never retrieved, which can increase the risk for long-term

complications such as DVT. Should be reserved for patients with the highest VTE risk

Diagnosing DVT Symptoms: Leg swelling, pain, warmth. Superficial veins may be dilated. The symptoms are often nonspecific and will require objective testing to establish the diagnosis. “Palpable cord” may be felt in the affected leg “Homan’s sign” is pain in the back of the knee upon dorsiflexion of the affected leg Laboratory Tests: The most important marker in the blood is D-dimer. It is a nonspecific marker of thrombotic activity, and is a sign of fibrin degradation. It is often used to rule out the dx of VTE [D-dimer] < 500ng/mL = Rule out DVT Diagnostic Tests Compression Ultrasound: Most common and non-invasive – visualize clot formation in veins of legs Venography: Gold standard for diagnosing DVT. It is invasive, using injections of radiopaque dye into a foot vein. Unfortunately, it is expensive, can cause anaphylaxis, and even nephrotoxicity

Diagnosing PE Warning: Most patients with risk factors for VTE will develop symptomatic DVT prior to PE, which may cause sudden death via shock and circulatory collapse before effective treatment can be initiated Symptoms: “Looks like a MI+Asthma attack”. Cough, chest pain, chest tightness, SOB, Hemoptysis, dizziness, lightheadedness. The patient may be exhibiting tachypnea, tachycardia, and diaphoresis Laboratory Tests: D-dimer should be elevated. If < 500ng/mL, we can rule out PE Diagnostic Tests: Computerized tomography pulmonary angiography (CTPA) is the most commonly used test, though some centers still use the ventilation-perfusion (V/Q) scan. VQ scans can measure the distribution of blood and airflow in the lungs – if there is a big mismatch – there is a high probability the patient has PE

- Pulmonary Angiography: Gold standard, though it is invasive, must inject radiopaque dye. Expensive and associated with mortality

Treatment of VTE

- Acute Phase (Days 0-7) o If PO is available

à Apixaban 10mg PO BID for the first 7 days -OR- rivaroxaban 15mg PO BID for first 21 days o If PO is unavailable, inject until INJR is over 2, then continue on warfarin

à UFH/LMWH/Fondaparinux for first 5-ish days, overlapping Warfarin PO Qdaily § Enoxaparin: 1mg/kg SC q12 or 1.5mg/kg SC q24 § Fondaparinux: Weight-based dosing SC q24. (<50kg = 5mg, 50-100kg = 7.5mg, >100kg = 10mg)

- Early Maintenance Phase (Days 8-90) o Continuing PO treatment, slightly lowering the dose

à Apixaban 5mg PO BID -OR- rivaroxaban 20mg PO Qdaily o Continuing PO Warfarin therapy, INR goal 2.5 with range (2-3)

Preferred Selection 2016 ACCP: - Acute DVT of leg or PE DOAC > Warfarin - Long-term Therapy Warfarin > DOAC - VTE + No Cancer: DOAC - VTE + Cancer: LMWH EINSTEIN + AMPLIFY trials - Safety data showed DOACs have a lower bleed risk than warfarin, which made the DOACs the standard of care EINSTEIN-CHOICE trial - Riva reduces the risk of recurrent VTE significantly (10mg>20mg) compared to ASA without a signif increase in bleeding

Duration of Therapy 2016 ACCP: - 3 Months is the preferred minimum duration of anticoag therapy

Monitoring for patients on DOACs - Renal Function (CrCl): Make sure their kidneys work - Complete Blood Count (CBC, Hb): Make sure they are not bleeding or have a problem bleeding

Long-Term Consequences of VTE – Reason to Treat - Post-Thrombotic Syndrome (PTS): Following thrombosis and inflammation, damage to leg

veins can cause leaky valves and pooling of blood. Physically, this can present as leg pain, swelling, and redness. PTS develops in 50% of patients experiencing a DVT in the leg

o Risk Factors: Undertreated, poorly managed blood clots, proximal DVT, obesity o Symptoms: Leg heaviness, itching, tingling, cramping, ulcerate, development of venous ectasia, edema

- Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Following an acute PE, up to 4% of patients will experience CTEPH in the first 6-24 months of their PE episode. Generally, it is an untreated persisting clot

o Dx: Right heart cath, Pulmonary Angiography o Sx: SOB upon activity, tiredness, fatigue, depression o Tx: Long-term anticoagulants, and in severe cases - pulmonary thromboendarterectomy

Switching on and off anticoagulants - Determining the Need for Bridge Therapy: Patients are stratified by their relative risk for bleeding and

appropriateness for anticoagulation therapy relevant to their indication (Mechanical heart valve, AFib, VTE) o (1) ASSESS BLEED RISK (2) ASSESS THROMBOTIC RISK

- Surgeries have been categorized by their immediate risk of bleeding, AND their extended period risk o Minimal: Dermatologic procedures (excise moles), Cataract procedures, dental cleanings/fillings o Low risk (2 day risk of MB < 2%): Minor dental procedures, biopsies, shoulder surgery, colonoscopy o High risk (2 day risk of MB > 2%): Cancer surgery, reconstructive plastic surgery, bowel resection,

pacemaker implantation o High Risk: Such as major surgery, do not use anticoagulation therapy due to high risk of bleeding

- Surgical Interruption and Bridge Therapy o HOLD WARFARIN 5 days before procedure, INR < 1.5 is required for most surgical procedures

§ Resume usual dose on day 0, if hemostasis is achieved § Start LMWH on day -4 before surgery, and continue until +5-7

o DOACs should be held for at least 2 half-lives for low-risk and 4-5 half-lives for high-risk surgeries - Guidelines

o Parenteral to DOAC o Warfarin to DOAC o DOAC to parenteral o DOAC to warfarin

Refer to the last few slides of the lecture to check renal function requirements and suggested dosing