Venous Thromboembolism Rony D. Gorges, MD Invasive Cardiologist Metro Heart and Vascular

No Disclosures (Unfortunately)

Incidence of VTE 75 to 269 per 100K patients 200 to 700 per 100K patients 70 or older 600K Hospitalizations in U.S. 300K Deaths/Year in U.S. LAST in the US we have about 600,000 hospitalizations for VTE and 300,000 deaths/year from VTE

Incidence of VTE Incidence on the rise Aging population Risk of VTE doubles every decade over the age of 40 Better diagnostic accuracy Readily available tests FIRST its a big problem and its growing

Recurrence 10-year recurrence rate of VTE is 25% Recurrence peaks in the first 6 months DVTs tend to recur as DVTs PEs tend to recur as PEs 2ND SENTENCE and trends down for 3 years before stabilizing at 2% per year. So the average yearly recurrence rate is about 4% per year for years 1-3 and 2% for years 4-10

Death Rates 30-day case-fatality: 10% for VTE 1-year case-fatality: 23% for VTE 30-day mortality: 3% for initial DVT 30-day mortality: 31% for initial PE

Cost Average LOS 4.7 for DVT Average LOS 5.1 for PE Treatment & Diagnosis $15.5 Billion 2011, LOS for joint replacement

Thrombus Genesis Blood pooling in valves “think cusps” or “little appendages” Avg. 23 min. IV contrast to clear +/- Tissue factor Vessel damage 1ST Blood stasis, concentrated coagulation factors and platelets. 3RD High inflammatory states, active cancer, autoimmune diseases, IBS

RISK Transient obstructions/impedance to flow are risk factor for a first and hopefully last VTE, whereas chronic issues tend to cause recurrence

Physical Exam Bancroft’s/Mose’s sign Homans sign Lisker’s sign Louvel’s sign Lowenberg’s sign Peabody’s sign Pratt’s sign Rose’s sign Cord sign I don’t know anyone who knows or uses these physical exam findings and I’m sure there are even less that are willing to diagnose and treat a DVT based on these, but on the other hand we have to make keen our other skills like history taking and awareness of signs, symptoms and risk factors for VTE

VTE Detection Ultrasound is the standard for DVT diagnosis If clinical suspicion remains high do serial exams Venography, “gold standard” Limited indications, invasive D-Dimer - Fibrin Degradation Product (FDP) 99.6% Negative Predictive Value Specificity of 50%

VTE Detection Multidetector Computed Tomography Angiogram (CTA) Standard Ventilation/Perfusion Scan (V/Q) Inhale radioactive isotope and inject radioactive isotope Not gonna work well if significant lug disease Pulmonary angiogram ‘gold standard” Limited indications, invasive v/q not as binary

Treatment Duration No clear guidelines on duration of treatment Provoked DVT treat for 3 months Provoked PE treat for 6 months Unprovoked PE or DVT treat lifelong 2nd provoked VTE treat lifelong Heritable clotting disorder and VTE treat life long LAST I do not refer patients with provoked DVT for hyper coagulable w/u unless they have a family history of a coagulable disorder.

anticoagulation treatment of VTE includes 3 phases (look up) anticoagulation treatment of VTE includes 3 phases (look up). Traditionally we used rapid onset IV or SQ anticoagulants and this is to achieve therapeutic levels to avoid early recurrence

VKA to NOAC INR <2.0 can start NOAC now INR 2.0-2.5 wait 24 hours and then start NOAC INR >2.5, consider value, retest follow above

Major Trials Non-inferiority, recurrence and VTE related deaths were the primary efficacy outcomes

MECHANISMS OF ACTION TF-tissue factor TFPI-tissue factor protein inhibitor - RCT 1700 patients thought to help in severe sepsis with high inflammation high levels of TF, they get more end organ damage, hyper coagulable, no effect on mortality, increased bleeding Andexanet - reversed Xarelto in 2 minutes, safely reverses xarelto and elquis, phase III

Untested Clinical Scenerios FIRST Use of apixiban/eliquis in renal severe/end stage failure patients. about 75% cleared by the intestine and about 25% by the liver. We do now that there are increased levels in ESRD patients.

Isolated Distal DVT DVTs below the level of the popliteal vein No definitive guidelines available 2 Approaches Treat as proximal DVT Repeat US in 1 week CACTUS trial: 2015 LAST CACTUS TRIAL about 250 patients 6 weeks of SC LMWH versus placebo DVT extension/PE at 6 weeks and 90 days was primary end points 7 had recurrence in placebo arm, 4 had recurrence in LMWH arm and 5 had major or clinically relevant bleeding all in the LMWH arm

Patients with Cancer 2.5% - 9.4% in clinical trials had cancer About 20% of patients with VTE have cancer Meta-analysis of the 6 major trials VTE recurrence 3.9% in patients on NOACs VTE recurrence 6% in patients on VKA Despite these findings NOACs were compared to VKA and not LMWH which is the treatment of choice.

NOAC Follow-up Normal renal function/abnormal renal function Cr/GFR/CBC at 1 month then q6 months More frequent testing needed for patients with renal function close to recommended adjustment dose values LAST and obviously those with fluctuating values

Post-Thrombotic Syndrome 20-50% of patient after DVT Destruction of valves Deep venous reflux Chronic thromboembolic pulmonary HTN (CTEPH) 0.1- 9.1% First varicose veins, lipodermatoscelrosis, LAST CTEPH this large margin of error is probably due to referral bias, absence of early symptoms, and the occasional difficulty in differentiating acute PE from an episode superimposed on pre-existing CTEPH CTEPH should be ruled out in patients with persistent dyspnea after acute PE and at least 3 months of anticoagulation treatment; however, routine screening for CTEPH is not recommended in asymptomatic survivors of PE

Advanced Treatment TPA for massive PE (5% of all PEs) 15+ mins of hypotension, SBP <90 mmHg HR <40 BPM with signs of hypo-perfusion 1 in 5 will have a major/clinically relevant bleed 6% will have intracranial hemorrhage Catheter directed thrombolysis +/- thrombectomy Symptomatic DVTs Submassive PEs 40% of PE, 55% are low risk, only 5% are massive

Submassive PE Hemodynamically stable (SBP >90 mmHg) Acutely symptomatic Elevated troponin Right Ventricular Dysfunction (RVD) RV/LV ratio >0.9 (CT/ECHO) RV dysfunction on echocardiogram ECG changes of RV strain (new RBBB)

PE Death Spiral

Importance of RV Dysfunction Strong independent predictor of poor outcomes Increased mortality Increased VTE recurrence Increased adverse outcomes (CTEPH)

Adverse outcomes associated with RVD – 3x higher mortality if RV/LV ≥ 0.9 Registry of 1,416 patients Mortality rate: 1.9% RV/LV < 0.9 6.6% RV/LV >/= 0.9 Mortality

RVD Increases Mortality Retrospective analysis 120 patients Hemodynamically stable PEs PE related mortality @ 90 days 17% RV/LV >/= 1.5 8% RV/LV <1.5 0% RV/LV <1.0

Presence of RV hypokinesis associated with 57% increase in mortality rate at 3 months Prospective study of 2,454 consecutive PE patients at 52 hospitals in 7 countries Mortality rates at 3 months 21% with hypokinesis 15% with no hypokinesis

Adoption of IV thrombolysis hampered by elevated risk of severe bleeds In randomized trials, systemic PE thrombolysis is associated with a 11.5% risk of major bleeding and a 6.3% risk of intracranial hemorrhage1 In clinical practice, systemic PE thrombolysis is associated with a 19.2% risk of major bleeding and a 5% risk of intracranial hemorrhage2 In clinical practice, systemic thrombolysis is withheld in up to two thirds of patients with high-risk (massive) PE3 Meyer G et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370: 1402-11. Fiumara, K et al. Predictors of Major Hemorrhage Following Fibrinolysis for Acute PE. Am J Cardiol 2006;97:127-9 Kucher, N et al. Massive PE. Circulation 2006;113:577-82

Emerging Treatment USING ULTRASONIC ENERGY TO DISSOLVE CLOT Ultrasonic energy causes fibrin strands to thin, exposing plasminogen receptor sites and fibrin strands to loosen Thrombus permeability and lytic penetration are dramatically increased Ultrasound pressure waves force lytic agent deep into the clot and keep it there