Venous Thromboembolism - Management (1 of 21)

DEEP VEIN 1 THROMBOSIS Patient presents w/ symptoms suggestive of DVT DVT

2 DIAGNOSIS What is the clinical pretest probability? Low (unlikely) clinical pretest probability Moderate or high (likely) clinical pretest probability

Is Is duplex D-dimer1,2 venous Positive 2 Positive positive or ultrasonography (US) negative? positive or negative?

A MANAGEMENT Negative Non-pharmacological therapy Negative Patient education Low (unlikely) clinical • pretest probability Bed rest & leg elevation • Graduated elastic compression stockings (GECS) B Parenteral anticoagulants ALTERNATIVE • DIAGNOSIS Low-molecular-weight Heparin (LMWH), or Moderate or high (likely) (Exclude DVT) • clinical pretest probability Unfractionated Heparin (UFH) • Fondaparinux C Oral anticoagulants • Non-vitamin K oral anticoagulants (NOACs) • Warfarin rombolytic therapy • FOLLOWUP STUDIES G Only in massive DVT • Repeat US in 1 week Invasive procedures Negative • Venography (magnetic Positive • rombectomy resonance venography if • Inferior vena cava (IVC) ﬁ lters available) when appropriate

D Follow-up © MIMS• Oral anticoagulant

1D-dimer may be used for excluding DVT in a moderate or intermediate pretest probability population if prevalence is approximately ≤15% 2Interim therapeutic anticoagulation may be given while awaiting test result; use an anticoagulant that can be continued if DVT is conﬁ rmed Not all products are available or approved for above use in all countries. Speciﬁ c prescribing information may be found in the latest MIMS.

B205 © MIMS 2020 VTE - MANAGEMENT • • • • • • • • • Factors Risk Other • • • • Persistent Provoking • • • • • • • Transient Provoking orReversible Factors Risk • • • Pathogenesis • • • • • • • • • • • • • ofDVT Suggestive &Symptoms Signs • • Blood transfusion & erythropoiesis-stimulating agents &erythropoiesis-stimulating transfusion Blood Varicose veins Obesity failure orrespiratory failure heart Congestive for atrial fl or hospitalization Myocardial infarction utter/fi 3 months the within failure past brillation or heart limbfracture Lower Spinal cord injury ofVTE history orfamily history medical Past age Increasing Chronic infl infl eg states, ammatory disease bowel ammatory syndrome Antiphospholipid antibody Active autoimmune disease Active cancer Lengthy travel, airline fl eg ight >8hours Pregnancy/postpartum Estrogen therapy for>3days Bedridden 3days foratImmobilization least traumaMajor (eg replacement) hiporknee 4weeks the within Surgery past VTE &previous fractures, spinal cord injury, procedures, surgical long bone of trauma, contributing Major include history factors risk - VLeiden mutation w/factor &prothrombin gene associated mutationHypercoagulability been has damage, &stasis Virchow’s Hypercoagulability, contributing 3factors tothe development ofVTE: theorizes triad endothelial - ofVTE prophylaxis starting before bleeding & ofVTE forrisk assessed shouldbe illness oracutemedical surgery All patients formajor trauma, admitted rates inAsia mortality incidence inthe &w/increasing & US diseases One ofthe common most life-threatening cardiovascular superfi as manifests Also ofDVT form severe aless (SVT), cial vein thrombosis - &⅔w/PE ⅓ofpatients ofDVT present w/symptoms - w/ significant morbidity &mortality &isassociated (DVT), venous thrombosis (PE)&deep embolism pulmonary as commonlyMost manifested exceeded capillary perfusion pressure perfusion capillary exceeded the interstitial tissuepressure has because -pallorinthe albadolens (paleleg) edematous legs Phlegmasia in the leg hue -deoxygenated hemoglobin leg) in the acyanotic stagnant cerulea dolens veins (blue causes Phlegmasia Superficial thrombophlebitis w/apalpable cord asuperfi over cial vein Warmth Erythema Collateral superficial veins (non-varicose) isgreaterPitting inthe edema symptomatic leg tibialtuberosity) 10cmbelow (measured >3cmcompared swelling leg Calf toasymptomatic Unilateral orentire isswollen leg venous system along the ofthe tenderness distribution deep Localized &venous outflDVT obstruction ow symptomatic w/ proximal extension ofthe butbecomes Patients are DVT generally w/acalf asymptomatic vein adeep clot inwhich blocking there isablood A frequent manifestation ofVTE © MIMS toeff secondary & also ofchemotherapeutic agentsects ahypercoagulableCancer produces also state malignant duetothe cells by procoagulant produced activity for VTE whoare patients at tosurgical given risk in Asia shouldbe Studies thatprophylaxis show appropriate VTE Venous Thromboembolism-Management(2of21) VENOUS THROMBOEMBOLISM (VTE) 1 DEEP VEIN THROMBOSIS (DVT) B206 © MIMS 2020 VTE - MANAGEMENT • • ofthrombosis severity fi or Clinical ofthepresence predictors butarepoor ofDVT tothediagnosis areimportant ndings • • VenousDuplex (DUS) Ultrasonography • • • Assay ELISA by Level D-dimer • TestsDiagnostic • Diff Diagnosis erential thrombophilia testing. https://www.nice.org.uk/guidance/ng158. 26 Mar 2020. https://www.nice.org.uk/guidance/ng158. 26Mar thrombophilia testing. management and *National diagnosis, Institute Excellence forHealth andCare Venous (NICE). diseases: thromboembolic 2013. treatment. January 13th ed. Modifi Institute Systems and from: forClinical diagnosis Improvement.ed guideline:venous Health care thromboembolism - excluding of DVT the diagnosis probability (w/compression) pretest ofclinical &duplexUS use iseffCombined inconfiective or rming Pretest probability is needed to guide the diagnostic process process the diagnostic toguide probabilityPretest isneeded isincomplete US by vein compressibility toestablish the presence criteria ofDVT diagnostic eprimary - - - ofproximal DVT forthe evaluation device radiologic Primary interrogation Doppler (eg &pulse-wave B-mode, 2D)imaging - evaluation radiologic forfurther the need todetermine duplexUS anegative after used be Can - are notcurrently takinganticoagulants & in patients settings w/ recentwho care ofsymptoms in ambulatory onset patients, in ED useful is is most - in conjunction when for imaging used thus w/ probability,clinical the reducing need VTE plethysmography, or US (<500ng/mL) assay ELISA by D-dimer level Normal - - butnonspecifiA highlysensitive forthe test presence ofVTE c screening Superficial thrombophlebitis - - (Baker’s cyst) cyst Ruptured popliteal - Cellulitis - lymphedema Lymphangitis, - leg inparalyzed swelling Leg - Muscle strain,rupture ortear - including the following: diff mustSince be are pain&swelling common presenting DVT complaints, erentiated other from causes hepatic function assessment, prothrombin time (PT) & activated partial thromboplastin time (aPTT) time(aPTT) thromboplastin partial &activated prothrombin time(PT) assessment, hepatic function when initiating anticoagulation tests renal & blood treatment count acomplete includes Baseline blood (CBC), Alte current palliative therapy) Active cancer (ongoing treatment 6months the within last or DVT documented Previously recent extremity oflower immobilization plaster paresis, Paralysis, 12weeks for≥3days within Immobilization ormajor surgery Collateral superficial veins (non-varicose) inthe (greater Pitting symptomatic leg) edema distribution venous system alongthe tenderness deep Localized tibialtuberosity) 10 cm below >3cmcompared by swollen side (measured totheCalf asymptomatic Entire swollen leg Clinical Features calf thrombosis or venography for suspected proximal in3-7days thrombosis orvenography thrombosis calf forsuspected In patients suspicionofDVT, w/ clinical consider forsuspected US D-dimer US, repeat &negative positive favorable results for calf vein & asymptomatic DVT vein &asymptomatic forcalf favorable results &specifi highsensitivity avery Has butless insymptomaticpatients, proximal DVT city fordiagnosing inpatients probability w/moderatepretest or highclinical DVT todiagnose test non-invasive used often Most & therefore patients inthese isnotuseful in<10%ofpatients butisnormal In elderly value the predictive orinpatients, D-dimer ahighnegative retains develop symptoms orprogressive new unless testing further without upclinically followed be &can DVT ofsubsequent risk low orhave a very DVT D-dimer &anegative are assay considered tohave probabilityPatients no pretest clinical ofDVT w/alow inthe disease rule to used be &cannot erefore, forDVT value highconcentration predictive positive apoor ofD-dimer has pregnancy, etc trauma, cancer,s, inpatients w/MI,sepsi elevated may be D-dimer infl levels also ecrosis, n ammation, infection, Venous insuffi ciency - Proximal & distal compression ultrasound for DVT has 90.3% sensitivity &97.8%specifi 90.3%sensitivity has Proximal &distalcompression forDVT ultrasound city - rnative diagnosis as likely orgreater than as thatrnative diagnosis ofDVT © MIMS WELLS SCALEOFCLINICALPRETESTPROBABILITYFORDVT Venous Thromboembolism-Management(3of21) 2 DIAGNOSIS B207 has a high negative predictive value & is useful to rule out out torule &isuseful value predictive ahighnegative has Points -2.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 Unlikely Likely Simplifi version*: ed side severe the more score symptomatic, are legs If both risk Low Moderate risk High risk Probability Pretest Points Total 1-2 ≥2 ≤0 ≥3 <2 © MIMS 2020 VTE - MANAGEMENT • • • Result: Probability Pretest Tests onClinical Diagnostic based Recommended • • Tomography Computed Spiral (sCT) • • Plethysmography • • • (MRI) Imaging Resonance Magnetic • • VenographyContrast • VenousDuplex (Cont’d) (DUS) Ultrasonography High pretest probability: Proximal venography w/compression, DUS probability: US, High pretest whole-leg D-dimer, probability: Moderate pretest proximal w/compression, DUS venography, US whole-leg D-dimer, probability: pretest Low w/compression, DUS venography, US whole-leg Visualizes &common, proximal superfi obstructions femoral veins cial &deep inpatients swelling w/leg tissuediseases &other soft ofDVT forthe promise diagnosis shown Has eff tobe for10-14days appears w/IPG testing Serial patients DVT w/extending calf foridentifying ective - - Impedance Plethysmography (IPG) - toperform Rapid &easy - straingauge plethysmographyComputerized proximal DVT tothat accuracy forassessing ofUS asimilardiagnostic Has fi inpatientsdeferred w/suspected extremityrst lower DVT shouldbe veins; orpelvic vena &inferior cava ofthe thrombosis superior inpatientsUseful w/suspected improvement needs inthe MRI image scan, quality to CT butcompared function &right heart lungperfusion information about &functional morphological Provides fordiffi reserved Generally - cases cult diagnostic venous US by supplanted been has use its countries, Insome - - of anallergic reaction/venous thrombosis a smallrisk & carries possible technically not always procedure, Excellent but it is an invasive veins, for calf clots old&new help between distinguish Can - Off ofthe detail venous anatomyers precise &the ability toreliably exclude inthe thrombosis calf - egold standard ofDVT forestablishing the diagnosis - - &avoid testing more invasive disease diagnosing of toimprovea PElikely probability, clinical likelihood clinical used shouldbe w/DUS evaluation further angiography (CTPA) D-dimer & In patients computed &positive w/negative pulmonary tomographic results © (2%) thrombosis fiNormal important ofclinically PE(<1%)orrecurrent venous risk w/alow isassociated IPG nding w/serial DVT femoral, oriliacvein) &66% fordistal(calf (popliteal, vein) of90%forproximal DVT asensitivity shown Has thrombi ofsecondary vein contrast cannulation, &possibility foot use IV Other disadvantages patient include signifi cost, discomfort, cant resource availability, use, requirement for angiography pulmonary & potentially avoid unnecessary improve accuracy can diagnostic For probability incorporation of pretest clinical (CPTP) result, a negative of PE confi result A positive treatment &requires ofthe presence regardless orabsence ofDVT therms diagnosis Venous Thromboembolism-Management(4of21) 2 DIAGNOSIS (CONT’D)

B208 MIMS © MIMS 2020 VTE - MANAGEMENT 4 3 2 1 Interim therapeutic anticoagulation may be given while awaiting test result; use ananticoagulant use Interim continued that therapeuticanticoagulation be result; can ifPEisconfi whileawaiting test given may be rmed Perform CTPA D-dimer, inpatients Ifnegative, w/ahighprobability ofPE. performed. may be orduplexultrasound VQscan CTPA perform orbilateral duplexultra- isnon-diagnostic, IfVQscan CTPA. perform Ifnot, ifavailablePerform &feasible. VQscan forD-dimer inpatients fortesting w/alow the need todetermine used may be (PERC) Criteria Rule-Out Embolism Pulmonary sound of lower limbs. If positive, give anticoagulation. give Ifpositive, limbs. oflower sound probability ofPEpresenting inthe emergency department. EMBOLISM PE EMBOLISM PULMONARY PULMONARY Is D-dimer ALTERNATIVE ASSESSMENT DIAGNOSIS or negative? Negative 5 4 positive positive clinical pretest pretest clinical intermediate intermediate probability (unlikely) (unlikely) © Low Venous Thromboembolism-Management(5of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not 1 or Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Positive suggestive of pulmonary embolism (PE) embolism ofpulmonary suggestive Patient presents w/ signs & symptoms &symptoms w/signs Patient presents No Is massive/sub-massive Is massive/sub-massive pretest probability of probability pretest What is the clinical theclinical What is Non-massive PE Non-massive ASSESSMENT EVALUATION pulmonary angiography angiography pulmonary PE suspected? non-massive non-massive Is VQscan (CTPA) ASSESSMENT B209 MIMS PE? 5 4 3 No for PE? 3,4 5 C B positive positive 2,4 NOACs orWarfarin Parenteral anticoagulant or CT orCT • • • Fondaparinux or (UFH), Heparin Unfractionated or (LMWH), Heparin Low-molecular-weight Yes Massive/sub- massive PE massive D High (likely) (likely) High probability Yes Yes Follow-up clinical clinical pretest pretest TREATMENT See next page See © MIMS 2020 VTE - MANAGEMENT F • orShock Syncope • Dyspnea Isolated • Pain Chest Pleuritic • • Typical &Symptoms Signs • rombolysis - repercussions isthe hemodynamic Syncope ofcentral orshock hallmark sign insevere PE& usuallyresults - painthat chest angina-like probably w/substernal is representing RV ischemia associated May be - Usually duetoamore central PE(notaff the pleura) ecting - may dyspnea occur suddenly weeks) orprogressively (overIsolated several irritation pleural the that distallynear pleura causes also May located suggest asmallembolism - isoneofthe frequent presentations most dyspnea painw/orwithout chest Pleuritic ofPE hypoxemia ofpostoperative incases suspected PEshouldbe - - frequent sign most whiletachypnea isits isthe frequent symptom, most Dyspnea - ofPE rate ≥20/minute) cases occur inmost &tachypnea (respiratory pain,syncope chest pleuritic Dyspnea, fi Clinical are nonspecifindings - PE todiagnose the onlycriteria c &shouldnotbe the by symptoms clinical Suspicion ofPEisusuallyraised &pelvis legs the veins inthe especially the from veins, clots intheusuallyduetoblood vessels lungs oftheBlockage blood • • hypotension, oliguria, cold ofacuteright HF) extremities signs &/orclinical oliguria, hypotension, compromise of hemodynamic Signs fl heart & reduced are usuallyow present also (eg arterial systemic disease Worsening maythe that only symptom dyspnea or pulmonary be PE in patients HF indicates w/ preexisting venous jugular pressure raised rub, pleural cyanosis, hypotension, wheezing, sound, heart fever, pulmoniccomponent increasing pain,apprehension, chest ofthe nonpleuritic 2nd rales, diaphoresis, Tachycardia that & symptoms present: Other may signs be rate >100/minute), (heart cough &hemoptysis, No or Urokinase Streptokinase Alternatives: Alteplase agent: Preferred Absolute contraindications contraindications Absolute to thrombolysis? © EVALU Venous Thromboembolism-Management(6of21) 4 Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not ATION Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Massive Massive E SUSPECTED MASSIVE/SUBMASSIVE PE MASSIVE/SUBMASSIVE SUSPECTED Yes PE 3 Prompt management of clinical instability Prompt management ofclinical PULMONARY EMBOLISM (PE) EVALUATION G Is massive PE Is massive confi rmed? Invasive procedures procedures Invasive • • B210 MIMS 4 directed treatmentdirected Percutaneous catheter- embolectomy Pulmonary Yes massive PE massive B Sub- No Bolus ofUFH Bolus • be considered be may rombolysis © MIMS 2020 VTE - MANAGEMENT • • • • • • • • • • • • Contraindications Relative • • • • • • • to Contraindications Absolute rombolysis • • • PE Low-Risk • • PE Sub-massive • Diff Diagnosis erential • • • • • &Symptoms Signs • PE Massive • • Evaluation Clinical • • Advanced liverAdvanced disease Oral anticoagulant therapy endocarditis Infective postpartum 1week orwithin Pregnancy Recent traumatic CPR ulcerActive disease peptic 10days the within last GI bleeding Ischemic 2months stroke the within last 1month the orophthalmologic within last surgery Neurosurgery DBP>100mmHg) (SBPUncontrolled >180mmHg, hypertension severe Puncture ofanon-compressible vessel Transient ischemic attack 6 months the within past diathesis) (bleeding forbleeding risk increased Known Active bleeding coagulationSevere disorders damage ortumors CNS Ischemic 6months stroke the within past surgery, 3weeks trauma, intheMajor past injury orhead at any origin time strokeHemorrhagic orstroke ofunknown stratifi risk suitable usingavalidated mined cation tool orconfiPatients w/suspected considered PEmay foroutpatient be low-risk treatmentrmed deter- being after biomarkers cardiac pressure &noelevated &right ventricular arterial function, PE that systemic w/normal presents Aff approximatelyects 70%ofpatients w/PE orBNP NT-proBNP troponin, Elevated - - PEpatientsSubgroup ofnon-massive whopresent w/the following: Occurs inapproximately 20-25%ofpatients MI massive pneumonia, dissection, aortic tamponade, cardiac Cardiogenic shock, - found at the bedside usuallybe can RV dysfunction unstable PEwhoare forlungimaging, too massive In patients w/suspected orhypoxemia distress (eg cyanosis) respiratory Severe Renal insuffi ciency, hepatic dysfunction Syncope mentation &altered - predominant sign isthe that support hypotension pressor requires arterial &systemic isusuallythesymptom prime Dyspnea Accounts for5-10%ofcases forVTE factors forrisk evaluated Patients be should also - - - strategy ofanappropriate &the importance selection inthe diagnostic results interpretation test ofdiagnostic Evaluating patient ofPEinanindividual the according likelihood tothe presentation clinical isofutmost toavoid ofPE suspicionisrequired clinical missingthe diagnosis A reasonable prognostic factors in patients who are hemodynamically stable inpatients factors whoare hemodynamically prognostic stratifi may be Acute PEseverity &imaging scores combined laboratory clinical, from usingvalidated ed or confi mortality ofearly w/ahighrisk those PEtoidentify rmed stratifi initialrisk It toperform isrecommended unstable patientscation w/suspected inhemodynamically necrosis BP,Normal ormyocardial ofRV dysfunction evidence orechocardiographic &clinical tissueperfusion normal w/ inspiration murmur regurgitationsthat veins jugular &systolic oftricuspid heave, distended increases parasternal Left ofshock orsymptoms w/signs (bpm) rate <40beats/minute heart absence orsustained ofpulse or orsepsis; hypovolemia arrhythmia, new-onset by notcaused inotropicminutes support) (or needing >15 Persistent isdefi hypotension BP(SBP) <90mmHgorapressure drop of<40mmHgfor asystolic as ned diff other PEfrom high-risk acutelife-threateningerentiate conditions suspected unstable doneinpatients may to be whoare hemodynamically transthoracic echocardiogram A bedside & comorbidity Index(PESI) identifi Severity Embolism ePulmonary thees patient's usingPEseverity risk mortality overall © Ascore of10.9%inthe a30-day risk simplifi of≥1indicates mortality - version ofPESI ed Venous Thromboembolism-Management(7of21) 4 EVALUATION

B211 MIMS © MIMS 2020 VTE - MANAGEMENT • • Wells Scale • ofPE Probability Pretest • Score Geneva • * incollaboration the with developed andmanagement embolism 2019 ESC Guidelines forthe diagnosis ofacutepulmonary 2013. treatment. January 13th ed. Modifi Institute Systems and from: forClinical diagnosis Improvement.ed guideline: venous Health care thromboembolism Eur J.2019Aug (ESC). Respir 31. ofCardiology the European Society (ERS): Society thewith European Respiratory eTask Force of andmanagement embolism forthe diagnosis ofacutepulmonary Modifi in collaboration developed andmanagement embolism 2019ESCGuidelines forthe from: diagnosis ed ofacutepulmonary European Society of Cardiology (ESC). Eur J.2019Aug (ESC). Respir 31. of Cardiology European Society (ERS): Society European Respiratory e Task Force ofthe andmanagement embolism forthe diagnosis ofacutepulmonary - Clinical probability may be estimated empirically or explicitly by a prediction rule probability empirically orexplicitly aprediction Clinical by estimated may be - 2. epresence factor ofamajor risk 1. eabsence explanation clinical ofanother reasonable Along w/2other features pain&/orhemoptysis) chest pleuritic without thatRequires the patient &/ortachypneaw/or features clinical suggestive ofPE(eg has breathlessness, All patients w/ possible PE should have clinical probability assessed &documented PEshouldhaveAll patients probability clinical w/possible assessed Requires arterial blood gas measurement radiograph &achest gas blood arterial Requires rule) score (Europe) &Wells probabilities ere ofPE:Geneva pretest are 2frequently used (Canadian scale Clinical signs & symptoms ofDVT &symptoms signs Clinical the past 4weeks the past for ≥3dayswithin Immobilization orsurgery Age >65years Previous DVT/PE Previous lentv igoi sls ieyta E3.0 likely isless Alternative than diagnosis PE Active cancer Hemoptysis Heart rateHeart ≥100bpm past monthpast Fracture the within orsurgery 6 months) (w/treatment the within last Malignancy 75-94bpm rateHeart ≥95bpm Hemoptysis nltrlpi nlwrlm 3 Unilateral painin lowerlimb palpation lower-limb venous deep Unilateral &painon edema orPE DVT Previous WELLS SCALEOFCLINICALPRETESTPROBABILITYFORPULMONARY EMBOLISM lnclFaue Points Clinical Features GENEVA CLINICAL PREDICTION RULE FOR PULMONARY EMBOLISM GENEVA CLINICALPREDICTIONRULEFORPULMONARYEMBOLISM © Clinical Features Venous Thromboembolism-Management(8of21) 1 2 2 3 5 2 4 3 5 ASSESSMENT Simplified Version Points B212 1.5 3.0 1.5 1.0 1.5 1.0 MIMS 1 PElikely 1 1 PE less likely PEless 1 High 1 Intermediate 2 Low 1 1 1 1 Based on likelihood ofPE onlikelihood Based According to risk groups torisk According Simplified Probability Version* Pretest 1 1 High 1 PElikely 1 Intermediate 1 1 PE less likely PEless 1 Low 1 According to risk groups torisk According Based on likelihood ofPE onlikelihood Based Unlikely Likely Simplifi version* ed Probability Pretest Points Total -02-4 4-10 1 ≥5 ≥11 - 0-2 0-5 - 0-1 0-3 ≥6 Simplified Version Points Total ≥3 2-6 ≤4 ≥2 >6 >4 <2 <2 © MIMS 2020 VTE - MANAGEMENT • • • • • • • D-Dimer • • Natriuretic Peptide &Troponin (BNP) B-type • • ECG • • • • X-rayChest • Gas Blood Arterial • • • • TestsDiagnostic • • • TomographicComputed (CTPA) Angiography Pulmonary • • (PERC) Criteria Rule-Out Embolism Pulmonary • • eg duplex US orCTPA duplex US eg studies w/ recent directly to radiologic or trauma surgery & should proceed VTE Inappropriate for suspected probability w/highclinical inthose ofPE performed D-dimer measurement shouldnotbe level D-dimer test Consider usinganage-adjusted cut-off oradapting probability toclinical analternative tothe as fi cut-offxed - toexclude PEadequately evaluation radiological D-dimer further requires A positive reliably orMDA methods excludes (Vidas) PEinpatients w/intermediate probability usingELISA result A negative probability, clinical w/ low such patients forVTE donotrequire imaging any (SimpliRED, via D-dimer D-dimerA negative test method Vidas orMDA) reliably excludes PEinpatients ofoutpatients inthe forevaluation emergency department used Best - - butanonspecifiA highlysensitive forthe test presence ofPE c screening namic instability in the absence even of mortality hemody- w/ RV strain & increased are associated & troponin BNP Elevated Consider inapatient fi orclinical w/substantial clot burden, abnormal echocardiogram suggestive ofPE ndings V1-V4) inleads waves right bundle or otherbranch of RV block may strain evidence (eg new show ECG T For inverted PE, massive tracing or anormal Can show right axis deviation, supraventricular S arrhythmia, deviation, right axis show Can the density diaphragm, above usuallysignifiHampton lump, wedge-shaped aperipheral infarction pulmonary es Westermark oligemia) may central (focal indicate massive sign occlusion embolic compromise PE ishighlysuggestive respiratory ofmassive w/severe Near-normal results radiographic vessels w/apaucity ofperipheral associated infi pleural-based May demonstrate atelectasis, ltrates oreff usions orrarely engorged artery central pulmonary Can show hypoxemia, hypocapnia & widened (A-a)O &widened hypocapnia hypoxemia, show Can ment, PT & aPTT &aPTT PT ment, assess- when renal initiating &hepatic anticoagulation function tests blood treatment aCBC, includes Baseline Multidetector computed angiography tomographic Multidetector (CTA) &96%specifi 83%sensitivity has city abnormal fi butsome normal be can results Lab the suspicionforPE increase ndings probability clinical of PE &generalassess condition ofpatient to are indicated X-ray chest gases (ECG), electrocardiography 1st-line eg blood tests &arterial diagnostic orD-dimer isnegative ifPERC tests imaging outwithout ruled be PEcan patients, In selected ventilation-perfusion isotope scanning isotope ventilation-perfusion inspecifi &issuperior anadjunct oralternative toother as modalities imaging used Increasingly city to PE forpatients the modality w/suspected initiallungimaging as Recommended the patient Does have unilateral at swelling leg the calves? - the patient Has 4weeks? ortrauma inthe hadsurgery previous - the patient ofVTE? Does have diagnosis prior - Isthe patient onexogenous estrogen? - the patient Does have hemoptysis? - Isthe patient’s <95%whilebreathing reading air? room oximetry pulse - Isthe patient’s rate >99bpm heart - Isthe patient >49years? - the patient If the inany positive: isPERC questions, yes patient ofthe answered following has ifadditionalinvestigations ofPE&todetermine forPEare warranted risk low at group very Use toidentify further diagnostic testing is needed isneeded testing diagnostic further probability, orintermediate pretest clinical w/low CTPA, A normal isconfi forPE&no negative rmed isneeded testing diagnostic further probability, w/intermediate pretest orhighclinical CTPA, A positive isconfi forPE&no positive rmed © &many infltrauma, age increasing well as as diseases ammatory cancer, disease, vascular peripheral infection, period, including postpartum obstetrics patients, hospitalized However, ofD-dimer do not confi levels raised are foundin such levels because therm presence of VTE patient ison Heparin manifestations &/orifthe is>2-3 totesting days ifthe prior duration ofVTE decreased may be Sensitivity Venous Thromboembolism-Management(9of21) 5 ASSESSMENT (CONT'D)

B213 MIMS 2 difference 1 Q 3 T 3 pattern sinus orP-pulmonale, tachycardia, © MIMS 2020 VTE - MANAGEMENT • • (MRA) Angiography Resonance Magnetic • • • • • Venous (US) Ultrasonography • • • • scan) Ventilation-Perfusion (V/Q Lung Scanning • • • • Angiography Conventional Pulmonary Tests Diagnostic Other • • • • • Echocardiography • • • • • TomographicComputed (CTPA) Angiography (Cont'd) Pulmonary for several years for several access & limited clots is likely for subsegmental sensitivity to continueIt a radiation poor avoids but has ionizing promising inhuman tobe &animalmodels appears MRA - (&PE) ofVTE the diagnosis inpatient demonstrating suspiciousforPEconfi aproximalA compression DVT (CUS) ultrasonography rms study lungimaging negative toimproveUsed estimation of the probability clinical ofPE&avoid inpatients testing more w/a invasive - VTE past from abnormalities residual ormay detect studies mayUS positive have false outPE notrule ofthe veins exam does leg US Normal PEpatients in suspected thus veins ofthe the legs from itisrational deep DVT foraresidual tosearch arise emboli pulmonary Most at islow <3% tests Rate ofnon-diagnostic - considered emission may ofPE computed for the be diagnosis also A VQsingle-photon tomography (SPECT) of PE incontext toestablish diagnosis suspicion the power ofreasonable predictive provide High probability scans incombination probability probabilityLow scans pretest makeprobability w/alow ofPElow are ornear-normal suffiNormal lungscans probability ofpretest cient regardless toexclude PE, diagnosis onpatient’s angiography may depend also Use ofpulmonary status clinical toobtainanabsolute &necessity available remain inconclusive forpatients tests orare inwhomnon-invasive not reserved Angiography shouldbe inter-observer there disagreement be clot, inupto1/3ofcases can W/subsegmental - risks ciated &interpretation,Limitations include &there inperformance requirement itisinvasive are asso- ofexpertise considered theHistorically gold standard ofPE forthe diagnosis therapy orhypotension present shock without ifthey confiIt not been has patients whowouldbenefi that identify can echocardiography rmed thrombolytic t from defi May also nitively confi - thrombi arterial ofproximal pulmonary visualization ofPEby diagnosis rm - - PE massive forrapidUseful triage inacutely illpatients w/suspected that found suggests another shouldbe ofshock angiogram cause orsCT lungscan Normal - are usuallyable toconfi (TEE) echocardiography transesophageal &bedside sCT Lung scan, diagnosis rm - adefi stabilized, If patient been has pursued shouldbe nitive diagnosis raphy findings onlyoncompatibleIf patient donebased echocardiog- treatment isunstable, be thrombolytic can orsurgery changes if acutePEisthe ofthe cause hemodynamic &RV overload hypertension ofacutepulmonary signs indirect shows which typically initialtest useful Most Patients w/ a good quality CTPA negative Patients w/agood investigation donotrequire ortreatment further forPE seen likelyis less tobe emain disadvantage ofCTPA tothat ofconventional angiography isthat clot subsegmental pulmonary ahighspecifiHas forcentralcity &sensitivity clots orasthma COPD forpatientsMore disease, w/underlying cardiac useful thatabnormalities might help toestablish analternative diagnosis parenchymal &may information about emboli provide ofthe pulmonary visualization Enables direct guide patient’sguide management confiIf PEwas proximal compression usingapositive ultrasonography,rmed consider to assessment risk oftherapy forthe start abasis as probability ahighclinical has ofPE)shouldserve Only defi but studies under certain circumstances clinical nite positive (eg ofVTE patient history without pressure arterial pulmonary ofincreased signs of Doppler May suggest/reinforce suspicionofPEw/the clinical fi inthe ofRV presencendings overload &dysfunction etc) dissection, aortic endocarditis, infective tamponade, pericardial AMI, Usually reliable to diff thaterentiate have illnesses diff radically between erent treatments compared to PE(eg

B214 MIMS © MIMS 2020 VTE - MANAGEMENT • • • • • • (GECS) Stockings Compression Elastic Graduated • Exercise • Ambulation Early • Elevation &Leg Rest Bed • • • • • Patient Education • • • • • • • • UFH • • &Low-Molecular-Weight (UFH) (LMWH) Heparin Heparin Unfractionated • • • General Heparin Regarding Principles erapy Some studies show the studies show ineffSome extremitylower cause skin damage also & they of GECS for prophylaxis ectiveness disease in patients artery Contraindicated w/peripheral w/caution inpatients syndrome w/postthrombotic used Should be - syndrome post-thrombotic at 1 tostart Recommended until aminimummonth of2 ofproximal DVT ofdiagnosis toprevent years pain &swelling of resolution faster &provides embolism pulmonary notincrease GECS combined ambulation w/early does continuousProvide fl stimulation ofblood &prevent dilation intheow ofvenous legs system Encourage patients confi exercise leg regular toperform toachair orbed ned inpatients w/acuteDVT when rest feasible bed over Preferred Aff subside until &tenderness ofthe the edema heart level above elevated extremity shouldbe ected itmay w/PE&discussing their assuage familiar publicmay emotional burdenLay notbe patients plentyAdvise todrink offluids w/patients issues lifestyle Discuss treatmentExplain optionstopatients the &discuss benefi &sideeff risks ts, ofanticoagulationects therapy ofgenetic predisposition disability the &about possibility oflong-term risk ofrecurrence risk of disease, & symptoms, signs its especially Educate patients DVT/PE, about &their families Most commonMost complication thrombocytopenia isHeparin-induced adjustment lab &dose w/close monitoring hospitalization requires typically UFH IV - disease totreat VTE used been rate mortality when has Studies UFH areduced have shown - Eff ects: renal inpatients failure w/severe LMWH over ispreferred UFH therapy Patients w/confi instability continuous given may PE&hemodynamic be w/thrombolytic infusion rmed UFH orundergoing procedures invasive receiving thrombolysis, risks, topatients given w/highbleeding be May also When ofeff rapid reversal required may be ect - Without instability PEpatients high-risk w/hemodynamic delay insuspected - For PE massive/sub-massive - a1st-dose As bolus - considered: shouldbe UFH treatment UFH IV inPEiswell-established <30 mL/min) monotherapy renal inpatientsIt orLMWH impairment UFH w/severe togive isnotrecommended (CrCl isappropriate orUFH Either forthe initialtreatment LMWH ofPE - short-course UFH &IV treatments confi SC LMWH are for objectively recommended Both PE non-massive rmed treatment DVT Same initial&long-term forasymptomatic isrecommended Treatment longer the site from could delayed surgical ifthere even be isany ofbleeding evidence - consultationafter w/surgeon If PE occurs postoperatively, until 12-24 therapy started & Heparin major should not be surgery hours after workup probability &inlow diagnostic patientsof PEduring once PEisconfi rmed Anticoagulation delay without administered shouldbe inpatients w/intermediate probability orhighclinical Use graduated compression,Use custom-fi graduated knee-high, 30-40mmHgonthe aff w/at least stockings tted leg ected control 24hours within are reached & when adequate levels value at arate the >1.5-2.5times that isunusual the prolongs when isinfused aPTT UFH Recurrence of VTE IV UFH has been proven eff been has UFH IV inthe therapyective ofPE&DVT B PARENTERAL ANTICOAGULANTS IN THE MANAGEMENT OF DVT DVT OF MANAGEMENT THE IN ANTICOAGULANTS PARENTERAL

© Venous Thromboembolism-Management(11of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing A NON-PHARMACOLOGICAL THERAPY & NON-MASSIVE PE & NON-MASSIVE

B215 MIMS © MIMS 2020 VTE - MANAGEMENT • ofDuration erapy • • • • Fondaparinux • • • • • • • LMWH • etexilate Dabigatran • Apixaban • • • • • • • (NOACs)Non-Vitamin Anticoagulants Oral KAntagonist • General Anticoagulant Regarding Principles erapy erapy C Warfarin &until isstable days therapeutic &≥2.0(range: INR 2.0-3.0)for2consecutive Treatment orFondaparinux LMWH, continued w/UFH, thedays shouldbe initiation 5-7 after of forat least Obtain aplatelet count oftherapy tothe prior start Warfarin 72hoursoftherapy usuallywithin isinitiated tomonitoreff used been (anti-factor assay Xa) has Heparin ofFondaparinuxects &PE initialtreatment apreferred Also forDVT treatment 2-3days ifLMWH iscontinuedthen every except platelet isnotrequired foraregular count monitoring Lab treatment before initiation &onthe 5th day, - - issafe,eff ofLMWH euse may stay hospital shorten ective, &improve the quality oflifeforpatients Warfarin toguide ofINR &formonitoring complications, therapy reserve, cardiorespiratory ofdecreased inthe because Patients treated hospital w/symptomaticPEshouldinitiallybe effi equal has A number that ofstudies have shown LMWH inpatients PE toUFH w/non-massive cacy treatment orFondaparinux PE orintermediate-risk LMWH oflow- forthe UFH over isrecommended acute-phase Kantagonists vitamin (VKA) over preferred Also - inpatients PE UFH over preferred isnow w/acutenon-massive LMWH - forthe initialinpatient possible whenever rather treatment used than UFH shouldbe ofDVT LMWH e been previously treated treated &PEinpatients previously whohav e been ofrecurrent &toreduce DVT risk for 5-10days, Approved forthe w/parenteral &PEinpatients management treated whohave been anticoagulant ofDVT treatment delay treatment when given there Heparin should be Prior isnotnecessary, is ofHeparin courses though short initialtreatment (dual after given Edoxaban w/Heparin shouldbe therapy) Apixaban are according &Rivaroxaban given approach tothe single-drug (monotherapy) whileDabigatran & topatients given May w/renal be impairment oractivecancer Studies suggest that have advantage NOACs asafety conventional over treatment patients therapy inAsian forVTE isnotrequired interactions &routine monitoring Drug are few treatment PE orintermediate-risk PEpatients ineligible oflow- forthe acute-phase VKA over Preferred - anticoagulantRecommended the orPEduring 1st3months agents oftherapy forpatients DVT w/leg oralanticoagulants direct as (DOACs) known Also Eg Apixaban, Dabigatran, Edoxaban, Rivaroxaban Treatment factors: risk which 3months orw/persisting isunprovoked after DistalDVT isstopped - Treat atransient by factor: risk provoked for6weeks DistalDVT - - - - managementFor orPE, of3months patients duration isrecommended w/DVT carefully screened for risk factors forhemorrhage factors forrisk screened carefully toincludeOutpatient stable extended patients shouldbe management w/stable PEwhohave been ofDVT concurrently given forpatients be w/activecancer May also orantiphospholipid w/aVKA syndrome - &coagulopathyin patients w/liver disease inpatients w/active cancer renal &considered used mayMonotherapy failure, orestablished be w/LMWH the during initialtherapy major bleeding &thefor risk mortality of reducing in terms for the to UFH initial treatment is superior ofDVT LMWH Treat anticoagulation w/extended activecancer syndrome: by orPEwhich orantiphospholipid isrecurrent antibody &provoked Proximal DVT 3-6 months Treat transient factor: w/anon-surgical risk orPEwhich for orassociated isunprovoked Proximal DVT ortrauma major Treatment that surgery by orPEprovoked istransient: Proximal 3months DVT after isstopped ORAL ANTICOAGULANTS IN THE MANAGEMENT OF DVT & NON-MASSIVE PE &NON-MASSIVE DVT OF MANAGEMENT THE IN ANTICOAGULANTS ORAL B PARENTERAL ANTICOAGULANTS IN THE MANAGEMENT OF DVT DVT OF MANAGEMENT THE IN ANTICOAGULANTS PARENTERAL

© Venous Thromboembolism-Management(12of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing & NON-MASSIVE PE (CONT'D) PE & NON-MASSIVE

B216 MIMS © MIMS 2020 VTE - MANAGEMENT • • • • • Warfarin • • • Rivaroxaban • • Edoxaban (NOACs)Non-Vitamin (Cont'd) Anticoagulants Oral KAntagonist • • • • • • • • Anticoagulant Oral • • LMWH C Patients w/ antiphospholipid antibody syndrome are toundergo recommended Patients syndrome w/antiphospholipid indefi antibody treatment nite VKA ofbleeding risk renal renal orincreased impairment, failure established Warfarin Enoxaparin considered may inpatients be ordose-reduced w/severe overlapping LMWH w/UFH, Kadministration w/vitamin easily reversed may be Overdose - - - isnoteff dose Bolus eff full therefore its 5daysective, toachieve at itrequires least ects therapy onday Start 1ofHeparin - reliably been confi has once VTE started Should only be rmed recurrence &complications toreduce theofVTE risk Warfarin &isused isaVKA analternative agent as forPEpatientsConsidered w/cancer toLMWH (except GIcancer) Xinhibitorthat factor toWarfarin isnon-inferior A direct inthe management ofacuteVTE additionalanticoagulation without Initial treatment PE&DVT forboth analternative agent as forPEpatientsConsidered w/cancer toLMWH (except GIcancer) 5-10 days w/parenteral &PEinpatients treated fortreatment whohave been anticoagulant used ofDVT May be for embolic pulmonary hypertension hypertension pulmonary embolic forchronic risk thrombo- &at whoare increased asymptomatic forPEsurvivors evaluation Consider further interactions drug & new changes adherence in hepatic or renal function, to therapy, & recurrent VTE, bleeding treatment preferences forpresence annually of upatPatients &checked treatment least receiving extended followed shouldbe other W/apersistent factor than syndrome risk antiphospholipid antibody - Have noidentifi orw/aminortransientable factor factor risk risk - anticoagulationExtended treatment considered patients inthe shouldbe w/anindexPEepisode: following - Patients up3-6months w/acutePEare tofollow recommended acuteepisode after - VTE oraprevious proximal DVT forrecurrence include factors Other strong aPE, risk - stoppinganticoagulation after rates at &5years 1year therapy have the recurrence highest VTE ofunprovoked episode &second w/persistent factors risk VTE Provoked switch toananticoagulantswitch w/adifferent otherofhypercoagulability ofaction,&address mechanism causes If anticoagulation patient's check treatment adherence occurs, failure totherapy, anticoagulant or increase dose - Symptomatic vein thrombosis calf Continue isolated x6-12weeks: - orcontinuing idiopathic Continue factor Recurrent, VTE x≥12months: risk - idiopathic Continue VTE 1st episode, x≥6months: - Continue w/transient 1st event x≥3months: factors risk - ofanticoagulationDuration &the ofevent coexistence factors: isdependent risk onthe ofprolonged type - Treatment w/oralanticoagulant management oflong-term isthe patients ofmost method preferred w/PE - anticoagulant therapy months oflong-term For forthe 1st6 patients used w/PE&cancer, &shouldbe VKAs over ispreferred LMWH ifthere istreatment increased may topresent failure dose be Dose - Treatment therapy toVKA unresponsive optionforpatients w/recurrent VTE to hemorrhage atoftherapy start patients &itpredisposes use noclinical ithas Warfarin as mg) isnotrecommended (>10 highloadingdose isstable readings therapeutic &>2.0(range: INR 2.0-3.0)in2consecutive that itisrecommended Warfarin us, therapy overlap w/parenteral anticoagulationdays until 4-5 at least require long-term anticoagulantrequire long-term treatment &therefore (20-50%)ofsymptomaticextension ofthrombus &/orrecurrentHave VTE ahighfrequency atransient without factor episodes VTE &≥1prior syndrome, inpatients recurrence w/activecancer, isseen forlong-term risk A high(>8%/year) antiphospholipid antibody high bleeding risk high bleeding Consider for indefi orpatients w/PE&cancer nite anticoagulation: without PE, of unprovoked 2ndepisode contraindicated orimpractical patients inwhomoralanticoagulants forselected indicated are may be orLMWH ofUFH doses Adjusted patients which, these After shouldreceive oralanticoagulant therapy indefinitely oruntil resolved cancer has ORAL ANTICOAGULANTS IN THE MANAGEMENT OF DVT & NON-MASSIVE PE PE &NON-MASSIVE DVT OF MANAGEMENT THE IN ANTICOAGULANTS ORAL

© Venous Thromboembolism-Management(13of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not D Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing FOLLOW-UP (DVT & NON-MASSIVE PE) &NON-MASSIVE (DVT FOLLOW-UP (CONT'D)

B217 MIMS © MIMS 2020

VTE - MANAGEMENT • • onVenous Registry Prevention Medical International Risk (IMPROVE) Bleeding romboembolism • • Aspirin • • Oral Anticoagulant(Cont'd) • • • Anticoagulation without Monitoring erapy • • • Anticoagulation during Monitoring erapy • • • • • • • • Anticoagulation during Factors Bleeding forMajor Risk Score Regularly monitor therapeutic levels toensure monitortherapeutic eff levels Regularly anticoagulationective inpatients weighing <50kgor>120 Score of≥7signifi risk bleeding increased es aconfi toassess Used patient’sned toinitiation prior oftherapy forbleeding risk tolerate oralanticoagulation inpatients orcannot prophylaxis whorefuse considered may VTE foranextended orSulodexide be Aspirin continued anticoagulantrefused therapy orPEwho inpatients considered proximalMay w/unprovoked forthe be DVT prevention ofrecurrent VTE contraindications the fi after given Apixaban be can or Rivaroxaban) rst 6 months & are Warfarin over preferred if without For tocontinue patients whoneed anticoagulant onextended therapy, (eg NOACs therapeutic orlow-dose agents &NOACs ForE patients VKA over ispreferred w/cancer LMWH VT - forpatients agents w/VTE are LMWH over preferred VKA - anticoagulant therapy agents forthe 1st3months are VKA over preferred NOACs oflong-term For orPE, patients DVT w/leg severe symptoms or risk factors ofextension factors orrisk symptoms severe without DVT forpatients distalleg issuggested w/isolated for2weeks legs ofboth imaging ultrasound Serial proximal PEwithout DVT leg involvement w/subsegmental D-Dimer), &those &positive ofmultiple veins, activecancer, ofVTE, inpatient persistent history factor, provoking status, proximal near veins, thrombosis of extension (eg factors orrisk symptoms &nosevere DVT forpatients distalleg Recommended w/isolated Target patients is2.5formost &3.0for patients INR w/recurrent VTE 4weeks then every 2weeks If stable, monitor every ofWarfarin weeks the therapy during 1stseveral weekly at least checked shouldbe INR Comorbid illness oftherapy monitoring Suboptimal Poor anticoagulant control Concomitant antiplatelet therapy Chronic hepatic &renal disease stroke noncardioembolic Previous GIbleeding Previous Age >75years 4.5 Active gastric or duodenal ulcer orduodenal Active gastric 4.5 2.5 Liver failure (INR >1.5); severe renal (GFR<30mL/min/1.73m failure >1.5);severe (INR failure Liver ofage ≥85years 2.5 3.5 1 40-84 years ofage; 40-84years male;moderate renal (GFR30-59mL/min/1.73m failure Central current rheumatic/autoimmune venous malignancy catheter; disease; 1 2 4 Bleeding event <3 months before consultation; thrombocytopenia (platelet count <3months event consultation; <50x10 before Bleeding thrombocytopenia 4 D

© Venous Thromboembolism-Management(14of21) FOLLOW-UP (DVT & NON-MASSIVE PE) (CONT'D) PE) &NON-MASSIVE (DVT FOLLOW-UP Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing Medical History B218 MIMS 2 ); ICU/CCU admission ); ICU/CCU 2 ) 9 © MIMS 2020 /L)

VTE - MANAGEMENT • • Inhalation Oxide Nitric • O • • PE Massive • • • • • General Principles erapeutic • • Epinephrine • • Dopamine • • Dobutamine • • Agonists Adrenergic • • Loading Fluid Support Hemodynamic • • • VentilationMechanical • • Norepinephrine • • 2 Supplementation risk vs benefi vs risk lifeexpectancy &≥1-year ofbleeding risk low status, functional good of<14days, t) w/symptoms (weigh therapyCatheter-directed considered thrombolytic may inpatients iliofemoral be DVT also w/massive Eff ects: &apatent hypertension foramen inpatients ovale indicated w/pulmonary May be evaluation further needs agents Dobutamine Combination eg w/other vasoactive resistance &right ventricular pressure vascular pulmonary output, pressure, cardiac contractility)cardiac blood systemic inimproved resulting rather than β - Massive hemodynamically signifi hemodynamically Massive orprofound hypoxemia hypotension cant systemic PEwithout - Free-floating right ventricular thrombus echocardiography orpatent by documented foramen ovale - oxygenation Compromised - therapy considered may inpatients be rombolytic also w/the following: - therapy individualized ofthrombolytic inPEshouldbe euse whoare symptomatic for6-14days inthose used be Treatment the benefi most provides onset 48 hoursofsymptom within started still though can thrombolysis t, ere were outcomes relevant noclinically fordeath rate ofsymptoms orforthe resolution - agentspatients thrombolytic whoreceived &anticoagulant agents conventional over anticoagulant agents alone Studies amore have rapid PE improvement shown inacutemassive abnormalities &hemodynamic in radiographic treatmentthrombolytic onanticoagulation deterioration Patients w/ hemodynamic therapy are toundergo recommended rescue PEpatients therapyHigh-risk are toreceive thrombolytic recommended systemic VasoconstrictorAction: eff inotropic eff similar to Norepinephrine, ect more due to potent β ect effMay be complicates when shock ective acutePE the by development oftachycardiaUse limited may be inPEpatients support forhemodynamic used been also Has right-sided fiwhile decreasing lling pressures Action: 1st-lineConsidered agent totreat right-sided &cardiogenic HF shock considered should be &/orNorepinephrine Dobutamine PEpatients, In high-risk BPorw/impending hypotension index&normal cardiac consideredShould forpatients be w/low ispresent hypotension when systemic harmful May be - offl eusefulness uid challenge iscontroversial 15-30minutes 500mLover &shouldnotexceed initially&cautiously, administered Fluids may be therapy shouldpromptly butother vasoactive follow ofapproximately tidalvolumes weightLow are recommended 6mL/kgbody - eff adverse hemodynamic taken tolimit its shouldbe Care ects inpatients toxic temporarily &hypoxic whoappear needed May be Stimulates both α-adrenergic (inducing vasoconstriction) &β StimulatesAction: α-adrenergic both (inducingvasoconstriction) appropriate PEwhenMay there cardiogenic be inacutemassive eg shock isprofound hypertension, Hypoxemia can usually be reversed w/ nasal O w/nasal reversed Hypoxemia usuallybe can inpatients w/hypoxemia necessary May be Patients w/ hemodynamically unstable PE who are at low risk of bleeding are the appropriate most unstable candidates PEwhoareofbleeding Patients at risk low w/hemodynamically Positive intrathoracic ventilation mechanical inducedpressures by may reduce venous &RV return worsen failure Aff ects vasodilatation of both systemic & pulmonary vascular beds, increases myocardial contractility myocardial Aff increases beds, vascular &pulmonary systemic ofboth vasodilatation ects May exchange improve status the &gas hemodynamic inpatients w/PE 2 eff resistance accounting vascular ect, pulmonary forimproved E PROMPT MANAGEMENT OF CLINICAL INSTABILITY F

© Venous Thromboembolism-Management(15of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not THROMBOLYSIS PE INMASSIVE/SUB-MASSIVE Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing 2 so that ventilation so mechanical israrely necessary

B219 MIMS 1 -adrenergic (augmenting receptors 1 stimulation © MIMS 2020 VTE - MANAGEMENT • • orUrokinase Streptokinase • • (rt-PA)Alteplase Agents rombolytic • PE Sub-massive • • • • VenaInferior Filters Caval Vena Interruption Caval • • VenousSurgical rombectomy • VenousPercutaneous rombectomy rombectomy • • Embolectomy Pulmonary • • Extraction Catheter • May consider fi the removing IVC &isnolongerlter contraindicated established ifanticoagulation been has - 12 hours of Urokinase have equivalent thrombolytic effi have12 hoursofUrokinase thrombolytic equivalent to24hoursofStreptokinase cacy alone w/Heparin 24 hours&3xthat seen as 2agents eff ese have similarthrombolytic PEcomparatively toresolve shown inPE&have at been ects administration shorter time ofits agent thrombolytic Preferred because duration (2hours) forashorter administered be comparable butcan &Urokinase Has capacity toStreptokinase thrombolytic - iscontroversial ofRV dysfunction) evidence stable patients inpatients w/echocardiographic PE (hemodynamically w/sub-massive ofthrombolytics euse Should not be used routinely in patients w/ DVT who are also being treated w/anticoagulants treated being whoare also routinely inpatients used Should w/DVT notbe thromboendarterectomy orpulmonary embolectomy surgical after indicated May be hypertension patients w/chronic w/pulmonary recurrent embolism considered inpatients be May also whosuff adequate anticoagulant despite er recurrent therapy from VTE & patients w/large, free-fl anticoagulation during thrombusoating orw/aPEthat therapy iliocaval developed patients w/contraindication consideredShould inDVT/PE be orcomplication ofanticoagulant therapy &in therapy patients ese have extensive &have venous thrombosis contraindications foranticoagulation &thrombolytic morbidity &post-thrombotic inpatients acutesymptoms Reduces w/acute iliofemoral DVT thrombectomy alone w/percutaneous treated shouldnotbe Patients w/acuteDVT - &resuscitation instability Heparin despite Hemodynamic - PE(preferably documented) Massive angiographically - patients: forthe following reserved Should be have inemergency failed Performed situations measures when more conservative therapy thrombolytic timetoinfuse notallow that status critical itdoes or whose isso forhighlycompromised patients therapy receive whocannot thrombolytic isapproach reserved shouldbe Catheter extractioninvolves the suctionextractionofPEunder fl monitoring w/ECG uoroscopy consideredmay incombination be w/acatheter-directed treatment embolectomy orsurgical collapse, membrane oxygenation extracorporeal circulatory (ECMO) In patients orrefractory arrest w/cardiac treatment traditionalanticoagulant over therapy patients inthese improvement relevant aclinically toshow Further inthe benefi are studies needed t-risk ratio ofthrombolytic to its use use to its therapy patients deteriorating ofthrombolytic orcontraindication w/failure PEorhemodynamically High-risk F THROMBOLYSIS PE(CONT'D) INMASSIVE/SUB-MASSIVE

© Venous Thromboembolism-Management(16of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing G INVASIVE PROCEDURES

B220 MIMS © MIMS 2020 VTE - MANAGEMENT Apixaban Factor XaInhibitors Direct (Fondaparin) Fondaparinux Edoxaban Drug ANTICOAGULANTS, ANTIPLATELETS &FIBRINOLYTICS (THROMBOLYTICS) Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products 7.5 mg body50-100 kg wt 24hrly30 mg PO Ketoconazole) are given Erythromycin, Dronedarone, (Ciclosporin, w/ another anticoagulant or treatment forDVT/PE completion of6mth To following initiated be 12hrly 2.5 mgPO &/orPE: DVT ofrecurrent Prevention 10mgPO dose: Max 12hrly PO 5mg dose: Maintenance 20mgPO dose: Max 12 hrly x 7 days 10mgPO dose: Initial Treatment orPE: ofDVT established until oralcoagulation is Continue for5-9days or SC 24hrly body>100 kg wt 24 hrly 5mgSC wt: <50 kgbody Treatment &PE: ofDVT inhibitors ofP-gp use orconcomitant kg body wt, 15-50mL/min),(CrCl ≤60 renalsevere impairment Patients w/moderate or 5 days anticoagulant forat least ofparenteralinitial use 24hrly following mg PO &PE: 60 DVT recurrent of & prevention Treatment &PE of DVT placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All

© Venous Thromboembolism-Management(17of21) SC24hrly Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Dosage Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing : 10mg : Dosage Guidelines • • • • Instructions Special • Reactions Adverse • • • • Instructions Special • Reactions Adverse • • • • Instructions Special • • Reactions Adverse therapy &thereafter totreatment prior &CrClatPerform of the LFT start impairment, concomitant aff ofmedicines use hemostasis ecting renal impairment, mildormoderate hepatic moderate orsevere ofbleeding, risk Use w/caution inpatients w/ anincreased centralopen catheter venous orarterial tomaintain an necessary therapy at orwhenisgiven doses UFH anticoagulants except oralanticoagulant when switching HTN,uncontrolled concomitant severe treatment w/any other w/coagulopathy risk, bleeding disease relevant &clinically hepatic orconditions at formajor bleeding, risk bleeding inpatientsContraindicated signifi w/clinically cant active monotherapyEdoxaban as 15mgisnotindicated pruritus) rash, &gammaglutamyltransferase, bilirubin Other eff(nausea); (abnormal LFT, blood ects increased Hematologic eff hemorrhage); GIeff (anemia, ects ect hepatic impairment renal impairment, severe malabsorption, glucose-galactose Use w/caution inhipfracture surgery, intolerance, galactose impairment ofneurological Monitor forsigns Discontinue hemorrhage insevere use risk bleeding relevant w/coagulopathy hepatic disease &clinically bleeding, in patientsContraindicated signifi w/clinically cant active eff (nausea) ect Hematologic eff hemorrhage, contusion); (anemia, ects GI end oftreatment &at at isrecommended ofplatelets the baseline Monitoring for thromboprophylaxis inpatientsemployed anticoagulated anticoagulated ortobe benefi vs Consider risk intervention is neuraxial t before of HIT,impairment, w/history elderly >75yr patients hepatic w/moderate renal impairment, severe <50 kg, w/caution inpatients use brain, spinalorophthalmic surgery; acute GIulcer, recent intracranial hemorrhage, after orshortly ofhemorrhage; risk Use w/ caution inpatients w/anincreased renal impairment w/confi orinthose HIT rmed Avoid inpatients signifi w/clinically severe cant bleeding, allergic Rare reactions pruritus); (rash, eff constipation, Dermatologic diarrhea); dyspepsia, ects eff CV headache); GIeff (hypotension); ect (N/V,ects commonLess eff eff CNS ects: (vertigo, dizziness, ects Other eff(fever); (edema) ect Hepatic eff purpura); anemia, eff CNS (abnormal LFT); ect ect Hematologic eff (hemorrhage, thrombocytopenia, ects

B221 MIMS Remarks © MIMS 2020 VTE - MANAGEMENT ANTICOAGULANTS, ANTIPLATELETS &FIBRINOLYTICS (THROMBOLYTICS) (CONT’D) Reteplase (rt-PA) Alteplase Enzymes etexilate Dabigatran Direct Inhibitor rombin Rivaroxaban Factor (Cont’d) XaInhibitors Direct Drug the start of1st injthe start once, 30minafter dose May repeat symptoms of the onset after 1-2min over IV slow via 10 units Treatment ofPE: 1.5 mg/kg dose: total max Patient <65kg 2hr over infusion 90 mgIV Followed by: 1-2 min over bolus anIV 10 mgas dose: Loading 12 hrly 150 mgPO &/or PE: DVT recurrent of Prevention anticoagulation) parenteral 5-10 days of 12 hrly (after PE: 150mgPO &/or DVT Acute Treatment of 20 mg/day dose: Max 24hrly PO onwards: 22 Days 30 mg/day dose: Max 12hrly PO 1-21:15mg Days &PE: DVT Treatment of Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All Dosage

© Venous Thromboembolism-Management(18of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not 20 mg Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing • • Instructions Special • Reactions Adverse • Instructions Special • • • • Reactions Adverse • • • Instructions Special • Reactions Adverse • • Instructions Special • Reactions Adverse Dosage Guidelines arrhythmias, cholesterol embolism arrhythmias, hepatic/renal impairment, severe hypertension, GU bleed, Use w/caution inpatients w/recent major surgery, recent CVD, GI/ contraindications management page 7ofthis forspecifi chart disease See c thrombosis) bradycardia, pericarditis, hypertension, (hypotension, Hematologic eff eff CV (hemorrhage, intracranialects bleeding); ects S prophylaxis forHeparin need hence elsewhere emboli the cause mayBreak-up ofclots occasionally ofreperfusion may & arrhythmias bradycardia occur because reperfusion), of aresult &as direct (both w/hypotension associated may be Infusion symptoms) anaphylactic sickness-like &serum fl Allergic (rashes, reactions Rarely: &rarely urticaria ushing, eff (N/V,ects eff pain);CNS abdominal (fever) ect GI intracranial hemorrhage occurred); has internal bleeding, severe Hematologic eff f (hemorrhage especially ects Discontinue inpatients acuterenal use failure whodevelop lumbarpuncture anesthesia, spinal/epidural risk, hemorrhagic Use w/caution inhepatic impairment, renal insuffi ciency, increased replacement valve prosthetic heart Ketoconazole, 6mth, the last significlinically (including stroke hemorrhagic within cant bleeding hemostatic impairment, atpharmacological organ of lesions risk patients or w/spontaneous diathesis, bleeding manifestations, renal in patientsContraindicated impairment, hemorrhagic w/severe discharge) postprocedural Otherabnormal hepatic function); eff (woundsecretion, ects N/V, gastroesophagitis, GIhemorrhage, pain,diarrhea, abdominal Renal effthrombocytopenia); (hematuria);ect GIeff (dyspepsia, ects Hematologic eff hematoma, (hemorrhage, anemia, ects intolerance, renal impairment w/moderate tosevere &those or galactose lactose Use w/caution inpatients risk, w/hemorrhagic ofbleeding risk torelevant lead can w/coagulopathy associated that lactating &hepatic disease pregnant, in patientsContraindicated signifi w/clinically cant activebleeding, hemorrhage) postprocedural edema, peripheral eff Dermatologic (nausea); Other eff rashes); (pruritus, ects (fever,ects eff CV syncope), headache, GIeff hypotension) (tachycardia, ects ect Hepatic eff ALT eff (increased ect CNS &AST); (dizziness, ects Hematologic eff hemoglobin); decreased (hemorrhage, anemia, ects ee page 7 of this disease management page 7ofthis forspecifiee chart disease c contraindications

B222 MIMS patients onconcomitant therapy w/systemic Remarks rom puncture sites, rom puncture sites, © MIMS 2020 VTE - MANAGEMENT ANTICOAGULANTS, ANTIPLATELETS &FIBRINOLYTICS (THROMBOLYTICS) (CONT’D) Streptokinase (Cont’d)Enzymes sodium Bemiparin Group Heparin Urokinase nxprn1.5mg/kg(150anti-Xa iu/kg)SC Enoxaparin sodium Dalteparin Drug Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed aPTT is<100sec aPTT orwhen infusion Streptokinase 3-4hrafter Heparin Begin thrombolysis for long-term x12-72hr infusion 0.1 MIU/hrIV short-term or thrombolysis x6hrfor infusion 1.5 MIU/hrIV Followed by: 30min over 250,000 iuIV dose: Loading to a max of3mthto amax 3,500IU/day SCup factors: risk &transitory Patients w/DVT >120 kg:115IUanti-Xa/kg/day 100-120 kg:12,500IUanti-Xa 70-100 kg:10,000IUanti-Xa 50-70 kg:7,500IUanti-Xa <50 kg:5,000IUanti-Xa days to: which corresponds anti-Xa/kg/day 7±2 SCduring Treatment ofDVT:115IU loading dose a donotgive isused, Heparin the control normal If value. to<2x decreased has once aPTT Anticoagulation started shouldbe 12-24 hr x infusion 4400 iu/kg/hrIV Followed by: 10 min over in15mLsoln 4400 iu/kgIV dose: Loading 12 hrly 1 mg/kg(100anti-Xa iu/kg)SC 24 hrly 18,000iu/day dose: Max continuous infusion IV 12hras 100 iu/kgover or ofbleeding risk w/ increased 100 iu/kgSC12hrly forpatients 200 iu/kgSC24hrly or & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All

© Venous Thromboembolism-Management(19of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not or Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing Dosage Dosage Guidelines

B223 MIMS • • Instructions Special • • • • Reactions Adverse • • • • Instructions Special • Reactions Adverse - Recommend not to administer Streptokinase Recommend nottoadminister Streptokinase - may resistance cause or antibodies ese - use Streptokinase 5daysabout after after are formed antibodies Anti-streptokinase specific contraindications management page 7ofthis for chart disease See thanw/ Urokinase w/Streptokinase likely allergic less may tooccur reactions Serious be elsewhere emboli cause mayBreak-up ofclots occasionally ofreperfusion mayarrhythmias occur because & bradycardia ofreperfusion), aresult &as direct (both w/hypotension associated may be Infusion occurred has syndrome Guillain-Barré chills w/ back pain);GI eff &abdominal (N/V); ects Other eff symptoms); sickness-like serum (fever,ects fl(rashes, &rarely anaphylactic urticaria & ushing, Allergic reactions hemorrhage occurred); has intracranial internal bleeding, severe puncture sites, Hematologic eff from (hemorrhage especially ects & periodically during treatment during & periodically at isrecommended ofplatelets baseline Monitoring anticoagulatedor tobe forthromboprophylaxis intervention inpatients isemployed anticoagulated benefi vs Consider risk neuraxial t before toHeparin hemorrhage, hypersensitivity renal at at for impairment, sites surgery risk uncontrolled hepatic or hypertension, disorders, ulcer, peptic thrombocytopenia), cerebrovascular ofHeparin-induced disorders (including history Use w/ caution inpatients w/hemorrhagic or ears the specifi eyes toCNS, orsurgery injury c heparin, forantiplatelet test to in vitro antibody w/ positive patientsAvoid inpatients w/activemajor bleeding, alopecia) (osteoporosis, use may occur w/long-term Eff (anaphylaxis); reactions hypersensitivity that ects Inj Rare sitereaction; thrombocytopenia); Hematologic eff (hemorrhage, ects used) may be notincluding Anistreplase thrombolytic mth days-12 1stadministration5 (alternative after Streptokinase of doses tosubsequent hypersensitivity Remarks © MIMS 2020 VTE - MANAGEMENT ANTICOAGULANTS, ANTIPLATELETS &FIBRINOLYTICS (THROMBOLYTICS) (CONT’D) • • • Tinzaparin sodium Heparin) (Unfractionated Heparin (Cont’d) Group Heparin Sulodexide 250-500 mg PO 12hrly or 250-500mgPO Sulodexide 6400anti-Xa iuSC12hrly x7-10days sodium Reviparin Parnaparin calcium Nadroparin UFH (UNFRACTIONATED HEPARIN) INFUSION RATE ACCORDING ADJUSTED TO Dose adjusted based onaPTT: based adjusted Dose therapeutic range once itisoutside dailyunless monitoraPTT ereafter - dosage accordingsubsequent toaPTT 6 Monitor aPTT hrly forthe 1st24 therapeutic within range (1.5-2.3xcontrol) aPTT &adjust hr tokeep 80 u/kgIV, 18 u/kg/hr dose: infusion IV Loading by followed • • • • • Drug aPTT <35 sec (<1.2 x mean normal) Give 80 u/kg IV bolus, then increase infusion rate infusion then increase bolus, 80u/kgIV Give normal) (<1.2xmean <35sec aPTT aPTT 35-45 sec (1.2-1.5 x mean normal) Give 40 u/kg IV bolus, then increase infusion rate infusion then increase bolus, 40u/kgIV Give normal) (1.2-1.5xmean 35-45sec aPTT PT4-0sc(.-. ennra)Nochange normal) (1.5-2.3 xmean 46-70sec aPTT aPTT 71-90 sec (2.3-3 x mean normal) Decrease infusion rate 2u/kg/hr by infusion Decrease normal) (2.3-3x mean 71-90sec aPTT aPTT >90 sec (>3 x mean normal) Stop infusion for 1 hr then decrease infusion rate infusion for1hrthen Stop decrease infusion normal) (>3xmean >90sec aPTT Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All SC 8 hrly (adjust dose based onaPTT) based SC 8hrly (adjust dose 15,000uSC12hrly UFH: or 10,000u SC or onaPTT) based (adjust dose 24hr over given 20,000-40,000uIV Followed by: 5000uIV dose: Loading or onaPTT) based (adjust dose infusion 15-25u/kg/hrIV Followed by: PE: 10,000uIV forsevere dose Loading 5000uIV dose: Loading infusion: IV UFH or nomogram on Wt-adjusted based dosing 171 anti-Xa iu/kg24hrly or 85 anti-Xa iu/kgSC12hrly forupto10days 175 anti-Xa iu/kgSC24hrly 24hrly IM/IV 600 LSU x 5-7days w/anoralanticoagulant given tobe Doses >60 kg:6300anti-Xa iuSC12hrly 46-60 kg: 35-45 kg:

© Venous Thromboembolism-Management(20of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing 4200 anti-Xa iuSC12hrly 3500 anti-Xa iuSC12hrly Dosage Dosage Guidelines BODY WT &APTT WT BODY

B224 MIMS by 4u/kg/hr by by 2u/kg/hr by by 3u/kg/hr by • • • • Instructions Special • • Reactions Adverse baseline & periodically during treatment during &periodically baseline at isrecommended ofplatelets Monitoring for thromboprophylaxis anticoagulated anticoagulated ortobe intervention inpatients isemployed benefi vs Consider risk neuraxial t before toHeparin hemorrhage, hypersensitivity at at for impairment, sites surgery risk hepatic orrenalhypertension, uncontrolled cerebrovascular disorders, ulcer, peptic thrombocytopenia), ofHeparin-induced history disordershemorrhagic (including Use w/caution inpatients w/ orears eyes CNS, specifi to orsurgery injury c heparin, forantiplatelettest tothe antibody in patients vitro w/positive bleeding, Avoid in patients w/activemajor N/V, Cap: epigastralgias diarrhea, - Sulodexide alopecia) (osteoporosis, use long-term Eff(anaphylaxis); that mayects occur w/ reactions hypersensitivity Rare Inj sitereaction; thrombocytopenia); Hematologic eff (hemorrhage, ects Remarks © MIMS 2020 VTE - MANAGEMENT 1 Combination of Aspirin 100 mg&Glycine 45 mgisavailable. SpecifiCombination ofAspirin information foundinthe may latest MIMS. be c prescribing ANTICOAGULANTS, ANTIPLATELETS &FIBRINOLYTICS (THROMBOLYTICS) (CONT’D) Aspirin Inhibitorexcluding Heparin Aggregation Platelet acid) (Acetylsalicylic Warfarin Vitamin KAntagonist Drug 1 Products listed above may not be mentioned in the disease management chart but have been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults & non-elderly All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All 24 hrly DVT: against Prophylaxis 2-10 mg/day dose: Maintenance range 2.0-3.0) =2.5(INR target INR to adjusted should be that dose subsequent Followed by 24hrly x2days PO/IV 5-10mg dose: Initial

© Venous Thromboembolism-Management(21of21) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not 100 mg PO 100mgPO Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing Dosage Please see the end of this section for the reference list. reference the for section this of end the see Please Dosage Guidelines • • • Instructions Special • Reactions Adverse • • • • Instructions Special • • Reactions Adverse ulceration, asthma insufficiency, fl fever,u, chickenpox,hemorrhagic GI Use w/caution inpatients w/renal impairment, G6PD contraindicated Combination w/>15mg/wkMethotrexate is renal failure ulcer,active peptic or cardiac severe diathesis, hemorrhagic asthma, in patientsContraindicated w/salicylate-induced hemorrhage) Hematologic eff GIeff (thrombocytopenia); ect (gastric ect on depending often wklyorless ismonitored en INR - 2-3x/wkfor2wk ismonitored en INR - achieved been therapeutic range (2.0-3.0)has dailyuntil the isusuallyperformed monitoring INR renal orhepatic impairment Use w/extreme caution ornotat allinpatients w/severe endocarditis cerebrovascular disorders &bacterial wounds, severe Avoid in patients w/activeorat ofhemorrhage, risk PUD, interactions &food w/ drug oftherapyPatients counseled onthe along risks shouldbe jaundice, pancreatitis, fever) dysfunction, Other effdiarrhea); hepatic skinreactions, (alopecia, ects discoloration GIeff &purple ofthenecrosis toes); (N/V,ects commonLess eff (skin Cholesterol embolization ects: levels therapeutic within INR Hemorrhage occur even can the stability ofINR B225 MIMS Remarks © MIMS 2020