pulmonary thromboembolism (1 of 16)

B1

Pulmonary Thromboembolism (1 of 16)

*Approach of suspected PE will vary according to the local availability of tests in each specifi c clinical setting

Not all products are available or approved for above use in all countries.Specifi c prescribing information may be found in the latest MIMS.

NoConsider Massive/

Submassive PE

Yes

Lowprobability

Yes

No

Intermediate probability

Highprobability

Positive

No

Yes

YesAssess

clinical risk

Negative

Negative

No

1Patient presents w/ signs & symptoms suggestive of pulmonary embolism (PE)*

2EVALUATION

Is patient clinically stable?

3ASSESSMENT

What is the clinical pretest probability

of PE?

3Is the PE

rule-out criteria (PERC)

met?

5CT

PULMONARY ANGIOGRAMIs PE visualized?

6Is PE

present in duplex ultrasound &/or

other tests?

Positive

4DDIMER

Is D-dimer positive or negative?

NegativeNegative

4DDIMER

Is D-dimer positive or negative?

MANAGEMENT OF MASSIVE/

SUBMASSIVE PESee next page

ALTERNATIVE DIAGNOSIS


B Pharmacological therapyParenteral Anticoagulant• Low molecular weight heparin

(LMWH) or• Unfractionated heparin (UFH) or• Fondaparinux orOral Anticoagulant• Non-vitamin K oral

anticoagulants (NOACs)

B Pharmacological therapyParenteral Anticoagulant• Low molecular weight heparin (LMWH) or• Unfractionated heparin (UFH) or• Fondaparinux orOral Anticoagulant• Warfarin• NOACs

C Follow-up

Assess clinical risk

Positive

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YesNo

Diagnosis of PE excluded

No Yes

SUSPECTED MASSIVE/SUBMASSIVE PE

A Prompt management of clinical instability

D Invasive procedures

B Pharmacological therapyParenteral Anticoagulant • Unfractionated Heparin

B Pharmacological therapy� rombolysis• Preferred agent: Alteplase• Alternatives: Reteplase,

Streptokinase or Urokinase


8EVALUATION

Absolute contraindications to thrombolysis?

7ASSESSMENT

Is massive/submassive PE confi rmed?


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2 EVALUATION

• Clinically unstable patients may have massive PE• � rombolytic therapy should be consideredSigns & Symptoms of PE• Dyspnea is usually the prime symptom & systemic arterial hypotension that requires pressor support is the

predominant sign- Hypotension is defi ned as a systolic BP <90 mmHg or a pressure drop of ≥40 mmHg for >15 minutes if not

caused by new-onset arrhythmia, hypovolemia, or sepsis- Syncope &/or cyanosis may be present

Signs & Symptoms of Massive PE• Hemodynamic instability (SBP <100 mmHg, or SBP drop to 40 mmHg; HR >110 bpm)• Syncope• Severe hypoxemia• Respiratory distressDiff erential Diagnosis• Cardiogenic shock, cardiac tamponade, acute valvular dysfunction, aortic dissection, pneumonia, massive

myocardial infarction (MI)Echocardiography• Most useful initial test which typically shows indirect signs of acute pulmonary hypertension & RV overload

if acute PE is the cause of hemodynamic changes• If patient is unstable, thrombolytic treatment or surgery can be done based only on compatible echocardiography

fi ndings• If patient has been stabilized, a defi nitive diagnosis should be pursued

- Both lung scan, spiral computed tomography (sCT) & bedside transesophageal echocardiography (TEE) are usually able to confi rm diagnosis

- Normal lung scan or sCT angiogram suggests that another cause of shock should be found

1 SIGNS & SYMPTOMS OF PE

Pulmonary Embolism (PE)• Blockage of one or more pulmonary arteries in the lungs usually due to blood clots from the veins, especially

the veins in the legs & pelvisMassive Pulmonary Embolism• Acute PE w/ <90 mmHg systolic BP for ≥15 minutes caused by PE which may or may not need inotropic therapySubmassive Pulmonary Embolism• Acute PE without systemic hypotension (≥90 mmHg systolic BP) accompanied by either right ventricular (RV)

dysfunction or myocardial necrosisTypical Signs & Symptoms• Suspicion of PE is usually raised by the clinical symptoms• Dyspnea, pleuritic chest pain, tachypnea (respiratory rate ≥20 breaths/minute) occur in most cases of PE

- Dyspnea is the most frequent symptom, while tachypnea is its most frequent sign- Other signs & symptoms that may be present: Tachycardia [heart rate (HR) >100 beats/minute (bpm)],

cough, hemoptysis, syncope, nonpleuritic chest pain, wheezing, & hypotension• Clinical instability or cardiac arrest is indicative of massive PEPleuritic Chest Pain• Pleuritic chest pain w/ or without dyspnea is one of the most frequent presentations of PE

- May suggest a small embolism located distally near the pleuraIsolated Dyspnea• Isolated dyspnea may occur suddenly or progressively (over several weeks)

- Usually due to a more central PE (not aff ecting the pleura)- May be associated w/ substernal angina-like chest pain that probably is representing RV ischemia- Worsening dyspnea may be the only symptom that indicates PE in patients w/ preexisting heart failure (HF)

or pulmonary diseaseSyncope or Shock• Syncope or shock are the hallmark signs of central PE & usually result in severe hemodynamic repercussions

- Signs of hemodynamic compromise & reduced heart fl ow are also usually present (eg systemic arterial hypotension, oliguria, cold extremities &/or clinical signs of acute right HF)

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3 ASSESSMENT

Clinical Pretest Probability of Pulmonary Embolism (CPTP)• Evaluating the likelihood of PE in an individual patient according to the clinical presentation is of utmost

importance in the interpretation of diagnostic test results & the selection of an appropriate diagnostic strategy• A reasonable clinical suspicion is required to avoid missing the diagnosis of PE• Clinical evaluation allows patients to be classifi ed into probability categories corresponding to an increasing

prevalence of PE• Clinical probability may be estimated implicitly by clinical judgment or explicitly by a validated prediction rule• All patients w/ possible PE should have clinical probability assessed & documented• Patients should also be evaluated for risk factors for venous thromboembolism (VTE)Prediction Rule versus Clinical Judgment• To identify a patient w/ a high likelihood of PE, prediction rules appear to be more accurate than clinical judgment• Clinical judgment is accurate to discern whether patient is of low likelihood of PE

- Patients that have low clinical probability of PE, no lower limb deep vein thrombosis (DVT) & nondiagnostic lung scan have low risk of PE

Estimation of Pretest Probability of PE• Methods: Wells, Wicki, Kline, revised Geneva score

- Wells method is the most frequently used clinical prediction rule • In any of the methods used, the proportion of patients w/ PE is around 10% in the category of low probability,

30% in moderate probability, & 65% in high probability• Clinical evaluation allows patients to be classifi ed into probability categories corresponding to an increasing

prevalence of PEWells (Canada) Method• Requires that the patient have clinical features suggestive of PE (eg breathlessness, &/or tachypnea w/ or without

pleuritic chest pain, &/or hemoptysis)• Along w/ 2 other features: Absence of another reasonable clinical explanation or presence of a major risk factor• If both are true then the probability is high• If only one of the above is true then the probability is intermediate• If neither is true then the probability is low

MODIFIED WELLS PRE-TEST PROBABILITY SCORING SYSTEMVariable Points Pretest

probabilityTotal points

Original Simplifi ed Original Simplifi edClinical signs & symptomsAlternative diagnosis is less likely than PEHR >100 beats/minuteImmobilization or surgery in the last 4 daysPrevious DVT/PEHemoptysisMalignancy (w/ treatment within the last 6 months)

33

1.51.51.511

1111111

Based on likelihoodPE less likelyPE likelyBased on risk groupsHighIntermediateLow

0-4≥5

≥72-60-1

01≥2

N/AN/AN/A

Modifi ed from: � e Task Force for the Diagnosis & Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis & management of acute pulmonary embolism. Eur Heart J. 2014 Nov;35(43):3033-3080.

Pulmonary Embolism Rule-Out Criteria (PERC)• Helps exclude patients at very low risk for PE• Studies show that PERC validation done prior to D-dimer testing is 100% sensitive• Presence of any of the following indicates a positive PERC

- Age > 49 years old- Pulse rate >99 bpm- Pulse oximetry <95% at room air- Hemoptysis

- Patient on exogenous Estrogen therapy- Clinical history of VTE- Unilateral leg (calf ) swelling

- Previously intubated due to surgery or trauma or hospitalization within the last 4 weeksPrognostic Risk Assessment• Assessed using Pulmonary Embolism Severity Index (PESI) & simplifi ed PESI (sPESI), Hestia criteria, cardiac

markers (eg cardiac troponin I, natriuretic peptide), & imaging tests • High risk: Hemodynamic instability (eg shock, persistent arterial hypotension), PESI class III-V or sPESI ≥1,

presence of signs of RV dysfunction upon imaging tests, & presence of cardiac markers • Intermediate risk: PESI class III-V or sPESI ≥1, presence of signs of RV dysfunction upon imaging tests, &/

or presence of cardiac markers - In intermediate-high risk patients, both cardiac markers & imaging results are positive for abnormalities - Either cardiac markers or signs of RV dysfunction are present in patients w/ intermediate-low risk

• Low risk: No signs of RV dysfunction on imaging tests (eg echocardiography, CT angiogram) & negative cardiac markers

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3 ASSESSMENT (CONT’D)

Diagnostic Tests• First-line diagnostic tests such as electrocardiography (ECG), chest X-ray (CXR) & arterial blood gases (ABG)

are indicated to assess clinical probability of PE & general condition of patient• Lab results can be normal but some abnormal fi ndings increase the suspicion for PEABG• Can show hypoxemia, hypocapnia, & widened (A-a) O2 diff erenceCXR• May demonstrate atelectasis, pleural-based infi ltrates or eff usions, or engorged central pulmonary artery

associated w/ a paucity of peripheral vesselsECG• Can show right axis deviation, supraventricular arrhythmia, S1Q3T3 pattern or P-pulmonaleB-type Natriuretic Peptide (BNP) & Troponin• Consider in a patient w/ substantial clot burden, abnormal echocardiogram, or clinical fi ndings suggestive of PE• Elevated BNP & troponin are associated w/ RV strain & increased mortality even in the absence of hemodynamic

instability, especially if considering massive PEEvaluate for VTE Risk Factors• � e presence of risk factors for VTE in hypotensive patients should raise the possibility of PE• � e probability of PE increases w/ the number of risk factors present• PE can also occur in individuals without risk factorsPrimary Risk Factors• Antithrombin defi ciency• Protein C defi ciency• � rombomodulin• Hyperhomocysteinemia• Anticardiolipin antibody• Prothrombin G20210A defi ciency• Factor XII defi ciency• Factor V Leiden (APC-R)• Plasminogen defi ciency• Dysplasminogenemia• Congenital dysfi brinogenemia• Excessive plasminogen activator• Protein S defi ciency• Positive history of proven VTE • Trauma/fracturesSecondary Risk Factors• Surgery• Advanced age• Central venous catheters• Heart failure• Pregnancy/puerperium• Paresis• Congenital heart disease• Long distance travel• Stroke• Hypertension• Chronic venous insuffi ciency• Obesity• Smoking• Oral contraceptives (eg Estrogen)• Prosthetic surfaces• Platelet abnormalities• Crohn’s disease• Lupus anticoagulant• Nephrotic syndrome• Malignancy w/ or without chemotherapy• Hyperviscosity (polycythemia, Waldenstrom)

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6 FURTHER WORK-UP

• Recommended for patients w/ persistent signs & symptoms despite a negative CTPA & D-dimer testVenous Duplex Ultrasonography (US)• Most pulmonary emboli arise from the deep veins of the legs thus it is rational to search for a residual DVT

in suspected PE patients• Normal US exam of the leg veins does not rule out PE• US studies may have false positive or may detect residual abnormalities from past VTE

- Only defi nite positive studies under certain clinical circumstances (eg patient without history of VTE but has a high clinical probability of PE) should serve as a basis for the start of therapy

• May improve estimation of the clinical probability of PE & avoid more invasive testing in patients w/ a negative lung imaging study

Ventilation-Perfusion Lung Scanning (V/Q Scan)• Preferred imaging study when CTPA is contraindicated• Normal or near normal lung scans are suffi cient to exclude PE, regardless of pretest probability• Low probability scans in combination w/ a low pretest probability make probability of PE low• High probability scans provide the predictive power to establish diagnosis in context of reasonable clinical

suspicion of PE• Presence of pulmonary vasculature occlusion of ≥50% may signify massive PE• Further tests should be performed in all other combinations of V/Q scan result & clinical probability

5 COMPUTED TOMOGRAPHIC PULMONARY ANGIOGRAPHY (CTPA)

• Recommended as the initial lung imaging modality for non-massive PE• Increasingly used as an adjunct or alternative to other imaging modalities & is superior in specifi city to isotope

lung scanning• Enables direct visualization of the pulmonary emboli & may provide information about parenchymal abnor-

malities that might help to establish an alternative diagnosis• More useful for patients w/ underlying cardiac & pulmonary disease• Has a high specifi city & sensitivity for central clots• � e main disadvantage of CTPA to that of conventional pulmonary angiography is that subsegmental clot is

less likely to be seen• In patients w/ a high pretest probability, negative CTPA may not be able to exclude signifi cant pulmonary

thrombi, therefore, these cases may require further investigation (refer to Section 6 - Further Work-up)• Most experts agree that a patient, in whom CTPA shows PE, may be treated without further tests

4 D-DIMER

• D-dimer is a highly sensitive but a nonspecifi c screening test for the presence of PE- Sensitivity may be decreased if the duration of VTE manifestations is >2-3 days prior to testing, if the patient

is on Heparin therapy, &/or w/ history of recent surgical procedure or trauma- Best used for evaluation of outpatients in the emergency department

• Recommended confi rmatory test for patients w/ low CPTP & positive for PERC• A negative D-dimer test via any D-dimer method (simpliRed, Vidas or MDA) reliably excludes PE in patients

w/ low clinical probability; such patients do not require imaging for VTE• A negative D-dimer test using ELISA (Vidas) reliably excludes PE in patients w/ intermediate probability• A positive D-dimer requires further evaluation to exclude PE adequately

- However, raised levels of D-dimer does not confi rm the presence of VTE because such levels are found in hospitalized patients, obstetrics, peripheral vascular disease, cancer & many infl ammatory diseases as well as increasing age

• CV D-dimer should not be performed in those w/ high CPTP- Computed tomographic pulmonary angiography (CTPA) is recommended as initial test for these cases; if

not available, or if patient is unstable or has contraindications, bedside echocardiography is recommended

• D-dimer is inappropriate for suspected VTE w/ recent surgery or trauma- � ese patients should proceed directly to radiologic studies (eg duplex US or CTPA)

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8 EVALUATION OF CONTRAINDICATION TO THROMBOLYSIS

• Absolute contraindications to thrombolysis in a life-threatening situation are rarely a factor for treatment Absolute Contraindications to � rombolysis • Hemorrhagic stroke or stroke of unknown origin• Ischemic stroke within the last 6 months• Presence of benign/malignant tumor or damage within the CNS • Major surgery, trauma, or injury within the past 3 weeks• GI bleeding within the last 30 days• Known bleeding riskRelative Contraindications• Transient ischemic attack within the past 6 months• On oral anticoagulants• Uncontrolled severe hypertension (SBP >180 mmHg, DBP >100 mmHg)• Pregnancy or within 1 week postpartum• Recent traumatic CPR• Infective endocarditis• Advanced liver disease• Active peptic ulcer• Puncture of a non-compressible vessel

7 ASSESSMENT OF MASSIVE PE

• In patients who are too unstable for lung imaging, RV dysfunction can usually be found at the bedside- Left parasternal heave, distended jugular veins & systolic murmur of tricuspid regurgitations that increases

w/ inspiration- ECG may show new right bundle branch block, RV failure, or other evidence of RV strain (eg inverted T

waves in leads V1-V4)• � e most useful initial test is echocardiography which is able to show indirect signs of acute pulmonary

hypertension & RV overload if acute PE is the cause of hemodynamic compromise• When patient has already been stabilized by supportive treatment, defi nite diagnosis should be determined• CTPA may be used to confi rm diagnosis (≥50% decreased perfusion) • For other tests to confi rm or exclude a diagnosis of PE, refer to previous page

6 FURTHER WORK-UP (CONT’D)

Echocardiography• Useful for rapid triage in acutely ill patients w/ suspected massive PE

- Usually reliable to diff erentiate between illnesses that have radically diff erent treatment compared to PE (eg AMI, pericardial tamponade, infective endocarditis, aortic dissection)

- May suggest/reinforce clinical suspicion of PE w/ the fi ndings of RV overload & dysfunction in the presence of Doppler signs of increased pulmonary arterial pressure

- May also defi nitively confi rm diagnosis of PE by visualization of proximal pulmonary arterial thrombi• It has not been confi rmed if echocardiography can identify patients who would benefi t from thrombolytic

therapy if they present without shock or hypotensionMagnetic Resonance Angiography (MRA)• Appears to be promising in human & animal models• It avoids ionizing radiation but has a poor sensitivity for subsegmental clots & limited access is likely to

continue for several yearsConventional Pulmonary Angiography• Historically considered the gold standard for the diagnosis of PE• Limitations include: Requirement of expertise in performance & interpretation, it is invasive & there are

associated risks- W/ subsegmental clot, there can be interobserver disagreement in up to ⅓ of cases

• Angiography should be reserved for patients in whom noninvasive tests remain inconclusive or are not available• Use of pulmonary angiography may also depend on patient’s clinical status & necessity to obtain an absolute

diagnosis

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PRINCIPLES OF THERAPYInpatient versus Outpatient Management• Intermediate- to high-risk patients w/ the following features should be managed in a hospital setting

- Hemodynamic instability- Oxygen saturation (O2 sat) <90%- Active bleeding or at risk for major bleeding- Currently on full-dose anticoagulants during assessment- Severe pain- W/ comorbidities requiring hospital confi nement- W/ chronic kidney disease stage 4/5 or severe hepatic disease- Socioeconomic reasons eg unfavorable living conditions, concern over treatment compliance

• Low-risk PE patients without abovementioned criteria should be considered for home treatment or early discharge• Patients w/ symptomatic PE should initially be treated in the hospital because of:

- Decreased cardiorespiratory reserve- Complications- Monitoring of INR to guide Warfarin therapy

A MANAGEMENT OF CLINICAL INSTABILITY• A considerable number of deaths occur within the 1st few hours after massive PE & therefore appropriate

supportive therapy could have a major role in PE w/ circulatory failureO2 Supplementation• May be necessary in patients w/ hypoxemia• Consider monitoring of O2 saturation & give supplementary O2 if necessaryMechanical Ventilation• May be needed temporarily in patients who appear toxic & hypoxic• Care should be taken to limit its hemodynamic adverse eff ects

- Positive intrathoracic pressures induced by mechanical ventilation, may reduce venous return & worsen RV failureHemodynamic SupportFluid Loading• Fluids may be administered initially & cautiously, but other vasoactive therapy should promptly follow• Aggressive fl uid challenge is not recommended

- May worsen RV function by causing ventricular overstretch, leading to decreased contractilityAdrenergic Agonists• Should be considered for patients w/ low cardiac index & normal BP or w/ impending hypotensionDobutamine• Considered 1st-line agent to treat right-sided HF & cardiogenic shock• Aff ects vasodilatation of both systemic & pulmonary vascular beds, increases myocardial contractility while

decreasing right-sided fi lling pressuresDopamine• Has also been used for hemodynamic support in PE patients• Use may be limited by the development of tachycardiaEpinephrine• May be eff ective when shock complicates acute PE• Vasoconstrictor eff ect similar to Norepinephrine, inotropic eff ect more due to potent beta1 stimulation rather

than beta2 eff ect, accounting for improved pulmonary vascular resistanceNorepinephrine• May be appropriate in acute massive PE when there is profound hypotension• Stimulates both alpha-adrenergic (inducing vasoconstriction) & beta1-adrenergic receptors (augmenting cardiac

contractility) resulting in improved systemic blood pressure, cardiac output, pulmonary vascular resistance, & right ventricular pressure

• Combination w/ other vasoactive agents such as Dobutamine needs further evaluationNitric Oxide Inhalation• May be indicated in patients w/ pulmonary hypertension & a patent foramen ovale• Based on clinical studies, may improve the hemodynamic status & gas exchange in patients w/ PE

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B PHARMACOLOGICAL THERAPYParenteral AnticoagulantsUnfractionated Heparin (UFH)• IV UFH treatment in PE is well-established• UFH should be considered as a 1st dose bolus & when rapid reversal of eff ect may be required, as in patients

w/ high risk of bleeding• Should be given as initial anticoagulation for patients w/ PE presenting w/ shock or hypotension, also referred

to as high-risk PE or clinically massive PE• Preferred over LMWH in patients w/ severe renal failure• IV UFH has been proven eff ective in the therapy of PE

- Studies have shown a reduced mortality rate when UFH has been used to treat VTE disease- Recurrence of VTE is unusual when UFH is infused at a rate that prolongs the aPTT >1.5 times the control

value & when adequate levels are reached within 24 hours• IV UFH typically requires hospitalization w/ frequent monitoring & dose adjustment

- aPTT should be measured 4-6 hours after bolus injection, then 3 hours after each dose adjustment, or once daily when the target therapeutic dose has been attained

• Heparin-induced thrombocytopenia is a rare but serious complicationLMWH• Eg Dalteparin, Enoxaparin, Nadroparin, Tinzaparin• LMWH is now preferred over UFH in patients w/ acute non-massive PE• A number of studies have shown that LMWH has equal effi cacy to UFH in patients w/ non-massive PE• � e use of LMWH is safe, eff ective, may shorten hospital stay & improve the quality of life for patients• Monitoring of platelet count is necessary before treatment initiation & on the 5th day, then every 2-3 days if

LMWH treatment is continued• LMWH is not recommended for high-risk PE w/ hemodynamic instability

PRINCIPLES OF THERAPY (CONT’D)Parenteral Anticoagulation• Heparin should be administered in patients w/ intermediate or high clinical probability of PE before imaging

studies are performed & in low probability patients once PE is confi rmed• If PE occurs postoperatively, Heparin therapy should not be started until 12-24 hours after major surgery &

after consultation w/ surgeon- Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site

• Both SC LMWH or IV UFH short course treatments are recommended for objectively confi rmed non-massive PE- Either LMWH or UFH is appropriate for the initial treatment of PE

� rombolytics• Studies have shown a more rapid improvement in radiographic & hemodynamic abnormalities in acute massive PE

patients who received thrombolytic agents & anticoagulant agents over conventional anticoagulant agents alone- � ere was no clinically relevant outcomes for death rate or for the resolution of symptoms

Massive PE• � e use of thrombolytic therapy in PE should be individualized

- Patients w/ hemodynamically unstable PE who are at low risk of bleeding are the most appropriate candidates• � rombolytic therapy is recommended in high-risk PE presenting w/ cardiogenic shock &/or persistent arterial

hypotension• � rombolytic therapy may also be considered in patients w/:

- Compromised oxygenation- Free-fl oating right ventricular thrombus or patent foramen ovale documented by echocardiography- Massive hemodynamically signifi cant PE without systemic hypotension or profound hypoxemia

Non-massive PE• � e use of thrombolytic therapy in non-high-risk patients (hemodynamically stable patients w/ echocardio-

graphic evidence of RV dysfunction) is controversial- Further studies are needed to show a clinically relevant improvement in the benefi t-risk ratio of thrombolytic

treatment over traditional anticoagulant therapy in these patients• � rombolytic therapy should not be used in patients w/ low-risk PE

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B PHARMACOLOGICAL THERAPY (CONT’D)Parenteral Anticoagulants (Cont’d)Fondaparinux• Also a preferred initial treatment for PE• Heparin assay (anti-factor Xa) has been used to monitor eff ects of Fondaparinux• Obtain a platelet count prior to the start of therapy & periodically to check for any bleeding• Not recommended for high-risk PE w/ hemodynamic instability & those w/ severe renal impairment• Recommended for patients w/ known history of heparin-induced thrombocytopeniaDuration of � erapy• Acute-phase treatment w/ UFH, LMWH, or Fondaparinux should be continued for at least 5-7 days after the

initiation of Warfarin & until therapeutic INR is stable & ≥2 (range: 2.0-3.0) for 2 consecutive daysNon-Vitamin K Oral Anticoagulants (NOACs)• Eg Apixaban, Edoxaban, Rivaroxaban, Dabigatran etexilate• Long-term anticoagulant treatment of PE is for prevention of fatal & nonfatal recurrent venous thromboembolic

events & complicationsApixaban• A direct factor Xa inhibitor that eff ectively prevents thrombin generation• W/ signifi cantly lower bleeding risk compared to Warfarin & other vitamin K antagonistsDabigatran etexilate• A direct thrombin inhibitor that eff ectively prevents thrombin generation • Approved for the management of PE in patients who have been treated w/ parenteral anticoagulant for 5-10

days, & to reduce risk of recurrent PE in patients who have been previously treatedEdoxaban• A direct factor Xa inhibitor that eff ectively prevents thrombin generation• May be used for treatment PE in patients treated w/ parenteral anticoagulant for 5-10 days Rivaroxaban• A direct factor Xa inhibitor that eff ectively prevents thrombin generation• An alternative treatment for parenteral anticoagulants in the initial treatment of patients w/ high clinical pretest

probability• Studies have shown that Rivaroxaban is comparable to Warfarin for the prevention of PEWarfarin• Should be started only when VTE has been reliably confi rmed

- Start on day 1 of Heparin therapy, except in patients w/ suspected hypercoagulable state (Protein C or Protein S defi ciency) wherein adequate anticoagulation w/ Heparin is needed before start of treatment to prevent Warfarin-induced skin necrosis or other transient hypercoagulable complications

• Bolus dose is not eff ective, therefore it requires at least 5 days to achieve its full eff ect- � us, it is recommended that Warfarin therapy overlap w/ Heparin at least 5 days until therapeutic INR is

stable & ≥2 x 2 consecutive days• � erapy w/ Warfarin remains unsatisfactory

- High rate of major bleeding despite optimal attempts at dose adjustment by INR� rombolysisAntithrombotics• Eg Alteplase (r-tPA), Reteplase, Streptokinase, Urokinase• Alteplase (r-tPA)

- Has comparable thrombolytic capacity to Streptokinase & Urokinase but can be administered for a shorter duration (2 hours)

- Preferred thrombolytic agent because of its shorter administration time• Streptokinase or Urokinase

- � ese 2 agents have similar thrombolytic eff ects in PE & have been shown to resolve PE comparatively at 24 hours & 3x that as seen w/ Heparin alone

- 12 hours of Urokinase has equivalent thrombolytic effi cacy to 24 hours of Streptokinase• Reteplase

- A thrombolytic agent used for catheter-based thrombolysis that functions by converting plasminogen to plasmin, resulting to fi brinolysis & clot dissolution

Investigational Drugs• Tenecteplase is a tissue plasminogen activator that is approved for acute myocardial infarction & is currently

being studied for PE in the context that it has better half life & fi brin specifi city compared to Alteplase

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D INVASIVE PROCEDURES• Main purpose is to remove the obstructing thrombi from the main pulmonary arteries• Preferred for patients w/ contraindications to systemic thrombolysis Catheter Extraction• Catheter extraction involves suction extraction of PE under fl uoroscopy w/ ECG monitoring• Reserved for highly compromised patients who cannot receive thrombolytic therapy due to contraindications,

as an adjunct when thrombolytic therapy failed to improve circulation, or as alternative to surgery if immediate access to cardiopulmonary bypass is not available

Inferior Vena Cava (IVC) Filter Placement• Recommended for patients unresponsive &/or intolerant to anticoagulant/thrombolytic therapy, patients w/

active bleeding complications, & those w/ recurrent acute PE w/ underlying pulmonary hypertension• Studies show decreased incidence of PE in patients w/ proximal DVT on anticoagulant therapyPulmonary Embolectomy• Performed in emergency situations when more conservative measures have failed• Reserved for patients w/ massive PE (preferably angiographically documented), hemodynamic instability despite

Heparin & resuscitation, or failure of thrombolytic therapy or contraindication to its use• May be considered in patients w/ submassive acute PE who are hemodynamically unstable, severe worsening

lung/RV failure, or cardiac necrosis

C FOLLOW-UP• Patients w/ acute PE have a high frequency (20-50%) of symptomatic extension of thrombus &/or recurrent

VTE & therefore require long-term anticoagulant treatment • Treatment w/ oral anticoagulant is the preferred method of long-term management of most PE patients • Adjusted doses of UFH or LMWH may be indicated for selected patients in whom oral anticoagulants are

contraindicated or impracticalLMWH• Preferred drug for patients w/ PE & cancer

- Should be used for the 1st 3-6 months of long-term anticoagulant therapy, then continued as oral therapy indefi nitely or until cancer has resolved

Oral Anticoagulant• Duration of anticoagulation is dependent on the type of event & the coexistence of prolonged risk factors:

- PE due to transient or reversible risk factor: Oral anticoagulation is recommended for at least 3 months- Unprovoked PE: Oral anticoagulation is recommended for at least 3 months- Unprovoked PE (1st episode), w/ low-risk of bleeding & in whom stable anticoagulation can be achieved:

Consider long-term oral anticoagulation- Unprovoked PE (2nd episode): Long-term treatment is recommended

Risk Factors for Major Bleeding During Anticoagulation• Age >75 years• Previous GI bleeding• Previous noncardioembolic stroke• Chronic hepatic & renal disease• Concomitant antiplatelet therapy• Poor anticoagulant control• Suboptimal monitoring of therapy• Comorbid illnessMonitoring During Anticoagulation• INR should be checked at least weekly during the 1st several weeks of Warfarin therapy• If stable, monitor every 2 weeks then every 4 weeks, but not >4 weeks • Target INR is 2.5 for most patients & 3.0 for patients w/ recurrent VTE


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All dosage recommendations are for non-pregnant & non-breastfeeding women, & non-elderly adults w/ normal renal & hepatic function unless otherwise stated.

Not all products are available or approved for above use in all countries.Products listed above may not be mentioned in the disease management chart but have been

placed here based on indications listed in regional manufacturers’ product information.Specifi c prescribing information may be found in the latest MIMS.

Dosage Guidelines

ANTICOAGULANTS, ANTIPLATELETS & FIBRINOLYTICS (THROMBOLYTICS)

Drug Dosage Remarks

Direct Factor Xa InhibitorsApixaban Treatment:

Initial dose: 10 mg PO 12 hrly x 7 daysMax dose: 20 mg POMaintenance dose: 5 mg PO 12 hrlyMax dose: 10 mg POPrevention:2.5 mg PO 12 hrlyTo be initiated following completion of 6-mth treatment w/ 5 mg PO 12 hrly or w/ another anticoagulant

Adverse Reactions• Hematologic eff ects (anemia, hemorrhage, contusion); GI

eff ect (nausea)Special Instructions• Contraindicated in patients w/ clinically signifi cant active

bleeding, hepatic disease w/ coagulopathy & clinically relevant bleeding risk

• Discontinue use in severe hemorrhage• Monitor for signs of neurological impairment• Use w/ caution in hip fracture surgery, galactose

intolerance, glucose-galactose malabsorption, severe renal impairment, hepatic impairment

Edoxaban 60 mg PO 24 hrly following initial use of parenteral anticoagulant for at least 5 daysPatients w/ moderate or severe renal impairment (CrCl 15-50 mL/min), ≤60 kg body weight, or concomitant use of P-gp inhibitors (Ciclosporin, Dronedarone, Erythromycin, Ketoconazole) are given 30 mg PO 24 hrly

Adverse Reactions• Hematologic eff ects (anemia, hemorrhage); GI eff ect

(nausea); Misc eff ects (abnormal LFT, increased blood bilirubin & gammaglutamyltransferase, rash, pruritus)

Special Instructions• Edoxaban 15 mg is not indicated as monotherapy• Contraindicated in patients w/ clinically signifi cant active

bleeding or conditions at risk for major bleeding, hepatic disease w/ coagulopathy & clinically relevant bleeding risk, uncontrolled severe HTN, concomitant treatment w/ any other anticoagulants except when switching oral anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter

• Use w/ caution in patients w/ an increased risk of bleeding, moderate or severe renal impairment, mild or moderate hepatic impairment, concomitant use of medicines aff ecting hemostasis

• Perform LFT prior to treatment & CrCl at the start of therapy & thereafter

Fondaparinux (Fondaparin)

<50 kg body wt: 5 mg SC 24 hrly50-100 kg body wt: 7.5 mgSC 24 hrly>100 kg body wt: 10 mg SC 24 hrlyContinue for 5-9 days or until oral coagulation is established

Adverse Reactions• Hematologic eff ects (hemorrhage, thrombocytopenia,

anemia, purpura); Hepatic eff ect (abnormal LFT); CNS eff ect (fever); Misc eff ect (edema)

• Less common eff ects: CNS eff ects (vertigo, dizziness, headache); CV eff ect (hypotension); GI eff ects (N/V, dyspepsia, constipation, diarrhea); Dermatologic eff ects (rash, pruritus); Rare allergic reactions

Special Instructions• Avoid in patients w/ clinically signifi cant bleeding, severe

renal impairment or in those w/ confi rmed HIT• Use w/ caution in patients w/ an increased risk of hemorrhage;

acute GI ulcer, recent intracranial hemorrhage, or shortly after brain, spinal or ophthalmic surgery; use w/ caution in patients <50 kg, patients w/ moderate renal impairment, severe hepatic impairment, w/ history of HIT, elderly >75 yr

• Consider risk versus benefi t before neuraxial intervention is employed in patients anticoagulated or to be anticoagulated for thromboprophylaxis

• Monitoring of platelets is recommended at baseline & at the end of treatment

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Dosage Guidelines

ANTICOAGULANTS, ANTIPLATELETS & FIBRINOLYTICS (THROMBOLYTICS) (CONT’D)

Drug Dosage Remarks

Direct Factor Xa Inhibitors (Cont’d)Rivaroxaban Days 1-21: 15 mg

PO 12 hrlyMax dose:30 mg/dayDays 22 onwards: 20 mg PO 24 hrlyMax dose: 20 mg/day

Adverse Reactions• Hematologic eff ects (hemorrhage, anemia, decreased hemoglobin);

Hepatic eff ect (increased ALT & AST); CNS eff ects (dizziness, headache, syncope), CV eff ects (tachycardia, hypotension) GI eff ect (nausea); Dermatologic eff ects (pruritus, rashes); Misc eff ects (fever, peripheral edema, postprocedural hemorrhage)

Special Instructions• Contraindicated in patients w/ clinically signifi cant active bleeding,

pregnant, lactating & hepatic disease associated w/ coagulopathy that can lead to relevant risk of bleeding

• Use w/ caution in patients w/ hemorrhagic risk, lactose or galactose intolerance, & those w/ moderate to severe renal impairment

Direct � rombin InhibitorDabigatran etexilate

150 mg PO 12 hrly

Adverse Reactions • Hematologic eff ects (hemorrhage, anemia, hematoma,

thrombocytopenia); Renal eff ect (hematuria); GI eff ects (dyspepsia, N/V, GI hemorrhage, abdominal pain, diarrhea, gastroesophagitis, abnormal hepatic function); Misc eff ects (wound secretion, postprocedural discharge)

Special Instructions • Contraindicated in patients w/ severe renal impairment, hemorrhagic

manifestations, bleeding diathesis, patients w/ spontaneous or pharmacological hemostatic impairment, organ lesions at risk of clinically signifi cant bleeding (including hemorrhagic stroke within the last 6 mth, patients on concomitant therapy w/ systemic Ketoconazole, prosthetic heart valve replacement)

• Use w/ caution in hepatic impairment, renal insuffi ciency, increased hemorrhagic risk, spinal/epidural anesthesia, lumbar puncture

• Discontinue use in patients who develop acute renal failureEnzymesAlteplase (rt-PA)

Loading dose: 10 mg as an IV bolus over 1-2 min Followed by: 90 mg IV infusion over 2 hr Patient <65 kg max total dose: 1.5 mg/kg

Adverse Reactions• Hematologic eff ects (hemorrhage especially from puncture sites,

severe internal bleeding, intracranial hemorrhage has occurred); GI eff ects (N/V, abdominal pain); CNS eff ect (fever)

• Rarely: Allergic reactions (rashes, fl ushing, urticaria & rarely anaphylactic & serum sickness-like symptoms)

• Infusion may be associated w/ hypotension (both direct & as a result of reperfusion), bradycardia & arrhythmias may occur because of reperfusion

• Break-up of clots may occasionally cause emboli elsewhere hence the need for Heparin prophylaxis

Special Instructions• See page 7 of this disease management chart for specifi c contraindications

Reteplase 10 units via slow IV over 1-2 min after the onset of symptomsMay repeat dose once, 30 min after the start of 1st inj

Adverse Reactions• Hematologic eff ects (hemorrhage, intracranial bleeding); CV eff ects

(hypotension, hypertension, pericarditis, bradycardia, thrombosis) Special Instructions• See page 7 of this disease management chart for specifi c

contraindications• Use w/ caution in patients w/ recent major surgery, CVD, recent GI/

GU bleed, hypertension, severe hepatic/renal impairment, arrhythmias, cholesterol embolism

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Dosage Guidelines


Drug Dosage Remarks

Enzymes (Cont’d)Streptokinase Long-term thrombolysis:

Loading dose:250,000 iu IV over 30 minFollowed by 100,000 iu/hr IV infusion x 24-72 hrBegin Heparin 3-4 hr after Streptokinase infusion or when aPTT is <100 sec

Adverse Reactions• Hematologic eff ects (hemorrhage especially from

puncture sites, severe internal bleeding, intracranial hemorrhage has occurred); Allergic reactions (rashes, fl ushing, urticaria & rarely anaphylactic & serum sickness-like symptoms); Misc eff ects (fever, chills w/ back & abdominal pain); GI eff ects (N/V); Guillain-Barré syndrome has occurred

• Infusion may be associated w/ hypotension (both direct & as a result of reperfusion), bradycardia & arrhythmias may occur because of reperfusion

• Break up of clots may occasionally cause emboli elsewhere

• Serious allergic reactions may be less likely to occur w/ Urokinase than w/ Streptokinase

Special Instructions• See page 7 of this disease management chart for

specifi c contraindications• Anti-streptokinase antibodies are formed after about

5 days after Streptokinase use- � ese antibodies may cause resistance or

hypersensitivity to subsequent doses of Streptokinase- Recommend not to administer Streptokinase

5 days-12 mth after 1st administration (alternative thrombolytic not including Anistreplase may be used)

Urokinase Loading dose: 4400 iu/kg IV in 15 mL soln over 10 min Followed by: 4400 iu/kg/hr IV infusion x 12-24 hrAnticoagulation should be started once aPTT has decreased to <2x the normal control value. If Heparin is used, do not give a loading dose

Heparin GroupDalteparin sodium

200 iu/kg SC 24 hrly or100 iu/kg SC 12 hrly for patients w/ increased risk of bleeding or100 iu/kg over 12 hr as continuous IV infusionMax dose: 18,000 iu/day

Adverse Reactions• Hematologic eff ects (hemorrhage, thrombocytopenia);

Rare hypersensitivity reactions (anaphylaxis); Eff ects that may occur w/ long-term use (osteoporosis, alopecia)

Special Instructions• Avoid in patients w/ active major bleeding, patients w/

positive in vitro test for antiplatelet Ab to the specifi c heparin

• Use w/ caution in patients w/ hemophilia or other hemorrhagic disorders (including history of Heparin-induced thrombocytopenia), peptic ulcer, recent cerebral hemorrhage, severe hypertension, severe liver disease, post-major trauma or recent surgery to brain, spinal or ophthalmic surgery, hypersensitivity to Heparin


• Monitoring of platelets is recommended at baseline & periodically during treatment

Enoxaparin 1.5 mg/kg (150 anti-Xa iu/kg) SC 24 hrly or1 mg/kg (100 anti-Xa iu/kg) SC 12 hrly

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Dosage Guidelines

UFH INFUSION RATE ADJUSTED ACCORDING TO BODY WEIGHT & APTT• Loading dose: 80 u/kg IV, followed by IV infusion 18 u/kg/hr• Monitor aPTT 6 hrly for the 1st 24 hr to keep aPTT within therapeutic range (1.5-2.3 x control) & adjust subse-

quent dosage according to aPTT- � ereafter monitor aPTT once daily unless it is outside therapeutic range

• Dose adjusted based on aPTT:

• aPTT <35 sec (<1.2 x mean normal) Give 80 u/kg IV bolus, then increase infusion rate by 4 u/kg/hr• aPTT 35-45 sec (1.2-1.5 x mean normal) Give 40 u/kg IV bolus, then increase infusion rate by 2 u/kg/hr• aPTT 46-70 sec (1.5-2.3 x mean normal) No change• aPTT 71-90 sec (2.3-3 x mean normal) Decrease infusion rate by 2 u/kg/hr• aPTT >90 sec (>3 x mean normal) Stop infusion for 1 hr then decrease infusion rate by 3 u/kg/hr


Drug Dosage Remarks

Heparin Group (Cont’d)Heparin (Unfractionated Heparin)

Weight-adjusted dosing based on nomogramorUFH IV infusion:Loading dose: 5000 u IV Loading dose for severe PE: 10,000 u IVFollowed by: 15-25 u/kg/hr IV infusion (adjust dose based on aPTT)orLoading dose: 5000 u IVFollowed by: 20,000-40,000 u IV given over 24 hr (adjust dose based on aPTT)orSC UFH: 15,000 u SC 12 hrly or 10,000 u SC 8 hrly (adjust dose based on aPTT)

Adverse Reactions• Hematologic eff ects (hemorrhage,

thrombocytopenia); Rare hypersensitivity reactions (anaphylaxis); Eff ects that may occur w/ long-term use (osteoporosis, alopecia)

• Sulodexide - Cap: N/V, diarrhea, epigastralgias- Inj: Pain, burning sensation &

hematoma at inj siteSpecial Instructions• Avoid in patients w/ active major

bleeding, patients w/ positive in vitrotest for antiplatelet Ab to the specifi c heparin

• Use w/ caution in patients w/ hemophilia or other hemorrhagic disorders (including history of Heparin-induced thrombocytopenia), peptic ulcer, recent cerebral hemorrhage, severe hypertension, severe liver disease, post-major trauma or recent surgery to brain, spinal or ophthalmic surgery, hypersensitivity to Heparin


• Monitoring of platelets is recommended at baseline & periodically during treatment

Nadroparin calcium

85 anti-Xa iu/kg SC 12 hrly for up to 10 days or 171 anti-Xa iu/kg SC 24 hrly

Parnaparin 6400 anti-Xa iu SC 12 hrly x 7-10 days Reviparin sodium 35-45 kg: 3500 anti-Xa iu SC 12 hrly

46-60 kg: 4200 anti-Xa iu SC 12 hrly>60 kg: 6300 anti-Xa iu SC 12 hrlyDoses to be given w/ an oral anticoagulant x 5-7 days

Sulodexide 250-500 LSU PO 12 hrly or 600 LSU IM/IV 24 hrly

Tinzaparin sodium 175 anti-Xa iu/kg SC 24 hrly




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Please see the end of this section for reference list.




Dosage Guidelines


Drug Dosage Remarks

Vitamin K AntagonistWarfarin 5-10 mg PO 24 hrly

Followed by subsequent dose that should be adjusted to Target INR=2.5 (range 2-3)

Adverse Reactions• Hemorrhage can occur even within therapeutic INR levels • Less common eff ects: Cholesterol embolization (skin necrosis &

purple discoloration of the toes); GI eff ects (N/V, diarrhea); Misc eff ects (alopecia, skin reactions, hepatic dysfunction, pancreatitis)

Special Instructions• Dosage must be adjusted based on regular monitoring of INR• Patients should be counseled on the risks of therapy along w/

drug & food interactions• Avoid in patients w/ active or at risk of hemorrhage, peptic

ulcer disease, severe wounds, cerebrovascular disorders & bacterial endocarditis

• Use w/ extreme caution or not at all in patients w/ severe renal or hepatic impairment

• INR monitoring is usually performed daily until the therapeutic range (2.0-3.0) has been achieved- � en INR is monitored 2-3x/wk for 2 wk- � en INR is monitored wkly or less often depending on the

stability of INR

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pulmonary thromboembolism (1 of 16)

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