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330 PART 3: Cardiovascular Disorders

only 11% would give thrombolytic therapy for a large PE without hypo- TABLE 39-6 Thrombolytic Dosing Strategies in Acute Massive Pulmonary Embolism
tension, severe hypoxemia, or RV strain. Nearly all would give throm-
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bolytics to a patient with shock due to PE, and there is modest evidence rt-PA, 100 mg over 2 hours a
to support this approach. When patients with massive PE were given Urokinase, 4400 U/kg bolus, followed by 4400 U/kg/h for 24 hours a
alteplase (1 mg/kg over 1 hour) in an uncontrolled trial, there was sig- Streptokinase, 250,000 U over 30 minutes, followed by 100,000 U/h for 24 hours a
nificant clinical improvement in 11 of 15 with shock. Right ventricular
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function improves more rapidly in patients given alteplase (100 mg over rt-PA, 0.6 mg/kg bolus over 2-15 minutes
2 hours) and heparin compared to heparin alone, and patients receiving rt-PA, 1 mg/kg over 10 minutes
alteplase for PE-associated shock were less likely to have an in-hospital Tenecteplase weight (wt) based bolus over 5 seconds: wt <60 kg, give 30 mg; 60-69 kg,
subsequent PE. The only randomized clinical trial comparing throm- give 35 mg; 70-79 kg, give 40 mg; 80-89 kg, give 45; ≥90 kg, give 50 mg
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bolysis (streptokinase, 1,500,000 over 1 hour) with heparin in patients Urokinase, 1,000,000 U bolus over 10 minutes, then 2,000,000 U over 110 minutes
with massive embolism and hypoperfusion enrolled only eight patients,
but showed a dramatic mortality benefit for thrombolytic therapy; all Urokinase, 15,000 U/kg bolus over 10 minutes
four patients receiving heparin alone died, while there were no deaths in Streptokinase, 1,500,000 U over 1 hour
the streptokinase group. 127 Note: Heparin is infused at 1300 U/h following the thrombolytic infusion when the aPTT falls below
Submassive PE Evidence of right ventricular dysfunction, even in the absence twice normal, and is adjusted to keep the aPTT between 1.5 and 2.5 times control.
of any hemodynamic instability, is indisputably associated with a higher a Regimens approved by the Food and Drug Administration. Tenecteplase has not been approved for
mortality. This clinical condition has been termed submassive PE: PE PE. The dosing regimen listed is approved for acute MI and is being tested in a clinical trial setting of
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which has not yet provoked hypotension, but where the risk for death is submassive PE. 134
high. The utility of echocardiography in prognostication has led to great
interest as to whether echocardiographic criteria should be used routinely
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to guide the use of thrombolytic therapy. 128,129 Two studies address this has been associate with increased bleeding at the central catheter site.
question. In a retrospective cohort study of patients with radiographically The particular thrombolytic agent is probably not of much importance.
large emboli and right ventricular dilation (but without hypotension or In a head-to-head comparison of alteplase (100 mg over 2 hours) and
shock), those who received thrombolytic therapy had better pulmonary urokinase (1,000,000 units over 10 minutes followed by 2,000,000 over
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perfusion on day one, but this advantage disappeared by day seven. 110 minutes), the two regimens yielded similar efficacy and safety.
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Mortality was 6% in the thrombolytic group compared to no deaths in the After the thrombolytic agent is discontinued, heparin is typically begun
heparin group, and severe bleeding in the thrombolytic group approached (without a bolus) when the thrombin time or the aPTT falls to less than
10%, with intracranial bleeds in 4% of patients. In a second, prospec- 2 times control. Heparin is begun as an intravenous infusion at 1300
tive study, patients with acute PE and right ventricular dysfunction (but U/h and titrated to a PTT of 1.5 to 2.5 times control. Careful attention
without shock) were randomized to heparin plus alteplase or heparin plus should be given to selecting patients appropriately to reduce the rate
placebo. While there was no difference in mortality between groups, of hemorrhagic complications (see Table 39-7). Especially important
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the alteplase group had a significantly lower rate of treatment escalation, is a concerted effort to avoid invasive procedures, including arterial
mostly consisting of secondary thrombolysis for worsened symptoms. No blood gases, arterial catheters, central venous punctures, and pulmo-
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significant difference in bleeding was found between groups, which was nary angiograms, where possible. When a patient is deemed to be at
surprising, as previous studies have never failed to show an increased risk too high a risk of bleeding to undergo thrombolysis, options include
of major hemorrhage with thrombolytic therapy compared to heparin. In mechanical clot disruption via catheter or surgical embolectomy, which
a large prospective registry of over 2400 patients with PE, the rate of major will be discussed below.
hemorrhage in patients receiving thrombolytics was almost 22%, and Various measures of the lytic state correlate poorly with both efficacy
intracranial bleeds were noted in 3%. The retrospective, nonrandom- and incidence of bleeding, so that outside of clinical research protocols,
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ized nature of the first study raises concerns for its validity, but the latter routine monitoring is not indicated. When streptokinase is given, the
has also been cited as potentially flawed in its design, both in its definition manufacturer recommends that the thrombin time be assayed at 4
of “right heart dysfunction” and its use of secondary thrombolysis based hours to ensure that a lytic state is achieved. An adequate lytic state can
on vague clinical criteria. A trial of thrombolytic plus heparin versus be assumed if the thrombin time is prolonged above the normal limits of
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placebo plus heparin in intermediate risk patients with PE was published
in 2014. Thrombolytic therapy reduced hemodynamic decompensation
but at a price of increased major bleeding and stroke. As no mortal- TABLE 39-7 Contraindications to Thrombolytic Therapy
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ity benefit has yet been established for patients with submassive PE who a
receive thrombolysis, we advocate restricting thrombolytic therapy for Absolute Recent puncture in a noncompressible site
those patients with clinically apparent shock. The ACCP has offered a Active or recent internal bleeding
Grade 2B recommendation to consider thrombolysis for normotensive Hemorrhagic diathesis
patients to receive thrombolysis if the patient is deemed “high-risk”— Recent neurosurgery or active intracranial lesion
based on echocardiographic right heart strain, an elevated troponin, or Uncontrolled hypertension (BP >180/110) on presentation
severe hypoxemia, dyspnea, or anxiety—if the patient is not at increased Known hypersensitivity to thrombolytic agent
risk of bleeding. Prior receipt of streptokinase within 6 months (for streptokinase only)
The optimal regimen for thrombolytic therapy has not been estab- Diabetic hemorrhagic retinopathy
lished, though the most commonly evaluated has been recombinant tis- Acute pericarditis
sue plasminogen activator (rt-PA), 100 mg over 2 hours. A number of Recent obstetrical delivery
41
approaches are listed in Table 39-6. 41,122,125,127 We recommend a 2-hour History of stroke
bolus, as opposed to 12- or 24-hour infusions, as hemodynamic studies Relative Trauma or major surgery within 10 days
show faster lysis and reduced hemorrhage with 2-hour infusions. 135-137 Cardiopulmonary resuscitation (CPR)
Studies of 15 minute infusion of alteplase compared to 2-hour infusion Pregnancy
found no significant difference in efficacy or rate of hemorrhage, and in High likelihood of left heart thrombus
practice we reserve the very short bolus to patients with cardiac arrest Advanced age
from apparent PE. 41,138-140 Infusion of thrombolytics via a peripheral vein Liver disease
is preferred over through a pulmonary arterial catheter since the latter a See text for discussion about “absolute” contraindications.

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