Thrombolytic Therapy in Acute Pulmonary Embolism with Literature Review

Thrombolytic therapy plays a pivotal role in the management of acute pulmonary embolism (PE), particularly in cases presenting with hemodynamic instability or signs of right heart strain. This chapter aims to provide an exhaustive review of the application of thrombolytics in acute PE, emphasizing the importance of risk stratification to guide therapeutic decisions.

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Thrombolytics in Massive PE

1. Agents

Alteplase (tPA)

Alteplase is the most commonly used thrombolytic agent for treating acute PE in the United States. Its fibrin-specific nature targets clot degradation with high specificity, thus minimizing systemic effects.

Tenecteplase

Less commonly used in the United States, Tenecteplase gained attention due to its utilization in the PEITHO trial. It’s administered as a weight-based single bolus infusion.

2. Dosing Strategies

Alteplase (tPA)

• Standard Dose: The FDA recommends a full dose of 100 mg of Alteplase administered intravenously over 2 hours.
• Alternative Dosing Regimens: In emergent scenarios, alternative options include:
  • Bolus administration
  • 15-minute infusion
  • 50 mg IV bolus followed by 50 mg infusion over 2 hours.

These alternative dosing strategies have yet to be directly compared with the standard 2-hour infusion in the context of PE.

Tenecteplase

• Weight-based Single Bolus Infusion: The dosing strategy, as studied in the PEITHO trial, is as follows:
  • 30 mg for weight <60 kg
  • 35 mg for weight 60-70 kg
  • 40 mg for weight 70-80 kg
  • 45 mg for weight 80-90 kg
  • 50 mg for weight >90 kg

3. Infusion Time

Alteplase (tPA)

The conventional infusion time for Alteplase is 2 hours. However, evidence suggests that shorter infusion times (≤ 2 hours) may lead to more rapid clot dissolution and potentially fewer bleeding complications. In cases of PE-related cardiac arrest, a bolus infusion of 50 mg tPA is indicated.

Tenecteplase

Tenecteplase is typically administered as a single bolus, enabling quicker drug administration compared to Alteplase’s 2-hour infusion, especially as demonstrated in the PEITHO trial for patients with RV dysfunction but hemodynamic stability.

4. Pharmacokinetics

Alteplase (tPA)

Alteplase possesses a short half-life of approximately 4-6 minutes, making continuous infusion crucial for sustained therapeutic effects. It is predominantly metabolized in the liver and has a low volume of distribution, focusing its action within the vascular compartment.

Tenecteplase

Tenecteplase has a longer half-life compared to Alteplase, which enables its administration as a single bolus. It is also primarily metabolized in the liver.

5. Adverse Effects

Both Alteplase and Tenecteplase come with a risk of bleeding, including the rare but severe risk of intracranial hemorrhage. Other adverse effects include allergic reactions, which are generally rare but can be severe.

Alteplase (tPA)

• Bleeding: The major risk associated with Alteplase is bleeding. Intracranial hemorrhage, although rare, is the most severe form of bleeding.
• Allergic Reactions: These are generally rare but can include anaphylaxis or other hypersensitivity reactions.

Tenecteplase

• Bleeding: Similar to Alteplase, Tenecteplase also has a significant risk of bleeding, including intracranial hemorrhage.
• Allergic Reactions: Hypersensitivity reactions including skin rashes or anaphylaxis are rare but possible.

6. Monitoring

Continuous monitoring of vital signs (blood pressure, heart rate, and respiratory status) is essential during and after the administration of both Alteplase and Tenecteplase. Coagulation profiles, specifically activated partial thromboplastin time (aPTT) and international normalized ratio (INR), should also be closely watched.

7. Starting Anticoagulation

Initiating anticoagulation therapy in conjunction with thrombolytic treatment or afterwards when aPTT  is less than twice its upper limit of normal  is generally recommended. However, the risk of bleeding mandates meticulous monitoring and possibly an adjusted initial dose of the anticoagulant.

Alteplase (tPA)

Upon completion of the Alteplase infusion, anticoagulation is typically resumed or initiated if it had been held prior to thrombolytic therapy. The specific anticoagulant and its dosing depend on various factors, including renal function and risk of bleeding.

Tenecteplase

Similar to Alteplase, anticoagulation is generally initiated or resumed after the bolus administration of Tenecteplase. The choice of anticoagulant and dosing may vary based on the patient’s clinical profile.

8. Contraindications and Drug Interactions

Alteplase (tPA)

Contraindications include a history of intracranial hemorrhage, active internal bleeding, or severe uncontrolled hypertension. Interactions with anticoagulants, antiplatelets, and other medications affecting the coagulation pathway must be thoroughly assessed before initiating therapy.

Tenecteplase

The contraindications are similar to those for Alteplase. Special attention should be paid to drug interactions, particularly with anticoagulants and antiplatelet agents, to mitigate the risk of bleeding.

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Thrombolytics in Submassive or Intermediate-High Risk PE

The management of submassive or intermediate-high risk pulmonary embolism (PE) remains a subject of much debate within the medical community. While the absence of hemodynamic instability might suggest a conservative approach, the presence of right ventricular (RV) dysfunction and elevated cardiac biomarkers implies a more ominous prognosis. This section aims to discuss in detail the use of thrombolytic therapy in this specific patient population, particularly focusing on indications, patient selection, dosing strategies, and alternative approaches.

Defining Submassive or Intermediate-High Risk PE

Intermediate-high risk PE, formerly known as submassive PE, is characterized by the absence of overt hemodynamic instability but the presence of RV dysfunction, confirmed either by echocardiography or CT angiography, and elevated cardiac biomarkers like troponin or BNP. Other supportive clinical findings that may push clinicians towards considering thrombolytic therapy include significant tachycardia, severe hypoxemia, respiratory distress, or an extensive clot burden.

Rationale for Thrombolysis

The consideration of thrombolysis in this subgroup is largely driven by the poor prognostic implications of RV dysfunction. Although randomized trials have not universally shown a mortality benefit, severe RV dysfunction—especially when worsening—is considered a strong candidate for thrombolytic intervention. The logic behind this strategy is that rapid clot resolution may prevent further RV strain and deterioration.

Patient Selection

Patient selection remains crucial. Not every patient with RV dysfunction may benefit from thrombolytic therapy. A nuanced approach, often involving multidisciplinary teams like the Pulmonary Embolism Response Team (PERT), is required to assess the risk-to-benefit ratio. Parameters like severity of RV dysfunction, cardiac biomarker levels, oxygen requirements, and heart rate can help refine the selection process.

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Thrombolytic Agents and Dosing

Alteplase (tPA)

• Standard Dosing: 100 mg IV over 2 hours.
• Alternative Strategies: For urgent cases, a 50 mg IV bolus followed by an infusion of 50 mg over the next 2 hours is considered. Rapid infusion over 15 minutes has been described but is not universally recommended.

Tenecteplase

• Weight-Based Single Bolus Infusion:

• <60 kg: 30 mg
  • 60-70 kg: 35 mg
  • 70-80 kg: 40 mg
  • 80-90 kg: 45 mg
  • 90 kg: 50 mg

Tenecteplase offers the advantage of single bolus administration, making it especially useful in settings where prolonged monitoring may be difficult.

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Reduced-Dose Systemic Thrombolysis

The concept of reduced-dose systemic thrombolysis has gained attention as a possible compromise between the urgency of clot resolution and the inherent risks of bleeding associated with full-dose thrombolytics. This approach is mainly applicable for alteplase (tPA).

Rationale

The rationale behind reduced-dose thrombolysis lies in its potential to achieve effective clot dissolution while minimizing the risk of hemorrhagic complications. This strategy becomes particularly pertinent for patients at higher risk of bleeding or those who have relative contraindications to full-dose thrombolytic therapy.

Clinical Trials and Evidence

• MOPETT Trial: This trial employed alteplase at a dose of ≤50% of the standard dose (100 mg) for patients weighing 50 kg or more, and 0.5 mg/kg for those weighing less than 50 kg. The outcomes suggested lower rates of pulmonary hypertension and similar rates of bleeding compared to full-dose therapy.
• Randomized Comparisons: A trial involving 118 patients with acute PE indicated that low-dose tPA (50 mg IV) resulted in a lower mortality rate (2% vs. 6%) and bleeding rate (3% vs. 10%) compared to full-dose tPA (100 mg IV).

Concerns and Limitations

Despite the promising results, the evidence supporting reduced-dose thrombolysis is not yet robust enough to change standard practices. Many of the studies have been criticized for their small sample sizes, lack of standard definitions, and inadequate follow-up.

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Catheter-Directed Thrombolysis (CDT)

CDT is increasingly being recognized as a viable alternative to systemic thrombolysis, especially in patients who have a moderate to high risk of bleeding or contraindications to systemic thrombolysis.

Technique and Procedure

CDT involves the placement of a catheter directly into the thrombus, usually under fluoroscopic guidance. The thrombolytic agent is then infused locally, allowing for a more targeted approach. The procedure is often individualized, taking into account factors such as clot location, volume, and the operator’s experience.

Dosing Strategies

The dosing of thrombolytic agents in CDT is generally lower than that used in systemic thrombolysis. For instance, alteplase doses can range from 8 to 24 mg during CDT, often infused over a period of 4 to 6 hours.

Advantages

• Targeted Therapy: By delivering the thrombolytic agent directly into the clot, CDT allows for a more targeted approach.
• Reduced Risk of Bleeding: Lower doses of thrombolytic agents are used, which potentially reduces the risk of systemic bleeding.

Clinical Trials and Evidence

• ULTIMA Trial: Compared CDT followed by IV heparin to IV heparin alone in 59 patients with intermediate- to high-risk PE. CDT showed a statistically significant improvement in the RV/LV ratio at 24 hours.
• OPTALYSE Trial: Examined different tPA CDT regimens and found that even low-dose, short-duration regimens could significantly improve RV/LV ratios.

Limitations and Risks

CDT is not without its risks, which include catheter-related complications and the still-present, albeit reduced, risk of bleeding. Moreover, it requires specialized expertise and equipment, which may limit its widespread applicability.

Catheter-Directed Thrombolysis (CDT) vs. Systemic Thrombolysis

• CDT: Preferred if expertise is available and bleeding risk is low. The dose ranges from 8 to 24 mg during CDT.
• Systemic: Suitable if local expertise is not available. Clinical trials for low-dose systemic thrombolysis are underway.

Monitoring and Follow-up

Patients should be closely monitored for signs of improvement or deterioration. The decision to administer thrombolytic therapy may need to be made promptly. Anticoagulation should be resumed or initiated as soon as it is safe to do so, usually after a period of stable vital signs and no evidence of bleeding.

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Guidelines Recommendations

Guidelines for Thrombolytic Therapy in PE

Massive PE

• The ACCP guidelines strongly recommend systemic thrombolytic therapy in patients with high-risk massive PE who present with persistent hypotension (systolic blood pressure <90 mmHg), pulselessness, or profound bradycardia (heart rate <40 bpm) (1). This Grade 2B recommendation is based on low quality evidence showing mortality benefit with thrombolytics versus anticoagulation alone.
• The AHA guidelines state thrombolytic therapy is reasonable for patients with massive PE and acceptable bleeding risk (Class IIa, Level B) (2). This recommendation is supported by observational studies and expert consensus showing hemodynamic improvement and survival benefit with thrombolytics.
• The ESC guidelines recommend thrombolytics as first-line treatment for high-risk massive PE patients with few absolute contraindications (Class I, Level C) (3). This is based on meta-analyses demonstrating mortality reduction with thrombolytics.
• The rationale is that thrombolytics rapidly decrease pulmonary artery pressure and resistance by lysing thrombus in massive PE. Contraindications should be considered relative given the high mortality risk without intervention.

Submassive PE

• The ACCP states thrombolytics should not be routinely used in submassive PE (Grade 1B) (1). This recommendation places value on avoiding bleeding complications from thrombolytic therapy.
• The AHA states thrombolytics may be considered in submassive PE patients judged to be at high risk for adverse outcomes (Class IIb, Level C) (2). Factors increasing risk of deterioration include new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis.
• Similarly, the ESC does not recommend routine thrombolytics in submassive PE but states they may be considered in select higher risk patients after carefully weighing risks versus benefits (Class IIb, Level C) (3). The ESC also proposes rescue thrombolysis if clinical deterioration occurs after starting anticoagulation.
• Patients at highest risk for clinical deterioration include those with elevated troponin, BNP, confirmed DVT, or RV dysfunction on imaging.

Summary of Guidelines for Thrombolytic Therapy in PE

PE Classification	ACCP	AHA	ESC
Massive	Recommended (Grade 2B)	Reasonable (Class IIa, Level B)	Recommended (Class I, Level C)
Submassive	Not routinely recommended (Grade 1B)	May be considered in high-risk subgroups (Class IIb, Level C)	Not routinely recommended, consider in select higher risk subgroups (Class IIb, Level C)

Landmark Trials

Massive PE

• An RCT of 8 patients with massive PE found IV heparin alone resulted in 100% mortality versus 0% mortality with streptokinase plus heparin, providing evidence for mortality benefit with thrombolytics (4). However, small sample size and differences in time to treatment between groups are limitations.
• Registry data from the ICOPER and RIETE studies demonstrated significantly increased odds of mortality in patients with massive versus nonmassive PE (5,6). In ICOPER, the mortality rate was 58% for unstable PE patients, supporting thrombolytics in this population.
• A meta-analysis of 15 trials with 2,057 patients showed thrombolytics significantly reduced overall mortality, PE-related mortality, PE recurrence, and need for escalation of care versus anticoagulation alone (7). However, there was an increased risk of major and intracranial bleeding with thrombolytics.

Submassive PE

• The PEITHO trial, a double-blinded RCT of 1006 patients, compared tenecteplase plus heparin to placebo plus heparin in submassive PE patients with RV dysfunction and positive troponin (Meyer et al. 2014) (8). Tenecteplase significantly reduced hemodynamic collapse but increased major bleeding (11.5% vs 2.4%) and stroke (2% vs 0.2%) at 7 days.
• A meta-analysis of four RCTs with 2115 patients found thrombolytic therapy was associated with a number needed to harm of 18 for major bleeding (Chatterjee et al. 2014) (9). The number needed to treat for mortality benefit was 59. The absolute risk reduction for mortality was small at 1.12%. Significant heterogeneity between studies is a limitation.
• A meta-analysis of six RCTs with 1510 patients found a 1.6% absolute risk reduction for mortality with thrombolytics, but this was not statistically significant (Nakamura et al. 2014) (10). Only one of the six trials demonstrated a mortality benefit with thrombolytics.
• A meta-analysis of 15 RCTs with 1247 patients showed thrombolytics significantly reduced recurrent PE and mortality versus anticoagulation alone (Chen et al. 2014) (11). However, thrombolytics were associated with increased minor but not major bleeding.
• The MOPETT trial randomized 121 patients to alteplase or placebo plus anticoagulation (Sharifi et al. 2013) (15). Alteplase significantly reduced pulmonary hypertension at 28 months with no difference in bleeding. The trial used an anatomical PE definition and lower 50 mg alteplase dose.
• The TOPCOAT trial randomized 83 submassive PE patients to tenecteplase or placebo plus anticoagulation (Kline et al. 2014) (16). Tenecteplase improved pulmonary pressures, right ventricular dilation, and quality of life at 3 months compared to placebo. One fatal intracranial hemorrhage occurred in the tenecteplase group.

Summary of Evidence for Thrombolytic Therapy in Submassive PE

Author/Year	Study Design	Intervention & Comparison	Outcomes
Meyer et al. 2014	Double-blind RCT, n=1006	Tenecteplase + heparin vs placebo + heparin	Reduced hemodynamic collapse but increased major bleeding and stroke
Chatterjee et al. 2014	Meta-analysis of 4 RCTs, n=2115	Thrombolytics vs anticoagulation	NNT 59 for mortality benefit; NNH 18 for major bleeding
Nakamura et al. 2014	Meta-analysis of 6 RCTs, n=1510	Thrombolytics vs anticoagulation	1.6% absolute risk reduction for mortality, not statistically significant
Chen et al. 2014	Meta-analysis of 15 RCTs, n=1247	Thrombolytics vs anticoagulation	Reduced PE recurrence and mortality; increased minor but not major bleeding
Sharifi et al. 2013	RCT, n=121	50 mg alteplase + anticoagulation vs anticoagulation	Reduced pulmonary hypertension at 28 months; no difference in bleeding
Kline et al. 2014	RCT, n=83	Tenecteplase + anticoagulation vs anticoagulation	Improved pulmonary pressures, RV function, and quality of life at 3 months

References

1. Kearon C, et al. Antithrombotic therapy for VTE disease. Chest. 2012.
2. Jaff MR, et al. Management of massive and submassive pulmonary embolism, iliofemoral DVT, and chronic thromboembolic pulmonary hypertension. Circulation. 2011.
3. Konstantinides SV, et al. 2014 ESC Guidelines on diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014.
4. Jerjes-Sanchez C, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism. J Thromb Thrombolysis. 1995.
5. Laporte S, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism. Circulation. 2008.
6. Goldhaber SZ, et al. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999.
7. Marti C, et al. Systemic thrombolytic therapy for acute pulmonary embolism. Eur Heart J. 2015.
8. Meyer G, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014.
9. Chatterjee S, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage. JAMA. 2014.
10. Nakamura S, et al. Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism. J Thromb Haemost. 2014.
11. Chen H, et al. Thrombolysis vs anticoagulation for submassive pulmonary embolism. Respir Care. 2014.
12. Dalla-Volta S, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. J Am Coll Cardiol. 1992.
13. Levine MN, et al. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990.
14. PIOPED Investigators. Tissue plasminogen activator for the treatment of acute pulmonary embolism. Chest. 1990.
15. Sharifi M, et al. Moderate pulmonary embolism treated with thrombolysis. Am J Cardiol. 2013.
16. Kline JA, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months. J Thromb Haemost. 2014.