Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med. 2014 Apr 10;370(15):1402–11.
Introduction and background
The history of thrombolytic therapy dates back to 1933 when William Smith Tillet, an Associate Professor of Medicine at the Johns Hopkins University, serendipitously observed that Lancefield Group A beta-hemolytic streptococci produced a fibrinolytic substance. Tillet called this substance “streptococcal fibrinolysin” (1). Years of research, along with his student Sol Sherry, fuelled an increasing interest in its potential application in acute myocardial infarction. It was finally left to Fletcher et al. to embark upon a pivotal clinical trial with streptokinase (2). They infused massive doses of streptokinase over prolonged periods in patients with acute myocardial infarction. Although a bleeding diathesis occurred in a few patients, mortality was lower in those who received streptokinase compared to other therapies. The 1960s witnessed animal studies that tested the efficacy of streptokinase and urokinase in lysing massive blood clots in the pulmonary arteries. One of the early pioneering studies involved 21 patients with massive pulmonary embolism, demonstrated by pulmonary angiography. In this 1968 study from Australia, 18 patients were treated with intravenous streptokinase, with clear improvement on pulmonary angiography and a perceptible increase in peripheral pulmonary perfusion 24 hours later. In contrast, pulmonary angiography on three patients who received heparin alone demonstrated little change, with persistent, high-grade obstruction of the main pulmonary arteries (3). Intravenous thrombolytic therapy was found to be clinically feasible, easy to administer, and relatively safe in acute pulmonary embolism, leading to the first multinational randomized controlled trial (RCT). The Urokinase in Pulmonary Embolism (UPETP) trial of 1970 compared urokinase combined with heparin compared to heparin alone in acute pulmonary embolism (4). The study revealed significantly greater clot resolution at 24 hours evidenced by pulmonary angiography, lung scans, and right heart pressure measurements. The only complication observed was a relatively higher incidence of bleeding with urokinase. Thrombolytic therapy for acute pulmonary embolism gained widespread acceptance in the 1980s, with focused research in specific clinical settings.
While acute pulmonary embolism with hypotension is a clear indication for fibrinolytic therapy, standard anticoagulation alone was considered adequate in hemodynamically stable patients (5). However, the presence of acute right ventricular pressure overload may also be an important determinant of the severity and impact outcomes from acute pulmonary embolism (6). Such patients may have acute right ventricular dysfunction and myocardial injury without overt hemodynamic instability. This group of patients may represent an “intermediate-risk” group and may benefit from early fibrinolytic therapy.
Although fibrinolytic therapy had been in use for acute pulmonary embolism for more than four decades, there were few RCTs that compared fibrinolysis with anticoagulation. Particularly, the potential efficacy of fibrinolytic therapy in improving clinical outcomes among patients who remained hemodynamically stable was not adequately investigated.
The Pulmonary Embolism Thrombolysis (PEITHO) was an RCT that evaluated patients who carried an intermediate risk of adverse outcomes following acute pulmonary embolism (7). The study aimed to assess the safety and efficacy of fibrinolytic therapy with a single dose of tenecteplase combined with standard anticoagulation therapy compared with anticoagulation alone in this setting.
Population and design
The PEITHO trial was conducted between November 2007 – July 2012 in 76 centers across 13 countries. Adult patients (>18 years old) who were diagnosed to have acute pulmonary embolism by V/Q scan, CT, or pulmonary angiogram within 15 days of symptom onset were eligible. Right ventricular dysfunction was confirmed by echocardiography or spiral CT scan of the chest; myocardial injury was confirmed by a positive test for troponin I or T.
Excluded
Patients with a contraindication to fibrinolytic therapy were excluded. Those with hemodynamic decompensation evidenced by the requirement for cardiopulmonary resuscitation, a systolic BP of <90 mm Hg for >15 minutes, a drop in systolic BP by >40 mm Hg for >15 minutes with features of end-organ hypoperfusion, and the requirement for catecholamine support were excluded. Block randomization, stratified by center, was carried out to ensure a balanced distribution of treatment groups. Randomization was aimed to be performed within 2 hours of identification of right ventricular dysfunction and myocardial injury.
Fibrinolysis group (tenecteplase)
Patients randomized to receive fibrinolysis were administered an intravenous bolus of 30–50 mg of tenecteplase, based on the body weight.
Control group (placebo)
In the control group, a single bolus dose of placebo of the same volume and appearance was administered.
Common management
Unfractionated heparin was administered as an intravenous bolus immediately after randomization in both groups, except among those who had already received a bolus dose or infusion of heparin. The bolus dose of unfractionated heparin was withheld among patients who had received a therapeutic dose of low-molecular-weight heparin or fondaparinux; the infusion of unfractionated heparin was commenced after 12 hours of the last dose of low-molecular-weight heparin and 24 hours after the last dose of fondaparinux. Heparin infusion was titrated to an activated partial thromboplastin time of 2.0–2.5 times the upper limit of normal. Anticoagulant drugs other than unfractionated heparin were not allowed until 48 hours post-randomization.
Sample size
The authors calculated the sample size based on a meta-analysis of trials on thrombolysis (8) and the MAPPETT 3 trial (9), the largest RCT on pulmonary embolism until the study date. The primary endpoint of death or hemodynamic collapse within 7 days was presumed to be approximately 7%. The study was planned to include 1000 patients, providing 80% power to detect a difference between the two groups.
Results
The study enrolled 1006 patients – 506 were assigned to receive tenecteplase combined with unfractionated heparin, and 500 to receive placebo combined with unfractionated heparin. Excluding the lone patient with missing informed consent, 1005 patients were included in the intention-to-treat analysis. The overall median age was 70 years; patients were normotensive at randomization. The diagnosis of pulmonary embolism was confirmed by CT in nearly 95% of patients. Right ventricular dysfunction was confirmed by either echocardiography or CT in all patients; myocardial injury was diagnosed based on Troponin T or I testing in all except nine patients.
Efficacy outcomes
The primary outcome
The primary composite endpoint of death or hemodynamic collapse within 7 days of randomization was significantly lower in patients assigned to receive tenecteplase (2.6% vs. 5.6%; odds ratio, 0.44, 95% CI, 0.23–0.87; P = 0.02). Among the individual components of the primary outcome, mortality at 7 days was not significantly different between the tenecteplase and the placebo groups (1.2% vs. 1.8%, P = 0.42). Hemodynamic collapse occurred more often in the placebo group (5% vs. 1.6%, P = 0.002). More patients in the placebo group received catecholamine support; cardiopulmonary resuscitation was required for five patients in the placebo group compared with one patient in the tenecteplase group.
On prespecified subgroup analysis, the primary outcome was more favorable in patients 75 years of age or younger, compared to older patients. Tenecteplase was equally efficacious in men and women.
Other outcomes
Twenty-three patients (4.6%) received open-label, rescue fibrinolysis; however, crossover occurred after the onset of hemodynamic instability in all except nine patients. The 30-day mortality was similar in both groups (tenecteplase: 2.4% vs. placebo: 3.2%, P = 0.42). In the tenecteplase group, eight patients (1.6%) underwent mechanical ventilation compared to 15 patients (3.0%) in the placebo group.
Safety
Major bleeding within 7 days was more common among patients who received tenecteplase (11.5% vs. 2.4%). Major extracranial bleeding was more common among those >75 years old compared to younger subjects. The incidence of stroke was also more common in the tenecteplase group. Ten patients suffered hemorrhagic stroke and two, ischemic stroke in the tenecteplase group compared with a lone patient who suffered a hemorrhagic stroke in the placebo group. The main outcomes are summarized in Table 1.
Table 1. Main outcomes
| Outcome | Tenecteplase (506 patients) | Placebo (499 patients) | OR (95% CI) | P value |
| 7-day mortality, hemodynamic instability | 13 (2.6%) | 28 (5.6%) | 0.44 (0.23–0.87) | 0.02 |
| 7-day mortality | 6 (1.2%) | 9 (1.8%) | 0.65 (0.23–1.85) | 0.42 |
| Hemodynamic instability | 8 (1.6%) | 25 (5.0%) | 0.30 (0.14–0.68) | 0.002 |
| Major extracranial bleeding | 32 (6.3%) | 6 (1.2%) | 5.55 (2.3–13.39) | <0.001 |
| Stroke by day 7 | 12 (2.4%) | 1 (0.2%) | 12.10 (1.57–93.39) | 0.003 |
Study conclusion
The findings of the study suggested that fibrinolytic therapy may reduce the likelihood of hemodynamic decompensation or death in intermediate-risk patients with acute pulmonary embolism. Patients who are hemodynamically stable with right ventricular dysfunction on echocardiography or CT and myocardial injury evidenced by positive troponin levels may represent patients with intermediate risk.
Strengths
The PEITHO trial evaluated a key clinical question – is timely fibrinolytic therapy efficacious among intermediate-risk patients with acute pulmonary embolism and stable blood pressure? In a double-blinded, randomized controlled design with an adequate sample size, the authors convincingly demonstrated that fibrinolytic therapy reduces hemodynamic instability, although the mortality was similar in both groups. Being multi-centered, the study provided external validity.
Limitations
The primary outcome was a composite of death or hemodynamic instability at 7 days; the beneficial effect was driven almost entirely by the latter outcome. Evaluation of longer-term mortality may have been a more appropriate clinical endpoint. Rescue fibrinolysis was administered in 23 (4.6%) patients in the control group, mostly after the onset of hemodynamic instability. The question arises whether it may be more appropriate to consider fibrinolysis expeditiously once hemodynamic instability is evident. The overall mortality was low, and the study was not powered to detect a mortality difference, a more relevant clinical outcome.
Long-term follow-up study
The long-term survival was evaluated in 28 study sites comprising a total of 709 patients who participated in the long-term follow-up (median of 37.8 months; interquartile range: 24.6 to 54.8 months) (10). Mortality was assessed in 353 of 359 (98.3%) of patients who received tenecteplase and 343 of 350 (98.0%) of patients in the placebo group. The overall mortality was 19.2%, with no difference between groups (tenecteplase vs. placebo, 2.2% vs. 2.9%). Mortality between 30 days and longer-term occurred due to cancer, acute or chronic respiratory failure, acute infections, or chronic systemic inflammatory disease.
Summary
Fibrinolytic therapy had previously been shown to be effective among high-risk patients with acute pulmonary embolism who were hemodynamically unstable. The PEITHO trial suggested that fibrinolytic therapy may be associated with improved hemodynamic stability among intermediate-risk patients with acute pulmonary embolism. As expected, fibrinolytic therapy was associated with a higher risk of major bleeding, including intracranial hemorrhage. The risk of hemorrhagic complications may be especially higher among the elderly population. Hence, the cornerstone of management lies in the assessment of the balance between risk and benefit and individualization of care. The trial underlined the impending need for robust risk stratification among patients who are at intermediate risk of death.
References
1. Tillett WS, Garner RL. THE FIBRINOLYTIC ACTIVITY OF HEMOLYTIC STREPTOCOCCI. J Exp Med. 1933 Sep 30;58(4):485–502.
2. Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S. The treatment of patients suffering from early myocardial infarction with massive and prolonged streptokinase therapy. Trans Assoc Am Physicians. 1958;71:287–96.
3. Hirsh J, Hale GS, McDonald IG, McCarthy RA, Pitt A. Streptokinase therapy in acute major pulmonary embolism: effectiveness and problems. Br Med J. 1968 Dec 21;4(5633):729–34.
4. Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970 Dec 21;214(12):2163–72.
5. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S-e496S.
6. Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med. 2008 Dec 25;359(26):2804–13.
7. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med. 2014 Apr 10;370(15):1402–11.
8. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004 Aug 10;110(6):744–9.
9. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism. N Engl J Med. 2002 Oct 10;347(15):1143–50.
10. Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, et al. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017 Mar;69(12):1536–44.
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Very useful summary. Thanks