Thrombolysis improves hemodynamics in patients with acute pulmonary embolism (PE), but its overall effect on clinical outcomes is questionable. Acute PE is the third most frequent acute cardiovascular syndrome. Depending on the clinical severity of PE and particularly the presence of hemodynamic instability at presentation, more than 20% of patients may die in the acute phase of the disease, within the first 30 days.¹ Of those who survive, at least 30% report persisting or deteriorating clinical symptoms or functional limitation over the long term.² Ultimately, a proportion of PE patients ranging between 1% and 9% are diagnosed with a devastating complication, chronic thromboembolic pulmonary hypertension (CTEPH), that leads to progressive right heart failure and death if not properly treated with surgical pulmonary endarterectomy.^3-5

Thrombolysis is the prototype of reperfusion treatment for PE and has been used in this clinical setting for almost half a century.⁶ At present, standard-dose systemic thrombolysis is recommended for the small group (approximately 3% of all PE patients) of hemodynamically unstable, high-risk patients whose survival depends upon immediate relief of the obstruction to flow and reversal of right ventricular (RV) pressure overload.^5,7 Randomized trials in the 1980s and early 1990s that compared thrombolysis with heparin alone showed rapid (within hours) reduction in angiographically assessed thrombus burden following thrombolytic treatment, along with significant hemodynamic improvement on right heart catheterization or echocardiography.^5,8 More recently, the PEITHO Pulmonary Embolism Thrombolysis Study, the largest randomized thrombolysis trial in acute PE to date, showed that thrombolytic treatment can also improve clinical outcomes, significantly reducing the incidence of death or hemodynamic decompensation at 7 days.⁹ However, these beneficial clinical effects came at a 2% rate of hemorrhagic stroke and a 6.3% rate of major extracranial bleeding.⁹ Those levels of frequency and severity of thrombolysis-related bleeding complications are considered prohibitive outside the setting of cardiogenic shock. Thus, thrombolysis is currently not recommended as first-line therapeutic option for the larger group of normotensive patients with intermediate-risk PE (i.e., those presenting with RV dysfunction).⁵

Is Early Thrombolysis Capable of Preventing Late Complications of PE?

Many clinicians believe that early thrombolytic treatment might, by reducing the thrombotic burden, minimize the risk of persistent thromboembolic obstruction, pulmonary hypertension, functional limitation, and possibly overall or cardiovascular mortality over the long term. Although this appears to be a reasonable assumption, there is very little and very preliminary evidence to support it. For example, 2 small trials suggested that thrombolysis might improve, compared with anticoagulation alone, functional capacity at 3 months¹⁰ or the persistence (or development) of pulmonary hypertension at 28 months.¹¹ Their results are hypothesis-generating but by themselves not conclusive. In the former study, with low absolute numbers of late events in both treatment arms, the small difference in favor of thrombolysis (versus heparin alone) over the long term was mainly driven by "low perception of wellness" based on the SF36 survey.¹⁰ In the latter study, mean estimated systolic pulmonary artery pressure at 28-month follow-up was 43 ± 6 mmHg in the control (anticoagulation-only) arm; an unexpectedly (and inexplicably) high proportion (57%) of the patients in that group were reported to have an estimated systolic pressure higher than 40 mmHg.¹¹

Population and Results of the Present Study

PEITHO was a multicenter, double-blind, placebo-controlled randomized trial.⁹ Patients were eligible for the study if they met all the following criteria: age 18 years or older, objectively confirmed acute PE with first symptoms 15 days or fewer before randomization, RV dysfunction confirmed by echocardiography or spiral computed tomography of the chest, and myocardial injury confirmed by a positive troponin I or T test. Eligible patients were centrally randomized within 2 hours after the investigator became aware of both the presence of RV dysfunction (by receiving the echocardiography or computed tomography report) and myocardial injury (by receiving a positive cardiac troponin test). Patients who were assigned to thrombolysis received a single weight-based intravenous bolus of the thrombolytic agent tenecteplase. Patients assigned to placebo were given a single intravenous bolus of the same volume and appearance. The primary efficacy outcome was defined as the clinical composite of all-cause mortality or hemodynamic decompensation (or collapse) within 7 days of randomization.

Following a protocol amendment, the patients' vital, clinical, and hemodynamic status was recorded 24 months or later after randomization. Clinical and (whenever possible) echocardiographic assessment was done during an appointment at the participating center. In patients whose symptoms and/or echocardiogram indicated pulmonary hypertension, further diagnostic work-up was performed as recommended by guidelines available at the time of the trial.

PEITHO enrolled 1,006 patients at 76 sites in 13 countries. For the present study, 28 PEITHO study sites, which had randomized a total of 709 patients, participated in the long-term follow-up (median period [interquartile range], 37.8 months [24.6-54.8]). At these sites, the survival rate and causes of death were assessed in 353 of 359 (98.3%) patients in the tenecteplase arm and 343 of 350 (98.0%) patients in the placebo arm. The overall mortality rate in the entire study population was 19.2%, and no significant differences were observed between patients who underwent thrombolysis with tenecteplase and those randomized to heparin anticoagulation alone (p = 0.43). Most late deaths occurring between day 30 and long-term follow-up resulted from cancer, acute or chronic respiratory failure, or other illness (mostly acute infections or chronic systemic inflammatory diseases).¹²

The clinical status could be obtained in 175 and 183 patients of the thrombolysis and placebo arm, respectively. Sixty-three (36.0%) of the patients in the tenecteplase and 55 (30.1%) of the patients in the placebo arm reported persistent clinical symptoms after PE (p = 0.23). In most cases, the leading symptom was mild exertional dyspnea. Only 21 patients (12.0%) randomized to tenecteplase and 20 (10.9%) patients randomized to placebo were in the New York Heart Association functional Class III or IV.¹² On echocardiography, which was performed in 144 and 146 patients respectively, one or more indicators of pulmonary hypertension and/or RV dysfunction were recorded in 63 (44.1%) of the patients randomized to tenecteplase and in 52 (36.6%) of the patients of those who received placebo (p = 0.20); however, estimated systolic pulmonary artery pressure was only mildly elevated (median 30.0 mmHg; interquartile range 25.0-35.0). A definitive diagnosis of CTEPH was made in 4 of 190 (2.1%) patients randomized to tenecteplase and in 6 of 186 (3.2%) patients allocated to placebo (p = 0.79).¹²

What is the Impact of these Results on the Indications and Possible Candidates for Reperfusion Treatment in Acute PE?

The present study focused on the long-term survival status and (partly) the clinical and echocardiographic follow-up of a large population randomized to receive thrombolysis versus placebo (both on top of standard anticoagulation) in the acute phase of PE. The first message of the study is clear and undisputed: Thrombolysis does not reduce long-term mortality in survivors of acute PE. The fact that PEITHO was the largest randomized thrombolysis trial ever performed in PE and the high rate (98%) of complete long-term (approximately 3-year) data regarding the patients' survival status strongly support this conclusion. Thus, PEITHO confirms the notion that the majority of deaths occurring after the first 30 days following acute PE are due to comorbidity or underlying disease rather than resulting from progressive right heart failure. Accordingly, if reperfusion treatment could be shown to improve clinical outcomes, it would do so only by preventing death from acute right heart decompensation and failure in the first hours or days after diagnosis of PE. Importantly, such an effect should not be offset by life-threatening complications of the thrombolytic treatment itself. Therefore, reperfusion trials that are currently in the planning phase should focus on reduced dosages of intravenously administered thrombolytic agents or on (pharmaco) mechanical catheter-directed reperfusion techniques as promising approaches for minimizing the significant bleeding risk that has been associated with full-dose systemic thrombolysis over the past 50 years.

The second message coming from the present trial, namely that thrombolysis might not affect the patients' long-term clinical or functional status or the echocardiographically assessed status of the RV is much less conclusive and should be used only as a hypothesis generator and a guide for future research. The reason for caution is that clinical and echocardiographic examination could not be performed in all survivors. Because of this, the echocardiographic findings cannot be considered as definitive evidence of how often pulmonary hypertension or RV dysfunction persist (or develop) after acute PE or what the impact of thrombolysis on the long-term hemodynamic course of these patients might be. Moreover, and for similar reasons, the present study cannot resolve the debate over the true incidence of CTEPH after acute PE and whether thrombolysis might help to prevent this late complication. Clearly, future trials investigating advanced reperfusion regimens and modalities for acute PE should prospectively include complete and adequately long clinical, functional, and echocardiographic follow-up. It will be imperative to use standardized questionnaires, methodology, and parameters to ensure an objective and reproducible assessment of the patients' clinical and hemodynamic course as well as their functional status and quality of life.

References

1. Becattini C, Agnelli G, Lankeit M, et al. Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model. Eur Respir J 2016;48:780-6.
2. Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev 2014;28:221-6.
3. Konstantinides SV, Barco S, Rosenkranz S, et al. Late outcomes after acute pulmonary embolism: rationale and design of FOCUS, a prospective observational multicenter cohort study. J Thromb Thrombolysis 2016;42:600-9.
4. Konstantinides SV, Barco S, Lankeit M, Meyer G. Management of Pulmonary Embolism: An Update. J Am Coll Cardiol 2016;67:976-90.
5. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3033-69.
6. Schulman S, Ageno W, Konstantinides SV. Venous thromboembolism: Past, present and future. Thromb Haemost 2017;117:1219-29.
7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.
8. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2015;36:605-14.
9. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.
10. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014;12:459-68.
11. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, "MOPETT" Investigators. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol 2013;111:273-7.
12. Konstantinides SV, Vicaut E, Danays T, et al. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol 2017;69:1536-44.

Keywords: Hypertension, Thromboembolism, Hypertension, Pulmonary, Angiography, Echocardiography

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