Thrombolytic agents have been used for the treatment of acute PE since the late 1960s [10]. Today, immediate systemic reperfusion treatment with intravenous thrombolysis continues to be the mainstay of therapy for high-risk (or massive) PE [6, 11, 12]. This recommendation is partly supported by meta-analyses of randomized trials which enrolled, in total, more than 2000 patients with acute PE and suggested that thrombolysis may reduce, by approximately two thirds, early mortality or hemodynamic decompensation requiring further “rescue” treatment (odds ratio [OR] 0.34, 95% CI: 0.22–0.52) [13]. Of course, this benefit is to be viewed against the risk of major bleeding which occurs much more frequently than under anticoagulation alone (OR 2.91, 95% CI: 1.95–4.36), particularly when fatal or intracranial hemorrhage is considered (OR 3.18, 95% CI: 1.25–8.11) [13]. In light of this delicate balance, current evidence-based guidelines point out that intermediate- or low-risk patients with acute PE are not likely to benefit from the routine use of systemic thrombolysis and that this treatment should therefore only be used as rescue treatment in case of hemodynamic decompensation under anticoagulation alone [6, 12]. The basis for this recommendation has been provided by the results of the Pulmonary Embolism Thrombolysis (PEITHO) trial, which compared a single bolus of tenecteplase (plus heparin) with placebo (plus heparin) in 1006 patients with acute PE and RV dysfunction plus myocardial injury detected by imaging and a positive cardiac troponin test; in this intermediate-high-risk group (Table 29.1), the clinical benefits of thrombolysis were counterbalanced by the intracranial and other major bleeding risks [14].

Emerging approaches to reperfusion treatment of PE might help to achieve comparable efficacy while minimizing the bleeding risk associated with systemic (intravenous) full-dose thrombolysis. Preliminary evidence from small studies suggests that reduced-dose systemic thrombolysis might represent an option for improving safety while maintaining efficacy of this treatment. In a prematurely terminated trial of 118 patients, half-dose recombinant tissue-type plasminogen activator (alteplase) was comparable to the full dose in terms of efficacy and possibly associated with improved safety [15]; in another study of 121 patients with (rather arbitrarily defined) “moderate PE,” reduced-dose rtPA appeared to be safe and effective over a follow-up period of more than 2 years (Table 29.3) [16]. However, until the hypothesis generated by these data is confirmed by larger, appropriately designed trials with standardized selection criteria and outcomes, the use of “low-dose” thrombolytic regimens cannot, at the moment, be proposed as an alternative to the dosage approved for systemic intravenous use.

Catheter-directed pharmacomechanical reperfusion with low-dose local thrombolysis has been developed as an option for clearing pulmonary emboli from larger arteries [22]; this procedure is an alternative to operative embolectomy if systemic thrombolysis is contraindicated or the bleeding risk is high [8]. A phase 2 randomized multicenter trial enrolled patients with acute PE and a right-to-left ventricular dimension ratio >1.0, comparing unfractionated heparin plus a 15-h catheter-directed, ultrasound-assisted regimen of 10–20 mg rtPA versus heparin alone [20]. Catheter-directed treatment led to significant recovery of RV function at 24 h, with no increased risk of major hemorrhage [20]. The efficacy and safety of the pharmacomechanical approach using low-dose local thrombolysis were more recently supported by the results of a prospective, single-arm multicenter trial [21], and those of a registry, both including patients with massive or submassive PE [19] (Table 29.3).

Like any other interventional procedures, catheter-directed pharmacomechanical reperfusion requires adequate operator expertise and institutional volume. Furthermore, it remains to be determined whether the speed of thrombus removal, and consequently of the relief of the RV from pressure overload, is adequately high in patients with overt or imminent hemodynamic decompensation and whether the use of ultrasound is really necessary for obtaining maximum efficacy [20].

Cohort studies with long-term follow-up suggest that a substantial proportion of patients who have survived an acute PE episode may complain of persistent functional limitation and/or reduced quality of life for long periods after the index event [2]. Moreover, some degree of persistent pulmonary hypertension or RV dysfunction was observed in as many as 40% of survivors followed over 6 months to 1 year after acute PE [23]. These data are to be interpreted with caution as the number of patients followed in observational studies performed so far was rather small, echocardiographic parameters of RV dysfunction were not standardized, and a correlation of ultrasound findings with the severity of patients’ symptoms or the degree of functional limitation could not be established [24]. Similarly, the broad range of the reported CTEPH incidence rates after symptomatic PE (0.1–9.1% of the patients within the first 2 years [3]) is probably due to referral bias, absence of early symptoms, and the occasional difficulty in differentiating truly acute PE at baseline from an acute episode superimposed on pre-existing CTEPH [25].