Thrombolytic treatment of life-threatening pulmonary embolism in times of alteplase shortage

In April 2022, Boehringer Ingelheim announced that its production capacity for recombinant tissue–type plasminogen activator will, for a variety of reasons, be unable to meet the current global demands for tenecteplase and alteplase, and thus, shortages in the supply of both drugs are to be expected in many countries throughout the years 2022 and 2023. This unexpected situation sparked intense discussions at multiple levels, within hospitals and national authorities, in an attempt to determine which patients the reduced quantities of the available drug should be reserved for. While consensus exists that patients with acute ischaemic stroke should not be deprived of thrombolytic treatment, this article wishes to draw awareness to the fact that clinically unstable patients with acute high-risk pulmonary embolism (PE) are also in urgent need of pharmacological thrombolysis, particularly alteplase, in order to survive the acute phase of the disease. Acute PE occurs approximately in 100 patients per 100 000 population each year. This incidence appears to be 1.5–2 times lower than that of acute ischaemic stroke. Age-standardized PE-related annual mortality (8.0 deaths per 100 000 population in the year 20101) is also clearly lower than that related to stroke (42.3 deaths per 100 000 population in the same year2). Thus, acute PE is overall a less deadly (and less incapacitating) disease than stroke, and this is largely due to the fact that the vast majority of patients with acute PE is haemodynamically stable at presentation and capable of recovering on anticoagulant treatment alone, without the need for pharmacological (thrombolytic) or interventional reperfusion therapy. Only a small minority (≤ 5%) of all patients present with high-risk (or massive) PE, which is characterized by obstructive shock, persistent hypotension, or even cardiac arrest. This is a life-threatening condition with a 30-day mortality risk of 15% or higher, and consequently, fast dissolution (lysis) of the thrombus is urgently necessary in order to restore patency in the pulmonary circulation, unload the failing right ventricle, and save the patient’s life.3 Clearly, heparin anticoagulation alone is not an option in this patient subgroup with high-risk PE. The first reports on the use of thrombolytic agents to treat acute PE date back to the late 1960s. Following early trials which tested long-duration treatment with streptokinase4 and urokinase,5 the efficacy and overall safety of alteplase in the acute PE setting could be demonstrated by its rapid effects on a number of clinical, haemodynamic, and imaging parameters.6,7 Importantly, when the accelerated 2 h infusion of alteplase was compared with 12 h or longer regimens of urokinase treatment, it was shown to result in faster clot lysis and haemodynamic improvement, and it also appeared to be safer in terms of bleeding.8,9 Consistently, fast normalization of haemodynamic parameters, evident from as early as 30 to 6 h after thrombolysis, was reported when the 2 h alteplase infusion was compared with a 12 h streptokinase regimen.10 A double-blind randomized controlled trial in 256 patients with submassive PE showed a significant reduction (from 24.6% to 11.0%; P = 0.006) in the clinical primary end point of in-hospital death or clinical deterioration requiring an escalation of treatment, with alteplase comparing to heparin alone; furthermore, that study found no cerebral or fatal bleeding events in the alteplase group.11 These results, supporting not only the clinical efficacy but also the safety of alteplase, gain in importance when viewed against the background of the more recent Pulmonary Embolism International Thrombolysis (PEITHO) trial; in the latter study, as many as 11.5% of the patients treated with the thrombolytic agent tenecteplase suffered major bleeding and 2.0% suffered a haemorrhagic stroke.12 Tenecteplase is currently not licenced for use in acute PE. A meta-analysis including 16 trials of intravenous or catheter-directed thrombolysis in a total of 2115 patients confirmed that the use of thrombolytics was associated with significantly lower all-cause mortality [odds ratio (OR) 0.53; 95% confidence interval (CI) 0.32–0.88] compared with heparin anticoagulation alone [number needed to treat (NNT) = 59].13 A further meta-analysis, apart from confirming these results with regard to both all-cause and PE-related mortality, suggested that the reduction in early mortality was confined to the studies which included patients with high-risk PE.14 Importantly, that publication also provided efficacy and safety data based on the thrombolytic agent used; the results of this subgroup analysis were in line with the findings of earlier individual studies, indicating a lower risk of intracranial or fatal haemorrhage, and of major bleeding in the broader sense, among patients who received alteplase as compared with urokinase, streptokinase, or tenecteplase.14 The latest (2019) clinical practice guidelines on the management of acute PE by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS),3 and those by other scientific societies across the globe, consistently recommend thrombolysis as lifesaving treatment for patients with acute high-risk PE. The highest level of recommendation applies both to patients presenting with overt haemodynamic instability and to those in whom clinical and haemodyamic decompensation occurs during the first hours or days of the hospital stay while on anticoagulants.3 Although the guidelines do not formally recommend preferring alteplase over other thrombolytic agents, they do underline the aforementioned advantages of the short alteplase infusion compared with the longer-duration urokinase and streptokinase regimens. Currently, a 10 mg alteplase bolus followed by a 2 h infusion of 90 mg is the standard of care for acute high-risk PE in Europe and in most other areas of the world. In fact, the clinicians’ experience with other thrombolytic agents is very close to zero as far as acute PE is concerned. This practical aspect is, apart from the scientific evidence, an additional important criterion when choosing emergency lifesaving treatment in patients presenting with PE leading to haemodynamic instability or collapse. Alternative, ‘thrombolysis-free’ options of thrombus removal in high-risk PE, notably percutaneous catheter-based embolectomy, are a rapidly evolving field in terms of technical progress, but they are yet to provide robust evidence confirming their effects on clinical outcomes and their safety in populations free of selection bias. Besides, the equipment and expertise required for these interventional procedures are, despite a growing tendency, still available in only a minority of hospitals to date. Importantly, based on current evidence and supported by the 2019 ESC/ERS guideline and recently released consensus statement on percutaneous treatment options for acute PE, upfront reperfusion treatment in general is only indicated in those patients presenting with cardiac arrest, obstructive shock, or persistent hypotension, i.e. high-risk PE.3,15 For the time being and until currently ongoing trials support a more aggressive treatment strategy, upfront (catheter-directed) reperfusion therapy (CDT) should be withheld in patients with intermediate-risk PE unless the anticoagulation therapy fails, i.e. progression to high-risk PE or a lack of improvement of compromised vital signs after 24–48 h. Rescue reperfusion treatment with systemic thrombolysis or CDT should only be initiated in the latter setting. In summary, undisputable scientific and epidemiological arguments as well as practical issues (Graphical Abstract) speak in favour of maintaining a high priority for alteplase use in patients with acute PE and overt or imminent haemodynamic instability. Even in times of supply constraints such as the present one, withholding lifesaving treatment from these patients in the absence of a validated or practicable alternative therapeutic option cannot be acceptable. The relatively small number of patients with high-risk PE who will need alteplase over the next 2 years or so is not expected to compromise the treatment of acute ischaemic stroke. Clinicians involved in the treatment of acute severe PE are hereby urged to engage in discussions with their hospital administration and central pharmacy, so that the problem can be placed into its right perspective and drug resources can be allocated appropriately on site. National scientific and professional societies in all countries facing supply shortages have the responsibility to explain the rationale backing the need for alteplase treatment for this small subgroup of patients with PE to their national competent authorities and policymakers. This will help to prevent unjustified central decisions that might result in an increase in PE-related mortality over the next months and years. Frederikus A. Klok, MD PhD, Piotr Pruszczyk, and Stavros Konstantinides No new data were generated or analysed in support of this viewpoint. All authors declare no funding for this contribution.