Pulmonary thromboembolism (PTE) is a disease caused by obstruction of the pulmonary artery or its branches by blood clots from the venous system or the right heart.
Deep vein thrombosis (DVT) is the predominant source of thrombosis, and usually PTE and DVT are collectively referred to as venous thromboembolism (VTE). Studies have shown that the high morbidity and mortality associated with PTE is only seen in hemodynamically unstable PTE, while most hemodynamically stable PTE has a low morbidity and mortality rate. In order to deepen the understanding of the new guidelines, this paper briefly introduces the research progress on the methods of acute PTE risk stratification, diagnosis and treatment strategies, clinical application of new oral anticoagulants, assessment of acute PTE recurrence risk and determination of optimal anticoagulation time for clinicians and patients’ reference.
I. PTE risk stratification
The key to early and effective treatment of acute PTE lies in the correct assessment and stratification of the patient’s risk of early death (hospitalization or 30-day morbidity and mortality). The 2008 European Society of Cardiology guidelines for the management of acute PTE [1] classify the risk of early death associated with acute pulmonary embolism into high risk (shock or hypotension), intermediate risk (presence of right heart insufficiency or myocardial injury markers) based on risk stratification indicators (including clinical features, manifestations of right heart insufficiency, and myocardial injury markers), and high risk (shock or hypotension). cardiac insufficiency or myocardial injury) and low risk (no shock or hypotension and no right heart insufficiency or myocardial injury).
High-risk PTE accounts for approximately 5% of all acute PTEs with a morbidity and mortality rate of 15% or higher, intermediate-risk PTE accounts for 30% to 50% with a morbidity and mortality rate of 3% to 15%, and the rest are low-risk PTEs with a morbidity and mortality rate of <1%. During the treatment of acute PTE, thrombolytic therapy in high-risk patients can effectively open the blood vessels and reduce the morbidity and mortality rate, while hemodynamically stable non-high-risk (low and medium-risk) patients need anticoagulation therapy.
II. Initial treatment of acute PTE
1.Heparin anticoagulation
According to the 9th edition of the American College of Chest Physicians (ACCP) revised guidelines for venous thromboembolic disease (VTE), anticoagulation is recommended for all patients with confirmed acute PTE; immediate anticoagulation should also be given to patients with high and intermediate risk acute PTE with high clinical suspicion, without waiting for imaging to confirm the diagnosis. Intravenous plain heparin anticoagulation is preferred in patients with severe renal insufficiency (creatinine clearance 20-30 ml/min), high risk of bleeding, hypotension, extreme overweight or underweight, and in elderly patients.
In other patients, low-molecular heparin or sulforaphane may be used, with dose adjustment according to body weight. The use of low-molecular heparin or sulforaphane, administered subcutaneously, is usually convenient because it does not require monitoring of anticoagulation therapy. Anticoagulation with regular heparin or low-molecular heparin/sulfadalactone sodium should be continued for at least 5 days. Oral anticoagulation (e.g., warfarin) should be started as early as possible in hemodynamically stable patients, preferably on the same day as heparin administration. Heparin/sulfadoxine-sodium heparin can be discontinued once the international normalized ratio (INR) reaches the therapeutic standard of 2.0 to 3.0 for 2 consecutive days.
2. Thrombolytic therapy
Many studies have consistently shown that thrombolytic therapy for thromboembolism in patients with high-risk acute PTE effectively resolves obstruction.
It also promptly reduces pulmonary artery pressure and resistance, improves right heart function, increases cardiac beat volume, and restores circulatory stability. For intermediate-risk PTE, one trial also demonstrated significant improvement in right ventricular function with thrombolytic therapy, reducing the need for urgent escalation of therapy during hospitalization. Overall, significant efficacy was achieved in 90% of patients with PTE after thrombolytic therapy, with the greatest clinical improvement improvement and echocardiographic observation at 36 hours after thrombolytic therapy. In general, thrombolysis is most desirable within 48 hours of symptom onset, and remains highly effective within 6 to 14 days of onset. The most serious complication of thrombolytic therapy is cerebral hemorrhage, with an incidence of 0.9%, which may increase in the elderly and in patients with renal insufficiency, so it is important to carefully ask about contraindications to thrombolysis and weigh the risk of bleeding benefit before thrombolysis. Commonly used drugs for thrombolytic therapy are streptokinase, urokinase and recombinant tissue-type fibrinogen activator (rt-PA).
3.Surgical or interventional treatment
(1) Pulmonary artery thrombectomy
Pulmonary artery thrombectomy is indicated for patients with high-risk PTE who have absolute contraindications to thrombolytic therapy or who have failed thrombolytic therapy. Recent technological advances, improvements in extracorporeal cardiac function assist devices, and especially early intervention by an interdisciplinary team including cardiac surgeons, have allowed patients with high-risk PTE to receive surgical treatment before circulatory collapse, and the success rate of pulmonary artery dissection thrombectomy has been greatly improved, with the morbidity and mortality rate falling below 23% [18].
(2) Pulmonary artery catheter de-embolization
As an alternative to surgery for patients with high-risk PTE, it may also be used selectively for patients with intermediate-risk PTE. When there is an absolute contraindication to thrombolytic therapy, catheters are used to remove intrapulmonary thrombus by fragmentation, rheologic retrieval, aspiration, or rotational thrombectomy. If there is no absolute contraindication, conventional catheter-based thrombolysis may also be used. A systematic review of catheter-based interventions and techniques has been performed, and although the evidence to date is mostly the result of nonrandomized controlled single-center studies, the efficacy is encouraging. Additional pharmacological mechanical thrombolytic therapy has also begun to be used in the clinic. Two multicenter clinical trials are currently underway in Europe and in the United States to determine the efficacy and safety of low-dose ultrasound-enhanced catheter-delivered thrombolytic agents for intermediate-risk PTE.
(3) Vena cava filters
may be used as a means of preventing PTE. However, their safety and efficacy have not been established to date. Anticoagulation can be very effective in preventing the recurrence of thromboembolism. In a meta-analysis, the incidence of fatal PTE in the first 3 months after heparin therapy and warfarin was 0.3-1.3%. Another study showed that vena cava filter therapy, with or without thrombolytic therapy, significantly reduced the morbidity and mortality of high-risk acute PTE. In recent years, retrievable inferior vena cava filters have been increasingly used in patients with VTE who have contraindications to anticoagulation or recurrence despite effective anticoagulation therapy because of the ease of removal.
Adjustment of the initial treatment strategy for acute PTE
For most patients with normotensive PTE, low-molecular-weight heparin or sodium fondaparinux has an adequate initial therapeutic effect. Thrombolytic therapy may be used selectively in patients with evidence of right ventricular insufficiency or myocardial injury, especially if the patient has both acute respiratory failure and/or a high risk of death (e.g., chronic cardiopulmonary disease resulting in reduced cardiopulmonary reserve function) and no contraindications to thrombolysis.
In patients with “intermediate-risk” PTE (right ventricular insufficiency on echocardiography or CT, combined with increased troponin suggesting myocardial injury), recent preliminary studies suggest that low-dose thrombolysis (halving the standard dose of rt-PA) may reduce the recurrence of PTE and persistent pulmonary hypertension with the same efficacy as the conventional dose, while Adverse effects (bleeding cases) were reduced. For patients with normal blood pressure without serious comorbidities or right heart insufficiency who belong to the low risk group, early discharge or direct outpatient treatment, the recurrence rate of VTE and the incidence of major bleeding are similar to the results of inpatient treatment.
IV. Anticoagulant drugs
1.Vitamin K antagonists
Worldwide, vitamin K antagonists such as warfarin (scientific name benzylacetone coumarin), vinblastine coumarin and phenprocoumarol are still the main anticoagulant agents for the treatment of PTE. For example, in 2010, there were more than 250,000 warfarin prescriptions in the United States. The shortcomings of vitamin K antagonists dose modulation is difficult, as it has been reported that about one-third of PTE patients over 65 years of age require emergency hospitalization related to adverse events with warfarin. Due to the greater risk of bleeding after the application of warfarin, its clinical application is still somewhat limited.
2.New oral anticoagulants
New oral anticoagulants, such as rivaroxaban and dabigatran, target specific coagulation enzymes and are characterized by rapid onset of action, precise anticoagulant effect, low possibility of interaction with drugs or food, no need for routine laboratory coagulation tests, no need to adjust the drug dosage, which greatly facilitates patients. For patients with warfarin allergy or difficulties in warfarin dose adjustment
V. Recurrence risk assessment and optimal anticoagulation time determination
The most common dilemma in treating patients with PTE is the determination of the optimal duration of anticoagulation therapy. Current international guidelines [3] recommend a 3-month duration of anticoagulation therapy for PTE triggered by surgery or a single non-surgical factor, and patients with PTE of unknown trigger will need to be evaluated for an extended duration of anticoagulation therapy after 3 months of anticoagulation. However, the recurrence rate after discontinuation of anticoagulation therapy for PTE is quite high. In a group of 1626 patients with primary proximal limb DVT or PTE, a cumulative recurrence rate of 11%, 20%, 29%, and 40% at 1, 3, 5, and 10 years after discontinuation has been reported [33], with a high risk of recurrence in those with an unknown cause of thrombus formation or what has been termed idiopathic. Therefore, the treatment of many patients is actually in a “zone of uncertainty” and requires individualized assessment to determine the optimal duration of anticoagulation therapy [34]. This “individualization” requires clinicians to assess patients for recurrence factors, and for those at high risk of recurrence, longer or lifelong anticoagulant therapy should be given.
What determines the risk of recurrence of acute PTE?
In a group of 929 patients, 19% of whom recurred after discontinuation of anticoagulation (median time 43 months after discontinuation), the most important risk factors were idiopathic (unknown etiology), male, proximal DVT, calf DVT combined with PTE and elevated D-dimer levels, whereas patients with thrombotic tendency alone did not have an increased rate of VTE recurrence. Other risk factors found in the study included overweight, persistent right ventricular insufficiency after discharge from hospital following acute pulmonary embolism, braking, cancer, chronic obstructive pulmonary disease, low HDL cholesterolemia, or a family history of thrombotic disease.
In the recent investigator-initiated, double-blind study, 6-18 months after completion of the first first occurrence of VTE treatment after oral anticoagulation were randomly assigned to aspirin or a blank control group, with aspirin administration of 100 mg daily for 2 years. Results The number of recurrences in the 2 groups was 28 (6.6% per year) and 43 (11.2% per year), respectively (hazard ratio was 0.85, 95% CI, 0.36-0.93). Compared to arterial thrombosis, platelet count is lower in venous thrombosis, but it is involved in the release of polyphosphates, particles, and inflammatory mediators and produces DNA-histidine-particle composition complexes through neutrophil interactions. Although aspirin provides less protection than vitamin K antagonists and new oral anticoagulants, if these results are supported by larger clinical trials, aspirin may have a second-line role in the prevention of recurrence after treatment of VTE with a high bleeding risk.