Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE), is an aggressive and lethal cardiopulmonary disease that poses a serious threat to human health and even endangers lives. In recent years, some large-scale clinical studies at home and abroad have achieved evidence-based medical results for the diagnosis and treatment of PTE, but also raised some questions and thoughts. Currently, risk stratification is used for the diagnosis of PTE, which provides a more reasonable method for the assessment of the disease and the development of treatment plans.
Risk stratification begins with an assessment of the patient’s hemodynamic profile and classifies the patient as high, intermediate, or low risk. Lower extremity venous ultrasound can be used as a means to confirm the diagnosis of DVT. Echocardiography (UCG) has important diagnostic and differential diagnostic implications in high- and intermediate-risk patients. It has important applications especially in emergency and critical care patients and during cardiopulmonary resuscitation.
In 2013 AnnInternMed published a randomized, controlled, multicenter study by Canadian scholars on the selective application of D-dimer in deep vein thrombosis, concluding that D-dimer results should be evaluated in conjunction with the clinical predictive probability (C-PTP). The study included 1723 patients with a first suspected DVT diagnosis in 5 hospitals, of whom 860 received selective testing and 863 received uniform testing.
The study defined selective testing as D-dimer testing in outpatients with low to moderate C-PTP and excluded DVT if D-dimer <1.0 μg/ml and low C-PTP or D-dimer <0.5 μg/ml and moderate C-PTP; outpatients with high C-PTP and patients admitted to the hospital were not tested for D-dimer and underwent direct venous ultrasound examination.
Uniform testing was defined as D-dimer testing in all subjects, and DVT was excluded when the D-dimer level was <0.5 μg/ml. follow-up after 3 months revealed that the incidence of symptomatic venous thromboembolism was 0.5% in both groups. There was a 7.6% reduction in the proportion of overall patients with ultrasound, including a 21.0% reduction in the proportion of outpatients with low-grade C-PTP, and a 21.8% reduction in the proportion of patients with selective testing with D-dimer testing, concluding that a selective D-dimer testing strategy is more advantageous for identifying DVT.
D-dimer testing is commonly used in the diagnosis of diffuse intravascular coagulation (DIC), deep vein thrombosis (DVT), pulmonary embolism, myocardial infarction, and cerebral infarction, and can be used for the diagnosis of thrombotic disease and as an indicator for monitoring the dose of thrombolytic drugs and observing their efficacy. The diagnosis will be more specific when combined with the assessment of the patient’s associated deep vein thrombotic potential. D-dimer can be helpful in ruling out venous thrombosis when the clinical judgment is low or moderate likelihood in their patients, while further imaging is required for high likelihood.
In July 2013, JAmCollCardiol published online the American College of Cardiology (ACC) in conjunction with nine other leading medical institutions on the rational use criteria for noninvasive vascular laboratory testing to reduce unnecessary tests and to quickly use the most effective tests.
According to this standard, venous Doppler ultrasound is not recommended to screen for DVT formation in the upper or lower extremities in the absence of symptoms such as pain or swelling, including patients with prolonged ICU stays, post-operative orthopedic surgery, those in a hypercoagulable state and those who test positive for D-dimers. In the new criteria, 116 conditions are scored according to 8 major categories, which are ultimately classified as reasonable (median score 7-9), probably reasonable (median score 4-6) and not very reasonable (median score 1-3).
Vascular examination is generally reasonable in the presence of signs and symptoms, such as lower extremity venous ultrasound in the presence of acute unilateral extremity swelling, nonarticular lower extremity pain or palpable striae, pulmonary embolism, and pre-existing lower extremity DVT with new pain or swelling. However, more clinical effectiveness and cost-effectiveness studies are needed for noninvasive screening of venous disease.
Renda et al. at Boston University School of Medicine found that the diagnosis of pulmonary embolism with computed tomography pulmonary angiography (CTPA) can lead to overdiagnosis of pulmonary embolism. They observed an increase in the detection rate of pulmonary embolism in the US adult population from 1998-2006 from 62.1/100,000 to 112.3/100,000, with an 80% increase in the incidence of pulmonary embolism, while the death rate from pulmonary embolism decreased slightly from 12.3/100,000 to 11.9/100,000 over the same period.
After correcting for age, the in-hospital mortality rate of pulmonary embolism decreased by 1/3, indicating that most of the detected pulmonary embolism patients were non-fatal pulmonary embolism. Because of the lack of specificity and sensitivity of clinical signs and symptoms of pulmonary embolism, clinicians often overstep the symptom- and sign-based scoring system and proceed directly to imaging. The main hazard of overdiagnosis is the subsequent anticoagulation therapy that results, which may cause an increased risk of drug-related death.
CTPA detects many small pulmonary emboli, but whether they all require treatment remains to be studied further. A study of anticoagulation for isolated subsegmental pulmonary embolism showed an incidence of major bleeding of up to 5.3% and a recurrence rate of VTE of only 0.7%. The study recommended that for those with suspected pulmonary embolism, the possibility of pulmonary embolism should first be assessed based on the wells score and D-dimer, and imaging is not required when the wells score is <4 and the D-dimer level is normal.
CTPA is more sensitive and other tests are recommended in patients with stable clinical conditions. Pulmonary ventilation/perfusion scanning is more appropriate in relatively young patients with low likelihood of pulmonary embolism and renal insufficiency. Patients with suspected pulmonary embolism in the presence of DVT by ultrasound do not require further pulmonary imaging, as anticoagulation is required regardless of the findings.
For patients with isolated subpulmonary segmental pulmonary embolism, it is recommended to withhold anticoagulation and monitor for new respiratory symptoms for 3-6 months and to screen for thrombosis in the deep veins of the lower extremities with ultrasound, as the risks of anticoagulation outweigh the benefits. Patients need to know the risks and benefits prior to anticoagulation in order to make a decision on whether or not to proceed with anticoagulation.
Of interest, while it was previously thought that patients with a diagnosis of acute pulmonary embolism required hospitalization, a study published online by TheLancet on June 23, 2011, suggests the idea of outpatient treatment for low-risk pulmonary embolism.
The study included 1,551 patients with pulmonary embolism from four countries: Switzerland, France, Belgium, and the United States. 342 patients with acute symptomatic pulmonary embolism with a pulmonary embolism severity index risk class I or II were randomized to the inpatient and outpatient treatment groups and given subcutaneous enoxaparin (≥5 d) followed by oral anticoagulant therapy (≥90 d). The results showed that outpatient treatment was a safe and effective alternative to hospitalization in patients with selective low-risk pulmonary embolism.
However, it is important to note that the premise of the above observation is based on the risk stratification of low risk for acute pulmonary embolism, which resulted in a reduction of hospitalization time with outpatient treatment and only 2 cases of bleeding and 1 death. With the clinical application of new anticoagulants, such as rivaroxaban, apixaban, and other factor Xa antagonists, which eliminate the need to monitor patients’ prothrombin time and international normalized ratio (INR) and make outpatient treatment more convenient, the outpatient treatment of low-risk pulmonary embolism has a more favorable outlook, regardless of drug costs.
However, there are certain risks associated with outpatient treatment, especially in the current domestic medical environment. First, risk stratification assessment of patients for acute pulmonary embolism is extremely important. Patients with an initial risk stratification of low risk may progress to intermediate or high risk over the course of the disease.
We followed up 90 hospitalized acute pulmonary embolism patients with intermediate and low risk risk stratification in 2010 for 30 d. We found that 7 cases developed complications: 2 cases received a second thrombolytic therapy; 2 cases developed new lower extremity deep vein thrombosis during treatment; 1 case developed multi-organ dysfunction requiring vasoactive drugs for maintenance; and 1 case developed a drop in blood pressure during treatment requiring vasoactive drugs for maintenance.
Therefore, it is proposed that the detection of myocardial markers cardiac troponin I (cTnl), N-terminal brain natriuretic peptide precursor and serum myocardial-type fatty acid binding protein (H-FABP) in patients with intermediate-risk and low-risk pulmonary embolism, combined with clinical manifestations and dynamic observation of echocardiography, can be used for early disease assessment and short-term prognostic evaluation of acute pulmonary embolism. Second, frequent monitoring of plasma prothrombin time and INR compliance is required during initial warfarin anticoagulation.
If patients have poor compliance or are not monitored in a timely manner, there is a risk of prolonged INR, which increases the risk of bleeding, or non-attainment of INR, which does not achieve the desired anticoagulant effect and leads to exacerbation of the disease. Third, the number of enrolled cases in this study was only 171, and more case accumulation and observation are needed to confirm this conclusion clearly.
The clinical management of patients with intermediate-risk pulmonary embolism has become a focus of attention in recent years. 2011 American College of Cardiology guidelines recommend thrombolysis for patients with intermediate-risk pulmonary embolism with poor prognosis, i.e., new hemodynamic instability, worsening dyspnea, severe right heart insufficiency, or massive myocardial damage combined with a low risk of bleeding; whereas for patients with low- or intermediate-risk pulmonary embolism with mild right heart insufficiency, thrombolysis is recommended. Thrombolysis is not recommended for patients with mild right heart insufficiency or without clinical exacerbation.
In the 2012 American College of Chest Physicians (ACCP) recommendations in the 9th edition of the Antithrombotic and Thromboprophylaxis Guidelines, thrombolysis is not recommended in most hemodynamically stable patients, but is recommended in low-risk patients with the potential for further clinical deterioration and a low risk of bleeding or the potential for development of hypotension despite anticoagulation therapy. Thrombolysis can reduce acute symptoms and improve right heart function in patients with intermediate-risk pulmonary embolism, but it will not improve survival, and further studies are needed for the evaluation and long-term prognosis of such patients.
In terms of anticoagulation, several large international multicenter clinical studies published in recent years have achieved impressive results.
(1) LIFENOX study: The purpose of this prophylactic study was to further strengthen the concept of patient prevention of deep vein thrombosis. A total of 8307 medical patients (2071 from China) hospitalized for acute medical conditions were randomized to the low molecular heparin combined with compression stockings group and the compression stockings alone group.
The results found no significant difference in all-cause mortality at 3 months between the two groups; the effectiveness of the drug in preventing the development of VTE was further confirmed; and it had a long-term benefit. Meanwhile, the benefit of low-molecular heparin was questioned, although it reduced the incidence of asymptomatic and symptomatic VTE, but not the overall morbidity and mortality rate.
(2) Einstein study: 4832 patients with PE were enrolled in 263 centers in 38 countries in 20072011 and randomly assigned to 2 groups according to whether they had combined DVT. Of these, 2419 patients received rivaroxaban and 2413 received (enoxaparin + warfarin) standard therapy. The results showed that for acute symptomatic PE, rivaroxaban was noninferior to the standard treatment group in reducing the time to recurrent VTE; the efficacy was comparable to conventional treatment; the risk of major bleeding was reduced by 50%; and the efficacy was not affected by weight, age, sex, presence of tumor, or renal function. It was concluded that rivaroxaban has potential cost-effectiveness in the treatment of PE, which may shorten the length of hospital stay and reduce major bleeding and related costs.
(3) Apixaban (amplify) study: 5395 patients with acute symptomatic proximal lower extremity VTE and/or PE were enrolled in 358 centers in 28 countries worldwide. Patients were randomized to oral apixaban or subcutaneous enoxaparin followed by warfarin. The primary efficacy endpoint was recurrence of symptomatic VTE or death due to VTE; the primary safety endpoint was major bleeding or hemorrhage and other clinically significant bleeding events.
The results showed that 2.3% and 2.7% of patients in the apixaban and standard treatment groups, respectively, met the primary efficacy endpoint (RR=0.84), and the difference in efficacy between the apixaban group and the standard treatment group was statistically significant; the recurrence of VTE within 30 d was 0.2% and 0.3% in the two groups, respectively; and the incidence of major bleeding was 0.6% and 1.8%, respectively (RR=0.31). The incidence of major bleeding and other clinically significant bleeding events was 56% lower in the apixaban group (4.3%) compared with the standard treatment group (9.7%, RR=0.44); the incidence of other adverse events was not significantly different between the two groups.
It is concluded that apixaban can be used in a variety of patients with acute VTE, and the efficacy and safety observations in various acute subgroups of VTE patients suggest that apixaban can be used in patients aged >75 years, weighing >100 kg and who have applied parenteral anticoagulation therapy before enrollment. In patients with VTE who completed 6 months of anticoagulation therapy, apixaban significantly reduced the risk of VTE recurrence and death with extended treatment for 6 months compared with continued placebo, and could be a simple, effective and safe option for the initial and long-term treatment of acute VTE.
(4) Edusaban study: A global, event-driven, randomized, double-blind, parallel-controlled phase III clinical study was published online by NEnglJMed in September 2013, looking at 8,292 patients with symptomatic deep vein thrombosis (DVT) and/or pulmonary embolism at 439 clinical trial sites in 38 countries and territories.
The primary efficacy endpoint was symptomatic VTE recurrence, defined as the rate of symptomatic DVT, nonfatal symptomatic pulmonary embolism, and composite recurrence of fatal pulmonary embolism during the 12-week study period; the primary safety endpoint was the incidence of clinically relevant bleeding (major or nonmajor) during treatment or within 3 d of treatment interruption/discontinuation; secondary efficacy endpoints included symptomatic DVT recurrence, nonfatal pulmonary embolism recurrence and all-cause death as a composite clinical prognosis.
Patients were randomized to the warfarin (4122) and edusaban (4170) groups, both of which received at least 5 d of open-label enoxaparin or unfractionated heparin (UFH) treatment with warfarin or placebo, followed by double-blind edusaban 60 mg (reduced for patients with renal insufficiency, low body weight, or P-glycoprotein use), respectively. inhibitors) or warfarin for 3-12 months, with the duration of treatment determined by the investigator according to the clinical characteristics of the patient.
The 12-month follow-up results showed that clinical practice using this flexible treatment duration (3-12 months) in a broad range of VTE patients (including those with severe pulmonary embolism), including primary efficacy data for initial heparin therapy, showed a slightly lower rate of symptomatic VTE recurrence in the edusaban group (3.2%) than in the warfarin group (3.5%), indicating the non-inferiority of edusaban relative to warfarin.
In addition, established primary safety results for clinically relevant bleeding showed that the edusaban group (8.5%) was superior to warfarin (10.3%). It was concluded that edusaban was noninferior to warfarin in the treatment and long-term prevention of VTE recurrence in patients with acute symptomatic VTE, and that the group using edusaban after initial heparin anticoagulation was noninferior to the group using warfarin in the prevention of symptomatic or fatal VTE recurrence.
The noninferiority of edusaban efficacy was established by 12-month follow-up and different treatment periods, and edusaban was superior to vitamin K antagonists (warfarin) for the primary safety outcome of major or clinically relevant nonmajor bleeding during the treatment period; the efficacy and safety were similar for the full dose of edusaban (60 mg once/d) and the halved dose, which was indicated for patients with weight <60 kg or reduced creatinine clearance (≥ In patients with severe pulmonary embolism, edusaban may be more effective than warfarin.
Sixty years after the introduction of warfarin, new anticoagulants have provided more options for patients with VTE in recent years, but it should be noted that there are many unknown issues with the new drugs, such as strategies to inhibit the activity of the new anticoagulants. Interactions with other drugs, the basis for drug dose selection based on body weight, monitoring of bleeding and thrombotic complications, and countermeasures after treatment failure all await further observational studies.