Summary
Introduction
New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated ...comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta‐analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE.
Methods
We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random‐effects models.
Results
Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval CI 0.74–1.05), 1.02 (95% CI 0.39–5.96), and 0.97 (95% CI 0.83–1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41–0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15–0.87) and 1111. A fixed‐effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban.
Conclusions
NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.
Summary
Introduction
Treatment of acute venous thromboembolism (VTE) in cancer patients is challenging, owing to a high risk of recurrent VTE and bleeding complications. The anticoagulants of choice ...are low molecular weight heparins (LMWHs), because of a proven higher efficacy than vitamin K antagonists (VKAs) and a similar bleeding profile. The recently introduced new oral anticoagulants (NOACs) have the potential to be alternative options for these patients, as these drugs share practical advantages with LMWH, are administered orally, and had similar efficacy to VKAs but a lower bleeding risk in phase 3 studies in the general VTE population.
Methods
A systematic literature search was performed to identify phase 3 trials investigating NOACs for the treatment of VTE. The efficacy outcome was recurrent VTE, and the safety outcome was major and clinically relevant non‐major bleeding. Pooled incidence rates and risk ratios (RRs) were calculated for cancer patients and non‐cancer patients separately.
Results and discussion
Five studies were included, with 19 060 patients, of whom 973 (5.1%) had active cancer. The pooled incidence rates of recurrent VTE were 4.1% (95% confidence interval CI 2.6–6.0) in cancer patients treated with NOACs, and 6.1% (95% CI 4.1–8.5) in patients treated with VKAs (RR 0.66, 95% CI 0.38–1.2). The pooled incidence rates of major or non‐major clinically relevant bleeding were 15% (95% CI 12–18) in cancer patients treated with NOACs, and 16% (95% CI 9.9–22) in patients treated with VKAs (RR 0.94, 95% CI 0.70–1.3). These results form a solid basis for the initiation of a head‐to‐head comparison of NOACs with LMWH in cancer patients.
Abstract Long-term follow-up studies have consistently demonstrated that after an episode of acute pulmonary embolism (PE), half of patients report functional limitations and/or decreased quality of ...life up to many years after the acute event. Incomplete thrombus resolution occurs in one-fourth to one-third of patients. Further, pulmonary artery pressure and right ventricular function remain abnormal despite adequate anticoagulant treatment in 10–30% of patients, and 0.5–4% is diagnosed with chronic thromboembolic pulmonary hypertension (CTEPH) which represents the most severe long term complication of acute PE. From these numbers, it seems that CTEPH itself is the extreme manifestation of a much more common phenomenon of permanent changes in pulmonary artery flow, pulmonary gas exchange and/or cardiac function caused by the acute PE and associated with dyspnea and decreased exercise capacity, which in analogy to post-thrombotic syndrome after deep vein thrombosis could be referred to as the post-pulmonary embolism syndrome. The acknowledgement of this syndrome would both be relevant for daily clinical practice and also provide a concept that aids in further understanding of the pathophysiology of CTEPH. In this clinically oriented review, we discuss the established associations and hypotheses between the process of thrombus resolution or persistence, lasting hemodynamic changes following acute PE as well as the consequences of a PE diagnosis on long-term physical performance and quality of life.
Essentials
We performed a pooled analysis of 926 patients with cancer‐associated incidental pulmonary embolism (IPE).
Vitamin K antagonists (VKA) are associated with a higher risk of major ...hemorrhage.
Recurrence risk is comparable after subsegmental and more proximally localized IPE.
Our results support low molecular weight heparins over VKA and similar management of subsegmental IPE.
Summary
Background
Incidental pulmonary embolism (IPE) is defined as pulmonary embolism (PE) diagnosed on computed tomography scanning not performed for suspected PE. IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer‐associated IPE is scarce. We aimed to provide the best available evidence on IPE management.
Methods
Incidence rates of symptomatic recurrent venous thromboembolism (VTE), major hemorrhage, and mortality during 6‐month follow‐up were pooled using individual patient data from studies identified by a systematic literature search. Subgroup analyses based on cancer stage, thrombus localization, and management were performed.
Results
In 926 cancer patients with IPE from 11 cohorts, weighted pooled 6‐month risks of recurrent VTE, major hemorrhage and mortality were 5.8% (95% confidence interval CI 3.7–8.3%), 4.7% (95% CI 3.0–6.8%), and 37% (95% CI 28–47%). VTE recurrence risk was comparable under low molecular weight heparins (LMWH) and vitamin K antagonists (VKAs) (6.2% vs. 6.4%; hazard ratio HR 0.9; 95% CI 0.3–3.1), while 12% in untreated patients (HR 2.6; 95% CI 0.91–7.3). Risk of major hemorrhage was higher under VKAs than under LMWH (13% vs. 3.9%; HR 3.9; 95% CI 1.6–10). VTE recurrence risk was comparable in patients with an subsegmental IPE and those with a more proximally localized IPE (HR 1.1; 95% CI 0.50–2.4).
Conclusion
These results support the current recommendation to anticoagulate cancer‐associated IPE with LMWH and argue against different management of subsegmental IPE.
Essentials
The YEARS algorithm was designed to simplify the diagnostic workup of suspected pulmonary embolism.
We compared emergency ward turnaround time of YEARS and the conventional algorithm.
...YEARS was associated with a significantly shorter emergency department visit time of ˜60 minutes.
Treatment of pulmonary embolism was initiated 53 minutes earlier with the YEARS algorithm
Summary
Background
Recently, the safety of the YEARS algorithm, designed to simplify the diagnostic work‐up of pulmonary embolism (PE), was demonstrated. We hypothesize that by design, YEARS would be associated with a shorter diagnostic emergency department (ED) visit time due to simultaneous assessment of pre‐test probability and D‐dimer level and reduction in number of CT scans.
Aim
To investigate whether implementation of the YEARS diagnostic algorithm is associated with a shorter ED visit time compared with the conventional algorithm and to evaluate the associated cost savings.
Methods
We selected consecutive outpatients with suspected PE from our hospital included in the YEARS study and ADJUST‐PE study. Different time‐points of the diagnostic process were extracted from the to‐the‐minute accurate electronic patients’ chart system of the ED. Further, the costs of the ED visits were estimated for both algorithms.
Results
All predefined diagnostic turnaround times were significantly shorter after implementation of YEARS: patients were discharged earlier from the ED; 54 min (95% CI, 37–70) for patients managed without computed tomography pulmonary angiography (CTPA) and 60 min (95% CI, 44–76) for the complete study population. Importantly, patients diagnosed with PE by CTPA received the first dose of anticoagulants 53 min (95% CI, 22–82) faster than those managed according to the conventional algorithm. Total costs were reduced by on average €123 per visit.
Conclusion
YEARS was shown to be associated with a shorter ED visit time compared with the conventional diagnostic algorithm, leading to faster start of treatment in the case of confirmed PE and savings on ED resources.
Essentials
A stand‐alone D‐dimer below 750 μg/L has been proposed to rule out acute pulmonary embolism (PE).
This was a post‐hoc analysis on data from 6 studies comprising 7268 patients with ...suspected PE.
The negative predictive value of a D‐dimer <750 μg/L ranged from 79% to 96% in various subgroups.
Stand‐alone D‐dimer testing seems to be unsafe to rule out PE in all patients.
Summary
Background
Recently, stand‐alone D‐dimer testing at a positivity threshold of 750 μg L−1 has been proposed as a safe and efficient approach to rule out acute pulmonary embolism (PE), without additional imaging, but this approach needs validation.
Objectives
To evaluate stand‐alone D‐dimer testing at a positivity threshold of 750 μg L−1 to rule out PE.
Methods
Individual data from 7268 patients with suspected PE previously enrolled in six prospective management studies were used. Patients were assessed by the Wells rule followed by quantitative D‐dimer testing in those with a ‘PE unlikely’ score. Patients were classified post hoc as having a negative (< 750 μg L−1) or positive (≥ 750 μg L−1) D‐dimer. Using a one‐stage meta‐analytic approach, the negative predictive value (NPV) of stand‐alone D‐dimer testing was evaluated overall and in different risk subgroups.
Results
The pooled incidence of PE was 23% (range, 13–42%). Overall, 44% of patients had a D‐dimer < 750 μg L−1, of whom 2.8% were diagnosed with PE at baseline or during 3‐month follow‐up (NPV, 97.2%; 95% confidence interval CI, 94.9–98.5). The NPV was highest in patients with a low probability of PE according to the Wells rule (99.2%; 95% CI, 98.6–99.5%) and lowest in those with a high probability of PE (79.3%; 95% CI, 53.0–92.8%). The NPVs in patients with active cancer, patients with previous venous thromboembolism and inpatients were 96.2% (95% CI, 85.6–99.1%), 94.7% (95% CI, 88.6–97.6%) and 92.7% (95% CI, 79.3–97.7%), respectively.
Conclusions
Our findings suggest that stand‐alone D‐dimer testing at a positivity threshold of 750 μg L−1 is not safe to rule out acute PE.
Essentials
Imaging is warranted in the majority of patients to confirm or rule out pulmonary embolism (PE).
The age‐adjusted D‐dimer (ADJUST) reduced the number of required imaging tests in patients ...≥ 50 years.
The YEARS algorithm was designed to improve the efficiency in patients with suspected PE.
There was no added value of implementing ADJUST in the YEARS algorithm in our cohort.
Summary
Background
The YEARS algorithm was designed to simplify the diagnostic work‐up of pulmonary embolism (PE) and to reduce the number of necessary computed tomography pulmonary angiography (CTPA) scans. An alternative strategy to reduce the number of CTPAs is the age‐adjusted D‐dimer cut‐off (ADJUST) in patients aged 50 years or older. We aimed to investigate whether a combination of both diagnostic strategies might save additional CTPAs.
Methods
The YEARS algorithm consists of three items (clinical signs of deep venous thrombosis, hemoptysis, ‘PE most likely diagnosis’) with simultaneous D‐dimer testing using a pre‐test dependent threshold. We performed a post hoc analysis in 3465 patients managed according to YEARS to compare the number of patients managed without CTPA scans and associated diagnostic failures in hypothetical scenarios with different YEARS‐ADJUST combinations.
Results
Following the YEARS algorithm, 1651 patients (48%) were managed without CTPA; PE was diagnosed in 456 (13%) patients at baseline and 18 patients with initial normal testing suffered venous thromboembolism (VTE) during 3‐month follow‐up (failure rate 0.61%; 95% confidence interval CI, 0.36–0.96). If ADJUST had been fully integrated in YEARS, 1627 patients (47%) would have been managed without CTPA (absolute decrease of 0.69%; 95% CI −1.7 to 3.0), at cost of four additional missed PE diagnoses at baseline, for a projected 3‐month VTE failure rate of 0.75% (95% CI, 0.49–1.13). None of the other studied scenarios showed relevant improvements in efficiency as well, but all led to more missed diagnoses.
Conclusion
In our cohort, there was no added value of implementing ADJUST in the YEARS algorithm.
Essentials
Decision rules for pulmonary embolism are used indiscriminately despite possible sex‐differences.
Various pre‐imaging diagnostic algorithms have been investigated in several prospective ...studies.
When analysed at an individual patient data level the algorithms perform similarly in both sexes.
Estrogen use and male sex were associated with a higher prevalence in suspected pulmonary embolism.
Summary
Background
In patients suspected of pulmonary embolism (PE), clinical decision rules are combined with D‐dimer testing to rule out PE, avoiding the need for imaging in those at low risk. Despite sex differences in several aspects of the disease, including its diagnosis, these algorithms are used indiscriminately in women and men.
Objectives
To compare the performance, defined as efficiency and failure rate, of three pre‐imaging diagnostic algorithms for PE between women and men: the Wells rule with fixed or with age‐adjusted D‐dimer cut‐off, and a recently validated algorithm (YEARS). A secondary aim was to determine the sex‐specific prevalence of PE.
Methods
Individual patient data were obtained from six studies using the Wells rule (fixed D‐dimer, n = 5; age adjusted, n = 1) and from one study using the YEARS algorithm. All studies prospectively enrolled consecutive patients with suspected PE. Main outcomes were efficiency (proportion of patients in which the algorithm ruled out PE without imaging) and failure rate (proportion of patients with PE not detected by the algorithm). Outcomes were estimated using (multilevel) logistic regression models.
Results
The main outcomes showed no sex differences in any of the separate algorithms. With all three, the prevalence of PE was lower in women (OR, 0.66, 0.68 and 0.74). In women, estrogen use, adjusted for age, was associated with lower efficiency and higher prevalence and D‐dimer levels.
Conclusions
The investigated pre‐imaging diagnostic algorithms for patients suspected of PE show no sex differences in performance. Male sex and estrogen use are both associated with a higher probability of having the disease.
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