Dr. Nicolas Meneveau,
A 48 year old female with hypertension, obesity, diabetes mellitus and diabetic nephropathy (glomerular filtration rate (GFR) = 53 mL/min) presented in June 2014 with unprovoked intermediate low-risk pulmonary embolism (PE) (echocardiographic right ventricular (RV) dysfunction, no troponin elevation), and normal (negative) compression ultrasonography (CUS). There was no deep vein thrombosis (DVT). Rivaroxaban was initiated at a dose of 15 mg b.i.d. for 3 weeks, and then 20 mg o.d. for 6 months.
In January 2015, the anticoagulation was discontinued. The patient’s course was uneventful and RV function had normalized at echocardiography.
In February 2015, she underwent planned investigation for heritable thrombophilia, and we found that she was heterozygous for Factor V Leiden, and she also had an increased D-Dimer (DD) concentration at 780 µg/L.
Regarding the risk of recurrent PE in this patient.
The risk of recurrent PE is…
Indeed, the recurrence rate after symptomatic VTE is high especially within the first 6 to 12 months and after discontinuation of anticoagulant therapy. The overall cumulative recurrence rate in a population-based cohort study by Heit et al was approximately 5% at 30 days, 10% at 6 months and 23% at 5 years (1) (Figure 1). In addition, patients with a first symptomatic unprovoked DVT and/or PE are 2.3 times more likely to have recurrent VTE than patients with a first secondary VTE (2) (Figure 2).
Regarding the risk of recurrence according to DD level, in the PROLONG study, the relative risk of recurrence was 2.5 times higher in patients with an abnormal DD level compared to those with normal DD level 1 month after discontinuation of anticoagulation (3) (Figure 3).
Similarly, patient’s sex is a major determinant of recurrent VTE after an initial episode of unprovoked VTE. The risk of recurrence is higher in men than in women with an adjusted relative risk of 3.6. At 5 years, the likelihood of recurrence was 31% among men compared to 8.5% among women, corresponding to an adjusted relative risk of 3.6 (4) (Figure 4).
Finally, the risk of recurrence is not strongly associated with heterozygous Factor V Leiden polymorphism. In a pooled analysis from 10 studies, Factor V Leiden was present in 21.4% of patients and associated with a 41% increase in recurrent VTE after discontinuation of anticoagulation (5) (Figure 5). However, in the LETS study, presence of thrombophilia did not appear to impact the cumulative incidence of recurrent thrombotic events at 10 years follow-up (6) (Figure 6). In summary, although there is some evidence in favour of an impact of thrombophilia, the magnitude of the impact does not justify recommending long-term therapy on the basis of that alone.
Therefore, in response to Question 1, the correct answers are A, B, C.
So, our patient was considered to be at high risk for recurrent PE. It is unclear whether baseline imaging tests are recommended in this setting. Indeed, there are very few data on the management of recurrent PE in the literature. The guidance published on behalf of the Scientific and Standardization Committee of the International Society on Thrombosis & Haemostasis recommends against routine CT pulmonary angiography (CTPA) or lung scan as baseline imaging tests in patients with a previous episode of PE, except in those considered to be at high risk of recurrence (7).
Accordingly, a ventilation perfusion scan was performed at 6 month follow-up as baseline imaging test in our patient. V/Q scan was preferred over CT scan due to diabetic nephropathy that deteriorated. There was a residual perfusion defect of the left upper lobe, corresponding to residual pulmonary vascular obstruction of approximately 10% (Figure 7).
Long-term anticoagulation or indefinite anticoagulation was considered in this patient at high risk of recurrence. The bleeding risk was assessed as intermediate, including hypertension, patient’s sex and renal insufficiency. However, the patient refused this therapeutic option. She was referred to the emergency ward 3 months later in May 2015 for acute dyspnea and chest discomfort lasting for 24 hours. At initial clinical examination, systolic blood pressure was 110 mmHg, and heart rate was 95 bpm. The patient presented with tachypnoea with a respiratory rate of 25 breaths per min. Blood-gas analysis revealed hypoxaemia and arterial saturation was 94% breathing room air.
A diagnosis of recurrent PE is considered in this patient
In patients with clinically suspected acute recurrent PE:
In a meta-analysis by Fabia Valls et al, recurrent PE was safely excluded based on a clinical prediction rule, followed by a DD test and/or CT pulmonary angiography (8). The 3-month VTE incidence rate was 0.8% after a PE unlikely clinical prediction rule and negative DD test, and 1.6% in patients in whom PE was excluded by a negative CT pulmonary angiography, and 1.4% overall. The efficiency of the algorithm is slightly lower in patients with a history of VTE compared to patients without a history of VTE. The combination of pretest probability and DD was able to exclude recurrence in approximately 15% of patients with prior VTE vs 30% in patients without prior VTE. The higher pretest probability, the lower specificity of the DD test and the lower sensitivity of the CT pulmonary angiography contribute to this lower efficiency (Figure 8).
The guidance from the ISTH suggests use of a validated clinical prediction rule to determine a pretest probability score to drive the diagnostic process in patients with suspected recurrent PE (7). In patients with suspected recurrent VTE and a likely or intermediate/high pretest probability, D-Dimer testing should not be performed and patients should be investigated initially with imaging tests (7). Lastly, imaging tests may be withheld in patients with suspected recurrent VTE if they have a low or unlikely pretest probability and a high sensitive D-dimer assay is negative (7).
Usual criteria for PE diagnosis in patients with no history of VTE should also be used for the diagnosis of PE in patients with suspected recurrence. CTPA is the preferred imaging test in this setting. The ISTH suggests ordering the same test used for the diagnosis of the first event in case of suspected recurrence, and evaluation by ventilation/perfusion (V/Q) lung scan may be carried out in patients with suspected recurrent PE who have an available baseline scan (7).
Therefore, in response to Question 2, the correct answers are C and E.
The simplified Geneva score and the Wells rule confirmed a likely pretest probability. Consequently, DD test was not performed. Repeat V/Q scan showed new filling defects of the right upper lobe and the middle lobe, while residual vascular obstruction of the left lung remained unchanged (Figure 9).
You consider the treatment strategy in this patient.
The risk of recurrence is too high (not low enough) to justify stopping anticoagulant therapy in patients with a first unprovoked VTE on the basis of 2 negative DD tests after a standard period of anticoagulation (9) (Figure 10).
There is clear evidence today that patients with PE have a substantial increase in the risk of recurrence after discontinuation of oral anticoagulation, regardless of treatment duration. A similar trend was observed in a randomised Italian trial (10), as well as in the RESONATE (11) and PADIS PE (12) trials. The benefit of additional anticoagulation was not maintained after discontinuation of anticoagulation therapy. These results plead in favour of indefinite treatment in the setting of unprovoked PE in low bleeding risk patients (Figure 11).
Regarding the duration of anticoagulation therapy, the ESC guidelines state that anticoagulation treatment of indefinite duration is recommended for patients with a second episode of unprovoked PE (Grade 1B) (13).
Regarding the indications of inferior vena cava (IVC) filter insertion, the PREPIC study reported that IVC filters reduced the risk of pulmonary embolism but increased the risk of deep-vein thrombosis and had no effect on survival at 8 year follow-up (14).
Therefore, in response to Question 3, the correct answer is D.
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