Mismetti P, Laporte S, Pellerin O, Ennezat PV, Couturaud F, Elias A, et al. Effect of a Retrievable Inferior Vena Cava Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism: A Randomized Clinical Trial. JAMA. 2015 Apr 28;313(16):1627
Introduction
More than half a century ago, Kazi Mobin-Uddin et al. reported the use of an intra-caval prosthetic device for the prevention of pulmonary embolism in 15 patients (1). A graduate of King Edward Medical College, Lahore, Mobin-Uddin underwent training in thoracic and vascular surgery at the Jackson Memorial Hospital, Miami. During his tenure as assistant professor, he conceptualized the passage of a filter into the inferior vena cava through the internal jugular vein that would impede the passage of clots. The umbrella device consisted of stainless-steel spokes arising from a central hub, enmeshed with a thin sheet of silicon rubber. In a later study, the umbrella filter was placed in a series of 100 patients (2). The device appeared effective, with recurrent embolism occurring in only two patients. There were no deaths directly related to the procedure. The authors concluded that the umbrella filter placement appeared to be a safe and effective technique to prevent recurrent pulmonary embolism. Refinements in technology led to the introduction of the Kimray-Greenfield filter, that carried a lower incidence of inferior vena caval occlusion compared to the groundbreaking Mobin-Uddin umbrella filter. In 1984, Tadavarthy et al. described the percutaneous insertion technique of the Kimray-Greenfield filter through the internal jugular or femoral approach (3).
The inferior vena cava filter is often used in conjunction with full-dose anticoagulant therapy in patients with acute pulmonary embolism with a large clot burden, compromised cardio-pulmonary function, or when the risk of recurrence is deemed to be high. Clinicians generally resorted to filter placement based on their judgment, considering the lack of prospective controlled studies that evaluated clinical outcomes. Despite the absence of robust evidence regarding clinical benefit, a sharp increase in filter placement was observed over the years; besides, guideline recommendations also remained variable (4,5). Inferior vena cava filters are associated with complications, including device migration, fracture and embolization, vena caval occlusion, and perforation.
The PREPIC 1 randomized controlled trial (RCT) had previously evaluated the placement of permanent inferior vena cava filters compared with anticoagulation alone in patients with proximal deep vein thrombosis who were considered to be at high risk for pulmonary embolism. At 12 days, pulmonary embolism, symptomatic or otherwise, was less common among patients who received filters compared to those who did not. However, at the 2-year follow-up, there was a significantly higher incidence of recurrent deep vein thrombosis in the filter group (6). A further follow-up study was carried out at 8 years to evaluate long term outcomes. Symptomatic pulmonary embolism remained significantly lower in the filter compared with the no-filter group. However, the incidence of deep vein thrombosis continued to remain higher in the filter group. There was no difference in all-cause mortality between the two groups (7).
The advent of retrievable filters held the potential to reduce the incidence of long-term, device-related complications. Temporary filter placement to cover the period of risk with subsequent removal, in combination with anticoagulation could potentially prevent early, recurrent pulmonary embolism, while minimizing filter-related complications.
The PREPIC 2 trial evaluated the potential benefit of placement of a retrievable inferior vena cava filter combined with anticoagulation compared with anticoagulation alone in patients with acute pulmonary embolism with a high risk of recurrence (8). Filter retrieval was mandatory after 3 months; anticoagulation was continued for a minimum duration of 6 months.
Population and design
The PREPIC 2 (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) multicenter trial was conducted between August 2006 and July 2012 across 17 centers in France. Adult patients, 18 years or older, with symptomatic acute pulmonary embolism and venous thrombosis of the lower limb were eligible. Pulmonary embolism was confirmed by standard testing, including spiral CT, ventilation-perfusion scan, or pulmonary angiography; lower limb venous thrombosis was diagnosed by compression ultrasonography and or venography. One of the following additional severity criteria had to be met for study inclusion.
- Age >75 years
- Chronic cardiac or respiratory insufficiency
- Ischemic stroke with paralysis of the lower limb in the preceding 6 months
- Deep vein thrombosis involving the ilio-caval segment or bilateral, or at least one sign of right ventricular dysfunction or myocardial injury, as evident on echocardiography, or by increase in the level of biomarkers
Excluded
- Insertion of vena cava filter was otherwise indicated
- Thrombosis of the vena cava that precluded insertion
- Full anticoagulation was administered for >72 hours before randomization
- Non-cancer surgery in the preceding 3 months or cancer surgery within 10 days
- Allergy to contrast media
- Raised serum creatinine level of >2.04 mg/dl
- Life expectancy <6 months
- Pregnancy
Patients were randomized to the filter group or the control group. Randomization was carried out in permuted blocks of 4 or 6, stratified by center and creatinine clearance.
Intervention (the filter group)
A retrievable vena cava filter was inserted within 72 hours of randomization; among those who underwent thrombolysis, insertion was performed after 36 hours of therapy. Adequately experienced vascular or interventional radiologists carried out the procedure according to standardized guidelines. Filter retrieval was planned 3 months after insertion.
Anticoagulation alone (the control group)
In both groups, anticoagulation therapy was continued for a minimum duration of 6 months; continued treatment was individualized and left to clinician discretion. Although the choice of anticoagulant medication was based on clinician choice, unfractionated heparin was recommended in the presence of renal dysfunction. Long-term anticoagulant therapy was continued with vitamin K antagonists. In patients with cancer, low-molecular-weight heparin was preferred over vitamin K antagonists.
Sample size
The primary outcome was recurrent pulmonary embolism at 3 months; recurrence could be fatal, or symptomatic, but non-fatal. The authors hypothesized a 75% reduction in the primary outcome in the filter group. A sample size of 400 patients provided the study with 80% power to detect a significant difference between groups.
Results
During the 6-year study period, the PREPIC 2 trial randomized a total of 399 patients – 200 to the filter group and 199 to the control group. In the filter group, device insertion was successful in 193 of 195 patients (99%) on whom it was attempted. Filter removal was attempted in 164 and successful in 153 patients. In the control group, six patients underwent filter insertion; these patients could not be anticoagulated – an invasive procedure or surgery was required in four patients, while bleeding complications occurred in the other two. Patients were well-matched at baseline. In the filter group, 55% of patients were aged >75 years, compared to 49.7% in the control group. Active cancer was present in 16.6% and 14.6% of patients, respectively. Bilateral deep vein thrombosis was identified in nearly 13% of patients in both groups. There was evidence of right ventricular dysfunction or myocardial injury in 66.7% patients in the filter group and 65.2% of patients in the control group. In most cases (74% in the filter group and 79.4% in the control group), pulmonary embolism was unprovoked.
Outcomes
Recurrent pulmonary embolism – the primary outcome
Recurrent pulmonary embolism at 3 months of follow-up occurred in six (3%) of patients in the filter group and three (1.5%) of patients in the control group. The absolute difference was +1.5% in the filter group. The relative risk (RR) with filter insertion was not significantly different compared with the control group (RR, 2.00 [95% CI, 0.51 to 7.89]; P = 0.50). Among the nine patients who developed recurrent pulmonary embolism, there was a lone survivor in the control group. Between 3–6 months, one patient developed pulmonary embolism in each group.
Other 3-month outcomes
The mortality at 3 months was not significantly different between the two groups (7.5% vs. 6.0%). Recurrent deep vein thrombosis, venous thromboembolism, and major bleeding also occurred with similar frequency in both groups.
Six-month outcomes
Clinical outcomes at 6 months were similar in both groups. By then, recurrent pulmonary embolism had occurred in 7 patients (3.5%) in the filter group and 4 (2.0%) in the control group. Among these 11 patients, there was just the lone survivor in the control group among those who developed recurrent pulmonary embolism. Recurrent deep vein thrombosis was uncommon (one patient in the filter group and 2 in the control group). Major bleeding occurred in 13 patients (6.5%) in the filter group and 15 (7.5%) in the control group. By 6 months, 21 patients (10.6%) had died in the filter group compared with 15 (7.5%) in the control group.
Adverse events related to filter insertion
Among 193 patients who underwent filter insertion, hematoma at the site of insertion occurred in 5 patients (2.6%) and filter thrombosis, in 3 (1.6%) patients. Cardiac arrest occurred in one patient during insertion. Retrieval was unsuccessful in 11 patients (5.7%) due to mechanical problems.
Strengths
Although the use of inferior vena cava filters had increased over the years, there was no firm evidence regarding its efficacy in the prevention of recurrent pulmonary embolism. Besides, the use of permanent filters carried their own share of complications. The introduction of retrievable filters in the early 2000s was a step forward in reducing filter-related complications. The PREPIC 2 trial addressed an important clinical question – does the use of retrievable filters combined with anticoagulation reduce the incidence of recurrent pulmonary embolism among patients at high risk? The trial was multicentric, including 17 centers in France. Analysis was by intention-to-treat and follow-up was nearly complete at 6 months. The study came up with robust findings regarding the lack of efficacy of the inferior vena cava filter in reducing the incidence of recurrent pulmonary embolism among patients who were appropriately anticoagulated.
Limitations
The trial was unblinded; however, a concealed randomization system and a central adjudication committee who were blinded to treatment assignment mitigated the risk of bias. The incidence of recurrent pulmonary embolism was only 1.5% in the control arm – well below the expected incidence of 8%, which may have led to an inadequate sample size. The filter retrieval rate was high (153/193 patients) which may be generally hard to achieve in the real world.
The PREPIC 2 trial studied a cohort of patients in whom full anticoagulant therapy was feasible. Filter placement may, however, be an alternative treatment option among patients in whom anticoagulation is contraindicated or ineffective. Furthermore, in patients with a large, mobile, lower limb thrombus, filter placement could potentially prevent massive pulmonary embolism.
Summary
The PREPIC 2 demonstrated that the use of a retrievable inferior vena cava filter in combination with anticoagulation compared with anticoagulation alone does not reduce the incidence of symptomatic recurrent pulmonary embolism associated deep vein thrombosis among patients at high risk of recurrence. The findings of the study fail to substantiate the placement of retrievable filters in patients who can be safely treated with anticoagulation. Based on the findings of this trial, inferior vena cava filter placement should probably be confined to patients with contraindications to anticoagulation, or those who have recurrent pulmonary embolism despite adequate anticoagulation. The PREPIC 2 trial enabled increased clarity regarding the appropriate use of inferior cava filters in patients who are at high risk of recurrent pulmonary embolism.
References
1. Mobin-Uddin K, McLean R, Bolooki H, Jude JR. Caval Interruption for Prevention of Pulmonary Embolism: Long-Term Results of a New Method. Arch Surg. 1969 Dec 1;99(6):711–5.
2. Mobin-Uddin K, Callard GM, Bolooki H, Rubinson R, Michie D, Jude JR. Transvenous Caval Interruption with Umbrella Filter. N Engl J Med. 1972 Jan 13;286(2):55–8.
3. Tadavarthy SM, Castaneda-Zuniga W, Salomonowitz E, Lund G, Cragg A, Hunter D, et al. Kimray-Greenfield vena cava filter: percutaneous introduction. Radiology. 1984 May;151(2):525–6.
4. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008 Sep;29(18):2276–315.
5. Caplin DM, Nikolic B, Kalva SP, Ganguli S, Saad WEA, Zuckerman DA, et al. Quality improvement guidelines for the performance of inferior vena cava filter placement for the prevention of pulmonary embolism. J Vasc Interv Radiol JVIR. 2011 Nov;22(11):1499–506.
6. Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998 Feb 12;338(7):409–15.
7. PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005 Jul 19;112(3):416–22.
8. Mismetti P, Laporte S, Pellerin O, Ennezat PV, Couturaud F, Elias A, et al. Effect of a Retrievable Inferior Vena Cava Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism: A Randomized Clinical Trial. JAMA. 2015 Apr 28;313(16):1627.
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