PREPIC 2

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Mismetti P, 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". The Journal of the American Medical Association. 2015. 313(16):1627-35.
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Clinical Question

In patients with acute pulmonary embolism and a high risk of recurrence, does the addition of an IVC filter to anticoagulation alone reduce the risk of symptomatic recurrent pulmonary embolism?

Bottom Line

In patients with pulmonary embolism at high risk of recurrence, the routine placement of a retrievable IVC filter does not reduce the risk of recurrent pulmonary embolism when compared to anticoagulation alone.

Major Points

Despite therapeutic anticoagulation, some patients with acute VTE experience recurrent events, and IVC filters have been theorized to reduce recurrence. The initial PREPIC study (1998) demonstrated that among patients with acute proximal DVT, permanent IVC filter placement reduced the rate of recurrent PE but markedly increased rates of DVT compared to anticoagulation alone, and had no impact on overall survival.[1] Consequently, standard practice is to offer IVC filters only to patients with contraindications to anticoagulation. PREPIC 2 sought to identify a subpopulation of patients with acute VTE in whom the risk of early recurrence was so great that perhaps temporary placement of a retrievable IVC filter may improve clinical outcomes compared to standard anticoagulation alone.

Published in 2015, PREPIC 2 enrolled 399 patients with acute PE associated with low-extremity deep or superficial venous thrombosis, who had ≥1 additional risk factor for recurrence (age >75 years, active malignancy, RV dysfunction, etc.). Patients were randomized to placement or no placement of a retrievable IVC filter in an open-label fashion with retrieval at 3 months; all patients received ≥6 months of anticoagulation at the investigators' discretion. There was no difference in the primary outcome of recurrent symptomatic PE at 3 months (3% vs. 1.5%; P=0.50), nor were there significant differences at 6 months. The authors conclude that among patients with acute PE at high risk of recurrence, temporary placement of a retrievable IVC filter should not be routinely performed; IVC filters should generally be reserved for patients with contraindications to anticoagulation. The authors acknowledge that the applicability of these findings to certain patient subgroups (including those with massive PE) is uncertain.

Guidelines

ESC Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism, 2014[2]
Routine use of IVC filters is not recommended (Grade 3A)
IVC filters should be considered in patients with acute PE and absolute contraindications to anticoagulation (Grade 2C)
IVC filters should be considered in cases of recurrence of PE, despite therapeutic levels of anticoagulation (Grade 2C)
ACCP Antithrombotic Therapy for VTE Disease, 2012[3]
In patients with acute PE who are treated with anticoagulants, we recommend against the use of an IVC filter (Grade 1B).
In patients with acute PE and contraindication to anticoagulation, we recommend the use of an IVC filter (Grade 1B).

These guidelines do not reflect the findings of this study.

Design

  • Multicenter, blinded end point, randomized, controlled trial
  • N=399 patients with acute PE and high risk of recurrence
    • IVC filter (n=200)
    • No IVC filter (n=199)
  • Setting: 17 centers in France
  • Enrollment: 2006-2012
  • Follow-up: 3 and 6 months
  • Analysis: Intention-to-treat
  • Primary outcome: Recurrent symptomatic PE at 3 months

Population

Inclusion Criteria

  • Acute, symptomatic pulmonary embolism, AND
  • Deep or superficial vein thrombosis, AND
  • At least one of the risk factors below:
    • Age > 75
    • Chronic heart failure
    • Chronic respiratory insufficiency
    • Active cancer
    • RV dysfunction or myocardial injury
    • Stroke <6 months prior with leg paralysis
    • Bilateral deep vein or ilio-caval thrombosis

Exclusion Criteria

  • Contraindication to anticoagulation or IVC filter
  • Recurrent thromboembolic event despite adequate anticoagulation
  • Recent surgery

Baseline Characteristics

  • Age 74 years
  • Female 51%
  • Unprovoked PE 74%
  • History of VTE 35%
  • History of cancer 7.5%
  • Hormone therapy 9%
  • Known thrombophilia 1%
  • Age >75 years 55%
  • Active cancer 17%
  • RV dysfunction or myocardial injury 67%

Interventions

  • Patients were randomized to IVC filter plus anticoagulation or to anticoagulation alone (with concealed allocation)
    • Both groups received full dose anticoagulation per guidelines, with choice of therapy left to physician discretion
    • Experimental group had a retrievable IVC filter inserted <72 hrs of randomization
  • All IVC filters were to be retrieved at 3 months (after US or venography to detect filter thrombosis).
  • All patients to return at 3 and 6 months for reassessment.

Outcomes

Comparisons are IVC filter vs. anticoagulation alone.

Primary Outcomes

Symptomatic or fatal recurrent pulmonary embolism at 3 months
3.0% vs. 1.5% (RR 2.00; 95% CI 0.51-7.89; P=0.50)

Secondary Outcomes

All-cause mortality at 6 months
10.6% vs 7.5% (RR 1.40; 95% CI 0.74-2.64; P=0.29)
Recurrent pulmonary embolism at 6 months
3.5% vs. 2.0% (RR 1.75; 95% CI 0.52-5.88; P=0.54)
Major bleeding
6.5% vs. 7.5% (RR 0.87; 95% CI 0.42-1.77; P=0.69)

Criticisms

  • Filter retrieval rates during a randomized controlled trial are likely to be higher than real world conditions, especially since every surviving patient in this arm attended their 3 month follow-up appointment.
  • The patients included in this study vary widely with respect to the clinical conditions that put them at risk for recurrent thrombosis, making it difficult to apply this study to a specific clinical context.

Funding

French Department of Health, Fondation de l'Avenir, Fondation de France, and University Hospital of Saint-Etienne. IVC filters provided by ALN Implants Chirurgicaux.

Further Reading

  1. 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. 112:416-22.
  2. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism
  3. ACCP Guidelines: Antithrombotic Therapy for VTE Disease. 2012.