PREPIC

Published

Decousus H, et al. "A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis". The New England Journal of Medicine. 1998. 338(7):409-416.
PubMed • Full text • PDF

Clinical Question

In patients with acute proximal DVT, does routine IVC filter placement in addition to anticoagulation reduce the short-term incidence of acute pulmonary embolism?

Bottom Line

The addition of IVC filter placement to routine anticoagulation for patients with proximal DVT leads to a 4% absolute reduction in PE risk. The modest benefit of IVC filter placement was offset by doubling the rate of recurrent DVT at 2 years.

Major Points

Inferior vena cava (IVC) filters sit within the inferior vena cava to mechanically prevent the translocation of thrombus from the lower extremity deep veins to the pulmonary vessels, which would otherwise result in a pulmonary embolism (PE). The role of IVC filters in acute venous thromboembolic (VTE) disease is often unclear and rigorously debated. Given the well known efficacy of anticoagulation and the relative invasiveness of IVC filter placement, early IVC filters were usually reserved for patients with contraindications to or failure of anticoagulant therapy. But in the late 1990s, routine IVC filter placement became increasingly common in the wake of newer devices that could be placed percutaneously with relatively low complication rates. Whether this increase in IVC filter placement yielded meaningful clinical benefits was unclear given the lack of randomized trial data.

Published in 1998, the Prevention du Risque d'Embolie Pulmonaire par Interruption Cave (PREPIC) study randomized 400 patients with acute proximal leg DVT to anticoagulation plus permanent IVC filter placement, or to anticoagulation alone. (The anticoagulation strategy was also tested as part of a 2x2 factorial design, but is not presented here.) At 12 days, IVC filter placement resulted in a 4% absolute reduction in incident PE. However, this benefit was attenuated by a doubling in recurrent DVT risk at 2 years (10% in no filter group vs. 20% with filter). Notably, there was no murvivalortality benefit with filter placement. These outcomes were confirmed at 8 years of follow-up, showing durable 9% absolute risk reduction in PE with 10% absolute risk increase in recurrent DVT and no survival benefit.

A major criticism of PREPIC is that its investigators used then-state-of-the-art permanent (rather than contemporary retrievable) IVC filters, which may represent a persistent thrombogenic nidus and therefore increase VTE recurrence risk. Several subsequent case series suggested that placement of a temporary IVC filter may reduce early mortality. PREPIC 2 (2015) tested this theory in a randomized prospective fashion, evaluating the routine placement of a modern retrievable IVC filter in patients with at least one risk factor for VTE recurrence (age >75 years, malignancy, or PE). PREPIC 2 demonstrated no benefit for temporary (3 months) placement of a retrievable IVC filter. In light of PREPIC and PREPIC 2, routine IVC filter placement is not recommended in most cases of VTE.

Guidelines

ESC Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism (2014, adapted)

• Routine use of IVC filters is not recommended (Grade 3A)
• IVC filters should be considered in patients with acute PE and absolute contraindication 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 (2016, adapted)

• In patients with acute DVT or PE who are treated with anticoagulants, recommend against the use of an IVC filter (Grade 1B).

Design

• Multicenter, unblinded, randomized-controlled trial
• N=400 patients with proximal DVT
  • IVC filter plus anticoagulation (n=200)
  • Anticoagulation alone (n=200)
• Setting: 44 centers in France
• Enrollment: 1991-1995
• Duration of follow-up: 2 years
• Analysis: Intention-to-treat
• Primary outcome: Incidence of PE at 12 days

Population

Inclusion Criteria

• Age >18 years
• Acute proximal DVT by venography
  • With or without concurrent PE

Exclusion Criteria

• Previous IVC filter in place
• Contraindication to or failure of anticoagulant therapy
• Curative anticoagulant therapy for >48h prior to enrollment
• Indication for thrombolysis
• Limited life expectancy
• Iodine allergy
• Hereditary thrombophilia
• Severe renal or hepatic disease
• Pregnancy
• Likelihood of noncompliance

Baseline Characteristics

From the filter group:

• Demographics: Mean age 75 years, female 51%
• Comorbidities: Chronic cardiac or pulmonary disease 20%
• VTE risk factors: Malignancy 12%, surgery within past 60 days 13%, hx of VTE 36%
• VTE characteristics: Popliteal 5%, femoral 52%, iliac 38%, caval 4%, symptomatic initial PE 34$, asymptomatic initial PE 14%

Interventions

2×2 factorial randomization

• IVC filter placement vs. no placement
• Unfractionated heparin (UFH) vs. low molecular weight heparin (LMWH)

IVC filter placement

• Four permanent IVC filter types acceptable (Vena Tech LGM, titanium Greenfield, Cardial, Bird's Nest)

Anticoagulation

• In the UFH group, patients received UFH 5000 IU bolus followed by 500 IU/kg infusion adjusted to achieve PTT 1.5-2.5× baseline PTT).
• In the LMWH group, patients received enoxaparin 1 mg/kg twice daily)
• All patients started warfarin or acenocoumarol on day 4 and continued for at least 3 months with goal INR 2-3
• UFH or LMWH was continued for 8-12 days (until INR was therapeutic for at least 48 hours)

Diagnostic imaging

• Screening
  • All patients underwent initial baseline V/Q scan
  • Patients with significant abnormalities on V/Q scan referred for pulmonary angiography
  • Initial PE considered present if high probability on V/Q scan or positive pulmonary angiography
• Monitoring
  • All patients underwent serial V/Q scan if clinical suspicion for new PE
  • All patients also underwent routine V/Q scan between days 8-12 to detect asymptomatic PE
  • PE diagnosed if positive pulmonary angiography or at least two new mismatched defects with no improvement in other areas
• New DVT diagnosed by new filling defect on venography, noncompressibility at a new site, or extension to a new venous segment on doppler ultrasound

Follow-up

• Patients followed routinely at 12 days, three months, one year, and two years

Outcomes

Comparisons are IVC filter vs. anticoagulation alone.

Primary Outcomes

Incident PE at 12 days

2 (1.1%) vs. 9 (4.8%) [OR 0.22; 95% CI 0.05-0.90; P=0.03)

Secondary Outcomes

Death at 12 days

5 (2.5%) vs. 5 (2.5%) [OR 0.99; 95% CI 0.29-3.42; P=0.99)

Death at 2 years

43 (21.6%) vs. 40 (20.1%) [OR 1.10; 95% CI 0.72-1.70; P=0.65)

Symptomatic PE at 2 years

6 (3.4%) vs. 12 (6.3%) [OR 0.50; 95% CI 0.19-1.33; P=0.16)

Recurrent DVT at 2 years

37 (20.8%) vs. 21 (11.6%) [OR 1.87; 95% CI 1.10-3.20; P=0.02)

Adverse Events

Major Bleeding at 12 days

9 (4.5%) vs. 6 (3.0%) [OR 1.49; 95% CI 0.53-4.20; P=0.44)

Major Bleeding at 2 years

17 (8.8%) vs. 22 (11.8%) [OR 0.77; 95% CI 0.41-1.45; P=0.41)

Criticisms

• Patients with an indication for lytic therapy were excluded, although these patients with higher-risk VTE lesions may be more likely to benefit from IVC filter placement for added protection from PE.
• It is unclear why the results of PREPIC and the PREPIC follow-up study are not corroborated by the later PREPIC 2 study, although these differences may relate to improvements in VTE management over time and the inclusion of patients receiving lytic therapy in the latter.
• This was an unblinded study, leaving the possibility of bias in event adjudication (by investigators) and event reporting (by subjects). This is somewhat mitigated by systematic performance of V/Q scans between days 8-12 regardless of symptoms.
• Long-term follow-up data obtained by reliance on patient report/self-presentation, possibly reducing event detection rate and leaving open possibility for asymmetric reporting between arms (eg, patients without filters more likely to request evaluation for symptoms compatible with PE).
• Study limited to French centers and specific IVC filter devices, possibly limiting generalizability to other countries.

Funding

• B. Braun Laboratories, the manufacturer of one of the four IVC filters studied in PREPIC, was a cosponsor.