ATTRACT

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Vedantham S, et al. "Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis". The New England Journal of Medicine. 2017. 377(23):2240-2252.
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Clinical Question

In patients with proximal LE deep-vein thrombosis, does pharmaco-mechanical catheter-directed thrombolysis reduce the risk of post-thrombotic syndrome?

Bottom Line

The addition of pharmacomechanical catheter-directed thrombolysis for patients with acute LE proximal deep-vein thrombosis did not lower the risk of post-thrombotic syndrome, and resulted in higher risk of major bleeding.

Major Points

Post-thrombotic syndrome (PTS) is a chronic and potentially debilitating complication of DVT characterized by chronic swelling and pain and occasionally ulcers due to venous insufficiency.[1] Approximately 50% of patients with a DVT develop some degree of PTS and up to 10% will develop severe PTS.[2] This syndrome is the result of chronic venous hypertension from inflammatory-mediated damage to the venous walls and valves in the weeks to months following development of a thrombus.[1] As there is a general lack of effective treatments for PTS, recent efforts have focused on prevention of the condition through accelerating resolution of the thrombus. Interventions like tPA/thrombolytics at time of acute DVT diagnosis may dissolve some or most of the clot and reduce the duration and severity of DVT-related inflammation, which may in turn reduce the risk of PTS development. The CaVenT study[3] assessed catheter-directed tPA among ~200 patients with an acute iliofemoral DVT with symptoms starting in the prior 21 days. Compared to standard anticoagulation, tPA was associated with a modest 14% reduction in PTS at 24 months (55% vs. 41%). Validation of these findings in a larger group plus understanding the utility of mechanical thrombus removal and stent placement was needed.

Published in 2017, the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) study enrolled 691 adults from 56 centers with symptomatic acute DVT in the iliac or femoral artery and symptom onset in <14 days. Participants were randomized to pharmacomechanical intervention (intrathrombus-delivered tPA plus mechanical thrombectomy and venous stenting if needed) or anticoagulation alone. At 24 months, there was no significant difference in the incidence of PTS between groups (47% intervention vs. 48% control, P=0.56). There was a modest reduction in severe PTS symptoms (18% vs. 24%; P=0.04). The intervention was associated with a modest increase in major bleeding at 10 days (1.7% vs. 0.3%, P=0.049) but not at 24 months (5.7% vs. 3.7%, P=0.23).

Given these findings, the role of adjunctive therapies beyond anticoagulation is of unclear significance in the management of acute DVT for prevention of PTS. Given that CaVenT studied tPA alone and ATTRACT studied tPA plus mechanical intervents and stenting, it isn't clear from these results if tPA alone remains a possibly useful intervention.

Guidelines

As of August 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, open-label, assessor-blinded, phase 3 controlled trial
  • N=691
    • Pharmacomechanical group (n=336)
    • Control Group (n=355)
  • Setting: 56 clinical centers in the United States
  • Enrollment: 2009-2014
  • Analysis: Modified intention-to-treat and per-protocol analysis
  • Primary outcome: Development of post-thrombotic syndrome - defined by Villalta score 5 or higher, or an ulcer in the leg any time between the 6 and 24 month follow-up visit. Outcomes assessed at 10 and 30 days, 6, 12, 18, and 24 months after randomization.

Population

Inclusion Criteria

  • Symptomatic proximal deep-vein thrombosis involving the femoral, common femoral, or iliac vein

Exclusion Criteria

  • Age <16 or >75
  • Pregnant
  • Symptoms >14 days
  • High bleeding risk (including severe liver disease) or active bleeding
  • Active cancer
  • Post-thrombotic syndrome or ipsilateral DVT in previous 2 years
  • Contralateral symptomatic acute DVT of iliac or common femoral vein or one planned to be treated by thrombolysis
  • PE with hemodynamic compromise
  • Recent surgery
  • Prior stroke, intracranial bleed, tumor, vascular malformation, aneurysm
  • Inability to tolerate the protocol
  • Hgb <9 mg/dL, INR >1.6 prior to warfarin, or platelets <100,000/mL
  • CKD
  • BP >180/105 mm Hg on multiple readings
  • Thrombolysis in the prior month
  • Participating in another study
  • Limited life expectance
  • Non-ambulatory status
  • No informed consent
  • Low likelihood of following up in the protocol

Baseline Characteristics

  • Demographics: Age 53 years, male sex 62%, white race 78%, black race 18%, other race 4%
  • Anthropomorphics: Weight 93kg, BMI 31 kg/m2,
  • DVT characteristics: Left leg 62%, extending into the common femoral vein, iliac vein, or both 57%
  • Villalta Score[4] (a PTS score, higher is worse and points are gained for symptoms including cramps, itching, pain, etc. and signs including pretibial edema, skin induration, erythema, etc.)
    • 0-4: 18%
    • 5-9: 35%
    • 10-14: 19%
    • >15: 19%
  • Previous DVT or PE: 25%
  • Outpatient:82%
  • DVT Risk Factors
    • Major Surgery 9%
    • Hospitalization 9%
    • Plaster cast immobilization 2%
    • Childbirth 1%
  • Aspirin use within 7 days before randomization: 21%
  • Median GFR: 86ml/min
  • Prerandomization anticoagulant therapy: 93%
    • LMWH: 60%
    • Unfractionated heparin: 31%
    • Rivaroxaban: 4%
    • Warfarin 52%
    • Other: 5%

Interventions

  • Randomized to a group:
    • Pharmacomechanical catheter-directed thrombolysis
      • <35 mg of rtPA was delivered to the thrombus in one of three methods: 1. rt-PA infusion through multi-side hole catheter, 2. single-session thrombus removal with rapid delivery of rt-PA through AngioJet Rheolytic Thromectomy System (Boston Scientific), or 3. Trellis Peripheral Infusion System (Covidien)
      • After delivery of rtPA, participants could receive balloon maceration, catheter aspiration, thrombectomy (AngioJet or Trellis) percutaneous transluminal balloon venoplasty and stent placement to the iliac or common femoral ein, or a combination of procedures.
      • Stenting was encouraged if lesions caused >50% narrowing, robust collateral filling, or if there was a mean pressure gradient >than 2 mm Hg.
      • Treatment aimed to remove ≥90% of the thrombus and flow restoration or was stopped if there was a serious complication.
    • Standard therapy - Anticoagulation alone
  • Both groups received initial and long-term anticoagulation and compression stockings with 30-40 mm Hg of pressure
  • 10 day and q6mo follow-up

Outcomes

Comparisons are Pharmacomechanical thrombolysis vs. standard therapy.

Primary Outcomes

Occurrence of post-thrombotic syndrome at anytime between 6-month and 24-month follow up visit if Villalta score was 5 or higher, or if patient underwent an unplanned endovascular procedure to treat venous symptoms
47% vs. 48% (risk ratio, 0.96; 95% CI, 0.82 to 1.11; P=0.56)

Secondary Outcomes

Occurrence of post-thrombotic syndrome at 6, 12, 18 and 24 months counted if Villalta score was 5 or higher
6 mo: 27% vs. 40% (risk ratio, 0.68; 95% CI, 0.53 to 0.86)
12 mo: 34% vs. 34% (risk ratio, 0.99; 95% CI, 0.78 to 1.26)
18 mo: 35% vs. 34% (risk ratio, 1.01; 95% CI, 0.79 to 1.30)
24 mo: 31% vs. 36% (risk ratio, 0.85; 95% CI, 0.66 to 1.09)
Moderate or severe post-thrombotic syndrome (Villalta score ≥10)
18% vs. 24% (risk ratio, 0.73; 95% CI, 0.54 to 0.98; P=0.04)

Safety Outcomes

Major Bleeding
First 10 days: 4% vs. 2% (risk ratio 2.64; 95% CI 1.04-6.68; P=0.03)
Total over 24 mo: 14% vs 11% (risk ratio 1.26; 95% CI 0.85-1.89; P=0.25)
Recurrent venous thromboembolism
First 10 days: 2% vs. 1% (risk ratio 1.53; 95% CI 0.44-5.28; P=0.50)
Total over 24 mo: 12% vs 8% (risk ratio 1.47; 95% CI 0.94-2.29; P=0.09)
Death
First 10 days: 0 vs 0
Total over 24 mo: 2% vs 2% (risk ratio 0.89; 95% CI 0.33-2.44; P=0.83)

Subgroup Analysis

Results were similar in prespecified subgroups, with exception of patients 65 years or older, who were less likely to benefit from pharmacomechanical thrombolysis (P=0.04).

Adverse Events

None noted that were not included in secondary outcomes.

Criticisms

  • Compared to the CaVenT[3] study, the ATTRACT trial did not show the same reduction in post-thrombotic syndromes with cathether-directed thrombolysis.
  • Limitations of the trial included substantial missing assessments of post-thrombotic syndrome. The occasional missed visits were balanced between treatment groups, however among 80 patients with no post-thrombotic assessments, two thirds were in the control group. This would have underestimated the treatment effect.
  • The generalization of this trial is limited, as a large number of patients were excluded during enrollment. Variation of pharmacomechanical thrombolysis was not randomized, which limited comparison of outcomes among the different methods.

Funding

National Heart, Lung, and Blood Institute of the National Institutes of Health. Boston Scientific and Covidien (now Medtronic)

Further Reading

  1. 1.0 1.1 Kahn SR & Ginsberg JS Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch. Intern. Med. 2004. 164:17-26.
  2. Baldwin MJ et al. Post-thrombotic syndrome: a clinical review. J. Thromb. Haemost. 2013. 11:795-805.
  3. 3.0 3.1 Enden T et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012. 379:31-8.
  4. Soosainathan A et al. Scoring systems for the post-thrombotic syndrome. J. Vasc. Surg. 2013. 57:254-61.