Reducing Post-Thrombotic Syndrome Through Reperfusion After DVT May Be Time-Sensitive
Key findings
- Randomized trials have demonstrated limited clinical benefit of adding catheter-based intervention to anticoagulation for managing acute proximal deep vein thrombosis (DVT), but those trials did not fully analyze the timing of the intervention to restore blood flow
- In a mouse model of DVT, early but not later restoration of blood flow reduced thrombus burden and vein wall fibrosis
- A post hoc analysis of the ATTRACT trial showed the greatest improvement in post-thrombotic syndrome quality-of-life scores when pharmacomechanical catheter-directed thrombolysis was administered 4–8 days after onset of DVT symptoms. No benefit was observed after day 9 or before day 3
- Future trials of pharmacomechanical thrombolysis for DVT should study the effect of time since symptom onset and the presence of blood flow through the DVT
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Despite therapeutic anticoagulation, up to half of patients with proximal deep vein thrombosis (DVT) will develop post-thrombotic syndrome (PTS), a morbid illness characterized by limb swelling, heaviness and skin changes. The "open-vein hypothesis" holds that timely thrombus removal will reduce complications such as vein wall injury, valvular reflux and venous hypertension, features underlying PTS.
However, three phase 3 randomized trials have demonstrated limited clinical PTS benefit when adding catheter-based intervention to anticoagulation. These studies did not fully analyze the timing of catheter intervention, though.
In Circulation, Farouc Jaffer, MD, PhD, investigator in the Cardiovascular Research Center and director of the Coronary Intervention and the Chronic Total Occlusion Percutaneous Coronary Intervention Program at Massachusetts General Hospital, Wenzhu Li, MD, postdoctoral fellow in the Jaffer Lab, and colleagues published experimental and clinical evidence that the outcomes for reducing the PTS after catheter-based thrombus removal in patients with acute proximal DVT may depend on the time since symptom onset.
Pre-clinical Study
The researchers created a mouse model of DVT by completely ligating the inferior vena cava. They then mechanically de-ligated the vessel to promote restored blood flow (RBF). Some animals also received recombinant tissue plasminogen activator (rtPA) two days after de-ligation.
The results demonstrated a time-dependent benefit of RBF:
- Mice that showed RBF by day 4 exhibited a significant reduction in thrombus burden and vein wall fibrosis at day 8
- Differences in DVT resolution between RBF+ and RBF− mice were not present at day 4 but evolved in a crucial time window between day 4 and day 8
- Thrombus reduction and its benefits did not occur if RBF was achieved late, by day 6 or day 8
- rtPA administered at day 4 improved DVT resolution, but only for occlusive thrombi without existing RBF
- rtPA administered at day 6 did not further improve DVT resolution
Reanalysis of the ATTRACT Trial
To assess the clinical relevance of the animal findings, the team reanalyzed data from the two-year randomized, phase 3 ATTRACT trial. Published in 2017 in The New England Journal of Medicine, it showed that pharmacomechanical catheter-directed thrombolysis (PCDT) for patients with acute proximal DVT did not reduce the risk of post-thrombotic syndrome or improve long-term Venous Insufficiency Epidemiological and Economic Study Quality-of-Life (QoL) scores beyond anticoagulation alone.
For the new analysis, the researchers categorized the 691 ATTRACT patients according to the time from symptom onset to randomization:
- Early: 0–3 days
- Intermediate: 4–8 days
- Late: 9–14 days
Results of the Reanalysis
- In the intermediate group, PCDT was associated with improved QoL scores at every follow-up visit compared with anticoagulation alone (P≤0.002)
- PCDT was not associated with significantly improved QoL scores in the early or late group
- Villalta scores, which reflect the presence of post-thrombotic syndrome and its severity, were also best in the intermediate group, but the interaction between treatment assignment (PCDT vs. anticoagulation) and timing of treatment was not statistically significant
The Way Forward
Because of the latter finding, the results of the new analysis should be considered hypothesis-generating only. Future trials of PCDT for DVT should incorporate a three-timeframe approach. For example:
Early group: Administer anticoagulation alone initially; use ultrasound on day 3–4 after DVT symptom onset to assess for RBF.
- If spontaneous RBF is present, continue anticoagulation alone
- If blood flow is absent, consider patients for PCDT as soon as possible
Intermediate group: Perform ultrasound at presentation to assess for RBF, then proceed as above.
Late group: Prescribe anticoagulation alone, given the lack of benefit of PCDT observed in the late group in this analysis.
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