The API-CALF Study: Apixaban to Treat Calf Vein Thrombosis (API-CALF)

July 22, 2021 updated by: Marc Righini, University Hospital, Geneva

Isolated distal DVT (iDDVT) is the most frequent clinical presentation of VTE and is associated with a significant morbidity and risks of long-term complications. Data from clinical trials highlighted that patients with iDDVT might require some level of AC treatment. However, the optimal anticoagulant intensity is uncertain, and it is plausible that the best benefit/risk ratio for AC might be achieved with lower intensity doses rather than therapeutic doses.

The principal research question of the Apixaban to treat calf vein thrombosis (API-CALF) study is to determine whether, after a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID (experimental arm) is non inferior to Apixaban 5 mg BID (standard arm) in preventing VTE recurrence and bleeding in patients with iDDVT. Patients will be treated with Apixaban for a total of 3 months. In that perspective we will conduct an international multicentre open-label assessor-blinded study

Study Overview

Status

Not yet recruiting

Detailed Description

Isolated distal deep vein thrombosis (iDDVT) is an infra-popliteal DVT, without concomitant proximal DVT and without pulmonary embolism (PE). Until recently, few large studies have focused on iDDVT, and the clinical significance and therapeutic management of iDDVT was mostly based on expert opinion and "gestalt" rather than on strong scientific data. iDDVT is the most frequent presentation of venous thromboembolic disease (VTE). Indeed, in the large French, multicentre, observational, OPTIMEV study, where all patients with suspected DVT underwent systematic whole leg compression ultrasound (CUS) exploration, iDDVT represented 56% of all DVTs. A similar high proportion of distal DVT among DVT (52.1%) was reported in Johnson's meta-analysis.

The risk of proximal extension of iDDVT to the proximal veins is substantial. In an extensive review of the literature published 15 years ago, the investigators reported that the risk of proximal extension of iDDVT, whether treated or left untreated, ranged from 0-44%, underlining the heterogeneity of the available data. Data from the CALTHRO study and CACTUS trial and extrapolation of data from management studies comparing the safety of serial proximal CUS vs. whole leg CUS for DVT diagnosis suggest that the rate of extension of untreated iDDVT to proximal deep veins was ~ 10% and up to 28% in high-risk populations, such as patients with cancer (3, 7-9). This 10% average risk of proximal extension is far above the usual 2% cut-off for an acceptable false-negative rate for negative findings in DVT diagnostic strategies. Hence, from a strict natural history standpoint, clinical significance of iDDVT is no longer in question. In summary, iDDVT is the most frequent clinical presentation of VTE and patients with iDDVT are at significant risk of proximal extension and of adverse outcomes both in the short and in the long-term.

Management of iDDVT is one of the most debated issue in the field of VTE. Thus, in all trials that validated the use of DOAC, distal location of DVT was an exclusion criterion.

While the American society of Hematology (ASH) guidelines do not comment on iDDVT specific treatment, the American college of chest physicians (ACCP) guidelines state that only 'high risk' distal DVT should be systematically treated with anticoagulation. Non high risk iDDVT could benefit from surveillance by repeated CUS. However, in the international CACTUS study, the investigators observed that a primary reason for refusal of participation and failure to fulfil recruitment was that patients and their treating physicians refused that iDDVT be left untreated. In routine clinical practice, data from observational registries showed that the majority iDDVT are treated with full dose of anticoagulants: 97% of iDDVT in the French OPTIMEV study, 98% in the Italian MASTER registry and 99% in the international RIETE registry. These therapeutic attitudes reflect physicians' beliefs (and patients' preference) that anticoagulation is important in case of iDDVT.

For proximal DVT and PE, "therapeutic" doses of anticoagulants are prescribed as use of lower doses was associated with an unacceptably high VTE risk. In contrast, for superficial vein thrombosis (SVT), "prophylactic" doses (fondaparinux 2.5mg or rivaroxaban 10 mg daily) were shown to be very effective and associated with a very low bleeding risk. Regarding iDDVT, risk of VTE recurrence and effectiveness of different dose regimen of anticoagulation are less clear and literature suggests that it could depend on patients' characteristics . Based on literature review, main risk factors for VTE extension/recurrence include cancer, calf trifurcation involvement, previous VTE, unprovoked character of DVT or presence of a permanent risk factor, and multiple vein distal vein thromboses.

In the CACTUS study, at 3 months, the proportion of extension to proximal deep veins in the therapeutic anticoagulation arm was lower than in the placebo arm (3.3% vs. 6.2% at 3 months; p=NS), but the risk of significant bleeding was significantly higher (4.1% vs. 0.0%)(3). Namely, in CACTUS, the benefit of therapeutic anticoagulation in terms of VTE risk reduction was offset by the excess in risk of bleeding.

In summary, iDDVT is the most frequent clinical presentation of VTE and is associated with a significant morbidity and risks of long-term complications. Data from clinical trials highlighted that patients with iDDVT might require some level of AC treatment. However, the optimal anticoagulant intensity is uncertain, and it is plausible that the best benefit/risk ratio for AC might be achieved with lower intensity doses rather than therapeutic doses.

The principal research question of the Apixaban to treat calf vein thrombosis (API-CALF) study is to determine whether, after a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID (experimental arm) is non inferior to Apixaban 5 mg BID (standard arm) in preventing VTE recurrence and bleeding in patients with iDDVT. Patients will be treated with Apixaban for a total of 3 months. In that perspective we will conduct an international multicentre open-label assessor-blinded study

Study Type

Interventional

Enrollment (Anticipated)

1300

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 120 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Consecutive patients with acute (symptoms <10 days) symptomatic iDDVT diagnosed on leg CUS who have none of the following exclusion criteria and who provided informed consent to participate. Diagnosis of iDDVT is made in the presence of an incompressible distal deep vein (deep calf vein (posterior tibial, anterior tibial or peroneal veins) or muscular vein (soleal or gastrocnemius veins)).

Exclusion Criteria:

  • Age < 18 years
  • Ipsi or contralateral Proximal DVT
  • Distal DVT involving the tibio-peroneal trunk (i.e. calf trifurcation)
  • DVT occurring while on anticoagulation (started ≥48hours before DVT diagnosis); However, inpatients that developed their iDDVT while on prophylactic anticoagulation are eligible if their expected date of discharge is <6 days post randomization.
  • Clinically suspected PE (patient eligible if PE ruled out with objective tests)
  • Active cancer, receiving cancer treatment or cured for < 6 months
  • Indication for long-term therapeutic anticoagulation (e.g. atrial fibrillation, mechanical heart valve…)
  • Thrombocytopenia (platelet count <100 g/l)
  • Severe renal impairment (creatinine clearance <30 ml/min)
  • Liver disease (including Child-Pugh Class B and C) associated with coagulopathy
  • Pregnant or breast-feeding woman
  • Body weight >120kg or <40 kg
  • Ongoing active bleeding or condition at high risk of bleeding with anticoagulation (e.g. peptic ulcer…)
  • Treatment with daily NSAIDs (aspirin ≤160 mg/day or clopidogrel ≤75 mg day permitted)
  • Allergy to Apixaban
  • Use of concomitant drugs that significantly interact with Apixaban: strong inhibitors of P-gp and CYP3A4 or strong inducers of CYP3A4
  • Treatment with anticoagulants at therapeutic dose >2 days after DVT diagnosis
  • Life expectancy < 1 year
  • Enrolled in another clinical trial within previous 30 days
  • Inability or refusal to provide informed consent

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental
After a conventional course of 7 days of Apixaban 10mg BID, Apixaban 2.5mg BID during 3 months.
Apixaban 5 MG BID versus Apixaban 2.5 MG BID
Other Names:
  • Apixaban 5 MG Oral Tablet
Active Comparator: Standard
After a conventional course of 7 days of Apixaban 10 mg BID, Apixaban 5 mg BID during 3 months.
Apixaban 5 MG BID versus Apixaban 2.5 MG BID
Other Names:
  • Apixaban 5 MG Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of i) symptomatic VTE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.
Time Frame: 1 year
The primary outcome is a composite of rate of i) symptomatic VTE (includes iDDVT involving a new distal deep vein, proximal DVT or PE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Individual components of the composite endpoint at 3 months and 1 year - Generic and venous disease-specific QOL scores at 1 year - Patient's compliance with treatment at 3 months - Serious adverse events during follow-up - PTS as measured at 1 year
Time Frame: 1 year
as above
1 year
Generic and venous disease-specific QOL scores at 1 year
Time Frame: 1 year
QOL score
1 year
Patient's observance with treatment at 3 months
Time Frame: 3 months
Observance of the patient
3 months
Serious adverse events during follow-up
Time Frame: 1 year
Adverse events
1 year
PTS as measured at 1 year
Time Frame: 1 year
Post thrombotic syndrome assessed with the Villalta scale
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Jean-Philippe Galanaud, MD, PhD, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, Canada
  • Principal Investigator: Marc Righini, MD, Geneva University Hospital, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 1, 2022

Primary Completion (Anticipated)

August 31, 2026

Study Completion (Anticipated)

August 31, 2027

Study Registration Dates

First Submitted

July 7, 2021

First Submitted That Met QC Criteria

July 22, 2021

First Posted (Actual)

July 29, 2021

Study Record Updates

Last Update Posted (Actual)

July 29, 2021

Last Update Submitted That Met QC Criteria

July 22, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

Individual research subjects' data cannot legally nor ethically be made available to non authorised people (HRA, cf. §7). According to the research subjects' informed consent, only the sponsor, the investigation team, reviewers, auditors and inspection authorities are entitled to access such data.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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