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

Deep Vein Thrombosis Clinical Trial

— API-CALF  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04981327
• Other study ID #: APICALF
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: September 1, 2022
• Est. completion date: August 31, 2027

Study information

• Verified date: July 2021
• Source: University Hospital, Geneva
• Contact: Jean-Philippe Galanaud, MD, PhD
• Phone: 001
• Email: Jean-Philippe.Galanaud[@]sunnybrook.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 1300
• Est. completion date: August 31, 2027
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Deep Vein Thrombosis
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Apixaban 2.5 MG Oral Tablet [ELIQUIS]
Apixaban 5 MG BID versus Apixaban 2.5 MG BID

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Geneva	Sunnybrook Health Sciences Centre

References & Publications (31)

Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10 — View Citation

Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, Kearon C, Schunemann HJ, Crowther M, Pauker SG, Makdissi R, Guyatt GH. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician — View Citation

Bauersachs RM, Herold J. Oral Anticoagulation in the Elderly and Frail. Hamostaseologie. 2020 Feb;40(1):74-83. doi: 10.1055/s-0040-1701476. Epub 2020 Jan 30. Review. — View Citation

Bernardi E, Camporese G, Büller HR, Siragusa S, Imberti D, Berchio A, Ghirarduzzi A, Verlato F, Anastasio R, Prati C, Piccioli A, Pesavento R, Bova C, Maltempi P, Zanatta N, Cogo A, Cappelli R, Bucherini E, Cuppini S, Noventa F, Prandoni P; Erasmus Study — View Citation

Beyer-Westendorf J, Schellong SM, Gerlach H, Rabe E, Weitz JI, Jersemann K, Sahin K, Bauersachs R; SURPRISE investigators. Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux: the open- — View Citation

Decousus H, Prandoni P, Mismetti P, Bauersachs RM, Boda Z, Brenner B, Laporte S, Matyas L, Middeldorp S, Sokurenko G, Leizorovicz A; CALISTO Study Group. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010 Sep 23; — View Citation

EINSTEIN-PE Investigators, Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral riva — View Citation

Galanaud JP, Bosson JL, Quéré I. Risk factors and early outcomes of patients with symptomatic distal vs. proximal deep-vein thrombosis. Curr Opin Pulm Med. 2011 Sep;17(5):387-91. doi: 10.1097/MCP.0b013e328349a9e3. Review. — View Citation

Galanaud JP, Sevestre MA, Genty C, Pernod G, Quere I, Bosson JL. Is it useful to also image the asymptomatic leg in patients with suspected deep vein thrombosis?: comment. J Thromb Haemost. 2015 Nov;13(11):2127-30. doi: 10.1111/jth.13123. Epub 2015 Sep 30 — View Citation

Galanaud JP, Sevestre MA, Pernod G, Kahn SR, Genty C, Terrisse H, Brisot D, Gillet JL, Quéré I, Bosson JL. Long-term risk of venous thromboembolism recurrence after isolated superficial vein thrombosis. J Thromb Haemost. 2017 Jun;15(6):1123-1131. doi: 10. — View Citation

Galanaud JP, Sevestre-Pietri MA, Bosson JL, Laroche JP, Righini M, Brisot D, Boge G, van Kien AK, Gattolliat O, Bettarel-Binon C, Gris JC, Genty C, Quere I; OPTIMEV-SFMV Investigators. Comparative study on risk factors and early outcome of symptomatic dis — View Citation

Galanaud JP, Trujillo-Santos J, Bikdeli B, Di Micco P, Bortoluzzi C, Bertoletti L, Pedrajas JM, Ballaz A, Alfonso J, Monreal M; RIETE Investigators. Management of isolated distal deep-vein thrombosis with direct oral anticoagulants in the RIETE registry. — View Citation

Gibson NS, Schellong SM, Kheir DY, Beyer-Westendorf J, Gallus AS, McRae S, Schutgens RE, Piovella F, Gerdes VE, Buller HR. Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective mana — View Citation

Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N — View Citation

Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLoughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979 Oct 18;301(16):855-8. — View Citation

Johnson SA, Stevens SM, Woller SC, Lake E, Donadini M, Cheng J, Labarère J, Douketis JD. Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis. JAMA. 2010 Feb 3;303(5):438-45. doi: — View Citation

Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb; — View Citation

Lohr JM, Fellner AN. Isolated calf vein thrombosis should be treated with anticoagulation. Dis Mon. 2010 Oct;56(10):590-600. doi: 10.1016/j.disamonth.2010.06.010. — View Citation

Masuda EM, Kistner RL, Musikasinthorn C, Liquido F, Geling O, He Q. The controversy of managing calf vein thrombosis. J Vasc Surg. 2012 Feb;55(2):550-61. doi: 10.1016/j.jvs.2011.05.092. Epub 2011 Oct 26. Review. — View Citation

Masuda EM, Kistner RL. The case for managing calf vein thrombi with duplex surveillance and selective anticoagulation. Dis Mon. 2010 Oct;56(10):601-13. doi: 10.1016/j.disamonth.2010.06.011. — View Citation

Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, Hutten BA, Jaff MR, Manja V, Schulman S, Thurston C, Vedantham S, Verhamme P, Witt DM, D Florez I, Izcovich A, Nieuwlaat R, Ross S, J Schünemann H, Wiercioch W, Zhang Y, Zhang Y. American Society o — View Citation

Palareti G, Agnelli G, Imberti D, Moia M, Ageno W, Pistelli R, Rossi R, Verso M; MASTER Investigators. Do Italian vascular centers look for isolated calf deep vein thrombosis? Analysis of isolated calf deep vein thromboses included in the ''Master'' Regis — View Citation

Palareti G, Cosmi B, Lessiani G, Rodorigo G, Guazzaloca G, Brusi C, Valdré L, Conti E, Sartori M, Legnani C. Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study. Thromb Haemost. 2010 — View Citation

Palareti G, Schellong S. Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost. 2012 Jan;10(1):11-9. doi: 10.1111/j.1538-7836.2011.04564.x. Review. — View Citation

Palareti G. How I treat isolated distal deep vein thrombosis (IDDVT). Blood. 2014 Mar 20;123(12):1802-9. doi: 10.1182/blood-2013-10-512616. Epub 2014 Jan 28. Review. — View Citation

Quéré I, Elias A, Maufus M, Elias M, Sevestre MA, Galanaud JP, Bosson JL, Bura-Rivière A, Jurus C, Lacroix P, Zuily S, Diard A, Wahl D, Bertoletti L, Brisot D, Frappe P, Gillet JL, Ouvry P, Pernod G. [Unresolved questions on venous thromboembolic disease. — View Citation

Righini M, Bounameaux H. Clinical relevance of distal deep vein thrombosis. Curr Opin Pulm Med. 2008 Sep;14(5):408-13. doi: 10.1097/MCP.0b013e32830460ea. Review. — View Citation

Righini M, Galanaud JP, Guenneguez H, Brisot D, Diard A, Faisse P, Barrellier MT, Hamel-Desnos C, Jurus C, Pichot O, Martin M, Mazzolai L, Choquenet C, Accassat S, Robert-Ebadi H, Carrier M, Le Gal G, Mermilllod B, Laroche JP, Bounameaux H, Perrier A, Kah — View Citation

Righini M. Is it worth diagnosing and treating distal deep vein thrombosis? No. J Thromb Haemost. 2007 Jul;5 Suppl 1:55-9. — View Citation

Schellong SM. Distal DVT: worth diagnosing? Yes. J Thromb Haemost. 2007 Jul;5 Suppl 1:51-4. Review. — View Citation

Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. — View Citation

* Note: There are 31 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of i) symptomatic VTE; ii) major bleeding and clinically relevant non major bleeding (CRNMB); iii) VTE and bleeding related death.	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	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	as above	1 year
Secondary	Generic and venous disease-specific QOL scores at 1 year	QOL score	1 year
Secondary	Patient's observance with treatment at 3 months	Observance of the patient	3 months
Secondary	Serious adverse events during follow-up	Adverse events	1 year
Secondary	PTS as measured at 1 year	Post thrombotic syndrome assessed with the Villalta scale	1 year