NCT02623049

Brief Summary

Background: The incidence of atrial fibrillation(AF) increases substantially with age and it is estimated that more than one third of AF patients are octogenarians. Direct oral anticoagulants (DOACs) were found favorable compared to warfarin with respect to efficacy and safety ( bleeding) across wide range of ages. Nevertheless, the rates of bleeding among elderly patients were shown to increase substantially with all anticoagulants. Dose-adjustments of DOAC are not universally performed among patients older than 80 years old and currently there is paucity of data regarding the actual drugs level among these patients. Accordingly, the investigators sought to investigate the drug levels of the different DOACs among "real world" octogenarians who receiving guideline-recommended dosage. Methods: A cross sectional, prospective study of 120 hospitalized and ambulatory patients who are treated with DOACs for AF. DOACs blood levels with be compared between octogenarians (n=70) and younger patient group ( age≤70 year-old; n=50).The cohort will include: 1)Sixty patients on APIXABAN: 40 octogenarians and 20 younger than 70 years, 2)Forty patients on RIVAROXABAN: 20 octogenarians and 20 younger than 70 years, and 3) Twenty patients treated with DABIGATRAN: 10 octogenarians and 10 younger than 70 years. DOACs Pharmacodynamic analysis will be performed using commercial kits for diluted thrombin time(DTT) and anti-factor Xa activity (AFXa). Drug level will be measured at steady state( through levels) and at Tmax after at least 4 days of complete adherence for DOAC consumption. Study End-Points:The study main objectives are: 1) DOACs levels in octogenarians in comparison to patients younger than 70 years and 2)percentage of patients, in each group, who have target DTT or AFXa ( predicted) at steady state. Potential significance of the study: The results of the study may provide new data on DOACs levels in octogenarians and thus would either support current recommendations or set the ground for further studies aim to optimize DOACs dosage in this vulnerable population.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
150

participants targeted

Target at P50-P75 for all trials

Timeline
Completed

Started Nov 2015

Longer than P75 for all trials

Geographic Reach
1 country

2 active sites

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

November 1, 2015

Completed
18 days until next milestone

First Submitted

Initial submission to the registry

November 19, 2015

Completed
18 days until next milestone

First Posted

Study publicly available on registry

December 7, 2015

Completed
4 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2019

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2019

Completed
Last Updated

January 11, 2019

Status Verified

January 1, 2019

Enrollment Period

4.1 years

First QC Date

November 19, 2015

Last Update Submit

January 10, 2019

Conditions

Atrial Fibrillation and Flutter

Keywords

New oral anticoagulantsBlood levelsOctogenarians

Outcome Measures

Primary Outcomes (2)

  • Diluted thrombin time (DTT) for Dabigatran

    trough and peak levels after at least 4 days of drug intake (trough will be taken just before the morning dose and peak levels 2 hours after the intake of Dabigatran)

  • anti FXa-activity for Apixaban and Rivaroxaban

    trough and peak levels after at least 4 days of drug intake (trough will be taken just before the morning dose and peak levels 3 hours after the intake of Apixaba/Rivaroxaban)

Study Arms (6)

octogenarians patients - Apixaban

octogenarians patients who will be treated with Apixaban

Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)

younger than 70 years patients - Apixaba

younger than 70 years patients who will be treated with Apixaba

Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)

octogenarians patients - Rivaroxaban

octogenarians patients who will be treated with Rivaroxaban

Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)

younger than 70 years patients - Rivaroxaban

younger than 70 years patients who will be treated with Rivaroxaban

Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)

octogenarians patients - Dabigatran

octogenarians patients who will be treated with Dabigatran

Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)

younger than 70 years patients - Dabigatran

younger than 70 years patients who will be treated with Dabigatran

Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)

Interventions

New oral anticoagulant pharmacodynamic analysis (blood level assesment)OTHER
octogenarians patients - Apixabanoctogenarians patients - Dabigatranoctogenarians patients - Rivaroxabanyounger than 70 years patients - Apixabayounger than 70 years patients - Dabigatranyounger than 70 years patients - Rivaroxaban

Eligibility Criteria

Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)
Sampling MethodNon-Probability Sample
Study Population

Candidate for the study will be patients older than 80 years (octogenarians) and those ≤70 years who are 1) admitted to the Internal Medicine division in Rabin Medical Center or to Beit Rivka rehabilitation hospital who are on treatment of DOAC prior to their hospitalization \\ rehabilitation , 2) hospitalized patients in whom DOAC will be initiated during hospitalization and 3) referred ambulatory patients on DOACs. Each potential patient will be screened for age and other risk factors for bleeding (specifically those that requires dose adjustment such as renal failure, weight, potentially interacting drugs) under DOAC treatment.

You may qualify if:

  • Octogenarian group : Age ≥ 80 years.
  • Younger age group: Age ≤ 70 years.
  • Previous diagnosis of non-valvular atrial fibrillation / flutter or new diagnosis, documented by electrocardiography
  • CHA2DS2-VASc score ≥1.
  • Hemodynamically stable patients (i.e., without cardiogenic shock or circulatory collapse).
  • Receiving DOACs for at least 4 days.
  • Stable renal function.

You may not qualify if:

  • Patients who are expected to stop DOACs within the 4-8 days (i.e. planned operation or invasive procedure)
  • Patients who require dose adjustment of DOACs based on clinical judgment and not on manufacturer recommendations (i.e. acute renal function deterioration with GFR less than 30 ml/min, need for dual antiplatelet therapy)
  • History of gastrointestinal conditions that could significantly impact drug absorption (such as Crohn's disease, gastrectomy).
  • A history of recent drug or alcohol abuse
  • Concomitant treatment with combined strong P-gp inhibitors and CYP3A4 inhibitors drugs (such as: grapefruit juice, itraconazole, lopinavir/ritonavir, clarithromycin, ritonavir, ketoconazole, indinavir/ritonavir, conivaptan).
  • Concomitant treatment with combined strong P-gp inducers and CYP3A4 inducers drugs (such as: avasimibe ,carbamazepine, phenytoin, phenobarbital, rifampin, St John's wort)
  • Estimated glomerular filtration rate \< 30 ml/min
  • Patients with elevated liver enzymes ALT/AST \> 3 x ULN or total bilirubin ≥ 1.5 x ULN.
  • Weight \> 120 kg.
  • Pregnant woman.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

Internal Medicine B Department

Petah Tikva, 49100, Israel

RECRUITING

Rabin Medical Center, Beilinson Hospital

Petah Tikva, 49100, Israel

RECRUITING

Related Publications (13)

  • Haim M, Hoshen M, Reges O, Rabi Y, Balicer R, Leibowitz M. Prospective national study of the prevalence, incidence, management and outcome of a large contemporary cohort of patients with incident non-valvular atrial fibrillation. J Am Heart Assoc. 2015 Jan 21;4(1):e001486. doi: 10.1161/JAHA.114.001486.

    PMID: 25609415BACKGROUND

  • Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, Hindricks G, Kirchhof P; ESC Committee for Practice Guidelines-CPG; Document Reviewers. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. Europace. 2012 Oct;14(10):1385-413. doi: 10.1093/europace/eus305. Epub 2012 Aug 24. No abstract available.

    PMID: 22923145BACKGROUND

  • January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014 Dec 2;130(23):e199-267. doi: 10.1161/CIR.0000000000000041. Epub 2014 Mar 28. No abstract available.

    PMID: 24682347BACKGROUND

  • Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001 May 9;285(18):2370-5. doi: 10.1001/jama.285.18.2370.

    PMID: 11343485BACKGROUND

  • Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.

    PMID: 19717844BACKGROUND

  • Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.

    PMID: 21830957BACKGROUND

  • Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.

    PMID: 21870978BACKGROUND

  • Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012 Aug 1;110(3):453-60. doi: 10.1016/j.amjcard.2012.03.049. Epub 2012 Apr 24.

    PMID: 22537354BACKGROUND

  • Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc. 2014 May;62(5):857-64. doi: 10.1111/jgs.12799. Epub 2014 May 1.

    PMID: 24786913BACKGROUND

  • Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J. 2014 Jul 21;35(28):1864-72. doi: 10.1093/eurheartj/ehu046. Epub 2014 Feb 20.

    PMID: 24561548BACKGROUND

  • Held C, Hylek EM, Alexander JH, Hanna M, Lopes RD, Wojdyla DM, Thomas L, Al-Khalidi H, Alings M, Xavier D, Ansell J, Goto S, Ruzyllo W, Rosenqvist M, Verheugt FW, Zhu J, Granger CB, Wallentin L. Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J. 2015 May 21;36(20):1264-72. doi: 10.1093/eurheartj/ehu463. Epub 2014 Dec 12.

    PMID: 25499871BACKGROUND

  • Stollberger C, Finsterer J. Concerns about the use of new oral anticoagulants for stroke prevention in elderly patients with atrial fibrillation. Drugs Aging. 2013 Dec;30(12):949-58. doi: 10.1007/s40266-013-0119-3.

    PMID: 24170233BACKGROUND

  • Nissan R, Spectre G, Hershkovitz A, Green H, Shimony S, Cooper L, Nakav S, Shochat T, Grossman A, Fuchs S. Apixaban Levels in Octogenarian Patients with Non-valvular Atrial Fibrillation. Drugs Aging. 2019 Feb;36(2):165-177. doi: 10.1007/s40266-018-0613-8.

    PMID: 30460518DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood sample

MeSH Terms

Conditions

Atrial Fibrillation

Condition Hierarchy (Ancestors)

Arrhythmias, CardiacHeart DiseasesCardiovascular DiseasesPathologic ProcessesPathological Conditions, Signs and Symptoms

Study Officials

  • Shmuel Fuches, MD

    Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital

    STUDY CHAIR

  • Ran Nissan, PharmD

    Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital

    PRINCIPAL INVESTIGATOR

  • Shai Shimoni, MD

    Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Ran Nisan, PharmD

CONTACT

972-544892333ranni@clalit.org.il

Maya Arlyuk

CONTACT

972-546841416mayaor@clalit.org.il

Study Design

Study Type
observational
Observational Model
COHORT
Time Perspective
CROSS SECTIONAL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Professor

Study Record Dates

First Submitted

November 19, 2015

First Posted

December 7, 2015

Study Start

November 1, 2015

Primary Completion

December 1, 2019

Study Completion

December 1, 2019

Last Updated

January 11, 2019

Record last verified: 2019-01

Locations

IL(2)