Atrial Fibrillation and FlutterNCT02623049
Direct Oral Anticoagulants Pharmacodynamics in Octogenarian Patients With Atrial Fibrillation
An observational study of Atrial Fibrillation and Flutter, run by Rabin Medical Center at 2 sites in Israel.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Atrial Fibrillation and Flutter
- What is being tested?
- New oral anticoagulant pharmacodynamic analysis (blood level assesment)
- Type of treatment
- Pill or oral medicine
- How many people
- 150 participants
- Where
- 2 sitesIsrael
- Study dates
- Nov 2015to Dec 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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.
Who may be able to join
- 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.
Who cannot join
- 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)
Show all 10Show fewer
- 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.
Trial locations and contacts
2 sites in 1 country.
Israel2 sites, 2 recruiting
- Recruiting
Internal Medicine B Department
Petah Tikva, 49100
Maya Arlyuk, 972546841416, mayaor@clalit.org.il
Dora Shechter, 972546339019, Doras2@clalit.org.il
- Recruiting
Rabin Medical Center, Beilinson Hospital
Petah Tikva, 49100
Shmuel Fuchs, Professor, 972-3-9376601\3, shmuelf@clalit.org.il
Maya Arlyuk, Study Coordinator, mayaor@clalit.org.il
About this study
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.
Read more
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.
Read the detailed description
A cross sectional, prospective study of hospitalized and ambulatory patients, who are treated with DOACs for AF.
Patient 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.
Study cohorts
The investigators plan to assess DOACS levels among 120 patients who will be treated by one of the three available agents:
Group 1) sixty patients who will be treated with the direct Xa inhibitor Apixaban - 40 octogenarians and 20 younger than 70 years.
Group 2) forty patients who will be treated with direct Xa inhibitor Rivaroxaban - 20 octogenarians and 20 younger than 70 years Group 3) twenty patients who will be treated with the direct Thrombin inhibitor Dabigatran - 10 octogenarian patients who will receive age-adjusted recommended reduced dosage (110 mg bid) and 10 patients younger than 70 years.
Decision to continue and/or to initiate DOAC as well the dosage, will be on the discretion of the treating physician. Patients in whom the prescribed dosage will not be according to current recommendations will be excluded, unless appropriate adjustment will be made prior to enrolment.
Informed consent will be obtained from all patients prior to study enrolment. Patient's demographic data will be documented at baseline and will include: age, sex, body weight and height, comorbidities, concurrent medications, blood test results (complete blood count, INR, aPTT, renal function tests, electrolytes and liver enzymes). CHA2DS2-VASc and HAS-BLED risk scores will be calculated for each enrolled patient. Actual body weight will be determined upon recruitment with a standardized, calibrated scale.
DOACs pharmacodynamic analysis will be performed using commercial kits for DTT and AFXa. Drug levels will be measured at steady state (through levels) and at Tmax (the time at which maximum serum peak concentration is observed).
DTT and AFXa will be sampled after at least 4 days of complete adherence for DOAC consumption. In the case of hospitalized patient, drug levels will be obtained prior to patients discharge. The steady state sample will be taken just before the morning dose (trough levels). Maximal DTT and AFXa (at Tmax) will be determined by blood sample taken 2 hours after the morning dose with dabigatran and 3 hours with Apixaban/Rivaroxaban.
All blood samples will be drawn when the patient clinical condition is stable and not differ from his/her baseline daily status (including stable kidney functions). In addition, an adherence to the prescribed dosage of the DOAC for at least 4 consecutive days will be assured prior to blood sampling. Accordingly, hospitalized patients may be discharged and invited later to the ward for drug level sampling based on the discretion of the enrolling physician (for example, in the case of questionable adherence in the last 4 days or to allow full recovery from significant change in medical condition).
All blood samples for the study will be drawn by the attending physician. The blood samples (2 tubes of 3 ml each) will be coded and collected in 3.2% citrated tubes for measurement of the pharmacodynamic effects, which will be performed in Beilinson hospital coagulation lab.
The coding system will be based on patients drug treatment. Dabigtran, Rivaroxaban and Apixaban samples will be coded with the first letter in the generic drug name and a running serial number (such as D-1,2,3…).
Immediately after collection, each tube will be transferred to the coagulation lab, inverted to achieve complete mixing and then centrifuged for 10 min at 3000xg. Platelet-poor plasma will then be transferred to a labeled transfer tube and stored at -20°C. The samples will be kept in the coagulation lab freezer for two months after collection. Chromogenic anti Xa assay analysis will be performed on thawed samples using commercial assay (Liquid anti Xa, Instrumentation Laboratory, MA, USA). Diluted thrombin time assay will be performed on the samples using a commercial assay ( Hemoclot Thrombin Inhibitors, Hyphen Biomed, France).
Inclusion criteria:
- 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.
Exclusion criteria:
- 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.
Study termination criteria:
•None.
Study duration- The study expected duration is 2 years.
Statistical analysis - The sample size for this study was chosen to provide a cohort large enough to identify differences between groups, based on previous studies. Descriptive statistics will be used to calculate summary data. Data will be represented as mean ± SD or as median [5th, 95th percentile], unless otherwise indicated.
Parametric, two-tailed Student's t-tests or ANOVA will be used for continuous variables and the χ2 and Fisher's exact test for categorical variables with a predetermined alpha level of P < 0.05. Statistical analysis will be performed using SAS statistical software (version 8.2, SAS Institute, Cary, NC).
- Conditions
- Atrial Fibrillation and Flutter
- Being tested
- New oral anticoagulant pharmacodynamic analysis (blood level assesment)
- Keywords
- New oral anticoagulants, Blood levels, Octogenarians
- Medical subject headings
- Atrial Fibrillation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
New oral anticoagulant pharmacodynamic analysis (blood level assesment)Other
| Study group | Role | What they receive |
|---|---|---|
| octogenarians patients - Apixaban | octogenarians patients who will be treated with Apixaban Receives: 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 Receives: Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment) | |
| octogenarians patients - Rivaroxaban | octogenarians patients who will be treated with Rivaroxaban Receives: 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 Receives: Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment) | |
| octogenarians patients - Dabigatran | octogenarians patients who will be treated with Dabigatran Receives: 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 Receives: Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diluted thrombin time (DTT) for Dabigatran
Measured: 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
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Dec 2015 (estimated)
- Study startNov 2015
- Primary completionDec 2019 (estimated)
- Study completionDec 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (13)Papers the sponsor has linked to this study.
- Other trials for Atrial Fibrillation and FlutterStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Enrolment
- 150 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rabin Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Pfizer
- Responsible party
- Principal investigator, shmuel fuchs, Rabin Medical Center
- Investigators
- Shmuel Fuches, MD, Study chair, Internal Medicine B Department, Rabin Medical Center, Beilinson HospitalRan Nissan, PharmD, Principal investigator, Internal Medicine B Department, Rabin Medical Center, Beilinson HospitalShai Shimoni, MD, Principal investigator, Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02623049
- Sponsor's protocol ID
- 0590-15
- Status last verified
- Jan 2019
- First submitted
- 19 Nov 2015
- Last updated
- 11 Jan 2019
- Results posted
- No
Publications
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.
PubMed 25609415Camm 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.
PubMed 22923145January 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.
PubMed 24682347Go 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.
PubMed 11343485Connolly 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.
PubMed 19717844Patel 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.
PubMed 21830957Granger 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.
PubMed 21870978Miller 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.
PubMed 22537354Sardar 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.
PubMed 24786913Halvorsen 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.
PubMed 24561548Held 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.
PubMed 25499871Stollberger 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.
PubMed 24170233Nissan 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.
PubMed 30460518
Study at a glance
From the registry record, last updated by the sponsor on 11 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Direct Oral Anticoagulants Pharmacodynamics in Octogenarian Patients With Atrial Fibrillation
- ClinicalTrials.gov ID
- NCT02623049
- Acronym / sponsor ID
- 0590-15
- Conditions
- Atrial Fibrillation and Flutter
- Keywords
- New oral anticoagulants, Blood levels, Octogenarians
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Rabin Medical CenterUniversity, hospital or other
- Collaborators
- Pfizer
- Study start
- Nov 2015
- Primary completion
- Dec 2019 (estimated)
- Study completion
- Dec 2019 (estimated)
- First posted
- 7 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
A cross sectional, prospective study of hospitalized and ambulatory patients, who are treated with DOACs for AF.
Patient 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.
Study cohorts
The investigators plan to assess DOACS levels among 120 patients who will be treated by one of the three available agents:
Group 1) sixty patients who will be treated with the direct Xa inhibitor Apixaban - 40 octogenarians and 20 younger than 70 years.
Group 2) forty patients who will be treated with direct Xa inhibitor Rivaroxaban - 20 octogenarians and 20 younger than 70 years Group 3) twenty patients who will be treated with the direct Thrombin inhibitor Dabigatran - 10 octogenarian patients who will receive age-adjusted recommended reduced dosage (110 mg bid) and 10 patients younger than 70 years.
Decision to continue and/or to initiate DOAC as well the dosage, will be on the discretion of the treating physician. Patients in whom the prescribed dosage will not be according to current recommendations will be excluded, unless appropriate adjustment will be made prior to enrolment.
Informed consent will be obtained from all patients prior to study enrolment. Patient's demographic data will be documented at baseline and will include: age, sex, body weight and height, comorbidities, concurrent medications, blood test results (complete blood count, INR, aPTT, renal function tests, electrolytes and liver enzymes). CHA2DS2-VASc and HAS-BLED risk scores will be calculated for each enrolled patient. Actual body weight will be determined upon recruitment with a standardized, calibrated scale.
DOACs pharmacodynamic analysis will be performed using commercial kits for DTT and AFXa. Drug levels will be measured at steady state (through levels) and at Tmax (the time at which maximum serum peak concentration is observed).
DTT and AFXa will be sampled after at least 4 days of complete adherence for DOAC consumption. In the case of hospitalized patient, drug levels will be obtained prior to patients discharge. The steady state sample will be taken just before the morning dose (trough levels). Maximal DTT and AFXa (at Tmax) will be determined by blood sample taken 2 hours after the morning dose with dabigatran and 3 hours with Apixaban/Rivaroxaban.
All blood samples will be drawn when the patient clinical condition is stable and not differ from his/her baseline daily status (including stable kidney functions). In addition, an adherence to the prescribed dosage of the DOAC for at least 4 consecutive days will be assured prior to blood sampling. Accordingly, hospitalized patients may be discharged and invited later to the ward for drug level sampling based on the discretion of the enrolling physician (for example, in the case of questionable adherence in the last 4 days or to allow full recovery from significant change in medical condition).
All blood samples for the study will be drawn by the attending physician. The blood samples (2 tubes of 3 ml each) will be coded and collected in 3.2% citrated tubes for measurement of the pharmacodynamic effects, which will be performed in Beilinson hospital coagulation lab.
The coding system will be based on patients drug treatment. Dabigtran, Rivaroxaban and Apixaban samples will be coded with the first letter in the generic drug name and a running serial number (such as D-1,2,3…).
Immediately after collection, each tube will be transferred to the coagulation lab, inverted to achieve complete mixing and then centrifuged for 10 min at 3000xg. Platelet-poor plasma will then be transferred to a labeled transfer tube and stored at -20°C. The samples will be kept in the coagulation lab freezer for two months after collection. Chromogenic anti Xa assay analysis will be performed on thawed samples using commercial assay (Liquid anti Xa, Instrumentation Laboratory, MA, USA). Diluted thrombin time assay will be performed on the samples using a commercial assay ( Hemoclot Thrombin Inhibitors, Hyphen Biomed, France).
Inclusion criteria:
- 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.
Exclusion criteria:
- 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.
Study termination criteria:
•None.
Study duration- The study expected duration is 2 years.
Statistical analysis - The sample size for this study was chosen to provide a cohort large enough to identify differences between groups, based on previous studies. Descriptive statistics will be used to calculate summary data. Data will be represented as mean ± SD or as median [5th, 95th percentile], unless otherwise indicated.
Parametric, two-tailed Student's t-tests or ANOVA will be used for continuous variables and the χ2 and Fisher's exact test for categorical variables with a predetermined alpha level of P < 0.05. Statistical analysis will be performed using SAS statistical software (version 8.2, SAS Institute, Cary, NC).
Study design
- Observational model
- Cohort
- Time perspective
- Cross-sectional
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| octogenarians patients - Apixaban | – | Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)octogenarians patients who will be treated with Apixaban |
| younger than 70 years patients - Apixaba | – | Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)younger than 70 years patients who will be treated with Apixaba |
| octogenarians patients - Rivaroxaban | – | Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)octogenarians patients who will be treated with Rivaroxaban |
| younger than 70 years patients - Rivaroxaban | – | Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)younger than 70 years patients who will be treated with Rivaroxaban |
| octogenarians patients - Dabigatran | – | Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)octogenarians patients who will be treated with Dabigatran |
| younger than 70 years patients - Dabigatran | – | Other: New oral anticoagulant pharmacodynamic analysis (blood level assesment)younger than 70 years patients who will be treated with Dabigatran |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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.
Key inclusion criteria (7 listed)
- 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).
Key exclusion criteria (10 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| New oral anticoagulant pharmacodynamic analysis (blood level assesment) | Other | octogenarians patients - Apixaban, octogenarians patients - Dabigatran, octogenarians patients - Rivaroxaban, younger than 70 years patients - Apixaba, younger than 70 years patients - Dabigatran, younger than 70 years patients - Rivaroxaban |
Primary outcome
Diluted thrombin time (DTT) for Dabigatran
Time frame: 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
Time frame: 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)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jan 2019.
- Background: PubMed 25609415Haim 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.
- Background: PubMed 22923145Camm 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.
- Background: PubMed 24682347January 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.
- Background: PubMed 11343485Go 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.
- Background: PubMed 19717844Connolly 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.
- Background: PubMed 21830957Patel 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.
- Background: PubMed 21870978Granger 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.
- Background: PubMed 22537354Miller 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.
- Background: PubMed 24786913Sardar 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.
- Background: PubMed 24561548Halvorsen 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.
- Background: PubMed 25499871Held 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.
- Background: PubMed 24170233Stollberger 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Shmuel Fuches, MD study chair
Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital
Ran Nissan, PharmD principal investigator
Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital
Shai Shimoni, MD principal investigator
Internal Medicine B Department, Rabin Medical Center, Beilinson Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Atrial Fibrillation and Flutter, run by Rabin Medical Center at 2 sites in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 11 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Ran Nisan, PharmD (972-544892333, ranni@clalit.org.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diluted thrombin time (DTT) for Dabigatran (time frame: 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)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02623049, which also lists 13 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jan 2019.