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.
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).
- 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.
- 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:
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 ?2 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).