Atrial Fibrillation, Coronary Artery Disease, Peripheral Arterial Disease
Conditions
Keywords
aspirin, clopidogrel, ticagrelor, rivaroxaban, pharmacodynamic (PD)
Brief summary
Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease manifestations. To date there is very little data, and not conducted in human subjects, on the interplay between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular how this affects profiles of platelet reactivity and thrombin generation. Given the potential role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients with atherothrombotic disease manifestations, including coronary artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban when used in combination with antiplatelet treatment regimens commonly used in clinical practice.
Detailed description
Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease manifestations. However, although the introduction of newer antithrombotic strategies has been associated with a reduction in ischemic recurrences in high-risk patients, these have been consistently associated with an increase in bleeding complications. These have been observed particularly with the combination of an oral anticoagulant agent, including low-dose rivaroxaban, with standard DAPT, also known as triple therapy. Observations from laboratory and clinical studies suggest that in the presence of effective blockade of other pathways triggering thrombotic complications aspirin may not offer added antithrombotic effects but contribute to the increased bleeding. These observations have set the basis for a large number of clinical outcomes studies evaluating whether dropping aspirin in the presence of more potent and effective blockade of other pathways triggering thrombosis has a better safety profile without a tradeoff in efficacy. Amongst these strategies, the use of low-dose rivaroxaban in adjunct to a P2Y12 inhibitor, also known as dual therapy, has been proposed. This approach may be of potential benefit to reduce atherothrombotic complications in high-risk patients following an acute coronary event. On the other hand, regimens with more modest antithrombotic effects compared with a combination of low-dose rivaroxaban and a P2Y12 receptor inhibitor such as low-dose rivaroxaban alone or in combination with aspirin may be more suitable in more stabilized patients. To date there is very little data, and not conducted in human subjects, on the interplay between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular how this affects profiles of platelet reactivity and thrombin generation. Given the potential role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients with atherothrombotic disease manifestations, including coronary artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban when used in combination with antiplatelet treatment regimens commonly used in clinical practice.
Interventions
DRUGRivaroxaban 2.5 mg Tablet
PD assessments will be conducted at 3 time points: i) baseline (while on standard of care antiplatelet therapy), ii) 7-10 days after adjunctive treatment with low dose rivaroxaban, and iii) 7-10 days after dropping aspirin.
Sponsors
Janssen Scientific Affairs, LLC
University of Florida
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The proposed investigation will be a prospective PD (pharmacodynamic) study conducted in cohorts of patients with CAD, PAD, or atrial fibrillation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Known CAD (defined as angiographic evidence of \>50% coronary artery stenosis or prior coronary revascularization) or PAD (defined as a positive ankle brachial index (ABI) or prior revascularization) * on treatment with either aspirin (81mg/qd), aspirin (81mg/qd) plus clopidogrel (75mg/qd), or aspirin (81mg/qd) plus ticagrelor (90mg/bid) for at least 3 months per standard of care OR * Atrial fibrillation (paroxysmal, persistent or permanent) on treatment with rivaroxaban 20 mg qd (if creatinine clearance \[CrCl\] \>50 mL/min) or 15 mg qd (if CrCl 15 - 50 mL/min) per standard of care. Patients with concomitant CAD or PAD who are also taking antiplatelet medications are not eligible. However, if these are only on oral anticoagulation with rivaroxaban (and no antiplatelet therapy) the person will be eligible.
Exclusion criteria
* Active pathological bleeding, history of clinically significant bleeding events, or deemed at increased risk of bleeding. * CrCL \<20 mL/min * Any clinical indication to be on triple antithrombotic therapy (DAPT plus an oral anticoagulant) * An acute coronary event in the past 90 days * Prior hemorrhagic stroke or intracranial hemorrhage * Ischemic stroke/transient ischemic attack in the past 6 months * Chronic use of nonsteroidal anti-inflammatory drugs * On treatment with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) or inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort). * Known moderate or severe hepatic impairment (Child-Pugh B and C) * Prior hypersensitivity reaction to rivaroxaban * On treatment with prasugrel in the past 10 days. * Platelet count \<80x106/mL * Hemoglobin \<10g/dL * Hemodynamic instability * Pregnant females \[women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet-Mediated Global Thrombogenicity | 20 days | Comparison of platelet-mediated global thrombogenicity measured by light transmittance aggregometry following collagen-related peptide+adenosine diphosphate+ tissue factor (CATF) stimuli between aspirin plus clopidogrel vs. aspirin plus clopidogrel plus rivaroxaban. This was reported as maximal aggregation %. The combination of agonists included in the CATF cocktail leads to activation of multiple platelet pathways including thrombin generation and is therefore a marker of thrombus formation mediated by platelets. |
| Platelet Aggregation Measured by VerifyNow PRU | 20 days | P2Y12 reaction units (PRU) by VerifyNow of dual antiplatelet therapy vs. dual antiplatelet therapy plus rivaroxaban. VerifyNow is a turbidimetric based optical detection system which measures platelet aggregation induced by ADP as an increase in light transmittance. |
| Thrombin Generation | 20 days | Comparison of thrombin generation, reported as peak thrombin level measured by a thrombin generation assay, between aspirin plus clopidogrel vs. aspirin plus clopidogrel plus rivaroxaban. This is reflective of the amount of thrombin that is generated following stimuli with tissue factor. The theombin generation assay will be carried out using Technothrombin® fluorogenic assay kit. |
Countries
United States
Participant flow
Recruitment details
Between January 14, 2019 and August 30, 2020 a total of 86 patients were consented for the study.
Pre-assignment details
1 patient withdrew the consent before initiation of the study and 3 patients were not eligible to start the study due to the presence of an exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Aspirin The cohort of patients on aspirin was treated with adjunctive vascular dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy was suspended for 7-10 days. | 20 |
| Aspirin Plus Clopidogrel The cohort of patients on aspirin plus clopidogrel was treated with adjunctive vascular dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy was suspended for 7-10 days. | 20 |
| Aspirin Plus Ticagrelor The cohort of patients on aspirin plus ticagrelor was treated with adjunctive vascular dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy was suspended for 7-10 days. | 20 |
| Rivaroxaban 20 mg The cohort of patients on rivaroxaban remained on rivaroxaban 20 mg daily. | 20 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Adjunctive Rivaroxaban 2.5 mg | Withdrawal by Subject | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Aspirin | Total | Rivaroxaban 20 mg | Aspirin Plus Ticagrelor | Aspirin Plus Clopidogrel |
|---|---|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 9 | 63 years STANDARD_DEVIATION 9 | 67 years STANDARD_DEVIATION 10 | 59 years STANDARD_DEVIATION 9 | 64 years STANDARD_DEVIATION 9 |
| peripheral arterial disease | 4 Participants | 17 Participants | 0 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 36 Participants | 4 Participants | 12 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 42 Participants | 16 Participants | 8 Participants | 7 Participants |
| Sex: Female, Male Female | 9 Participants | 28 Participants | 9 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 11 Participants | 52 Participants | 11 Participants | 16 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 21 | 0 / 21 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 1 / 21 | 0 / 21 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 21 | 0 / 21 | 0 / 20 |
Outcome results
Primary
Platelet Aggregation Measured by VerifyNow PRU
P2Y12 reaction units (PRU) by VerifyNow of dual antiplatelet therapy vs. dual antiplatelet therapy plus rivaroxaban. VerifyNow is a turbidimetric based optical detection system which measures platelet aggregation induced by ADP as an increase in light transmittance.
Time frame: 20 days
Population: For the purpose of this analysis, assessments were conducted in patients with an antithrombotic treatment regimen that paralleled that of the VOYAGER PAD trial, which included patients on triple therapy (DAPT with aspirin 81mg/qd and clopidogrel 75 mg/qd plus rivaroxaban 2.5 mg/bid) and DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). Comparative PD assessments were also made with patients on standard DAPT (aspirin and clopidogrel). Only patients with complete data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin Plus Clopidogrel | Platelet Aggregation Measured by VerifyNow PRU | 156 PRU | Standard Deviation 75 |
| Aspirin Plus Clopidogrel Plus Rivaroxaban | Platelet Aggregation Measured by VerifyNow PRU | 139 PRU | Standard Deviation 72 |
| Clopidogrel Plus Rivaroxaban | Platelet Aggregation Measured by VerifyNow PRU | 156 PRU | Standard Deviation 73 |
| Aspirin | Platelet Aggregation Measured by VerifyNow PRU | 223 PRU | Standard Deviation 30 |
| Aspirin Plus Rivaroxaban | Platelet Aggregation Measured by VerifyNow PRU | 217 PRU | Standard Deviation 36 |
| Rivaroxaban | Platelet Aggregation Measured by VerifyNow PRU | 229 PRU | Standard Deviation 34 |
| Aspirin Plus Ticagrelor | Platelet Aggregation Measured by VerifyNow PRU | 32 PRU | Standard Deviation 53 |
| Aspirin Plus Ticagrelor Plus Rivaroxaban | Platelet Aggregation Measured by VerifyNow PRU | 29 PRU | Standard Deviation 57 |
| Ticagrelor Plus Rivaroxaban | Platelet Aggregation Measured by VerifyNow PRU | 36 PRU | Standard Deviation 61 |
| Rivaroxaban 20 mg | Platelet Aggregation Measured by VerifyNow PRU | 241 PRU | Standard Deviation 38 |
p-value: 0.488Wilcoxon (Mann-Whitney)
Primary
Platelet-Mediated Global Thrombogenicity
Comparison of platelet-mediated global thrombogenicity measured by light transmittance aggregometry following collagen-related peptide+adenosine diphosphate+ tissue factor (CATF) stimuli between aspirin plus clopidogrel vs. aspirin plus clopidogrel plus rivaroxaban. This was reported as maximal aggregation %. The combination of agonists included in the CATF cocktail leads to activation of multiple platelet pathways including thrombin generation and is therefore a marker of thrombus formation mediated by platelets.
Time frame: 20 days
Population: For the purpose of this analysis, assessments were conducted in patients with an antithrombotic treatment regimen that paralleled that of the VOYAGER PAD trial, which included patients on triple therapy (DAPT with aspirin 81mg/qd and clopidogrel 75 mg/qd plus rivaroxaban 2.5 mg/bid) and DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). Comparative PD assessments were also made with patients on standard DAPT (aspirin and clopidogrel). Only patients with complete data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin Plus Clopidogrel | Platelet-Mediated Global Thrombogenicity | 66 percentage of aggregation | Standard Deviation 18 |
| Aspirin Plus Clopidogrel Plus Rivaroxaban | Platelet-Mediated Global Thrombogenicity | 59 percentage of aggregation | Standard Deviation 19 |
| Clopidogrel Plus Rivaroxaban | Platelet-Mediated Global Thrombogenicity | 69 percentage of aggregation | Standard Deviation 18 |
| Aspirin | Platelet-Mediated Global Thrombogenicity | 71 percentage of aggregation | Standard Deviation 12 |
| Aspirin Plus Rivaroxaban | Platelet-Mediated Global Thrombogenicity | 63 percentage of aggregation | Standard Deviation 21 |
| Rivaroxaban | Platelet-Mediated Global Thrombogenicity | 74 percentage of aggregation | Standard Deviation 10 |
| Aspirin Plus Ticagrelor | Platelet-Mediated Global Thrombogenicity | 37 percentage of aggregation | Standard Deviation 24 |
| Aspirin Plus Ticagrelor Plus Rivaroxaban | Platelet-Mediated Global Thrombogenicity | 32 percentage of aggregation | Standard Deviation 25 |
| Ticagrelor Plus Rivaroxaban | Platelet-Mediated Global Thrombogenicity | 35 percentage of aggregation | Standard Deviation 24 |
| Rivaroxaban 20 mg | Platelet-Mediated Global Thrombogenicity | 75 percentage of aggregation | Standard Deviation 14 |
p-value: 0.275Wilcoxon (Mann-Whitney)
Primary
Thrombin Generation
Comparison of thrombin generation, reported as peak thrombin level measured by a thrombin generation assay, between aspirin plus clopidogrel vs. aspirin plus clopidogrel plus rivaroxaban. This is reflective of the amount of thrombin that is generated following stimuli with tissue factor. The theombin generation assay will be carried out using Technothrombin® fluorogenic assay kit.
Time frame: 20 days
Population: For the purpose of this analysis, assessments were conducted in patients with an antithrombotic treatment regimen that paralleled that of the VOYAGER PAD trial, which included patients on triple therapy (DAPT with aspirin 81mg/qd and clopidogrel 75 mg/qd plus rivaroxaban 2.5 mg/bid) and DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). Comparative PD assessments were also made with patients on standard DAPT (aspirin and clopidogrel). Only patients with complete data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin Plus Clopidogrel | Thrombin Generation | 235 µM | Standard Deviation 57 |
| Aspirin Plus Clopidogrel Plus Rivaroxaban | Thrombin Generation | 135 µM | Standard Deviation 79 |
| Clopidogrel Plus Rivaroxaban | Thrombin Generation | 121 µM | Standard Deviation 56 |
| Aspirin | Thrombin Generation | 248 µM | Standard Deviation 77 |
| Aspirin Plus Rivaroxaban | Thrombin Generation | 130 µM | Standard Deviation 54 |
| Rivaroxaban | Thrombin Generation | 160 µM | Standard Deviation 59 |
| Aspirin Plus Ticagrelor | Thrombin Generation | 263 µM | Standard Deviation 66 |
| Aspirin Plus Ticagrelor Plus Rivaroxaban | Thrombin Generation | 162 µM | Standard Deviation 83 |
| Ticagrelor Plus Rivaroxaban | Thrombin Generation | 155 µM | Standard Deviation 58 |
| Rivaroxaban 20 mg | Thrombin Generation | 103 µM | Standard Deviation 85 |
p-value: <0.001Wilcoxon (Mann-Whitney)