Rivaroxaban + Aspirin for Blood Clot Prevention After Joint Surgery
(EPCATIII Trial)
Recruiting in Palo Alto (17 mi)
Overseen bySudeep P Shivakumar, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Sudeep Shivakumar
Must not be taking: Strong P-gp/CYP3A4 inhibitors/inducers
Disqualifiers: VTE, Metastatic cancer, Major bleeding, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?
Consented patients undergoing elective total hip and total knee arthroplasty will be randomized to receive either aspirin alone or aspirin and rivaroxaban for prevention of venous thromboembolism.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using certain drugs that strongly affect liver enzymes (like ketoconazole or rifampicin). It's best to discuss your current medications with the trial team.
What evidence supports the effectiveness of the drug combination of Rivaroxaban and Aspirin for preventing blood clots after joint surgery?
The COMPASS trial showed that combining Rivaroxaban with Aspirin reduced the risk of cardiovascular events compared to Aspirin alone, although it increased the risk of major bleeding. Additionally, a study found that both Aspirin and Rivaroxaban were effective in preventing blood clots after knee surgery, with no significant difference in safety outcomes.12345
Is the combination of Rivaroxaban and Aspirin generally safe for humans?
Aspirin, a common medication, has been used for many years and is generally considered safe, but it can cause stomach issues like ulcers and kidney problems, especially in older adults or those with existing kidney issues. It's important to monitor for these side effects when using aspirin long-term.16789
How is the drug combination of Rivaroxaban and Aspirin unique for preventing blood clots after joint surgery?
The combination of Rivaroxaban and Aspirin is unique because it combines two different mechanisms: Rivaroxaban is an anticoagulant that prevents blood clots by inhibiting a specific protein involved in clotting, while Aspirin is an antiplatelet drug that prevents platelets from clumping together. This dual approach may offer a more comprehensive prevention of blood clots compared to using either drug alone.410111213
Eligibility Criteria
This trial is for adults undergoing elective hip or knee replacement surgery without a history of significant liver disease, kidney failure, low platelets, recent major surgery, chronic high-dose aspirin use, potential pregnancy or breastfeeding. They must not have had a blood clot before and can't be on certain other medications.Inclusion Criteria
Written informed consent in accordance with federal, local and institutional guidelines
I am scheduled for elective hip or knee replacement surgery at a participating hospital.
Exclusion Criteria
I am younger than 18 years old.
I have liver disease or another condition that prevents me from taking rivaroxaban.
You have previously taken part in the EPCAT III study.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either aspirin alone or aspirin and rivaroxaban following total hip or knee arthroplasty
14-35 days
Follow-up
Participants are monitored for safety and effectiveness after treatment, focusing on venous thromboembolism and bleeding events
90 days
Treatment Details
Interventions
- Acetylsalicylic acid 81 mg (Antiplatelet Agent)
- Rivaroxaban (Anticoagulant)
Trial OverviewThe study is testing whether taking Rivaroxaban along with aspirin is better at preventing blood clots after hip or knee replacement surgery compared to just taking aspirin alone. Participants will be randomly assigned to one of the two treatment groups.
Participant Groups
4Treatment groups
Experimental Treatment
Active Control
Group I: TKA-study armExperimental Treatment1 Intervention
Total Knee Arthroplasty: 14 days of aspirin
Group II: THA-study armExperimental Treatment1 Intervention
Total Hip Arthroplasty: 35 days of aspirin
Group III: TKA-control armActive Control1 Intervention
Total Knee Arthroplasty: 5 days of rivaroxaban, followed by 9 days of aspirin
Group IV: THA-control armActive Control1 Intervention
Total Hip Arthroplasty: 5 days of rivaroxaban, followed by 30 days of aspirin
Acetylsalicylic acid 81 mg is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Aspirin for:
- Pain relief
- Fever reduction
- Inflammation
- Migraine
- Arthritis
- Cardiovascular disease prevention
- Venous thromboembolism prevention
🇪🇺 Approved in European Union as Acetylsalicylic acid for:
- Pain relief
- Fever reduction
- Inflammation
- Migraine
- Arthritis
- Cardiovascular disease prevention
🇨🇦 Approved in Canada as Aspirin for:
- Pain relief
- Fever reduction
- Inflammation
- Migraine
- Arthritis
- Cardiovascular disease prevention
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Queen Elizabeth II HSCHalifax, Canada
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Who Is Running the Clinical Trial?
Sudeep ShivakumarLead Sponsor
Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) NetworkCollaborator
Canadian Institutes of Health Research (CIHR)Collaborator
Nova Scotia Health AuthorityCollaborator
References
[Ascolong: a new buccal dosage form of acetylsalicylic acid to be used and antiaggregant]. [2013]Study of the tolerance and pharmacodynamic and pharmacokinetic characteristics of ascolong, a new buccal dosage form of aspirin containing a very low dose of acetylsalicylic acid (ASA): 12.5 mg.
Comparative effects of immediate-release and extended-release aspirin on basal and bradykinin-stimulated excretion of thromboxane and prostacyclin metabolites. [2021]A goal of aspirin therapy is to inhibit thromboxane production and platelet aggregation without inhibiting endothelial production of the vasodilator and anti-thrombotic prostacyclin. This study tested the hypothesis that extended-release aspirin (NHP-554C) would have increased selectivity for inhibition of basal and simulated thromboxane formation compared to immediate-release aspirin (ASA). Thirty-six healthy subjects were randomized to NHP-554C or ASA groups. Within each group, subjects were randomized to 5-day treatment with 81 mg/d, 162.5 mg/d and placebo in a crossover design in which treatment periods were separated by 2-week washout. On the fifth day of treatment, 81 mg/d and 162.5 mg/d ASA reduced basal urinary excretion of the stable thromboxane metabolite 11-dehydro-thromboxane B2 62.3% and 66.2% and basal excretion of the stable prostacyclin metabolite 2,3-dinor-6-keto-PGF1α 22.8% and 26.5%, respectively, compared to placebo. NHP-554C 81 mg/d and 162.5 mg/d reduced 11-dehydro-thromboxane B2 53% (P = 0.03 vs. ASA 81 mg/d) and 67.9% and 2,3-dinor-6-keto-PGF1α 13.4% and 18.5%, respectively. NHP-554C 81 mg/d did not significantly reduce basal excretion of the prostacyclin metabolite. Both doses of ASA and NHP significantly reduced excretion of both thromboxane and prostacyclin metabolites following intravenous bradykinin. During NHP-554C 162.5 mg/d, but not during ASA, bradykinin significantly increased urinary 2,3-dinor-6-keto-PGF1α. Nevertheless, 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-PGF1α responses to bradykinin were statistically similar during ASA and NHP-554C. In conclusion, at doses of 81 and 162.5 mg/d immediate- and extended-release aspirin selectively decrease basal thromboxane production. Both forms of aspirin decrease bradykinin-stimulated thromboxane and prostacyclin production, but some stimulated prostacyclin production remains during treatment with NHP-554C.
Patients receiving knee arthroplasty with pre-existing long-term aspirin use suffer lower risk of perioperative complications but feel more postoperative pain. [2023]Aspirin has gained increasing use-popularity on account of its multiple benefits. The present study aimed to investigate how a pre-existing long-term aspirin use (L-AU) would affect perioperative complications and postoperative pain in primary total knee arthroplasty (TKA) patients.
Aspirin versus Rivaroxaban to Prevent Venous Thromboembolism after Total Knee Arthroplasty: A Double-blinded, Randomized Controlled Trial. [2022]Objective  Aspirin (acetylsalicylic acid, ASA) and rivaroxaban are anticoagulants that have increased in popularity due to ease of use in the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA). The present study aimed to evaluate the efficacy of ASA compared with that of rivaroxaban on VTE prophylaxis in patients who underwent TKA. Method  Forty patients who had primary knee osteoarthritis and would undergo TKA were randomized into two groups. In total, 20 patients in the ASA group used oral aspirin, at a dose of 300 mg/day, for VTE prophylaxis after TKA, while 20 patients in the rivaroxaban group received oral rivaroxaban, at a dose of 10 mg/day. On days 4 and 14 after the operation, deep vein thrombosis (DVT) in the lower limbs on the operated side was detected through duplex ultrasonography. Other complications were recorded for 14 days. Results  There were no positive findings of DVT detected with duplex ultrasonography in the groups of patients, and the occurrence of pulmonary embolism was not observed. In total, 4 patients had subcutaneous ecchymosis on the fourth postoperative day (2 patients in the ASA group and 2 patients in the rivaroxaban group; p  = 1.0), and another 4 patients on the fourteenth postoperative day (1 patient in the ASA group and 3 patients in the rivaroxaban group; p  = 0.292). No cases of wound hematoma, major organ bleeding, wound infection, or reoperation were observed in the sample. Conclusion  Aspirin and rivaroxaban had comparable efficacy to prevent VTE, without increasing the incidence of wound complications and bleeding after TKA.
The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease. [2021]Rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid (aspirin; ASA) 100 mg reduced the risk of cardiovascular events as compared with ASA monotherapy in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) but increased the risk of major bleedings. Analysis of net clinical benefit (NCB) is of key clinical relevance and represents an integrated measure of overall patient outcome.
Pharmacology of nonsteroidal anti-inflammatory drugs. Practical review for clinicians. [2019]Aspirin and the newer nonsteroidal anti-inflammatory drugs are the mainstay of basic therapy in rheumatoid arthritis and the other rheumatic diseases. Despite its many years of clinical use, the pharmacologic actions of aspirin are still not fully understood; those of many of the newer nonsteroidals may offer significant advantages in terms of long-term safety. Studies in animals and normal human volunteers, as well as clinical trials, provide useful information about the absorption, metabolism, excretion, efficacy, appropriate dosage, and safety of a given nonsteroidal agent. Because all of the newer agents have been developed using the same basic animal tests of efficacy, they all closely resemble indomethacin. Differences in half-life, however, may be important in determining the relative safety of a nonsteroidal, especially in older patients. Most of the nonsteroidals bind only to albumin, and therefore have a kind of built-in safety mechanism: once the albumin binding sites are saturated, free drug is rapidly excreted by the kidney and drug accumulation is prevented. Despite this fact, the clinician must be concerned about two frequent sorts of problems that may arise from the prostaglandin-inhibiting effects of the nonsteroidals. Gastrointestinal side effects may include minor symptoms; diffuse gastritis; small erosions of the gastric mucosa, visible only by endoscope; and frank ulceration, which may rarely be life-threatening. Animal studies, various tests in normal volunteers, and pre-marketing clinical studies may all shed light on the relative ulcerogenicity of a given nonsteroidal agent. Long-term clinical experience especially helps indicate which agents appear to be more ulcerogenic than average and which appear to be less than average. Renal effects of the nonsteroidals are also related to their inhibition of prostaglandin synthesis. The most serious of these--a characteristic kind of interstitial nephritis, renal papillary necrosis, and hyperkalemia--are fortunately rare, but some classes of patients--the elderly, those with impaired renal function, and those receiving diuretics--are at increased risk. For these patients, any nonsteroidal anti-inflammatory drug should be prescribed with caution and appropriate monitoring of renal function.
Comparison of cardiovascular thrombotic events in patients with osteoarthritis treated with rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs (ibuprofen, diclofenac, and nabumetone). [2019]Aspirin, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), and specific cyclooxygenase-2 (COX-2) inhibitors each have distinctive effects on COX-1-mediated thromboxane biosynthesis, the major determinant of platelet aggregation. It is unclear whether these effects are associated with differences in thrombogenic risks. To compare the risk for thrombotic cardiovascular events among patients receiving rofecoxib, nonselective NSAIDs, and placebo, cardiovascular safety was assessed in 5,435 participants in 8 phase IIB/III osteoarthritis trials. The median treatment exposure was 31/2 months. The primary end point assessed was the risk of any arterial or venous thrombotic cardiovascular adverse event (AE). A second analysis assessed differences in the Anti-Platelet Trialists' Collaboration (APTC) events, a cluster end point that consists of the combined incidence of (1) cardiovascular, hemorrhagic, and unknown death; (2) myocardial infarction; and (3) cerebrovascular accident. Similar rates of thrombotic cardiovascular AEs were reported with rofecoxib, placebo, and comparator nonselective NSAIDs (ibuprofen, diclofenac, or nabumetone). In trials that compared rofecoxib with NSAIDs, the incidence of thrombotic cardiovascular AEs was 1.93/100 patient-years in the rofecoxib treatment group compared with 2.27/100 patient-years in the combined nonselective NSAID group. In trials that compared rofecoxib with placebo, the incidence of thrombotic cardiovascular AEs was 2.71/100 patient-years in the rofecoxib group compared with 2.57/100 patient-years in the placebo group. Consistent with the risks of cardiovascular AEs, similar rates of APTC events were reported with rofecoxib, placebo, and comparator nonselective NSAIDs. Thus, in the rofecoxib osteoarthritis development program, there was no difference between rofecoxib, comparator nonselective NSAIDs, and placebo in the risks of cardiovascular thrombotic events.
[Aspirin. Acetylsalicylic acid and aspirinlike drugs. A review.]. [2006]In this review acetylsalicylic acid and aspirin with little "a" are considered as synonyms. A short acount is given of the history preceeding the synthesis of acetylsalicylic acid from salicylic acid by Felix Hoffmann in 1897 and its marketing in 1899 as Aspirin(R) by the Bayer Company. Aspirin was originally considered a prodrug to salicylic acid since it was at that time thought to have the same pharmacodynamic effects as salicylic acid and is rapidly transformed to it in vivo. Later aspirin was also found to be effective in its own right. During the years aspirin has gradually become the standard drug among an increasing number of aspirinlike drugs having similar effects as aspirin and often collectively, and somewhat misleading, named "nonsteroidal antiinflammatory drugs" (NSAIDs). The seminal work of John Vane and his colleagues in the 1970s and later has irrefutably tied the effects and side effects of aspirin and aspirinlike drugs to blocking of cyclooxigenase activity and therefore to reduced production of prostaglandins and related biogenic lipids. The anticoagulant effect, where aspirin itself is the cardinal drug, is thus due to decreased synthesis of thromboxan, whereas the antipyretic effect is due to reduced synthesis of prostaglandins in the central nervous system. The analgesic effect is obviously both related to decreased synthesis of prostaglandins in the central nervous system and outside it. On the other hand the antiinflammatory effect is seemingly mostly due to blocking inflammatory phenomena, without involvement of cyclooxigenase, in the walls of vessels although blocking the synthesis of prostaglandins also has a role. All aspirinlike drugs have until quite recently been mixed blockers of cyclooxigenases (COX 1 and COX 2) with aspirin itself being the most outstanding COX 1 blocker. New aspirinlike drugs with selective COX 2 blocking effect are apparently not any better on classical indications than the older drugs with mixed COX 1 and COX 2 blocking effect and their use might moreover be limited by some severe side effects. These drugs might, however, become of value for use on new indications.
Comparison of long-term safety of ketorolac tromethamine and aspirin in the treatment of chronic pain. [2013]A double-blind, randomized trail was conducted in 823 patients who required long-term analgesic therapy for chronic pain such as that caused by osteoarthritis, fibromyopathies or fibromyalgias, other nonarticular chronic soft tissue pain syndromes, or headaches. The safety and analgesic efficacy of ketorolac tromethamine 10 mg 4 times a day as needed was compared with that of aspirin 650 mg 4 times a day as needed. The primary emphasis of this 52-week study was on evaluating the safety of the drugs. Patients returned to the clinics at 2, 5, 10, 15, 20, 28, 36, 44, and 52 weeks for assessments of safety and efficacy. Both patients' and investigators' evaluations of overall efficacy and safety favored ketorolac over aspirin. The probability of early withdrawal from the study was significantly higher with aspirin than with ketorolac, primarily because of lack of efficacy. Early withdrawal for safety-related reasons alone was similar for those taking aspirin and ketorolac.
Aspirin compared to enoxaparin or rivaroxaban for thromboprophylaxis following hip and knee replacement. [2021]Background The risk of venous thromboembolism following major orthopaedic surgery is among the highest for all surgical specialties. Our hospital guidelines for thromboprophylaxis following elective primary total hip or knee replacement are based on American College of Chest Physicians guidance. The most recent change to local guidelines was the introduction of the extended aspirin regimen as standard thromboprophylaxis. Objective To establish the appropriateness of this regimen by comparing venous thromboembolism rates in patients receiving extended aspirin to previous regimens. Setting The largest dedicated orthopaedic hospital in Ireland. Methods This was a retrospective cohort study. Data were collected from patient record software. All eligible patients undergoing primary total hip or knee replacement between 1st January 2010 and 30th June 2016 were included. Main outcome measure Venous thromboembolism up to 6 months post-operatively. Results Of the 6548 participants (55.3% female, mean age 65.4 years (± 11.8 years, 55.8% underwent total hip replacement), venous thromboembolism occurred in 65 (0.99%). Venous thromboembolism rate in both the inpatient enoxaparin group (n = 961) and extended aspirin group (n = 3460) was 1.04% and was 0.66% in the modified rivaroxaban group (n = 1212). Non-inferiority analysis showed the extended aspirin regimen to be equivalent to the modified rivaroxaban regimen. History of venous thromboembolism was the only significant demographic risk factor for post-operative venous thromboembolism (0.87% vs. 3.54%, p = 0.0002). Conclusion In daily clinical practice, extended aspirin regimen is at least as effective as modified rivaroxaban for preventing clinically important venous thromboembolism among patients undergoing hip or knee arthroplasty who are discharged from the hospital without complications. Aspirin can be considered a safe and effective agent in the prevention of venous thromboembolism after total hip or total knee replacement.
A retrospective analysis of bleeding risk with rivaroxaban, enoxaparin, and aspirin following total joint arthroplasty or revision. [2022]Rivaroxaban, enoxaparin, and aspirin are commonly used medications for thromboprophylaxis following lower extremity joint arthroplasty or revision. Previous research has demonstrated efficacy in preventing venous thromboembolism with each medication, however, the comparative risk of bleeding between them remains poorly understood. The aim of this study was to compare the odds of bleeding between rivaroxaban, enoxaparin, and aspirin following lower extremity joint arthroplasty or revision.
Rivaroxaban 2.5 mg. No justification for using this anticoagulant after an acute coronary syndrome. [2015]Aspirin is the antithrombotic drug of choice for preventing recurrences after a first acute coronary syndrome. The addition of clopidogrel, another antiplatelet agent, is helpful in case of angioplasty with stenting. Following the acute phase, warfarin, an anticoagulant, alone or in combination with aspirin, may be used only in specific situations, particularly for patients with a high thrombotic risk (due to atrial fibrillation for example). Rivaroxaban, an oral factor Xa inhibitor anticoagulant, has been authorised for use following an acute coronary syndrome, but at a new dose strength of 2.5 mg, in combination with aspirin alone or aspirin plus clopidogrel. Rivaroxaban has not been compared with warfarin in patients with a high thrombotic risk following an acute coronary syndrome. In a double-blind, randomised, placebo-controlled trial in 15 526 patients, who were not at particularly high risk of thrombosis, the addition of the rivaroxaban to aspirin or to aspirin plus clopidogrel appeared to reduce mortality during the first year of treatment (2.6% versus 3.8% with placebo). However, there is a large amount of missing data, exceeding the inter-group difference in the number of deaths, seriously undermining the results. In the subgroup of about 1000 patients in whom antiplatelet therapy consisted of aspirin alone, addition of rivaroxaban did not lead to a statistically significant decrease in the incidence of cardiovascular events or death. The addition of rivaroxaban increased the incidence of "clinically relevant" bleeding episodes, as defined in the study protocol (11.2% of patients per year in the rivaroxaban group versus 6.4% in the placebo group), as well as the incidence of major bleeding events (respectively 1.2% and 0.3% of patients per year) and intracranial haemorrhage (14 versus 5 cases). The patients selected for this trial were considered to have a low risk of bleeding, so the risk is likely to be higher in many patients who have had an acute coronary syndrome. In practice, it has not yet been demonstrated that adding rivaroxaban to aspirin or to aspirin plus clopidogrel is beneficial following an acute coronary syndrome. In addition, the bleeding risk is likely to be higher in routine practice than in the conditions under which the comparative trial was conducted. It is therefore best not to use rivaroxaban in this setting but to stick with best-known antithrombotic drugs.
Rivaroxaban, Aspirin, or Both to Prevent Early Coronary Bypass Graft Occlusion: The COMPASS-CABG Study. [2019]Patients with recent coronary artery bypass graft (CABG) surgery are at risk for early graft failure, which is associated with a risk of myocardial infarction and death. In the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) trial, rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced the primary major adverse cardiovascular events (MACE) outcome of cardiovascular death, stroke, or myocardial infarction. Rivaroxaban 5 mg twice daily alone did not significantly reduce MACE.