Low-dose Rivaroxaban Research Articles

Safety and efficacy of combined antiplatelet and low-dose rivaroxaban in patients with chronic limb threatening ischaemia in Singapore

Dear Editor, Peripheral artery disease (PAD) is characterised by the debilitating atherosclerotic occlusion of arteries in the lower extremities, with chronic limb threatening ischaemia (CLTI) representing the most advanced stage of this disease process. Left untreated, these sequelae will invariably progress to major lower extremity amputation (LEA) and premature death. In Singapore, the rate of

Aspirin Monotherapy Is More Cost Effective than Rivaroxaban + Aspirin in Peripheral Arterial Disease Patients after Revascularization

Considerable debate exists on optimal antithrombotic therapy after lower extremity revascularization in peripheral arterial disease (PAD) patients. Multiple studies have investigated the addition of additional agents to the widely accepted aspirin monotherapy, including low-dose rivaroxaban in the Vascular Outcomes Study of Aspirin Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial. While rivaroxaban + aspirin reduced the composite limb and cardiac event outcome, insufficient evidence exists regarding the cost-effectiveness of this regimen.

Population Pharmacokinetics and Dose Optimization Based on Renal Function of Rivaroxaban in Thai Patients with Non-Valvular Atrial Fibrillation.

Low-dose rivaroxaban has been used in Asian patients with direct oral anticoagulants (DOACs) eligible for atrial fibrillation (AF). However, there are few pharmacokinetic (PK) data in Thai patients to support precise dosing. This study aimed to develop a population PK model and determine the optimal rivaroxaban doses in Thai patients. A total of 240 Anti-Xa levels of rivaroxaban from 60 Thai patients were analyzed. A population PK model was established using the nonlinear mixed-effect modeling approach. Monte Carlo simulations were used to predict drug exposures at a steady state for various dosages. Proportions of patients having rivaroxaban exposure within typical exposure ranges were determined. A one-compartment model with first-order absorption best described the data. Creatinine clearance (CrCl) and body weight significantly affected CL/F and V/F, respectively. Regardless of body weight, a higher proportion of patients with CrCl < 50 mL/min receiving the 10-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. In contrast, a higher proportion of patients with CrCl ≥ 50 mL/min receiving the 15-mg once-daily dose had rivaroxaban exposures within the typical exposure ranges. The study’s findings suggested that low-dose rivaroxaban would be better suited for Thai patients and suggested adjusting the medication’s dose in accordance with renal function.

Thromboinflammation in cardiovascular disease: lessons learned for the management of hypertension, heart failure, and aortic valve stenosis.

Thromboinflammation has emerged as a new term to describe the interconnection between the simultaneous activation of the coagulation and the immune system. It is the flipside of immunothrombosis, an evolutionary highly conserved mechanism of innate immunity that has developed to allow trapping and compartimentalization of invaded pathogens and to improve host defence. In contrast to immunothrombosis, it occurs in the absence of a pathogen, but is triggered mainly by endothelial dysfunction. This may lead to release of pro-inflammatory cytokines as well as chemokines and adhesion molecules, activation of myeloid cells, decryption of tissue factor on the surface of neutrophils and monocytes, release of von Willebrand factor (vWF) from platelets and endothelial cell Weibel–Palade bodies, and netting of neutrophils with consecutive activation of the contact phase of the coagulation cascade and FXa/thrombin activation, implying both thrombin propagation via the FXI feedback activation and increased fibrin deposition.1 In cardiovascular diseases (CVDs), paradigmatic conditions of thromboinflammation are endothelial erosion as a mechanism of acute coronary syndrome in the absence of plaque rupture [Type II myocardial infarction (MI)],2 deep vein thrombosis induced by low flow,3 and atherogenesis propelled by a chronically activated coagulation cascade.4 In some indications, recent advances in pharmacotherapy were successful in ameliorating the disease burden evoked by thromboinflammation. For example, long-term FXa inhibition can reduce thrombosis-associated morbidity and mortality in cancer, when administered for primary prevention of venous thromboembolism in selected patients,5 and low-dose rivaroxaban in addition to aspirin can lower major adverse cardiovascular events and all-cause mortality in patients with coronary artery disease who had an MI in the past.6 These findings of the COMPASS trial merit special consideration, because one-fourth of the anticoagulant dose of rivaroxaban was efficient for reaching this endpoint including reduction in thrombotic events, which has been attributed to vascular protection mediated through protease-activated receptor inhibition instead of reducing thrombin and fibrin formation in this population of non-atrial fibrillation patiens. The identification of the thrombin-FXI feedback amplification loop for thrombin propagation holds promise to avoid blood clotting without abolishing haemostasis and has sparked the development of novel FXI(a) inhibitors for safer anticoagulation7 that seamlessly align into the concept of thromboinflammation (Figure 1).

Low-dose aspirin and rivaroxaban combination therapy to overcome aspirin non-sensitivity in patients with vascular disease.

Approximately 20% of vascular patients treated with acetyl salicylic acid (i.e., aspirin) demonstrate less than expected platelet inhibition – putting them at a four-fold increased risk of adverse cardiovascular events. Low-dose rivaroxaban (2.5 mg twice daily) in combination with low-dose aspirin has been shown to reduce adverse cardiovascular and limb events when compared to aspirin alone. In this study, light transmission aggregometry was used to measure arachidonic acid-induced platelet aggregation to evaluate the potential of combining low-dose rivaroxaban and aspirin in attenuating or overcoming aspirin non-sensitivity. In the discovery phase, 83 patients with peripheral arterial disease (PAD) taking 81 mg aspirin daily were recruited from the outpatient vascular surgery clinic at St Michael's Hospital between January to September 2021. 19 (23%) were determined to be non-sensitive to aspirin. After ex-vivo addition of 2.5 mg dosage equivalent of rivaroxaban, aspirin non-sensitivity was overcome in 11 (58%) of these 19 patients. In the validation phase, 58 patients with cardiovascular risk factors who were not previously prescribed aspirin were recruited. In this group, ex-vivo addition of 2.5 mg dosage equivalent of rivaroxaban significantly reduced arachidonic acid-induced platelet aggregation in the presence of aspirin. These results demonstrate the potential for low-dose rivaroxaban to overcome aspirin non-sensitivity in patients with PAD. Further studies are needed to evaluate and confirm these findings.

Antithrombotic Therapy for Symptomatic Peripheral Arterial Disease: A Systematic Review and Network Meta-Analysis.

BackgroundHigh-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD.MethodsA systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group.ResultsTwenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66–0.93], ticagrelor (RR 0.79, 95% CI 0.65–0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64–0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76–0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55–0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78–0.97) and MALE (RR 0.89, 95% CI 0.81–0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking.ConclusionClopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-022-01756-6.

Rivaroxaban, a New Molecule with Potential to Balance Bleeding Risk and Ischemic Events in Patients with Chronic Coronary Syndrome.

Globally, the prevalence of chronic coronary syndrome (CCS) increases with age. In India, there is a rapidly growing burden of coronary artery disease (CAD), which has become the leading cause of morbidity and mortality. Despite recommended medical therapy, patients with CCS are still at risk of ischemic events. Currently, dual antiplatelet therapy (DAPT) is recommended in the form of aspirin and a P2Y12 inhibitor or low dose rivaroxaban in patients with stable CAD and/or peripheral artery disease (PAD). A low dose of rivaroxaban in combination with aspirin is a promising approach; however, for patients who might benefit the most, it still remains a challenge. Clinical trial data on this new drug was certainly very encouraging, with evidence from the COMPASS trial and prespecified subgroups of COMPASS trials suggesting that the addition of rivaroxaban to aspirin was associated with a significantly lower risk of ischemic events, mortality, and tolerable bleeding profile in patients with CCS and high-risk factors. This combination is cost-effective and generally well tolerated in patients with CAD and/or PAD, as well as patients with CCS and multimorbidity or high-risk populations.

Aspirin with Low-Dose Ticagrelor or with Low-Dose Rivaroxaban for Secondary Prevention: A Cost per Outcome Analysis.

Secondary prevention of cardiovascular events among patients with diagnosed cardiovascular disease and high ischemic risk poses a significant challenge in clinical practice. The combinations of aspirin with low-dose (LD) ticagrelor or LD rivaroxaban have shown superiority in preventing major adverse cardiovascular events (MACE) compared with aspirin treatment alone. The comparative value for money of these two regimens remains unexplored. We analyzed each regimen's annual cost needed to treat (CNT) by multiplying the annualized number needed to treat (aNNT) by the annual cost of each drug. The aNNTs were based on outcome data from PEGASUS TIMI-54 and COMPASS trials. Scenario analyses were performed to overcome variances in terms of population risk. Costs were calculated as 75% of US National Average Drug Acquisition Cost (NADAC), extracted in January 2022. The primary outcome was defined as CNT to prevent one MACE across the two regimens. Secondary value analysis was performed for myocardial infarction (MI), stroke, and cardiovascular death as separate outcomes. The aNNTs to prevent MACE with LD ticagrelor and with LD rivaroxaban were 229 [95% confidence interval (CI) 141-734] and 147 (95% CI 104-252), respectively. At an annual cost of US$3726 versus US$4533, the corresponding CNTs were US$853,254 (95% CI 525,366-2,734,884) with LD ticagrelor and US$666,351 (95% CI 471,432-1,142,316) with LD rivaroxaban. Combining aspirin with LD rivaroxaban provides better value for money than with LD ticagrelor for secondary prevention of MACE.

O070 Can the compass trial recommendations be implemented following symptomatic carotid endarterectomy (CEA)?

Abstract Introduction The paradigm changing COMPASS trial (1) demonstrated that in stable atherosclerotic disease, low-dose Rivaroxaban and Aspirin has a significantly greater protective effect on subsequent cardiovascular events (death, stroke or myocardial infarct) than antiplatelet medication alone. This included carotid endarterectomy patients. We assessed our success at implementing COMPASS in our symptomatic CEA patients Methods At the four-week virtual post-CEA review, in suitable patients the general practitioner was advised to change from single antiplatelet to COMPASS regimen. At 6-month follow-up the success and safety of the conversion was assessed. Results For 18 months up to February 2021, 47 patients underwent successful CEA. 29 were recommended for COMPASS, 3 were lost to follow up and 15 were not suitable (6 on DOAC for AF/VTE, 9 complex drug regimen). At 6 months 18 of 29 patients were on the COMPASS regimen (9 not started; 2 withdrawn due to bruising). All patients reported compliance to the regimen. There were no reported haemorrhagic events. 1 patient (not in the COMPASS group) had further multi-territory cerebrovascular events. Conclusion COMPASS is well tolerated in this cohort. Conversion from established drug regimens has yet to gain traction. The benefits on future cardiovascular events post-CEA is yet to be determined. Take-home message Changing post-op medications after a carotid endarterectomy can reduce the later risk of Cardiovascular events. We demonstrate it is possible to successfully do this, but should aim for a higher rate of uptake. (1): N Engl J Med 2017; 377:1319–1330 DOI: 10.1056/NEJMoa1709118

Current approaches to the selection of acetylsalicylic acid dosage forms in cardiology

The article is devoted to modern approaches to the selection of optimal dosage forms of acetylsalicylic acid (ASA), which ensure high bioavailability of ASA drugs. The relevance of improving the tactics of ASA use for both primary and secondary prevention of cardiovascular diseases is discussed. Changes in the role of ASA in the prevention of cardiovascular disease complications are discussed, including as part of combined antithrombotic therapy, including ASA and either P2Y12 inhibitor or low-dose rivaroxaban. Evidence is presented that has led to doubts about the sufficient bioavailability of the enteric form of ASA, as well as the predictability of the response to therapy. A separate part of the article is devoted to the safety of different forms of ASA, in particular - the effect on the mucosa of the small intestine. The results of clinical studies evaluating the effect of ASA intake in enteric-soluble and buffered forms on the small intestinal mucosa and the risk of bleeding are presented. In addition, the problem of decreased effectiveness of ASA intake in overweight or obese individuals is considered. The article provides information on ongoing randomized trials to assess the effectiveness of increasing the frequency of ASA intake, as well as the effectiveness of chronopharmacological approaches to optimize the use of ASA. The analysis performed leads it to conclude that the buffer form can now be considered the preferred acetylsalicylic acid (ASA) dosage form, which, on the one hand, exerts a less pronounced effect on the gastric and small intestinal mucosa, and on the other hand, ensures high bioavailability, as well as minimal variability of treatment response.

Rivaroxaban and Risk of Venous Thromboembolism in Patients With Symptomatic Peripheral Artery Disease After Lower Extremity Revascularization

Prior studies have observed an association between the burden of atherosclerotic vascular disease and the risk of venous thromboembolism (VTE). The association is not well described in peripheral artery disease (PAD) after lower extremity revascularization (LER). To describe the risk of, factors associated with, and outcomes after VTE, as well as the association of low-dose rivaroxaban plus antiplatelet therapy with VTE after LER. This global, multicenter cohort study used data from the Vascular Outcomes Study of ASA (acetylsalicylic acid) Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) randomized clinical trial, which enrolled patients from 2015 to 2018 with median follow-up of 28 months. Participants included patients with PAD undergoing LER. Patients with an indication for therapeutic anticoagulation were excluded. Data were analyzed from September 2020 to September 2021. Randomization to rivaroxaban 2.5 mg twice daily or placebo on a background of aspirin 100 mg daily; short-term clopidogrel was used at the discretion of the treating physician. Symptomatic VTE was a prespecified secondary outcome and prospectively collected. Among 6564 patients (median [IQR] age, 67 [61-73] years; 4860 [74.0%] men), 66 patients had at least 1 VTE. The 3-year rate of VTE in patients receiving placebo was 1.7%, and the pattern of risk was linear (year 1: 0.5%; year 2: 1.1%). After multivariable modeling, weight (hazard ratio [HR], 3.04; 95% CI, 1.09-8.43), hypertension (HR, 2.11; 95% CI, 0.91-4.89), prior amputation (HR, 2.07; 95% CI, 0.95-4.53), and older age (HR, 1.81; 95% CI, 1.06-3.11) were associated with increased risk of VTE. VTE was associated with risk of subsequent mortality (HR, 7.22; 95% CI, 4.66-11.19). Compared with aspirin alone, rivaroxaban plus aspirin was associated with lower VTE risk (HR, 0.61; 95% CI, 0.37-0.998; P = .047), with benefit apparent early and sustained over time. This association was not modified by use of clopidogrel at randomization (without clopidogrel: HR, 0.55; 95% CI, 0.29-1.07; with clopidogrel: HR, 0.69; 95% CI, 0.32-1.48; P for interaction = .67). In this cohort study, there was continuous risk for VTE after LER in patients with PAD, with greater risk in patients who were older and had obesity and those with more severe PAD, as reflected by prior amputation. Low-dose rivaroxaban plus aspirin was associated with lower VTE risk compared with aspirin alone, with benefits apparent early and continued over time. The spectrum of venous and arterial thrombotic events and overall benefits of more potent antithrombotic strategies for prevention should be considered after LER for PAD.

Cost-Effectiveness Analysis of Rivaroxaban in Chinese Patients With Stable Cardiovascular Disease.

Objective: This study aimed to investigate the cost-effectiveness of low-dose rivaroxaban plus aspirin versus aspirin alone for patients with stable cardiovascular diseases in the China. Methods: We used TreeAge 2019 to construct a Markov model to assess the direct healthcare costs and quality-adjusted life years for three therapies, namely low-does rivaroxaban plus aspirin, rivaroxaban alone, and aspirin alone. Transitional probabilities were derived from the COMPASS trial, and the costs and utilities were obtained from the Chinese Health Care Statistical Yearbook and published studies. Use the Incremental cost-effectiveness ratio to describe the results. The willingness-to-pay threshold is set at US$11,000 (China’s 2020 Gross National Product per capita). Result: In patients with stable cardiovascular disease, the increased cost per quality-adjusted life year gained in the low-dose rivaroxaban combined with aspirin group compared to the aspirin alone group was US$7937.30. The increased cost per quality-adjusted life year gained in the rivaroxaban alone group versus the aspirin alone group was US$15,045.78. Conclusion: A low-does rivaroxaban plus aspirin therapy may be cost-effective in the secondary prevention of stable cardiovascular disease in patients.

Study protocol for aspirin plus rivaroxaban efficacy and safety in embolic stroke of undetermined source: A randomized, placebo controlled, outcome assessor blind, feasibility study

Background &amp; Objectives: Despite recent scientific advances in acute ischemic stroke treatment, there has been limited progress for the secondary prevention of cryptogenic ischemic stroke. The present proposed study is designed for evaluation of efficacy and safety of rivaroxaban plus aspirin in reducing stroke recurrence in patients with embolic stroke of undetermined source (ESUS). Methods: This is a randomized, parallel-group, outcome assessor blind, placebo-controlled study on the recent (7-60 days) ESUS patients identified only one risk factor of potential embolic source. After meeting all inclusion and exclusion criteria patients will be randomized to rivaroxaban 2.5 mg BID plus ASA 80 mg daily or ASA 80 mg plus placebo (1:1 ratio) and will be visited every three months until one year. Any adverse events, serious side effects, outcome events will be recorded. Results: The primary outcome is defined as the rate and time of stroke occurrence and major bleeding events. Conclusions: Low dose rivaroxaban plus aspirin is expected to be a safe and effective for prevention of recurrence in ESUS.

Differential Inhibition of Platelet Reactivity by Dual Therapy With Aspirin and Low-Dose Rivaroxaban in Peripheral Arterial Disease: A Pilot Study.

Patients with peripheral arterial disease (PAD) benefit from combination therapy with acetylsalicylic acid (ASA, 100 mg, one time per day) plus low-dose rivaroxaban (2.5 mg, two times per day) compared to ASA monotherapy. In particular, major adverse cardiac and limb events were significantly reduced after peripheral endovascular revascularization (EVR). In this pilot study, the platelet activation status in vivo and platelet reactivity in vitro were longitudinally analyzed by flow cytometric assays and calibrated automated thrombography in platelet-rich plasma (PRP) from 10 patients with PAD receiving ASA (100 mg, one time per day) before EVR, ASA plus clopidogrel (75 mg, one time per day) after EVR, and ASA plus rivaroxaban (2.5 mg, two times per day) during a long-term follow-up. Platelet responsiveness to clopidogrel was compared to additional 10 patients with stable PAD and clopidogrel (75 mg, one time per day) monotherapy. ASA plus rivaroxaban treatment resulted in a significantly decreased thrombin peak in PRP for two triggers, namely, low concentration of tissue factor (TF) and thrombin, compared to ASA monotherapy. TF-controlled thrombin generation was additionally characterized by a significantly prolonged lag time in PRP and platelet-free plasma during ASA plus rivaroxaban combination therapy. In comparison, ASA plus clopidogrel treatment presented a significant reduction of the thrombin peak in PRP, which was less pronounced than during subsequent ASA plus rivaroxaban therapy. Platelet responsiveness to clopidogrel was observed for 60% of patients receiving ASA plus clopidogrel and clopidogrel monotherapy, respectively. Blocking of CD36 on the platelet surface further reduced the thrombin peak in PRP induced by TF for all three therapy regimes. Platelet activation in vivo and in response to the GPVI-agonist convulxin or thrombin in vitro was similar, whereas integrin αIIbβ3 activation and α-granule release induced by the PAR-1 activating peptide TRAP-6 were significantly diminished during ASA plus rivaroxaban treatment compared to ASA monotherapy. In conclusion, the data of this pilot study indicate an inhibitory effect of rivaroxaban on the thrombin propagation phase of CD36-sensitive platelet thrombin formation in patients with PAD treated with ASA plus rivaroxaban combination therapy, which is associated with decreased PAR-1 but not thrombin-mediated platelet activation.

Antithrombotische Therapie bei Diabetes mellitus

Cardiovascular disease (CVD) is the leading cause of death in patients with diabetes mellitus (DM) and despite modern therapeutic strategies, patients with DM have at least a two-fold increased risk of cardiovascular events. The prothrombotic state in patients with DM is associated with multiple determinants such as platelet alterations and endothelial dysfunction. Thus, proper antithrombotic strategies to reduce the risk of CVD in this population are critical. Recently, the COMPASS trial showed a net clinical benefit of the combination therapy of low-dose rivaroxaban plus acetylsalicylic acid, called dual antithrombotic therapy (DAT), when compared to acetylsalicylic acid in patients with chronic vascular disease (either peripheral artery disease [PAD] or chronic coronary syndrome [CCS]) and DM, even when it comes to all-cause mortality. Therefore, guidelines currently advise to evaluate DAT or dual antiplatelet therapy (DAPT) for high-risk patients with DM.

May 2022 Stroke Highlights

May 2022 <i>Stroke</i> Highlights

DOACs and Atherosclerotic Cardiovascular Disease Management: Can We Find the Right Balance Between Efficacy and Harm.

The balance between efficacy and harm remains a challenge in the adoption of non-vitamin K antagonist direct oral anticoagulants (DOACs) for secondary atherosclerotic disease prevention. We provide a comprehensive review of the evidence for and against the addition of DOACs to the current management of atherosclerotic cardiovascular disease, including stable coronary artery disease (CAD), acute coronary syndrome (ACS), peripheral artery disease (PAD), and percutaneous coronary interventions (PCI). The DOAC class exerts pleiotropic effects on atherosclerotic progression through coagulation and inflammatory pathways. In ACS, low-dose DOAC provides no added efficacy in the setting of dual antiplatelet therapy; however, full-dose DOAC increases bleeding. Efficacy-safety profile favor use of low-dose rivaroxaban in select stable CAD or PAD patients. Atrial fibrillation patients undergoing PCI resort to dual therapy with DOAC due to prohibitory bleeding with triple anti-thrombotic therapy. Evidence favors DOAC use in CAD and PAD; however, careful individual considerations must be undertaken.

Prophylactic Rivaroxaban Therapy forLeft Ventricular Thrombus After Anterior ST-Segment Elevation Myocardial Infarction.

The aim of this study was to investigate the effects of rivaroxaban on left ventricle thromboprophylaxis in patients with anterior ST-segment elevation myocardial infarction (STEMI). Anterior STEMI is associated with an increased risk of left ventricular thrombus (LVT) formation. The contemporary role of prophylactic rivaroxaban therapy remains unclear. We randomly assigned 279 patients with anterior STEMI who had undergone primary percutaneous coronary intervention to receive, in a 1:1 ratio, low-dose rivaroxaban (2.5mg twice daily for 30days) and dual antiplatelet therapy (DAPT) or only DAPT. The primary efficacy outcome was the LVT formation within 30days. Net clinical adverse events were assessed at 30days and 180days, including all-cause mortality, LVT, systemic embolism, rehospitalization for cardiovascular events, and bleeding. The addition of low-dose rivaroxaban to DAPT reduced LVT formation within 30days compared with only DAPT (0.7% vs 8.6%; HR: 0.08; 95%CI: 0.01-0.62; P=0.015; P< 0.001 for superiority). Net clinical adverse events were lower within 30days in the rivaroxaban group versus those in the only DAPT group and remained relatively low throughout the follow-up period. There were no significant differences in bleeding events between the 2 groups in 30days and 180days. However, 1 case of intracranial hemorrhage (major bleeding) occurred in the rivaroxaban group within 30days. Our results supported that the short-duration addition of low-dose rivaroxaban to DAPT could prevent LVT formation in patients with anterior STEMI following primary percutaneous coronary intervention. A larger multiple-institution study is necessary to determine the generalizability.

A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration. Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters. Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range. Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF.

Antiplatelet therapy in cardiovascular disease: Current status and future directions.

Antiplatelet medications remain a cornerstone of therapy for atherosclerotic cardiovascular and cerebrovascular diseases. In primary prevention (patients with cardiovascular risk factors but no documented events, symptoms or angiographic disease), there is little evidence of benefit of any antiplatelet therapy, and such therapy carries the risk of excess bleeding. Where there is documented disease (secondary prevention), stable patients benefit from long‐term antiplatelet monotherapy, aspirin being first choice in those with coronary heart disease and clopidogrel in those with cerebrovascular disease; moreover, recent evidence shows that low‐dose rivaroxaban in combination with aspirin confers added benefit, in patients with stable cardiovascular and peripheral arterial disease. In patients with acute cerebrovascular disease, aspirin combined with clopidogrel reduces subsequent risk, while in acute coronary syndrome, dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) confers greater protection than aspirin monotherapy, with prasugrel and ticagrelor offering greater antiplatelet efficacy with faster onset of action than clopidogrel. Although greater antiplatelet efficacy is advantageous in preventing thrombotic events, this must be tempered by increased risk of bleeding, which may be a particular issue in certain patient groups, as will be discussed. We will also discuss possible future approaches to personalisation of antiplatelet therapy.