Coronary artery disease (CAD) is the most common clinical manifestation of ischaemic heart disease and a leading cause of people’s heart failure (HF) in developed countries and mortality worldwide. CAD strongly reduces patients’ quality of life and the ability to work, leading to a great impact on patients’ life. And Coronary artery disease is characterized by coronary atherosclerosis in the absence of acute coronary thrombosis. Patients might present with stable angina due to one or more ischaemia-inducing lesions, or with no symptoms in the presence of known obstructive or non-obstructive coronary artery disease, or have silent ischaemia (i.e., in the absence of clinical symptoms). Additionally, the common final symptom for CAD is heart failure with reduced ejection fraction (HF-rEF).
Currently, the most effective pharmacological therapies for HF-rEF target the activation of the renin-angiotensin-aldosterone system and the β-adrenergic sympathetic nervous system that occurs in HF. However, even with these treatments, the morbidity and mortality of patients remain unacceptably high, and these rates will continue to increase after episodes of acute decompensation. Recently there was a comprehensive review that focuses on warfarin anticoagulation treatment in HF patients with normal sinus rhythm including randomized trials of both the WASH and HELAS. In this review, researchers found no convincing evidence that oral anticoagulant therapy modifies mortality or vascular events in patients with HF and sinus rhythm.
Nonetheless, thrombin plays a critical role in multiple pathophysiological processes that occur in CAD patients with symptomatic decompensation of HF-rEF. Targeted reduction of thrombin generation with rivaroxaban (a specific inhibitor of activated Factor Xa or FXa), rather than non-selective depletion of multiple vitamin K dependent clotting factors with warfarin, may hold promise in treatment of CAD patients.
Case Study
The selection of patients is a key challenge for most clinical trials. In our study, patients must have following symptoms: suffering coronary artery disease, a recent symptomatic exacerbation of HF, increased plasma concentrations of natriuretic peptides (B-type natriuretic peptide 200 pg/mL or N-terminal pro B-type natriuretic peptide 800 pg/mL), left ventricular ejection fraction 40%. Another challenge is dosage selection. Many data has demonstrated that a wide spectrum of rivaroxaban doses can effectively inhibit the generation of thrombin. In the body of healthy volunteers receiving single doses of rivaroxaban (5 mg or 30 mg), the generation of thrombin is potently inhibited within 24 hours. According to the ATLAS-2 trial, both rivaroxaban 5 mg b.i.d. and rivaroxaban 2.5 mg b.i.d. can reduce the composite efficacy endpoint; however, the 2.5 mg b.i.d. dose comes with fewer episodes of major bleeding. Thus, rivaroxaban 2.5 mg b.i.d. is approved in Europe for the treatment of biomarker-positive patients after an ACS, and additional studies of rivaroxaban are under way in the USA. Given the data and the considerations above, researchers choose the dose of rivaroxaban 2.5 mg b.i.d. as the best dosage to offer an optimal combination of safety and efficacy.
According to the criteria mentioned above, we recruited appropriate patients, determined applicable dose, and analyzed results. We found that rivaroxaban is superior in patients with HF and serious CAD, and it reduces the risk of the composite of ACM, MI or stroke following a recent exacerbation of HF.
Design:
The trial is an international prospective, randomized, double-blind, placebo-controlled, event-driven, parallel-group comparison trial between rivaroxaban and placebo (Figure 1), and the whole trial includes a screening phase, a double-blind treatment phase and follow-up. Subjects are tracked for a minimum of approximately 7 months and a maximum of 31 months.
Figure 1. Study design
Participants:
We enrolled adult (over 18 years old) patients who are clinically stable for up to 30 days after a symptomatic index event. All recruited patients had symptoms as follows:
- Patients must have HF documented at a level of NT-proBNP ≥800 pg/mL or B-type natriuretic peptide (BNP) ≥200 pg/mL (obtained between the onset of the index event and randomization).
- They must have left ventricular ejection fraction ≤40%.
- They have documented significant CAD according to predefined criteria (Table 1).
- Patients with significant valvular heart disease or atrial fibrillation before randomization will be excluded, and so will be those with other indications of chronic anticoagulation (Table 1).
Table 1. Inclusion and exclusion criteria
HF, heart failure; LVEF, left ventricular ejection fraction; CAD, coronary artery disease; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro–B-type natriuretic peptide; MI, myocardial infarction; PCI, percutaneous coronary intervention; HIV, human immunodeficiency virus; eGFR, estimated glomerular filtration rate; Hb, hemoglobin.
Length of Enrollment Period:
Until the estimated 984 primary outcome events occur.
Interventions:
Patients randomized to rivaroxaban will receive rivaroxaban orally for 2.5 mg twice a day without an adjustment for renal function. The dose is consistent with that approved in the European Union for post-ACS management. Subjects are advised to take the study drug at approximately the same times each day. And it is prohibited to use strong inhibitors of either cytochrome P450 3A4 or P-glycoprotein (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, or human immunodeficiency virus protease inhibitors), Factor IIa inhibitors, low molecular weight heparin, or unfractionated heparin. Strong inducers of cytochrome P450 3A4 are prohibited within 4 days before randomization or during the study. Patients who are receiving concomitant non-steroidal anti-inflammatory drugs, platelet aggregation inhibitors, or other antithrombotic agents should be monitored carefully. Patients at risk of suffering ulcerative gastrointestinal disease or gastrointestinal bleeding can receive prophylactic treatment with proton pump inhibitors (except omeprazole or esomeprazole) at the investigators’ discretion. These drugs will be captured as concomitant medications in the electronic case report form.
Main Outcomes:
- Primary efficacy outcomes
- All-cause death and cardiovascular death
- Myocardial infarction
- Stroke
- Secondary efficacy outcomes
Results:
A mean follow-up of 13 months shows that taking rivaroxaban 2.5 mg b.i.d. reduced the primary outcome events of death of cardiovascular diseases, MI or stroke from 18.6% with placebo to 11.6% with rivaroxaban 2.5 mg b.i.d. (P < 0.001), death of cardiovascular diseases from 10.4% with placebo to 5.2% with rivaroxaban 2.5 mg b.i.d. (P < 0.001), and death of any cause from 11.1% with placebo to 5.3% with rivaroxaban 2.5 mg b.i.d. (P < 0.001). In this subgroup, according to the thrombolysis in myocardial infarction (TIMI) criteria, patients receiving rivaroxaban 2.5 mg b.i.d. are a bit less likely to suffer major bleeding than those taking placebo (0.4% vs. 0.7%).
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References:
1. Lala, A., Desai, A. S. (2014) ‘The role of coronary artery disease in heart failure’, Heart Failure Clinics, 10(2), 353-365.
2. Zannad, F., et al. (2015) ‘Rationale and design of a randomized, double-blind, event-driven, multicentre study comparing the efficacy and safety of oral rivaroxaban with placebo for reducing the risk of death, myocardial infarction or stroke in subjects with heart failure and signif’, European Journal of Heart Failure, 17(7), 735-742.
3. Piccolo, R., Giustino, G., Mehran, R., Windecker, S. (2015) ‘Stable coronary artery disease: revascularisation and invasive strategies’, Lancet, 386(9994), 702-713.