BACKGROUND: Patients at high risk for bleeding who undergo percutaneous coronary intervention (PCI) often receive bare-metal stents followed by 1 month of dual antiplatelet therapy. We studied a polymer-free and carrier-free drug-coated stent that transfers umirolimus (also known as biolimus A9), a highly lipophilic sirolimus analogue, into the vessel wall over a period of 1 month.
METHODS: In a randomized, double-blind trial, we compared the drug-coated stent with a very similar bare-metal stent in patients with a high risk of bleeding who underwent PCI. All patients received 1 month of dual antiplatelet therapy. The primary safety end point, tested for both noninferiority and superiority, was a composite of cardiac death, myocardial infarction, or stent thrombosis. The primary efficacy end point was clinically driven target-lesion revascularization.
RESULTS: We enrolled 2466 patients. At 390 days, the primary safety end point had occurred in 112 patients (9.4%) in the drug-coated-stent group and in 154 patients (12.9%) in the bare-metal-stent group (risk difference, -3.6 percentage points; 95% confidence interval [CI], -6.1 to -1.0; hazard ratio, 0.71; 95% CI, 0.56 to 0.91; P<0.001 for noninferiority and P=0.005 for superiority). During the same time period, clinically driven target-lesion revascularization was needed in 59 patients (5.1%) in the drug-coated-stent group and in 113 patients (9.8%) in the bare-metal-stent group (risk difference, -4.8 percentage points; 95% CI, -6.9 to -2.6; hazard ratio, 0.50; 95% CI, 0.37 to 0.69; P<0.001).
CONCLUSIONS: Among patients at high risk for bleeding who underwent PCI, a polymer-free umirolimus-coated stent was superior to a bare-metal stent with respect to the primary safety and efficacy end points when used with a 1-month course of dual antiplatelet therapy. (Funded by Biosensors Europe; LEADERS FREE ClinicalTrials.gov number, NCT01623180.).
Clopidogrel high on treatment platelets reactivity (HTPR) has burdened achieving optimum therapeutic outcome. Although there are known genetic and non-genetic factors associated with clopidogrel HTPR, which explain in part clopidogrel HTPR, yet, great portion remains unknown, often hindering personalizing antiplatelet therapy. Nuclear magnetic resonance (1H NMR) pharmacometabolomics analysis is useful technique to phenotype drug response. We investigated using 1H NMR analysis to phenotype clopidogrel HTPR in urine. Urine samples were collected from 71 coronary artery disease (CAD) patients who were planned for interventional angiographic procedure prior to taking 600mg clopidogrel loading dose (LD) and 6h post LD. Patients' platelets function testing was assessed with the VerifyNow® P2Y12 assay at 6h after LD. Urine samples were analysed using 1H NMR. Multivariate statistical analysis was used to identify metabolites associated with clopidogrel HTPR. In pre-dose samples, 16 metabolites were associated with clopidogrel HTPR. However, 18 metabolites were associated with clopidogrel HTPR in post-dose samples. The pathway analysis of the identified biomarkers reflected that multifactorial conditions are associated with clopidogrel HTPR. It also revealed the implicated role of gut microbiota in clopidogrel HTPR. Pharmacometabolomics not only discovered novel biomarkers of clopidogrel HTPR but also revealed implicated pathways and conditions.
BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.
METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.
FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012).
INTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.