Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From ...Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD.
Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups.
In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects.
URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.
BackgroundThere are a paucity of randomised data on the optimal timing of invasive coronary angiography (ICA) in higher-risk patients with non-ST elevation myocardial infarction (N-STEMI). ...International guideline recommendations for early ICA are primarily based on retrospective subgroup analyses of neutral trials.AimsThe RAPID N-STEMI trial aims to determine whether very early percutaneous revascularisation improves clinical outcomes as compared with a standard of care strategy in higher-risk N-STEMI patients.Methods and analysisRAPID N-STEMI is a prospective, multicentre, open-label, randomised-controlled, pragmatic strategy trial. Higher-risk N-STEMI patients, as defined by Global Registry of Acute Coronary Events 2.0 score ≥118, or >90 with at least one additional high-risk feature, were randomised to either: very early ICA±revascularisation or standard of care timing of ICA±revascularisation. The primary outcome is the proportion of participants with at least one of the following events (all-cause mortality, non-fatal myocardial infarction and hospital admission for heart failure) at 12 months. Key secondary outcomes include major bleeding and stroke. A hypothesis generating cardiac magnetic resonance (CMR) substudy will provide mechanistic data on infarct size, myocardial salvage and residual ischaemia post percutaneous coronary intervention. On 7 April 2021, the sponsor discontinued enrolment due to the impact of the COVID-19 pandemic and lower than expected event rates. 425 patients were enrolled, and 61 patients underwent CMR.Ethics and disseminationThe trial has been reviewed and approved by the East of England Cambridge East Research Ethics Committee (18/EE/0222). The study results will be submitted for publication within 6 months of completion.Trial registration numberNCT03707314; Pre-results.
Aims
Heart failure (HF) in the elderly carries a poor prognosis. We used the SENIORS dataset of elderly HF patients aged ≥70 years in order to develop a risk model for this population.
Methods and ...results
The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥70 years with HF (ejection fraction ≤35%, or recent HF admission). We randomly selected 1400 patients from the full dataset to produce a derivation cohort and the remaining 728 patients were used as a validation cohort. Baseline variables were entered into a bootstrap model with 200 iterations to determine their association with two outcomes, the composite of all‐cause mortality or cardiovascular hospitalization, or all‐cause mortality alone. Variables retaining a significant association with these outcomes in a multivariate model were used to develop a risk prediction score tested in the validation cohort. Five factors were associated with increased risk of both outcomes in the multivariate model: higher New York Heart Association class, higher uric acid level, lower body mass index, prior myocardial infarction, and larger left atrial (LA) dimension. For the composite outcome, peripheral arterial disease, years with heart failure, right bundle branch block, diabetes mellitus, and orthopnoea were also retained. For all‐cause mortality, creatinine, 6 min walk test distance, coronary artery disease, and age were retained.
Conclusion
In addition to conventional prognostic markers, uric acid and LA dimension appear to be important novel risk prediction markers in elderly patients with heart failure, and could be useful in guiding management.
Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between ...self-reported tooth loss- a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial.
Baseline blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: “26–32 (All)” lowest level, “20–25”, “15–19”, “1–14”, and “No Teeth” highest level. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively.
After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14–1.29), interleukin 6 1.14 (1.10–1.18), lipoprotein-associated phospholipase A2 activity 1.05 (1.03–1.06), growth differentiation factor 15 1.11 (1.08–1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11–1.25). No association was detected for high-sensitivity troponin T 1.02 (0.98–1.05). Some attenuation of the relationship between tooth loss and outcomes resulted from the addition of biomarkers to the multivariable analysis, of which NT-proBNP had the biggest impact.
A graded and independent association between tooth loss and several prognostic biomarkers was observed, suggesting that tooth loss and its underlying mechanisms may be involved in multiple pathophysiological pathways also implicated in the development and prognosis of CHD. The association between tooth loss and cardiovascular death and stroke persisted despite comprehensive adjustment including prognostic biomarkers.
Clinical trial registration:www.clinicaltrials.gov; NCT00799903.
In so doing, 31% (n=4287) of our trial population was over the age of 70 and 13% (n=1795) over 75, giving us the unique ability to test the efficacy and tolerability of beta blockers according to age ...using randomised controlled data that will hopefully stimulate further research. 1 We agree with Messerli and colleagues that different risk-benefit assessments should be performed according to treatment indication. 4 However, the 20-30% relative reduction in deaths in patients with heart failure, reduced ejection fraction, and sinus rhythm 4 is clearly different from hypertension, where other agents with equivalent (or better) prognostic value are widely available. 5 Regarding treatment discontinuation in our study, it is important to reiterate that overall withdrawal was about the same (or possibly marginally lower) in the beta blocker arm as in the placebo group, both in women (14.4% beta blockers, 16.0% placebo) and men (14.3% beta blockers, 15.4% placebo).
Acute coronary syndrome (ACS) represents a heterogenous spectrum of conditions. The Global Registry of Acute Coronary Events (GRACE) describes the epidemiology, management, and outcomes of patients ...with ACS. Data were collected from 11,543 patients enrolled in 14 countries. Of these patients, 30% had ST-segment elevation myocardial infarction (STEMI), 25% had non–ST-segment elevation myocardial infarction (NSTEMI), 38% had unstable angina pectoris, and 7% had other cardiac or noncardiac diagnoses. Over half of these patients (53%) were ≥65 years old. Reperfusion therapy was used in 62% of patients with STEMI. Percutaneous coronary intervention was performed in 40% of these subjects during the index admission. Intravenous glycoprotein IIb/IIIa blockers were used in 23%, 20%, and 7% of patients with STEMI, NSTEMI, and unstable angina, respectively (STEMI vs NSTEMI, p = 0.0018, and for either group vs unstable angina, p <0.001). Coronary artery bypass grafting was performed in 4%, 10%, and 5% of patients, respectively (p <0.0001). Hospital case fatality rates were markedly different among patients with STEMI, NSTEMI, and unstable angina (7%, 6%, and 3%, respectively; STEMI vs NSTEMI, p = 0.0459, and for either group vs unstable angina, p <0.001). Congestive heart failure complicated the hospital course in 18%, 18%, and 10% of the patients, respectively (p <0.0001), and recurrent angina with ST-segment changes occurred before discharge in 10%, 10%, and 9% of patients, respectively (p = 0.2644). GRACE provides a detailed and comprehensive global description of the spectrum of patients with ACS.
Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 ...genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events.
A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints.
No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications.
This study is registered with ClinicalTrials.gov number, NCT00050817.
To determine the rates of patient adherence to key evidence-based therapies at 6 months after hospital discharge for an acute coronary syndrome.
In this nonrandomized, prospective, multinational, ...multicenter study, adherence to aspirin, beta-blockers, statins, or angiotensin-converting enzyme (ACE) inhibitors 6 months after discharge for myocardial infarction or unstable angina was assessed in 21,408 patients aged 18 years or older. Patients were enrolled at 104 tertiary and community hospitals representing a broad range of care facilities and practice settings (e.g., teaching vs. nonteaching).
Of 13,830 patients, discontinuation of therapy was observed at 6-month follow-up in 8% of those taking aspirin on discharge, 12% of those taking beta-blockers, 20% of those taking ACE inhibitors, and 13% of those taking statins. In a multivariate analysis, adherence to beta-blocker therapy was higher in patients with a myocardial infarction (odds ratio OR = 1.25; 95% confidence interval CI: 1.06 to 1.47), hypertension (OR = 1.33; 95% CI: 1.15 to 1.54), ST-segment elevation myocardial infarction (OR = 1.33; 95% CI: 1.11 to 1.61), or non–ST-segment elevation myocardial infarction (OR = 1.25; 95% CI: 1.08 to 1.45). Aspirin adherence was higher among patients cared for by cardiologists (OR = 1.45; 95% CI: 1.19 to 1.75;
P <0.001) than among those cared for by nonspecialists. Male sex and prior heart failure were associated with improved adherence to ACE inhibitor therapy. Hypertension was associated with poorer adherence to statin therapy (OR = 0.85; 95% CI: 0.74 to 0.99;
P = 0.04).
Among patients prescribed key evidence-based medications at discharge, 8% to 20% were no longer taking their medication after 6 months. The reasons for noncompliance are complex, and may be elucidated by future studies of medical and social determinants.
PDF
