Country and health expenditure are major predictors of withholding anticoagulation in atrial fibrillation patients at high risk of stroke.

BACKGROUND: Guidelines for patients with atrial fibrillation (AF) at high thromboembolic risk recommend oral anticoagulants (OACs) for preventing stroke and systemic embolism (SE). The reasons for guideline non-adherence are still unclear. AIM: The aim is to identify clinical, demographic and non-patient characteristics associated with withholding OAC in patients with AF at high stroke risk. METHODS: Patients in the Global Anticoagulant Registry in the FIELD-AF, newly diagnosed with AF between March 2010 and August 2016, and with CHA2DS2-VASc Score≥2 (excluding sex), were grouped by OAC treatment at enrolment. Factors associated with OAC non-use were analysed by multivariable logistic regression. RESULTS: Of 40 416 eligible patients, 12 126 (30.0%) did not receive OACs at baseline. Globally, OAC prescription increased over time, from 60.4% in 2010-2011 to 74.7% in 2015-2016. Country of enrolment was the major predictor for OAC withholding (χ2-df=2576). Clinical predictors of OAC non-use included type of AF (χ2-df=404), history of bleeding (χ2-df=263) and vascular disease (χ2-df=99). OACs were used most frequently around the age of 75 years and decreasingly with younger as well as older age beyond 75 years (χ2-df=148). Non-cardiologists (χ2-df=201) and emergency room physicians (χ2-df=14) were less likely to prescribe OACs. OAC prescription correlated positively with country health expenditure. CONCLUSIONS: Approximately one out of three AF patients did not receive OAC, while eligible according to the guidelines. Country of enrolment was the major determinant of anticoagulation strategy, while higher country health expenditure was associated with lower likelihood of withholding anticoagulation.

Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials: a consensus report from the Non-adherence Academic Research Consortium (NARC).

Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives.

Stroke prevention, 1-year clinical outcomes and healthcare resource utilization in patients with atrial fibrillation in France: Data from the GARFIELD-AF registry.

BACKGROUND: GARFIELD-AF is a non-interventional worldwide study of adults with atrial fibrillation. AIMS: To analyse the characteristics of the 1399 patients recruited in France from August 2010 to July 2015, their 1-year outcomes and healthcare resource utilization. METHOD: Patients aged ≥18 years with newly diagnosed atrial fibrillation (≤6 weeks' duration) and ≥1 stroke risk factor were eligible. Patient demographics, medical history and antithrombotic treatment were recorded at baseline. The incidences of stroke/systemic embolism, major bleeding, all-cause mortality, cardiovascular and non-cardiovascular mortality, new acute coronary syndrome and congestive heart failure were recorded during a 1-year follow-up. RESULTS: The median age was 76.0 years; 44.5% of patients were female. The median CHA2DS2-VASc and HAS-BLED scores were 4.0 and 2.0, respectively. At diagnosis, 78.9% of patients received anticoagulant therapy±antiplatelet therapy; more patients received vitamin K antagonists (VKAs; 46.0%) than direct oral anticoagulants (DOACs; 32.9%). The median proportion of time in the therapeutic range for VKAs was 65.6%. Between 2010 and 2015, anticoagulant prescription increased, driven by the growing use of DOACs±antiplatelet therapy (1.1% to 50.0%), whereas prescription of VKAs±antiplatelet therapy decreased (74.4% to 32.3%). All-cause mortality was the most frequent event (6.75 per 100 person-years). Risk-adjusted event rates for France showed that stroke/systemic embolism and all-cause mortality occurred more frequently than in GARFIELD-AF overall, whereas the rates of major bleeding were similar. In terms of healthcare resource utilization, the highest cost was associated with inpatients. CONCLUSIONS: Patients enrolled in France had higher rates of mortality and stroke/systemic embolism than in GARFIELD-AF overall. Conversely, the risk of major bleeding was not higher.

Risk Score to Predict Need for Intensive Care in Initially Hemodynamically Stable Adults With Non-ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: Intensive care unit (ICU) use for initially stable patients presenting with non-ST-segment-elevation myocardial infarction (NSTEMI) varies widely across hospitals and minimally correlates with severity of illness. We aimed to develop a bedside risk score to assist in identifying high-risk patients with NSTEMI for ICU admission. METHODS AND RESULTS: Using the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry linked to Medicare data, we identified patients with NSTEMI aged ≥65 years without cardiogenic shock or cardiac arrest on presentation. Complications requiring ICU care were defined as subsequent development of cardiac arrest, shock, high-grade atrioventricular block, respiratory failure, stroke, or death during the index hospitalization. We developed and validated a model and integer risk score (Acute Coronary Treatment and Intervention Outcomes Network (ACTION) ICU risk score) that uses variables present at hospital admission to predict requirement for ICU care. Of 29 973 patients with NSTEMI, 4282 (14%) developed a complication requiring ICU-level care, yet 12 879 (43%) received care in an ICU. Signs or symptoms of heart failure, initial heart rate, initial systolic blood pressure, initial troponin, initial serum creatinine, prior revascularization, chronic lung disease, ST-segment depression, and age had statistically significant associations with requirement for ICU care after adjusting for other risk factors. The ACTION ICU risk score had a C-statistic of 0.72. It identified 11% of patients as having very high risk (>30%) of developing complications requiring ICU care and 49% as having low likelihood (<10%) of requiring an ICU. CONCLUSIONS: The ACTION ICU risk score quantifies the risk of initially stable patients with NSTEMI developing a complication requiring ICU care, and could be used to more effectively allocate limited ICU resources.

Predictors of contemporary coronary artery bypass grafting outcomes.

OBJECTIVES: The study objective was to identify the predictors of outcomes in a contemporary cohort of patients from the Reduction in cardiovascular Events by acaDesine in patients undergoing CABG (RED-CABG) trial. Despite the increasing risk profile of patients who undergo coronary artery bypass grafting, morbidity and mortality have remained low, and identification of the current predictors of adverse outcomes may permit new treatments to further improve outcomes. METHODS: The RED-CABG trial was a multicenter, randomized, double-blind, placebo-controlled study that determined that acadesine did not reduce adverse events in moderately high-risk patients undergoing nonemergency coronary artery bypass grafting. The primary efficacy end point was a composite of all-cause death, nonfatal stroke, or the need for mechanical support for severe left ventricular dysfunction through postoperative day 28. Logistic regression modeling with stepwise variable selection identified which prespecified baseline characteristics were associated with the primary outcome. A second logistic model included intraoperative variables as potential covariates. RESULTS: The 4 independent preoperative risk factors predictive of the composite end point were (1) a history of heart failure (odds ratio, 2.9); (2) increasing age (odds ratio, 1.033 per decade); (3) a history of peripheral vascular disease (odds ratio, 1.6); and (4) receiving aspirin before coronary artery bypass grafting (odds ratio, 0.5), which was protective. The duration of the cardiopulmonary bypass (odds ratio, 1.8) was the only intraoperative variable that contributed to adverse outcomes. CONCLUSIONS: Patients who had heart failure and preserved systolic function had a similar high risk of adverse outcomes as those with low ejection fractions, and new approaches may mitigate this risk. Recognition of patients with excessive atherosclerotic burden may permit perioperative interventions to improve their outcomes. The contemporary risks of coronary artery bypass grafting have changed, and their identification may permit new methods to improve outcomes.

Would tirofiban have been shown non-inferior to abciximab had the TENACITY trial not been terminated for financial reasons?

OBJECTIVES: To investigate whether tirofiban would have been non-inferior to abciximab had the trial completed enrollment and place the termination of this trial in a broader research ethics context. BACKGROUND: TENACITY was terminated by the sponsor for financial reasons. At the time, event rates for the 2 treatment arms were unknown. METHODS: TENACITY was designed to compare tirofiban with abciximab in approximately 8,000 patients; however, enrollment was terminated after 383 (4.8%) patients. The primary end-point was a composite of 30-day death, myocardial infarction, and urgent target vessel revascularization. Non-inferiority was defined as the likelihood that tirofiban would preserve at least 50% of the ability of abciximab to reduce the primary end-point at 30 days, based on abciximab's demonstrated ability to reduce such events by 43% (relative risk, 0.573; 95% confidence interval [CI], 0.507-0.648; P < 0.001). To determine the probability of non-inferiority given the patients already enrolled, a Bayesian approach was used. RESULTS: The primary composite end-point occurred in 8.8% of patients randomized to abciximab versus 6.9% receiving high-bolus-dose tirofiban (odds ratio, 0.77; 95% CI, 0.37-1.64). The estimated conditional power for the test that tirofiban would be non-inferior to abciximab if all patients been enrolled is 93.7%. Using the estimated predictive power method, the likelihood was 84.8%. CONCLUSIONS: TENACITY was well powered to identify non-inferiority with tirofiban versus abciximab, and the patients enrolled strengthened the probability that this would have been the outcome had the trial been completed. When a clinical trial is terminated solely for financial reasons, it is incumbent upon the sponsor to provide proper patient follow-up and publication of the findings.

Variations in practice and outcomes in patients undergoing primary percutaneous coronary intervention in the United States and Canada: insights from the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX AMI) trial.

BACKGROUND: Information on practice patterns and outcomes in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary interventions (PCIs) in Canada vs United States is limited. METHODS: We evaluated differences in clinical and angiographic features, practice patterns, and outcomes between Canada and United States in 2,086 patients with ST-elevation myocardial infarction undergoing primary PCI in the APEX AMI trial. RESULTS: Of 2,086 patients, 335 (19%) were enrolled in Canada. Compared with US patients, Canadians were older with lower body mass index and creatinine clearance and less likely to have history of hypertension, smoking, or prior revascularization. Baseline infarct artery patency was higher, and the use of intra-aortic balloon pump and drug-eluting stents was lower in Canadian patients. Median door-to-PCI time was significantly shorter among Canadian patients (0.9 hours [interquartile range 0.6-1.3] vs 1.2 hours [interquartile range 0.8-1.7]). Clinical outcomes at 90 days were lower among Canadian patients, including shock (2.7% vs 4.2%), heart failure (3.6% vs 5.6%), bleeding (3.6% vs 9.6%), and atrial (3.6% vs 7.4%) and ventricular (3.0% vs 6.4%) arrhythmias. However, 90-day mortality (2.7% vs 4.8%, adjusted hazard ratio 0.62, 95% CI 0.47-1.28) and composite of death, shock, or heart failure (6.8% vs 11.5%, adjusted hazard ratio 0.77, 95% CI 0.47-1.27) were similar in the 2 cohorts. CONCLUSIONS: Compared with US patients, Canadian patients had shorter door-to-PCI time but similar 90-day outcomes. These data suggest an opportunity for US sites to examine and learn from the Canadian systems of processes of care and implement changes so as to improve the timeliness of primary PCI.

Inference on treatment effects from a randomized clinical trial in the presence of premature treatment discontinuation: the SYNERGY trial.

The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) was a randomized, open-label, multicenter clinical trial comparing 2 anticoagulant drugs on the basis of time-to-event endpoints. In contrast to other studies of these agents, the primary, intent-to-treat analysis did not find evidence of a difference, leading to speculation that premature discontinuation of the study agents by some subjects may have attenuated the apparent treatment effect and thus to interest in inference on the difference in survival distributions were all subjects in the population to follow the assigned regimens, with no discontinuation. Such inference is often attempted via ad hoc analyses that are not based on a formal definition of this treatment effect. We use SYNERGY as a context in which to describe how this effect may be conceptualized and to present a statistical framework in which it may be precisely identified, which leads naturally to inferential methods based on inverse probability weighting.

Representation of women in randomized clinical trials of cardiovascular disease prevention.

BACKGROUND: The 2007 American Heart Association guidelines for cardiovascular disease prevention in women drew heavily on results from randomized clinical trials; however, representation of women in trials of cardiovascular disease prevention has not been systematically assessed. METHODS AND RESULTS: We abstracted 156 randomized clinical trials cited by the 2007 women's prevention guidelines to determine female representation over time and by clinical indication, prevention type, location of trial conduct, and funding source. Both women and men were represented in 135 of 156 (86.5%) trials; 20 trials enrolled only men; 1 enrolled only women. Among all trials, the proportion of women increased significantly over time, from 9% in 1970 to 41% in 2006. Considering only trials that enrolled both women and men, female enrollment was 18% in 1970 and increased to 34% in 2006. Female representation was higher in international versus United States-only trials (32.7% versus 26.7%) and primary versus secondary prevention trials (42.6% versus 26.6%). Female enrollment was comparable in government/foundation-funded versus industry-funded trials (31.9% versus 31.5%). Representation of women was highest among trials in hypertension (44%), diabetes (40%), and stroke (38%) and lowest for heart failure (29%), coronary artery disease (25%), and hyperlipidemia (28%). By contrast, women accounted for 53% of all individuals with hypertension, 50% with diabetes, 51% with heart failure, 49% with hyperlipidemia, and 46% with coronary artery disease. Sex-specific results were discussed in only 31% of primary trial publications. CONCLUSIONS: Enrollment of women in randomized clinical trials has increased over time but remains low relative to their overall representation in disease populations. Efforts are needed to reach a level of representation that is adequate to ensure evidence-based sex-specific recommendations.

Prevalence, predictors, and impact of conservative medical management for patients with non-ST-segment elevation acute coronary syndromes who have angiographically documented significant coronary disease.

OBJECTIVES: We sought to characterize the utilization and impact of a conservative medical management strategy for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and significant coronary artery disease on early angiography. BACKGROUND: Practice guidelines recommend an early invasive management strategy for NSTE ACS, but revascularization procedures may not always be performed after early angiography, even when significant coronary artery disease is present. METHODS: We evaluated 8,225 intermediate- to high-risk NSTE ACS patients with at least 1 coronary lesion >50% stenosis on early angiography from the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial (2001 to 2003), comparing patients treated with conservative medical management with those who underwent in-hospital percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 7 days of randomization. RESULTS: A total of 2,633 patients (32%) were medically managed, 4,294 (52%) underwent PCI, and 1,298 (16%) underwent CABG. The strongest independent predictors of conservative medical management versus any intervention were prior CABG, lower body weight, lack of a reinfarction between randomization and catheterization, and 3-vessel disease. With conservative medical management, the cumulative risk of 1-year mortality after discharge increased rapidly during the first 90 days and thereafter remained higher at 7.7% compared with that seen in patients treated with PCI (3.6%) or CABG (6.2%). CONCLUSIONS: One-third of patients with NSTE ACS and significant coronary disease on early angiography were managed without in-hospital revascularization in the SYNERGY trial, and these patients had an increased risk of late mortality. These findings highlight the need for novel treatment approaches for NSTE ACS patients who are not candidates for revascularization. (SYNERGY trial; NCT00043784).

Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes.

AIMS: To evaluate whether there is an association between 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) included in clinical trials and country gross national income (GNI). METHODS AND RESULTS: A retrospective analysis of the databases of five randomized trials including 50 310 patients with STEMI (COBALT 7169, GIK-2 2931, HERO-2 17,089, ASSENT-2 17,005, and ASSENT-3 6116 patients) from 53 countries was performed. Countries were divided into three groups according to their GNI based on the World Bank data: low (less than 2900 US dollars), medium (between 2900 US dollars and 9000 US dollars), and high GNI (more than 9000 US dollars per capita). Baseline characteristics, in-hospital management variables, and 30-day outcomes were evaluated. A previously defined logistic regression model was used to adjust for differences in baseline characteristics and to predict mortality. The observed mortality was higher than the predicted mortality in the low (12.1 vs. 11.8%) and in the medium income groups (9.4 vs. 7.9%), whereas it was lower in the high income group (4.9 vs. 5.6%). CONCLUSION: An inverse relationship between mortality and GNI was observed in STEMI clinical trials. Most of the variability in mortality can be explained by differences in baseline characteristics; however, after adjustment, lower income countries have higher mortality than the expected.