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.(AU)

Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE)Follow-up

PURPOSE: Short-term outcomes have been well characterized in acute coronary syndromes; however,longer-term follow-up for the entire spectrum of these patients, including ST-segment-elevation myocardialinfarction, non-ST-segment-elevation myocardial infarction, and unstable angina, is more limited. Therefore,we describe the longer-term outcomes, procedures, and medication use in Global Registry of AcuteCoronary Events (GRACE) hospital survivors undergoing 6-month and 2-year follow-up, and the performanceof the discharge GRACE risk score in predicting 2-year mortality.METHODS: Between 1999 and 2007, 70,395 patients with a suspected acute coronary syndrome wereenrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronarysyndrome diagnosis in 57 sites.RESULTS: From 2004 to 2007, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge,14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery,and 24.2% were re-hospitalized. In patients with 2-year follow-up, acetylsalicylic acid (88.7%), betablocker(80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heartfailure occurred in 6.3%, (re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE riskscore was highly predictive of all-cause mortality at 2 years (c-statistic 0.80).CONCLUSION: In this large multinational cohort of acute coronary syndrome patients, there were importantlater adverse consequences, including frequent morbidity and mortality. These findings were seen in thecontext of additional coronary procedures and despite continued use of evidence-based therapies in a highproportion of patients. The discriminative accuracy of the GRACE risk score in hospital survivors forpredicting longer-term mortality was maintained.

Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE)Follow-up

PURPOSE: Short-term outcomes have been well characterized in acute coronary syndromes; however,longer-term follow-up for the entire spectrum of these patients, including ST-segment-elevation myocardialinfarction, non-ST-segment-elevation myocardial infarction, and unstable angina, is more limited. Therefore,we describe the longer-term outcomes, procedures, and medication use in Global Registry of AcuteCoronary Events (GRACE) hospital survivors undergoing 6-month and 2-year follow-up, and the performanceof the discharge GRACE risk score in predicting 2-year mortality.METHODS: Between 1999 and 2007, 70,395 patients with a suspected acute coronary syndrome wereenrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronarysyndrome diagnosis in 57 sites.RESULTS: From 2004 to 2007, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge,14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery,and 24.2% were re-hospitalized. In patients with 2-year follow-up, acetylsalicylic acid (88.7%), betablocker(80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heartfailure occurred in 6.3%, (re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE riskscore was highly predictive of all-cause mortality at 2 years (c-statistic 0.80).CONCLUSION: In this large multinational cohort of acute coronary syndrome patients, there were importantlater adverse consequences, including frequent morbidity and mortality. These findings were seen in thecontext of additional coronary procedures and despite continued use of evidence-based therapies in a highproportion of patients. The discriminative accuracy of the GRACE risk score in hospital survivors forpredicting longer-term mortality was maintained.

Has the frequency of bleeding changed over time for patients presenting with an acute coronary syndrome? The Global Registry of Acute Coronary Events

To determine whether changes in practice, over time, are associated with altered rates of major bleeding in acutecoronary syndromes (ACS). Methodsand results Patients from the Global Registry of Acute Coronary Events were enrolled between 2000 and 2007. The main outcome measureswere frequency ofmajor bleeding, including haemorrhagic stroke, over time, after adjustment for patient characteristics,and impact of major bleeding on death and myocardial infarction.Of the 50 947 patients, 2.3% sustained a majorbleed; almost half of these presented with ST-elevation ACS (44%, 513). Despite changes in antithrombotic therapy (increasing use of low molecular weight heparin, P, 0.0001), thienopyridines (P, 0.0001), and percutaneous coronary interventions (P, 0.0001), frequency of major bleeding for all ACS patients decreased (2.6 to 1.8%; P , 0.0001). Most decline was seen in ST-elevation ACS (2.9 to 2.1%, P » 0.02). The overall decline remained after adjustment for patient characteristics and treatments (P » 0.002, hazard ratio 0.94 per year, 95%confidence interval 0.91–0.98).Hospital characteristics were an independent predictor of bleeding (P , 0.0001). Patients who experienced major bleeding were at increased risk of death within 30 days from admission, even after adjustment for baseline variables.Conclusion Despite increasing use of more intensive therapies, there was a decline in the rate of major bleeding associated with changes in clinical practice. However, individual hospital characteristics remain an important determinant of the frequency of major bleeding.

Association of Elevated Fasting GlucoseWith Increased Short-term and 6-Month Mortality in ST-Segment Elevation and Non–ST-Segment Elevation Acute Coronary Syndromes

Background: Elevated blood glucose level at admission is associated with worse outcome after a myocardial infarction. The impact of elevated glucose level, particularly fasting glucose, is less certain in non–ST-segment elevation acute coronary syndromes. We studied the relationshipbetween elevated fasting blood glucose levels and outcome across the spectrum of ST-segment elevation andnon–ST-segment elevation acute coronary syndromes in a large multicenter population broadly representative of clinical practice.Methods: Fasting glucose levels were available for 13 526 patients in the Global Registry of Acute Coronary Events. A multivariate logistic regression analysis was used forassessing the association between admission or fasting glucose level and in-hospital or 6-month outcome, adjustedfor the variables from the registry risk scores. Results: Higher fasting glucose levels were associated with a graded increase in the risk of in-hospital death (odds ratios [95% confidence intervals] vs 100 mg/dL: 1.51 [1.12-2.04] for 100-125 mg/dL, 2.20 [1.64-2.60] for 126-199 mg/ dL, 5.11 [3.52-7.43] for 200-299 mg/dL, and 8.00 [4.76-13.5] for 300 mg/dL). When taken as a continuous variable, higher fasting glucose level was related to a higherprobability of in-hospital death, without detectable threshold and irrespective of whether patients had a history ofdiabetes mellitus. Higher fasting glucose levels were found to be associated with a higher risk of postdischarge deathup to 6 months. The risk of postdischarge death at 6 monthswas significantly higher with fasting glucose levels between 126 and 199 mg/dL (1.71 [1.25-2.34]) and 300mg/dL or greater (2.93 [1.33-6.43]), but not within the 200- to 299-mg/dL range (1.08 [0.60-1.95])...

Early versus delayed invasive intervention in acute coronary syndromes

Earlier trials have shown that a routine invasive strategy improves outcomes in patients with acute coronary syndromes without ST-segment elevation. However, the optimal timing of such intervention remains uncertain.Methods We randomly assigned 3031 patients with acute coronary syndromes to undergo either routine early intervention (coronary angiography ¡Ü24 hours after randomization)or delayed intervention (coronary angiography ¡Ý36 hours after randomization). The primary outcome was a composite of death, myocardial infarction, or stroke at 6 months. A prespecified secondary outcome was death, myocardial infarction, orrefractory ischemia at 6 months.Results Coronary angiography was performed in 97.6% of patients in the early-intervention group (median time, 14 hours) and in 95.7% of patients in the delayed-intervention group (median time, 50 hours). At 6 months, the primary outcome occurred in 9.6%of patients in the early-intervention group, as compared with 11.3% in the delayedintervention group (hazard ratio in the early-intervention group, 0.85; 95% confidence interval [CI], 0.68 to 1.06; P = 0.15). There was a relative reduction of 28% in the secondary outcome of death, myocardial infarction, or refractory ischemia in the early-intervention group (9.5%), as compared with the delayed-intervention group(12.9%) (hazard ratio, 0.72; 95% CI, 0.58 to 0.89; P = 0.003). Prespecified analyses showed that early intervention improved the primary outcome in the third of patients who were at highest risk (hazard ratio, 0.65; 95% CI, 0.48 to 0.89) but not in the two thirds at low-to-intermediate risk (hazard ratio, 1.12; 95% CI, 0.81 to 1.56; P = 0.01 for heterogeneity)...

Mortality following placement of drug-eluting and bare-metal stents for ST-segment elevation acute myocardial infarction in the Global Registry of Acute Coronary Events

To assess mortality after drug-eluting stent (DES) or bare-metal stent (BMS) for ST-segment elevation myocardialinfarction (STEMI). Methodsand results In this multinational registry, 5093 STEMI patients received a stent: 1313 (26%) a DES and 3780 (74%) only BMS. Groups differed in baseline characteristics, type, or timing of percutaneous coronary intervention, with a higher baseline risk for patients receiving BMS. Two-year follow-up was available in 55 and 60% of the eligible BMS and DES patients, respectively. Unadjusted mortality was lower during hospitalization, similar for the first 6 months after discharge, and higher from 6 months to 2 years, for DES patients compared with that of BMS patients. Overall, unadjusted 2-year mortality was 5.3 vs. 3.9% for BMS vs. DES patients (P » 0.04). In propensity- and risk-adjusted survival analyses (Cox model), post-discharge mortality was not different up to 6 months (P » 0.21) or 1 year (P » 0.34). Late post-discharge mortality was higher in DES patients from 6 months to 2 years (HR 4.90, P » 0.01) or from 1 to 2 years (HR 7.06, P » 0.02). Similar results were observed when factoring in hospital mortality. Conclusion The observation of increased late mortality with DES vs. BMS suggests that DES should probably be avoided inSTEMI, until more long-term data become available.

Unprotected left main revascularizationin patients with acute coronary syndromes

In acute coronary syndromes (ACS), the optimal revascularization strategy for unprotected left main coronary disease (ULMCD) has been little studied. The objectives of the present study were to describe the practice of ULMCD revascularization in ACS patients and its evolution over an 8-year period, analyse the prognosis of this population and determine the effect of revascularization on outcome. Methods and results Of 43 018 patients enrolled in the Global Registry of Acute Coronary Events (GRACE) between 2000 and 2007, 1799 had significant ULMCD and underwent percutaneous coronary intervention (PCI) alone (n » 514), coronary artery bypass graft (CABG) alone (n » 612), or no revascularization (n » 673). Mortality was 7.7% in hospital and 14% at 6 months. Over the 8-year study, the GRACE risk score remained constant, but there was a steady shift to more PCI than CABG over time. Patients undergoing PCI presented more frequently with ST-segment elevationmyocardial infarction (STEMI), after cardiac arrest, or in cardiogenic shock; 48% of PCI patients underwent revascularization on the day of admission vs. 5.1% in the CABG group. After adjustment, revascularization was associated with an early hazard of hospital death vs. no revascularization, significant for PCI (hazard ratio (HR) 2.60, 95% confidence interval (CI) 1.62–4.18) but not for CABG (1.26, 0.72–2.22). From discharge to 6 months, both PCI (HR 0.45, 95% CI 0.23–0.85) and CABG (0.11, 0.04–0.28) were significantly associated with improved survival in comparison with an initial strategy of no revascularization...