Biological therapies need definitive randomized controlled clinical trials.

Adequate and well-controlled clinical trials remain critical tools for helping to bring benefit to patients in medical need.

Future of Personalized Cardiovascular Medicine: JACC State-of-the-Art Review.

Previous decades have seen significant progress in the biological understanding of cardiovascular disease, as well as major advances in computational and information technologies. However, anticipated improvements in outcomes, quality, and cost of cardiovascular medicine at the individual and population levels from these advances have lagged expectations. Further, trends showing widening gaps in the pace of technological development and its successful uptake and application in practice suggests that substantial systemic changes are needed. Recent declines in key U.S. health outcomes have added further urgency to seek scalable approaches that deliver the right treatment to the right patient and to develop information-driven policies that improve health. The clinical care and research enterprises are currently in the midst of assimilating changes entrained by a "fourth industrial revolution" marked by the convergence of biology, physical sciences, and information science. These changes, if managed appropriately, can simultaneously enable cost-effective personalized medical care as well as more effective and targeted population health interventions. In this paper derived from a lecture in honor of cardiologist Paul Dudley White, the author explores how White's prescient insights into prevention and treatment continue to resonate today as we seek to assimilate ubiquitous computing, sophisticated sensor technologies, and bidirectional digital communication into the practice of cardiology. How the ongoing acceleration in basic science and information technologies can be wedded to the principles articulated by White as we pursue scalable approaches to personalized medicine is also examined.

Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban.

OBJECTIVE: To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD). METHODS: Using Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis. RESULTS: Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p<0.05) and MR or AR (HR 1.30, 1.07 to 1.57, p<0.01) than in no SVD, but there was no difference between AS and MR or AR (HR 1.24, 0.78 to 1.97). The relative efficacy of rivaroxaban versus warfarin was consistent among patients with and without valvular disease. Rivaroxaban was associated with higher rates of major bleeding than warfarin in patients with MR or AR (HR 1.63, 1.15 to 2.31). CONCLUSIONS: We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD. TRIAL REGISTRATION NUMBER: NCT00403767; Post-results.

The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations.

Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment.

Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial.

AIMS: We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial. METHODS AND RESULTS: ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban. CONCLUSIONS: Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.

Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: results from the ROCKET AF trial.

BACKGROUND: Antiarrhythmic drugs (AADs) and anticoagulation are mainstays of atrial fibrillation (AF) treatment. OBJECTIVE: To study the use and outcomes of AAD therapy in anticoagulated patients with AF. METHODS: Patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial (N = 14,264) were stratified by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across AAD groups as well as across treatment assignment (rivaroxaban or warfarin). RESULTS: Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone and 537 [3.8%] with other AADs). Amiodarone-treated patients were less often female (38% vs 48%), had more persistent AF (64% vs 40%), and more concomitant heart failure (71% vs 41%) than were patients receiving other AADs. Patients receiving no AAD more closely resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone than in those receiving no AAD (50% vs 58%; P < .0001). Compared with no AAD, neither amiodarone (adjusted hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.74-1.31; P = .9) nor other AADs (adjusted HR 0.66; 95% CI 0.37-1.17; P = .15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Treatment effects of rivaroxaban vs warfarin in patients receiving no AAD were consistent with results from the overall trial (primary end point: adjusted HR 0.82; 95% CI 0.68-0.98; Pinteraction = .06; safety end point: adjusted HR 1.12; 95% CI 0.90-1.24; Pinteraction = .33). CONCLUSION: Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The effect of amiodarone on outcomes in patients receiving rivaroxaban requires further investigation.

Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial.

BACKGROUND: Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons. METHODS AND RESULTS: TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values. CONCLUSIONS: The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial.

BACKGROUND: In ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation. OBJECTIVE: To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients. DESIGN: Prespecified subgroup analysis. (ClinicalTrials.gov: NCT00403767). SETTING: Global. PATIENTS: 14,264 persons with atrial fibrillation. MEASUREMENTS: Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients. RESULTS: Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003). LIMITATION: The trial was not designed to detect differences in these subgroups. CONCLUSION: The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy. PRIMARY FUNDING SOURCE: Johnson & Johnson and Bayer HealthCare.

End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience.

BACKGROUND: To evaluate the previously reported excess of thromboembolic events during the 30 days after the end of study (EOS) visit when participants transitioned from blinded therapy to open-label vitamin K antagonist. METHODS AND RESULTS: At the EOS visit, open-label vitamin K antagonist was recommended, and the international normalized ratio (INR) was not to be measured until 3 days later to preserve blinding. We analyzed transition strategies, clinical outcomes, and INR values. Event rates are per 100 patient-years. A total of 9248 (65%) participants were taking study drug at EOS, and, between days 3 and 30, an excess of stroke and systemic embolic events were observed in participants assigned to rivaroxaban (rivaroxaban 22 events, event rate 6.42; warfarin 6 events, event rate 1.73; hazard ratio, 3.72; 95% confidence interval, 1.51-9.16; P=0.0044). No INR values were reported for ≈5% of participants transitioned to warfarin. By 30 days after EOS, 83% of the warfarin group and 52% of the rivaroxaban group had ≥1 therapeutic INR value. Median time to first therapeutic INR was 3 days in the warfarin group and 13 days in the rivaroxaban group. CONCLUSIONS: The excess of events at EOS was likely because of a period of inadequate anticoagulation in rivaroxaban participants switched to vitamin K antagonist therapy. If transition from rivaroxaban to vitamin K antagonist is needed, timely monitoring and careful dosing should be used to ensure consistent and adequate anticoagulation.

Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF.

BACKGROUND: In Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with nonvalvular atrial fibrillation. We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF). METHODS AND RESULTS: A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient-years) by intention to treat. The safety outcomes were major or nonmajor clinically relevant bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 versus 74 years), more likely to have persistent atrial fibrillation (83.0% versus 77.6%), and had higher mean CHADS2 scores (3.7 versus 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 versus 2.09) and without HF (2.10 versus 2.54; P-interaction=0.62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 versus 14.02) and without HF (16.12 versus 15.35; P-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with HF as in the overall trial (adjusted hazard ratio, 0.38; 95% confidence interval, 0.19-0.76; P-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar, irrespective of ejection fraction <40 or ≥ 40% (P-interaction=0.38), New York Heart Association class I-II versus III-IV (P-interaction=0.68), HF preserved or reduced ejection fraction (P-interaction=0.35), or CHADS2 score 2 versus ≥ 3 (P-interaction=0.48). CONCLUSIONS: Treatment-related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with atrial fibrillation and HF. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial.

BACKGROUND: Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial. METHODS AND RESULTS: TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals. CONCLUSIONS: Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Rivaroxaban, an oral direct factor Xa inhibitor.

Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists. Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis. A broad search of Medline, clinicaltrials.gov and the annual proceedings of the American Society of Hematology and the International Society on Thrombosis and Hemostasis was conducted. This review addresses the findings of this systematic search, including the need for new oral anticoagulants, the development and pharmacology of rivaroxaban, and the results of completed as well as ongoing trials with rivaroxaban. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The drug may have its greatest impact in providing a much-needed and attractive alternative to warfarin. Further data (especially large Phase III trials) are required.

Effect of intensive lipid-lowering therapy on mortality after acute coronary syndrome (a patient-level analysis of the Aggrastat to Zocor and Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trials).

Compared with moderate lipid lowering with standard-dose statin therapy, intensive lipid lowering with high-dose statin therapy after acute coronary syndromes (ACS) significantly reduces cardiovascular events. However, the 2 trials of high-dose versus standard-dose statin therapy in patients with ACS, Aggrastat to Zocor (A to Z) and Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE-IT-TIMI 22), were not individually powered to evaluate the impact on mortality alone. In this study, a pooled, patient-level analysis of these trials of 8,658 post-ACS patients was performed to provide a more robust estimate of the impact of intensive statin therapy on mortality. By 8 months, achieved low-density lipoprotein levels were lower in the group with intensive statin therapy (median 64 mg/dl, interquartile range 51 to 81) than in the group with moderate statin therapy (median 87 mg/dl, interquartile range 71 to 107) (p <0.001). All-cause mortality was significantly reduced in the group with intensive statin therapy compared with the group with moderate statin therapy (3.6% vs 4.9%, hazard ratio 0.77, 95% confidence interval 0.63 to 0.95, p = 0.015), without significant interaction by trial (interaction p = 0.63). The reduction in all-cause mortality with intensive statin therapy was consistent across key subgroups. In conclusion, in this analysis of >8,600 patients, intensive lipid lowering with high-dose statin therapy after ACS was associated with reduced mortality compared with moderate lipid lowering with standard-dose statin therapy. On the basis of these findings, 1 death was prevented for every 95 patients treated with high-dose statin therapy for 2 years. The results of this pooled analysis provide further evidence for early intensive statin therapy after ACS.

Evaluation of diagnostic imaging technologies and therapeutics devices: better information for better decisions: proceedings of a multidisciplinary workshop.

We are entering an era in which the success of biomedical science and the increasing understanding of the value of evidence for practice are in a state of tension. This tension is especially notable in the device arena, in which the short life cycles and iterative nature of development are at odds with current design constructs of the types of clinical trials that provide evidence for medical decision making. The financial pressure arising from strained budgets and expanding costs from the aging of the population and the continued development of new technology heightens the need for a focus on new approaches. Given this background, a group of experts representing constituencies with different perspectives were convened for a day and a half to discuss key issues and their potential solutions. Because of the complex and heterogeneous nature of the environments in which devices are used, the meeting focused on 3 broad, general uses of devices: imaging, risk stratification, and therapeutics. The goal of the meeting was to develop a preliminary list of ideas that could be framed as researchable questions or constructs for consideration by policy makers that ultimately might lead to improvements in the current system. Across diagnostic imaging, risk stratification devices, and therapeutic devices, the crosscutting issues can be identified: We need better methods of collaborative funding and priority setting, improved and more flexible methods, and new approaches to the integration of federal agencies in overseeing the system.

International differences in evolution of early discharge after acute myocardial infarction.

BACKGROUND: Early discharge of low-risk patients with acute myocardial infarction is feasible and can be achieved at no additional risk of adverse events. We aimed to identify the extent to which countries have taken advantage of the opportunity for early discharge. METHODS: The study population consisted of 54174 patients enrolled in GUSTO-I, GUSTO-III, and ASSENT-2 studies (enrollment period 1990-98) in the USA, Canada, Australia, New Zealand, Belgium, France, Germany, Spain, and Poland. We identified patients with uncomplicated acute myocardial infarction who were eligible for early discharge on the basis of previously established criteria, and assessed the extent to which these patients were discharged early--defined as discharged alive within 4 days of admission. The economic consequences (defined as potentially unnecessary hospital days consumed per 100 patients enrolled) were also investigated. FINDINGS: Patients in all European countries had significantly longer stays than did those from non-European countries. Over the study period, the number of eligible patients discharged on or before day 4 increased in the USA, Canada, Australia, and New Zealand. Despite this increase, no more than 40% of patients who were eligible for early discharge were actually discharged early. The rate of early discharge of eligible patients was consistently low (<2%) in Belgium, France, Germany, Spain, and Poland. In ASSENT-2, which is the most recent trial in this study, the number of potentially unnecessary hospital days (per 100 patients enrolled) ranged from 65 in New Zealand to 839 in Germany. INTERPRETATION: Despite more than a decade of research, there is still a lot of variation between countries in international length-of-stay patterns in acute myocardial infarction. The potential for more efficient discharge of low-risk patients exists in all countries investigated, but was especially evident in the European countries included in the study (Belgium, France, Germany, Spain, and Poland).

Troponin T and quantitative ST-segment depression offer complementary prognostic information in the risk stratification of acute coronary syndrome patients.

OBJECTIVES: Our primary objective was to examine the prognostic relationship between baseline quantitative ST-segment depression (ST) and cardiac troponin T (cTnT) elevation. The secondary objectives were to: 1) examine whether ST provided additional insight into therapeutic efficacy of glycoprotein IIb/IIIa therapy similar to that demonstrated by cTnT; and 2) explore whether the time to evaluation impacted on each marker's relative prognostic utility. BACKGROUND: The relationship between the baseline electrocardiogram (ECG) and cTnT measurements in risk-stratifying patients presenting with acute coronary syndromes (ACS) has not been evaluated comprehensively. METHODS: The study population consisted of 959 patients enrolled in the cTnT substudy of the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B trial. Patients were classified as having no ST (n = 387), 1 mm ST (n = 433), and ST > or =2 mm (n = 139). Forty-percent (n = 381) were classified as cTnT-positive based on a definition of > or =0.1 ng/ml. RESULTS: Six-month death/(re)myocardial infarction rates were 8.4% among cTnT-negative patients with no ST and 26.8% among cTnT-positive patients with ST > or =2 mm. On ECGs done after 6 h of symptom onset, ST > or =2 mm was associated with higher risk compared to its presence on ECGs done earlier (odds ratio [OR] 7.3 vs. 2.1). In contrast, the presence of elevated cTnT within 6 h of symptom was associated with a higher risk of adverse events compared with elevations after 6 h (OR 2.4 vs. 1.5). CONCLUSIONS: Quantitative ST and cTnT status are complementary in assessing risk among ACS patients and both should be employed to determine prognosis and assist in medical decision making.