Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial.

Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.

PIPELINEs: Creating Comparable Clinical Knowledge Efficiently by Linking Trial Platforms.

Adaptive, seamless, multisponsor, multitherapy clinical trial designs executed as large scale platforms, could create superior evidence more efficiently than single-sponsor, single-drug trials. These trial PIPELINEs also could diminish barriers to trial participation, increase the representation of real-world populations, and create systematic evidence development for learning throughout a therapeutic life cycle, to continually refine its use. Comparable evidence could arise from multiarm design, shared comparator arms, and standardized endpoints-aiding sponsors in demonstrating the distinct value of their innovative medicines; facilitating providers and patients in selecting the most appropriate treatments; assisting regulators in efficacy and safety determinations; helping payers make coverage and reimbursement decisions; and spurring scientists with translational insights. Reduced trial times and costs could enable more indications, reduced development cycle times, and improved system financial sustainability. Challenges to overcome range from statistical to operational to collaborative governance and data exchange.

Adaptive Biomedical Innovation: Evolving Our Global System to Sustainably and Safely Bring New Medicines to Patients in Need.

The current system of biomedical innovation is unable to keep pace with scientific advancements. We propose to address this gap by reengineering innovation processes to accelerate reliable delivery of products that address unmet medical needs. Adaptive biomedical innovation (ABI) provides an integrative, strategic approach for process innovation. Although the term "ABI" is new, it encompasses fragmented "tools" that have been developed across the global pharmaceutical industry, and could accelerate the evolution of the system through more coordinated application. ABI involves bringing stakeholders together to set shared objectives, foster trust, structure decision-making, and manage expectations through rapid-cycle feedback loops that maximize product knowledge and reduce uncertainty in a continuous, adaptive, and sustainable learning healthcare system. Adaptive decision-making, a core element of ABI, provides a framework for structuring decision-making designed to manage two types of uncertainty - the maturity of scientific and clinical knowledge, and the behaviors of other critical stakeholders.

Genetic modifiers of response to glucose-insulin-potassium (GIK) infusion in acute coronary syndromes and associations with clinical outcomes in the IMMEDIATE trial.

Modifiers of response to glucose, insulin and potassium (GIK) infusion may affect clinical outcomes in acute coronary syndromes (ACS). In an Immediate Myocardial Metabolic Enhancement During Initial Assessment And Treatment In Emergency Care (IMMEDIATE) trial's sub-study (n = 318), we explored effects of 132,634 genetic variants on plasma glucose and potassium response to 12-h GIK infusion. Associations between metabolite-associated variants and infarct size (n = 84) were assessed. The 'G' allele of rs12641551, near ACSL1, as well as the 'A' allele of XPO4 rs2585897 were associated with a differential glucose response (P for 2 degrees of freedom test, P2df ⩽ 4.75 × 10(-7)) and infarct size with GIK (P2df < 0.05). Variants within or near TAS1R3, LCA5, DNAH5, PTPRG, MAGI1, PTCSC3, STRADA, AKAP12, ARFGEF2, ADCYAP1, SETX, NDRG4 and ABCB11 modified glucose response, and near CSF1/AHCYL1 potassium response (P2df ⩽ 4.26 × 10(-7)), but not outcomes. Gene variants may modify glucose and potassium response to GIK infusion, contributing to cardiovascular outcomes in ACS.

Genetic variation at glucose and insulin trait loci and response to glucose-insulin-potassium (GIK) therapy: the IMMEDIATE trial.

The mechanistic effects of intravenous glucose, insulin and potassium (GIK) in cardiac ischemia are not well understood. We conducted a genetic sub-study of the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care (IMMEDIATE) Trial to explore effects of common and rare glucose and insulin-related genetic loci on initial to 6-h and 6- to 12-h change in plasma glucose and potassium. We identified 27 NOTCH2/ADAM30 and 8 C2CD4B variants conferring a 40-57% increase in glucose during the first 6 h of infusion (P<5.96 × 10(-6)). Significant associations were also found for ABCB11 and SLC30A8 single-nucleotide polymorphisms (SNPs) and glucose responses, and an SEC61A2 SNP with a potassium response to GIK. These studies identify genetic factors that may impact the metabolic response to GIK, which could influence treatment benefits in the setting of acute coronary syndromes (ACS).

A proposal for integrated efficacy-to-effectiveness (E2E) clinical trials.

We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.

Balancing the benefits of primary angioplasty against the benefits of thrombolytic therapy for acute myocardial infarction: the importance of timing.

CONTEXT: A meta-analysis found that primary percutaneous transluminal coronary angioplasty (PTCA) was more effective than thrombolytic therapy in reducing mortality from acute myocardial infarction. However, fewer than 20% of U.S. hospitals have facilities to perform PTCA and many clinicians must choose between immediate thrombolytic therapy and delayed PTCA. COUNT: The number of minutes of PTCA-related delay that would nullify its benefits. CALCULATION: For 10 published randomized trials, we calculated the following: PTCA-related delay = median "door-to-balloon" time--median "door-to-needle" time Survival benefit = 30-day mortality after thrombolytic therapy--30-day mortality after PTCA The relationship between delay and benefit was assessed with linear regression. RESULTS: The reported PTCA-related delay ranged from 7 to 59 minutes, while the absolute survival benefit ranged from -2.2% (favoring thrombolytic therapy) to 7.4% (favoring PTCA). Across trials, the survival benefit decreased as the PTCA-related delay increased: For each additional 10-minute delay, the benefit was predicted to decrease 1.7% (P < 0.001). Linear regression showed that at a PTCA-related delay of 50 minutes, PTCA and thrombolytic therapy yielded equivalent reductions in mortality. CONCLUSIONS: In clinical trials with short PTCA-related delays, PTCA produced better outcomes, while trials with longer delays favored thrombolytic therapy. A more precise estimate of the time interval to equipoise between the two therapies needs to be modeled with patient-level data. At experienced cardiac centers, PTCA is probably still preferable, even with delays longer than 50 minutes.

The future of capitation: the physician role in managing change in practice.

Capitation-based reimbursement significantly influences the practice of medicine. As physicians, we need to assure that payment models do not jeopardize the care we provide when we accept higher levels of personal financial risk. In this paper, we review the literature relevant to capitation, consider the interaction of financial incentives with physician and medical risk, and conclude that primary care physicians need to work to assure that capitated systems incorporate checks and balances which protect both patients and providers. We offer the following proposals for individuals and groups considering capitated contracts: (1) reimbursement for primary care physicians should recognize both individual patient encounters and the administrative work of patient care management; (2) reimbursement for subspecialists should recognize both access to subspecialty knowledge and expertise as well as patient care encounters, but in some situations, subspecialists may provide the majority of care to individual patients and will be reimbursed as primary care providers; (3) groups of physicians should accept financial risk for patient care only if they have the tools and resources to manage the care; (4) physicians sharing risk for patient care should meet regularly to discuss care and resource management; and (5) physicians must disclose the financial relationships they have with health plans and medical care organizations, and engage patients and communities in discussions about resource allocation. As a payment model, capitation offers opportunities for primary care physicians to influence the future of health care by improving the management of resources at a local level.

Acute cardiac ischemia in patients with cocaine-associated complaints: results of a multicenter trial.

STUDY OBJECTIVE: To describe the characteristics of a large group of patients who presented to emergency departments with cocaine-associated symptoms consistent with acute cardiac ischemia (ACI) and to determine the incidence of confirmed ACI including acute myocardial infarction (AMI) in this population. METHODS: We performed a substudy on all patients in a multicenter prospective clinical trial (the Acute Cardiac Ischemia-Time Insensitive Predictive Instrument [ACI-TIPI] Clinical Trial) that enrolled ED patients with chest pain or other symptoms consistent with ACI including subjects with identified cocaine use. Demographic and clinical features, including initial and follow-up clinical data, ECGs, and tests to determine serum creatine kinase isoenzyme MB subunit concentrations, were analyzed. Diagnoses of AMI followed the World Health Organization criteria for AMI and of angina pectoris, the Canadian Cardiovascular Society Classification. RESULTS: Of the 10,689 patients enrolled in the trial, 293 (2.7%) had cocaine-associated complaints. Among the 10 participating hospitals, the incidence of patients with cocaine-associated symptoms varied from 0.3% to 8.4%. Only 6 patients (2.0%, 95% confidence interval [CI] 0.76% to 4.4%) had a diagnosis of ACI; 4 (1.4%, 95% CI 0.37% to 3.5%) had unstable angina, and 2 (0.7%, 95% CI 0.08% to 2.4%) had AMI. Although patients with cocaine-induced complaints were as likely to be admitted to the coronary care unit compared with all study patients without cocaine use (14% versus 18%, P =.14, difference not significant), these patients were much less likely to have confirmed unstable angina (1.4% versus 9.3%, P <.001) or AMI (0. 7% versus 8.6%, P <.001). Compared with patients younger than 45 years, patients with cocaine usage were more likely to be admitted to the ICU (14% versus 8.0%, P =.0018) but less likely to have confirmed AMI (0.7% versus 2.8%, P =.033). CONCLUSION: Patients presenting to EDs with cocaine-associated chest pain or related symptoms infrequently had ACI, and even less so, AMI. This suggests the need for selectivity in the hospitalization of patients with such cocaine-associated symptoms.

National Heart Attack Alert Program position paper: chest pain centers and programs for the evaluation of acute cardiac ischemia.

The National Heart Attack Alert Program (NHAAP), which is coordinated by the National Heart, Lung, and Blood Institute (NHLBI), promotes the early detection and optimal treatment of patients with acute myocardial infarction and other acute coronary ischemic syndromes. The NHAAP, having observed the development and growth of chest pain centers in emergency departments with special interest, created a task force to evaluate such centers and make recommendations pertaining to the management of patients with acute cardiac ischemia. This position paper offers recommendations to assist emergency physicians in EDs, including those with chest pain centers, in providing comprehensive care for patients with acute cardiac ischemia.

Missed diagnoses of acute cardiac ischemia in the emergency department.

BACKGROUND: Discharging patients with acute myocardial infarction or unstable angina from the emergency department because of missed diagnoses can have dire consequences. We studied the incidence of, factors related to, and clinical outcomes of failure to hospitalize patients with acute cardiac ischemia. METHODS: We analyzed clinical data from a multicenter, prospective clinical trial of all patients with chest pain or other symptoms suggesting acute cardiac ischemia who presented to the emergency departments of 10 U.S. hospitals. RESULTS: Of 10,689 patients, 17 percent ultimately met the criteria for acute cardiac ischemia (8 percent had acute myocardial infarction and 9 percent had unstable angina), 6 percent had stable angina, 21 percent had other cardiac problems, and 55 percent had noncardiac problems. Among the 889 patients with acute myocardial infarction, 19 (2.1 percent) were mistakenly discharged from the emergency department (95 percent confidence interval, 1.1 to 3.1 percent); among the 966 patients with unstable angina, 22 (2.3 percent) were mistakenly discharged (95 percent confidence interval, 1.3 to 3.2 percent). Multivariable analysis showed that patients who presented to the emergency department with acute cardiac ischemia were more likely not to be hospitalized if they were women less than 55 years old (odds ratio for discharge, 6.7; 95 percent confidence interval, 1.4 to 32.5), were nonwhite (odds ratio, 2.2; 1.1 to 4.3), reported shortness of breath as their chief symptom (odds ratio, 2.7; 1.1 to 6.5), or had a normal or nondiagnostic electrocardiogram (odds ratio, 3.3; 1.7 to 6.3). Patients with acute infarction were more likely not to be hospitalized if they were nonwhite (odds ratio for discharge, 4.5; 95 percent confidence interval, 1.8 to 11.8) or had a normal or nondiagnostic electrocardiogram (odds ratio, 7.7; 95 percent confidence interval, 2.9 to 20.2). For the patients with acute infarction, the risk-adjusted mortality ratio for those who were not hospitalized, as compared with those who were, was 1.9 (95 percent confidence interval, 0.7 to 5.2), and for the patients with unstable angina, it was 1.7 (95 percent confidence interval, 0.2 to 17.0). CONCLUSIONS: The percentage of patients who present to the emergency department with acute myocardial infarction or unstable angina who are not hospitalized is low, but the discharge of such patients is associated with increased mortality. Failure to hospitalize is related to race, sex, and the absence of typical features of cardiac ischemia. Continued efforts to reduce the number of missed diagnoses are warranted.

The potential use of ECG-based prognostic instruments in clinical trials and cost-effectiveness analyses of new therapies in acute cardiac ischemia.

The dramatic improvements in outcomes in acute cardiac ischemia because of therapeutic advances has led to "diminishing returns" with increasingly intensive therapies. This article explores the potential of electrocardiograph (ECG)-based prognostic instruments to identify patients likely to benefit from intense regimens, even in the absence of overall average benefit in the population, with 2 clinical examples: 1) Reperfusion therapy in acute myocardial infarction (AMI); and 2) anticoagulation/antiplatelet therapy in unstable angina. Based on previously developed, ECG-based prognostic instruments we explored the distribution of potential benefits in individual patients from increasingly intense therapy in both AMI and unstable angina. Predictions were obtained on community-based patient samples with both AMI and unstable angina to examine the distribution of effectiveness and cost-effectiveness. For both AMI and unstable angina, much of the benefit of intensifying therapy can be obtained by targeting a subgroup of patients that can be identified in multivariable dimensions by clinical and ECG characteristics. Treatment of these patients with more potent agents (such as hirudin or the glycoprotein inhibitors in unstable angina) is likely to be both effective and cost-effective. However, treatment of "low benefit" patients is unlikely to be effective or cost-effective, and some candidates for therapy are more likely to be harmed, than to benefit, by the more intensive regimens. Multivariable stratification can improve clinical and economic outcomes in acute cardiac ischemia, particularly when such models help identify "high benefit" patients early in their clinical course. Additionally, using validated models in the planning and execution of clinical trials of new therapies can improve the power of the trial and help target the therapies to patients most likely to benefit.

Use of the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI) to assist with triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia. A multicenter, controlled clinical trial.

BACKGROUND: Approximately 6 million U.S. patients present to emergency departments annually with symptoms suggesting acute cardiac ischemia. Triage decisions for these patients are important but remain difficult. OBJECTIVE: To test whether computerized prediction of the probability of acute ischemia, used with electrocardiography, improves the accuracy of triage decisions. DESIGN: Controlled clinical trial. SETTING: 10 hospital emergency departments in the midwestern, southeastern, and northeastern United States. PATIENTS: 10689 patients with chest pain or other symptoms suggestive of acute cardiac ischemia. INTERVENTION: The probability of acute ischemia predicted by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI), either automatically printed or not printed on patients' electrocardiograms. MEASUREMENTS: Emergency department triage to a coronary care unit (CCU), telemetry unit, ward, or home. Other measurements were the bed capacity of the CCU relative to that of the telemetry unit; training or supervision status of the triaging physician; and patient diagnoses and outcomes based on clinical, electrocardiographic, and creatine kinase data. RESULTS: For patients without cardiac ischemia, in hospitals with high-capacity CCUs and relatively low-capacity cardiac telemetry units, use of ACI-TIPI was associated with a reduction in CCU admissions from 15% to 12%, a change of -16% (95% CI, -30% to 0%), and an increase in emergency department discharges to home from 49% to 52%, a change of 6% (CI, 0% to 14%; overall P=0.09). Across all hospitals, for patients evaluated by unsupervised residents, use of ACI-TIPI was associated with a reduction in CCU admissions from 14% to 10%, a change of -32% (CI, -55% to 3%); a reduction in telemetry unit admissions from 39% to 31%, a change of -20% (CI, -34% to -2%); and an increase in discharges to home from 45% to 56%, a change of 25% (CI, 8% to 45%; overall P=0.008). Among patients with stable angina, in hospitals with high-capacity CCUs, use of ACI-TIPI was associated with a reduction in CCU admissions from 26% to 13%, a change of -50% (CI, -70% to -17%), and an increase in discharges to home from 20% to 22%, a change of 10% (CI, -29% to 71%; overall P=0.02). At hospitals with high-capacity telemetry units, use of ACI-TIPI was associated with a reduction in telemetry unit admissions from 68% to 59%, a change of -14% (CI, -27% to 1%), and an increase in emergency department discharges to home from 10% to 21%, a change of 100% (CI, 22% to 230%; overall P=0.02). Among patients with acute myocardial infarction or unstable angina, use of ACI-TIPI did not change appropriate admission (96%) to the CCU or telemetry unit at hospitals with high-capacity CCUs or telemetry units. CONCLUSIONS: Use of ACI-TIPI was associated with reduced hospitalization among emergency department patients without acute cardiac ischemia. This result varied as expected according to the CCU and cardiac telemetry unit capacities and physician supervision at individual hospitals. Appropriate admission for unstable angina or acute infarction was not affected. If ACI-TIPI is used widely in the United States, its potential incremental impact may be more than 200000 fewer unnecessary hospitalizations and more than 100000 fewer unnecessary CCU admissions.

A national survey of emergency department chest pain centers in the United States.

Although chest pain centers are promoted as improving emergency cardiac care, no data exist on their structure and processes. This national study determines the 1995 prevalence rate for emergency department (ED)-based chest pain centers in the United States and compares organizational differences of EDs with and without such centers. A mail survey was directed to 476 EDs randomly selected from the American Hospital Association's database of metropolitan hospitals (n = 2,309); the response rate was 63%. The prevalence of chest pain centers was 22.5% (95% confidence interval 18% to 27%), which yielded a projection of 520 centers in the United States in 1995. EDs with centers had higher overall patient volumes, greater use of high-technology testing, lower treatment times for thrombolytic therapy, and more advertising (all p <0.05). Hospitals with centers had greater market competition and more beds per annual admissions, cardiac catheterization, and open heart surgery capability (all p <0.05). Logistic regression identified open heart surgery, high-admission volumes, and nonprofit status as independent predictors of hospitals having chest pain centers. Thus, chest pain centers have a moderate prevalence, offer more services and marketing efforts than standard EDs, and tend to be hosted by large nonprofit hospitals.

Insurance type and the transportation to emergency departments of patients with acute cardiac ischemia: the ACI-TIPI Trial Insurance Study.

The relationship of insurance type to treatment-seeking behavior (ie, the transportation to emergency departments of patients with symptoms suggestive of acute cardiac ischemia) was evaluated. The focus was on comparing patients belonging to a health maintenance organization (HMO) with patients who had indemnity insurance. Data were collected prospectively on 10,783 patients presenting to emergency departments of 10 adult care hospitals in the Eastern and Midwestern United States between April and December 1993 as part of a clinical trial. A total of 6,604 patients presented within 24 hours of symptom onset. Although these patients as a group had a wide range of demographic and clinical characteristics, persons belonging to an HMO and those with indemnity insurance were very similar. The main outcome measures were whether the patient was transported by ambulance and the duration of time from symptom onset to emergency department arrival. A hospital-matched sample of HMO-insured and indemnity-insured patients allowed multivariable regression: HMO membership was not associated with a different rate of ambulance use (odds ratio = 1.0; 95% confidence interval = 0.73, 1.35) or duration of time from symptom onset to emergency department presentation (6 minutes less, P = 0.8). HMO participation was not related to treatment-seeking behavior, as reflected by ambulance use and duration of time from symptom onset to emergency department arrival. However, studies of more constrained managed care organizations and of broader ranges of patients are needed.