key: cord-1026214-kpzlpizf
authors: Apple, Fred S; Fantz, Corinne R; Collinson, Paul O
title: Implementation of High-Sensitivity and Point-of-Care Cardiac Troponin Assays into Practice: Some Different Thoughts
date: 2020-12-05
journal: Clin Chem
DOI: 10.1093/clinchem/hvaa264
sha: d48e48b4fdb722386b2b6d13cc5d452824eba578
doc_id: 1026214
cord_uid: kpzlpizf

BACKGROUND: The primary role of the International Federation of Clinical Chemistry (IFCC) Committee on Clinical Application of Cardiac Bio-Markers (C-CB) is to provide educational materials about cardiac biomarker use, emphasizing high-sensitivity cardiac troponin assays. CONTENT: This mini-review, regarding high-sensitivity cardiac and point-of-care troponin assays, addresses 1) new IFCC C-CB/AACC Academy laboratory practice recommendations; 2) new and updated concepts from the Fourth Universal Definition of Myocardial Infarction; 3) the role of point-of-care assays in practice and research; 4) regulatory challenges concerning point-of-care assays; e) testing in the COVID-19 world. SUMMARY: Implementation of high-sensitivity cardiac troponin assays makes a difference now and into the future in clinical practice and research. Providing point-of-care high-sensitivity cardiac troponin assays and optimizing studies to allow clearance of these assays by regulatory agencies, in a timely fashion, may provide improved patient management and outcomes.

How to implement high-sensitivity cardiac troponin (hs-cTn) assays in practice is not a harmonized process (1) . The International Federation of Clinical Chemistry (IFCC) Committee on Clinical Application of Cardiac Bio-Markers (C-CB) provides educational materials about cardiac biomarkers, emphasizing hs-cTn assays (2, 3) . Growth of regulatory clearances for hs-cTnI and hs-cTnT assays ( Fig. 1) is found on the IFCC C-CB website (4). This mini-review regarding hs-cTn assays 1) highlights new IFCC C-CB/AACC Academy laboratory practice recommendations; 2) addresses new/updated concepts from the Fourth Universal Definition of Myocardial Infarction (UDMI) recommendations; 3) discusses role of point-of-care (POC) assays in practice; 4) identifies regulatory challenges concerning POC assays.

Consensus recommendations by the AACC Academy, in collaboration with the IFCC TF-CB, address conversion of contemporary assays to hs-cTn. Expert opinion clinical laboratory practice recommendations for hs-cTn assays focused on 10 topics: 1) quality control (QC) utilization; 2) validation of lower reportable analytical limits; 3) units used in reporting measurable concentrations for patients and QC materials; 4) 99th percentile sex-specific upper reference limits (URLs); 5) criteria required to define hs-cTn assays; 6) communicating with and educating clinicians regarding preanalytical and analytical problems that confound results; 7) how authors need to document analytical assay details in hs-cTn studies; 8) harmonizing assay results and commutable materials; 9) time to reporting of results from sample collection to receipt; 10) changes in serial hs-cTn concentrations over time and role of biological variation in interpreting results. New practices, shown in Table 1 , include using QC at sex-specific URLs, emphasizing not to perform an underpowered study to establish an URL, role of appropriate statistics to define 99th percentiles, importance of limit of detection (LoD) in defining hs-assays measuring 50% of normal males and females individually (not combined), and reporting hs-cTn results with whole numbers, designated ng/L, to distinguish from contemporary assays.

A recent study determined overall and sex-specific 99th percentiles in 9 hs-cTnI and 3 hs-cTnT assays using a universal sample bank screened by health questionnaire and surrogate biomarkers (5) . Subjects were age, ethnic, and racially diverse. Overall and sex-specific 99th percentiles showed substantial differences between and within both hs-cTnI and hs-cTnT assays. Men had higher 99th percentiles than women ( Fig. 2: A-cTnI; B-cTnT). Both overall and sex-specific 99th percentiles varied according to statistical method and assay used. Not all assays provided a high enough percentage of measurable concentrations in women to qualify as hsassays, and the surrogate exclusion criteria used to define normality tended to lower the 99th percentiles.

Following a meeting between US laboratory medicine, emergency medicine, and cardiology biomarker experts and FDA, guidelines for uniform analytical and clinical standards for studies performed by manufacturers seeking cTn 510k assay clearance were published (6) . Recommendations addressed 1) number of reference individuals for determination of 99th percentiles; 2) limit of quantification; 3) total imprecision requirements; 4) enrollment of subjects for diagnostic studies; 5) patient adjudication processes; and 6) clinical end points and outcomes. The focus was to ensure common protocols applied to hs-cTn assays. Unfortunately, published recommendations were not endorsed by the FDA.

For global harmonization of care in patients presenting with symptoms suggestive of myocardial injury, the UDMI assists clinicians in a common focus on how to utilize biomarkers in alignment with IFCC C-CB and AACC Academy guidelines (7) . First, it recommends myocardial injury be used when there is evidence of increased cTn with at least one value above the 99th percentile sex-specific URL (3). Myocardial injury is considered acute with a rise and/or fall of cTn between serial samplings. Fig. 3 shows representative myocardial injury. Complexity of clinical circumstances may make it difficult to discriminate specific individual mechanism(s) of injury. Second, greater attention was placed on recognition of type 2 MI, defined in settings with oxygen demand and supply imbalance unrelated to acute coronary thrombosis (8) . If myocardial injury is not acute and related to chronic structural heart disease, serial cTn values may be stable and unchanging. Third, cTnI and cTnT remain standard biomarkers for ruling in/out MI and myocardial injury. cTn release into the circulation is dependent on blood flow around injured myocardium, and kinetics of increasing, peaking, and falling values are assay dependent (9) since cTn assays are not standardized. Utilizing hs-cTn assays, most rule in/rule out decisions are made within 3 hours of initial sampling, based on assay-dependent algorithms (10) . Fourth, analytical sensitivity provided by hs-cTn assays 2. Quality control materials should be considered at concentrations consistent with the limit of detection (LoD) of each hs-cTnI and hs-cTnT assay to provide ongoing confidence when used for rule out protocols.

3. Avoid implementing upper reference limits that use underpowered subject numbers to establish 99th percentiles.

4. Appropriate statistical analyses to define 99th percentiles include the non-parametric and Harrell Davis methods, with the Robust method not acceptable.

5. High sensitivity assays are now defined base on measuring 50% of normal males and 50% normal females individually, not combined.

6. Beware of contemporary assays that report results using whole numbers, designated ng/L, that are only designated for high sensitivity assays.

is critical for early rule out and assists in defining assay dependent deltas. Recommendations emphasize that clinicians become educated about details of the specific assay used in their practice. Fifth, the UDMI supports IFCC guidelines for defining hs-cTn assays based on imprecision (10%CV at sex-specific URL) and ability to measure normal subjects above the LoD in 50% of measurements in both males and females, separately (2, 3), differentiating hs assays from contemporary and POC assays that are generally analytically and clinically inferior for diagnostic use and unable to define biological variation (1). (16) . A systematic evidence-based review of POC testing identified the need for integration of POC within the decision-making pathway as a key requirement to demonstrate benefit (17) . Studies utilized cTn POC methods with comparable analytical sensitivity to those in the central laboratory at the time trials were performed; using diagnosis based on exceeding a diagnostic cutoff in use or the 99th percentile. Although these studies support a role for POC testing, they are not compatible with current clinical diagnostic strategies.

Two key requirements for any study are that POC testing has 1) comparable analytical performance with the central laboratory cTn assay, which is now hs-cTn, and 2) provision of test results is demonstrably the ratelimiting step in the diagnostic pathway.

Introduction of hs-cTn assays into routine clinical practice has led to a transformation in the way cTn measurements are used in decision making. No longer are diagnostic pathways based solely upon serial sampling over a 6 (or more) hour period post admission until the value exceeds the 99th percentile with a significant change between consecutive measurements (delta value). Diagnostic pathways now exploit 2 key features of hs assays, the ability to measure 1) low values such as the LoD, and 2) low cTn values above the LoD, both with acceptable %CVs. Users need to be cautious regarding the recently published assay specific hs-cTn cut-off concentrations by the European Society of Cardiology (ESC) for 0 h/1 h and 0 h/2 h algorithms, since the values posted in Table 5 from the ESC guidelines (18) are not consistent with the larger evidence-based literature not referenced in the 2020 guideline (18) . Measurement of hs-cTn values above the LoD have been shown to be assay specific, which also reliably identify patients at low risk of subsequent adverse events (MI, injury, mortality) within 30 days (18) (19) (20) (21) . Patients can often be safely and immediately discharged from the emergency department (ED) based on a single cTn measurement on admission when combined with clinical assessment, electrocardiogram. This strategy is attractive to ED physicians because it permits immediate discharge of 20% of patients presenting with ischemic symptoms. The ability to measure low cTn values with hs-assays with low %CVs has also been exploited with the use of short sampling intervals. cTn measurements are made on admission and repeated 1, 2, or 3 hours later (10, (18) (19) (20) (21) , allowing rapid categorization of patients for discharge (rule out), immediate admission (rule in), or in need of further investigation (observational). This approach is followed when the initial cTn is still <99th percentile sex-specific URL but not low enough to drive a 'one and done' protocol. The European Society of Cardiology has endorsed such rapid diagnostic algorithms (22) . Support for rapid diagnosis based on hs-cTn algorithms underwent systematic review by the UK National Institute for Health and Care Excellence (23) . When admission measurement exceeds the 99th percentile, serial testing needs to be carried out to determine whether myocardial injury is acute (rising pattern) or chronic (static, flat pattern) to allow appropriate triage, and may require a further 6-hour sample. Rapid diagnostic algorithms seem to be ideally suited for POC testing. The absolute caveat is cTn POC testing must demonstrate high-sensitivity analytical performance. Currently, the majority of POC cTn assays have, at best, performed as contemporary assays. Such systems are perfectly adequate for ruling in myocardial injury but require repeat sampling, typically at 3 to 6 hours post admission, to achieve adequate clinical sensitivity for rule out. Admission measurement of cTn by POC may in fact be diagnostically inferior to an admission risk score alone (24) . When sampling over 6 hours is compared with the possibility of immediate discharge based on a single measurement or the possibility of complete diagnostic categorization within 1-3 hours from admission, the advantages of central laboratory-based hs-cTn assays are obvious, even with 60-min turnaround time. Diagnosis within 1 to 3 hours of admission outweighs having to wait 3-6 hours by POC testing, even where a whole blood sample can be used with results available in 10-15 min.

Independent analytical validation of performance claims of a putative hs-cTn POC assay is important, but is only the background to clinical implementation and use. POC testing must have the ability to permit immediate safe discharge by single sample rule out or support a rapid diagnostic, serial testing algorithm. The majority of POC assay studies claiming comparability to a hs-cTn assay for diagnostic clinical utility and adverse outcomes (25, 26) have not been performed appropriately. POC assay studies that evaluated rapid rule out algorithms utilized stored, plasma samples, not fresh 'whole blood, which will be required for a universally, acceptable validation' (27) (28) (29) . To date, there have been no whole blood or prospective studies, either observational or randomized controlled trials, that have demonstrated that POC testing with high sensitivity analytical performance is clinically reliable, safe, and confers patient benefit. This is in contrast with central laboratory hs-cTn methods, demonstrated by meta-analysis of trials (30, 31) . While one assay (Pathfast) has FDA clearance for POC with preliminary data that meets hs-criteria along IFCC guidelines (32) , in practice users of this large instrument are often laboratorians and not designated POC operators. Several novel, in development POC technologies, will hopefully provide diagnostic data to be utilized in practice soon.

cTn POC testing does have a clinical role, but it is complimentary to hs-cTn laboratory measurements. When timely access to laboratory facilities for decision-making is not possible, POC testing may be a solution. This is particularly the case in rural healthcare where sample transportation time may impact turnaround time and where the decision to move a patient to a more centralized facility, which performs intervention, may require a long land journey or air evacuation. POC cTn measurement has been shown to significantly improve management of patients with suspected acute coronary syndromes in the rural Australian environment (33) . In the Randomized Assessment of Treatment using Panel Assay of Cardiac markers trial, with a contemporary POC assay and diagnosis based on the 99th percentile, measurements on admission and 90 min were diagnostically accurate and safe in low risk patients. This study did not evaluate single sample rule out, but did demonstrate serial testing performed well by POC. However, there can be downsides with diagnoses missed by overreliance on test measurement which is insufficiently sensitive (34) . POC cTn limitations must be appreciated (potential for false negative results on admission because lack of analytical sensitivity) and the need for repeat testing (up to 6 hours) are built into the diagnostic protocol for rule out. However, a positive test by POC testing would allow immediate patient characterization and expedite management (35) . There are risks if POC and central laboratory testing are mixed within a single health system. Degradation of diagnostic sensitivity may occur as a result of attempting to harmonize different assays by arbitrarily matching diagnostic cut offs (36) since cTn assays are neither standardized or harmonized.

Innovation and investments in research and development have led to disruptive technologies that fundamentally change patient management and/or yield incremental improvements in assay performance (37) . Innovations must prove their value before there can be widespread acceptance with stakeholders (physicians, regulators, payers). Potential harm when introducing new products to market is real, and regulatory bodies are tasked with ensuring safety and efficacy of devices.

It took nearly a decade after regulatory clearance outside the USA, supported by numerous publications, for manufacturers to convince the FDA that hs-cTn tests were not only more analytically sensitive than contemporary and POC assays but also safe and effective for patient care. To remedy this, the 21st Century Cures Act, signed into US law in 2016, is designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently (38). It provides new authority to the FDA to 1) improve recruitment and retention of scientific, technical, and professional experts, 2) receive alternative sources of data for regulatory approvals such as real-world evidence, provided adequate quality of the data are maintained and 3) establish new expedited product development programs, including the Breakthrough Devices program. This allows opportunities for manufacturers to expand claims for on-market devices if technologies exist to capture quality real-world data. Introduction of In Vitro Diagnostic Medical Device Regulation is strengthening the oversight and review process in the European Union (39). Manufacturers of currently approved in vitro diagnostic medical devices will have a transition time of 5 years to meet the requirements of the In Vitro Diagnostic Medical Device Regulation. Some of the key changes are more stringent documentation, rigorous clinical evidence, and reclassification of devices according to risk.

As technology advances, the ability to offer POC hs-cTn assays has been developed. New guidance from regulatory bodies demand manufacturers conduct their clinical studies for registration in the intended care environment or as similar to the intended care environment as possible (40). In the US, if a manufacturer desires to achieve a CLIA waiver for a POC device, that device must be challenged in the environment where it will be used and operated by typical end-users found in that environment. FDA studies are extremely difficult to execute and are expensive because most applied research sites prefer to provide dedicated research personnel, who qualify under CLIA as operators, to separate research from clinical staff. It is a misconception by the FDA that research staff may not be under the same stressors as a typical end-user managing patient care aspects while performing testing. Yet, the FDA mandates these POC studies be performed by typical end-users (such as nurses) who are responsible for routine clinical duties rather than allow research personnel focused only on testing. This adds burden to nurses, in an already financially stressed, FTE-short workplace, in the pandemic COVID-19 world hospitals are living through, and is not realistic.

Currently, there are no CLIA-waived POC hs-cTn assays on the market. The challenge for cTn in obtaining CLIA waiver lies with the interpretation and judgement aspects of testing. CLIA waiver requires the operators to be able to run the test without formal training. The test must be designed so a lay person can run it with only the instructions packed in the kit and to be able to easily interpret the result. With the exception of providers (nurses, clinicians, residents, technologists), rarely would a CLIA-waived operator with another job class know what to do with these results unless driven by protocol within the institution. Technology has advanced such that simplicity of testing is seldom a concern for these devices. Performing the testing in whole blood with limited knowledge on the part of the end user, and little to no interaction with calibration and quality control is a baseline expectation for POC devices. Manufacturers are tasked with demonstrating that typical end users can perform testing and results are comparable to a predicate device. For POC hs-cTn, the expectation is that manufacturers compare their POC device to a 510 K cleared laboratory cTn instrument. Analytical precision, linearity, accuracy, and reportable range need to be demonstrated because only quantitative assays are recommended for hs-cTn (3) . POC devices will need to establish their own 99th percentile URL studies. Diagnostic accuracy needs to be performed, meaning analytical accuracy is not enough to demonstrate safety and effectiveness for FDA clearance. POC hs-cTn testing is expected to be validated no different than a central laboratory method. However, in the US, the FDA requirements for POC assay clearance are more difficult than a central laboratory method.

Globally, 2 important questions must be considered: 1) are clinical studies still necessary if analytical validity can be demonstrated from one platform to the next, and 2) do matrix studies that demonstrate similar performance with plasma and whole blood need to be repeated in fresh whole blood collections for POC studies? It is unclear what more regulation will bring in terms of cost, timelines, and innovation in relation to balance improvements in safety and efficacy of in vitro diagnostic products.

A regulatory system that allows well-characterized tests to be evaluated for modifications to occur without having to submit new evidence of performance, waiting years to bring the next generation test to market, is needed. Trust in the system to allow for regulation without stifling innovation could bring devices to market more efficiently and safely. The 'risk' of bringing new hs-cTn devices to market is substantially lower today, based on evidence-based analytical and clinical literature amassed for known intended uses. Post market analysis can help serve to mitigate risks for new intended uses or incremental improvements over previous generations, without having to refile for new regulatory clearances. Being able to mitigate these risks with innovative regulatory processes will balance the need for improved products without compromising patient safety. Adverse patient outcomes will be better predicted, with improved patient management providing considerable cost savings to hospitals and patients.

We propose the FDA consider the following process for patient enrollments into manufacturers' 510 K submissions.

1. Regulatory agencies, including the FDA, should write a guidance document describing the minimal requirements needed to submit for clearance as they have done for glucose POC testing. With guidance, manufacturers would have more consistent study protocols, populations, and potential use of predicate devices. Presently, there is too much variation between study protocols, and the feedback manufacturers receive is inconsistent. 2. Revise the inconsistent and biased enrollment of subjects identified in the ED using the IRB informed consent process based on new blood draws. This practice is time consuming, expensive, and misses over 70% of eligible patients who would qualify for enrollment, making the study population biased compared to the real practice. 3. Obtain IRB approved waste specimen use from patients' orders from their clinical indications by the provider that are already in the laboratory for testing for plasma and serum, and likely EDTA whole blood remnant samples, except for capillary samples that would need to be fresh. 4. As patients present for treatment and are registered before entering the hospital system, provide the patient with an authorization and consent form that includes a section that clearly defines that the institution conducts research. The patient can, at their choice, agree or not to agree to participate in medical research to allow for better understanding of diseases and how care is provided, and by signing the document agrees that investigators may use health information and waste specimens already collected. This will allow for consecutive enrollment of patients, 24/7, without the bias of time delays of blood draws by informed consent, testing whole blood in real time with matched plasma or serum specimens allowing rapid sample processing, and use of fresh specimens that match real practice testing instead of freezing and thawing for analysis, often in batches. 5. This novel practice will allow manufacturers to enroll over 2500 patients in >3 selected institutions in 3 to 4 months, allow more rapid acquisition and compilation data, creating draft documents more quickly for submission to FDA for review, and provide substantial financial savings by cutting a 2 to 3-year process to < 1 year.

Finally, the FDA is capable of rapid review and has been extremely flexible during the COVID-19 pandemic (review times days to weeks vs the normal months to years). We feel the FDA should also find more efficient paths to 510k clearances. The FDA should consider Emergency Use Authorization for novel hs-cTnI and hs-cTnT POC devices and assays, without sacrificing quality during the COVID-19 pandemic. While it is understood that when the Emergency Use Authorization period is over, the test will require a 510k clearance to remain on the market; this period would allow manufacturers the ability to collect data for 510k submissions. This would assist inner-city and rural providers to rapidly measure of hs-cTn, the cardiac biomarker that makes a difference now and into the future; "the times they are a-changin'." 1 Nonstandard Abbreviations: hs-cTn, high-sensitivity cardiac troponin; cTnT, cardiac troponin T; cTnI, cardiac troponin I; IFCC, International Federation of Clinical Chemistry; C-CB, Committee on Clinical Application of Cardiac Bio-Markers; UDMI, Universal Definition of Myocardial Infarction; POC, point-of-care; QC, quality control; URL, upper reference limits; LoD, limit of detection; ESC, European Society of Cardiology Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. 

Ordonez-Llanos J; for the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers. Cardiac troponin assays: guide to understanding analytical characteristics and their impact on clinical care

on behalf of the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers. IFCC educational materials on selected analytical and clinical applications of high-sensitivity cardiac troponin assays

Clinical laboratory practice recommendations for the use of cardiac troponin in acute coronary syndrome: expert opinion from the Academy of the American Association for Clinical Chemistry and the Task Force on Clinical Applications of Cardiac Bio-Markers of the International Federation of Clinical Chemistry and Laboratory Medicine

Sex-specific 99th percentile upper reference limits for high sensitivity cardiac troponin assays derived using a universal sample bank

Improving the 510k FDA process for cardiac troponin assays: in search of common ground

Fourth universal definition of myocardial infarction

Myocardial infarction type 2 and myocardial injury

Early kinetic profiles of troponin I and T measured by high sensitivity assays in patients with myocardial infarction

Comparison of 0/3-hour rapid rule-out strategies using high-sensitivity cardiac troponin I in a United States population: UTROPIA

A prospective randomized controlled trial of point-of-care testing on the coronary care unit

A multicenter randomized controlled trial comparing central laboratory and point-of-care cardiac marker testing strategies: the Disposition Impacted by Serial Point-of-care Markers in Acute Coronary Syndromes (DISPO-ACS) trial

Impact of point-of-care testing in the emergency department evaluation and treatment of patients with suspected acute coronary syndromes

Point-ofcare troponin decreases time in the emergency department for patients with possible acute coronary syndrome: a randomised controlled trial

The Randomised Assessment of Treatment using Panel Assay of Cardiac Markers (RATPAC) trial: a randomised controlled trial of point-of-care cardiac markers in the emergency department

Interhospital variation in the RATPAC trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers)

Point-of-care testing (POCT) and evidence-based laboratory medicine (EBLM)-does it leverage any advantage in clinical decision making?

2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation

High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study

One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T

Rapid identification of patients at high risk for acute myocardial infarction using a single high-sensitivity cardiac troponin I measurement

ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the

Diagnostics Guidance [DG40] Diagnostics Assessment Committee National Institute for Health and Care Excellence

Diagnostic accuracy of the Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid with a point-of-care cardiac troponin assay

Clinical performance of cardiac troponin I: a comparison between the POCT AQT90 FLEX and the Dimension Vista analyzer in an emergency setting

Three-month outcome of patients with suspected acute coronary syndrome using point-of-care cardiac troponin-T testing compared with laboratory-based cardiac troponin-T testing: a randomised trial

Early diagnosis of myocardial infarction with point-of-care high-sensitivity cardiac troponin I

A randomized trial of a 1-hour troponin T protocol in suspected acute coronary syndromes: the rapid assessment of possible acute coronary syndrome in the emergency department with highsensitivity troponin T study (RAPID-TnT)

Validity of a novel pointof-care tropinin assay for single test rule out of acute myocardial infarction

High-sensitivity cardiac troponin and the early rule out of myocardial infarction: time for action

Serial highsensitivity cardiac troponin T measurements to rule out acute myocardial infarction and a single high baseline measurement for swift rule-in: a systematic review and meta-analysis

Validation of highsensitivity performance for a United States Food and Drug Administration cleared cardiac troponin I assay

Impact of a regionalised clinical cardiac support network on mortality among rural patients with myocardial infarction

Cost consequences of point-of-care troponin T testing in a Swedish primary health care setting

Predictive value of routine point-of-care cardiac troponin T measurement for prehospital diagnosis and risk-stratification in patients with suspected acute myocardial infarction

Pick a number, any number: choosing your troponin cutoff wisely

Ten innovations that will transform medicine. Harvard Business Review Healthcare Innovations Insight Center