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STATE-OF-THE-ART REVIEW

Point-of-Care Technologies for PrecisionCardiovascular Care and Clinical ResearchNational Heart, Lung, and Blood Institute Working Group

Kevin R. King, MD, PHD,a,b Luanda P. Grazette, MD, MPH,c Dina N. Paltoo, PHD, MPH,d John T. McDevitt, PHD,e

Samuel K. Sia, PHD,f Paddy M. Barrett, MD,g Fred S. Apple, PHD,h Paul A. Gurbel, MD,i Ralph Weissleder, MD, PHD,b

Hilary Leeds, JD,d Erin J. Iturriaga, MSN,j Anupama K. Rao, MD,j Bishow Adhikari, PHD,j

Patrice Desvigne-Nickens, MD,j Zorina S. Galis, PHD,j Peter Libby, MDa

SUMMARY

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Point-of-care technologies (POC or POCT) are enabling innovative cardiovascular diagnostics that promise to improve

patient care across diverse clinical settings. The National Heart, Lung, and Blood Institute convened a working group to

discuss POCT in cardiovascular medicine. The multidisciplinary working group, which included clinicians, scientists, engi-

neers, device manufacturers, regulatory officials, and program staff, reviewed the state of the POCT field; discussed op-

portunities for POCT to improve cardiovascular care, realize the promise of precision medicine, and advance the clinical

research enterprise; and identified barriers facing translation and integration of POCT with existing clinical systems. A POCT

development roadmap emerged to guide multidisciplinary teams of biomarker scientists, technologists, health care pro-

viders, and clinical trialists as they: 1) formulate needs assessments; 2) define device design specifications; 3) develop

component technologies and integrated systems; 4) perform iterative pilot testing; and 5) conduct rigorous prospective

clinical testing to ensure that POCT solutions have substantial effects on cardiovascular care. (J Am Coll Cardiol Basic Trans

Sci 2016;1:73–86) ©2016TheAuthors. PublishedbyElsevieronbehalfof theAmericanCollegeofCardiologyFoundation. This

is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

m the aCardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; bMassachusetts General Hospital,

rvard Medical School, Boston, Massachusetts; cDivision of Cardiovascular Medicine, University of Southern California, Los

geles, California; dOffice of Science Policy, Office of the Director, National Institutes of Health, Bethesda, Maryland; eDepart-

nts of Bioengineering and Chemistry, Rice University, Houston, Texas; fDepartment of Biomedical Engineering, Columbia

iversity, New York, New York; gScripps Translational Science Institute, La Jolla, California; hHennepin County Medical Center

d University of Minnesota, Department of Laboratory Medicine and Pathology, Minneapolis, Minnesota; iInova Center for

rombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia; and the jNational Heart,

ng, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Support for the Working Group was provided by the

ision of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH). Any opinions,

dings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect

views of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Dr. King has received the following

nts: AHA 15MCPRP25690031, NIH-NHLBI 1K99HL129168, and Harvard Medical School LaDue Memorial Fellowship. Ms. Leeds,

. Iturriaga, and Drs. Paltoo, Rao, Adhikari, Desvigne-Nickens, and Galis are employees of the NIH. Dr. Grazette is a consultant

St. Jude, Amgen, and Relypsa; is an investigator for Novartis; and is a contractor for St. Jude. Dr. McDevitt serves as the

entific founder and has financial interests in LabNow and Force Diagnostics; and owns stock in SensoDx. Dr. Sia is a cofounder

Claros Diagnostics, acquired by OPKO Health. Dr. Barrett has received grant support from the U.S. NIH National Center for

vancing Translational Sciences (NCATS) grant (KL2TR000112). Dr. Apple has received grant support (nonsalaried) through the

nneapolis Medical Research Foundation, Abbott Diagnostics, Siemens, Ortho-Clinical Diagnostics, Roche Diagnostics, Radi-

eter, BRAHMS, Genentech, Arkray, BioMerieux, Alere, and Beckman Coulter; has been a paid consultant (<$10,000) for

trumentation Laboratory T2 Biosystems and Philips Healthcare Incubator; and has served on the scientific advisory boards of

re, Beckman Coulter, Instrumentation Laboratory, and Abbott Diagnostics. Dr. Gurbel has been a consultant for Daiichi Sankyo,

yer, AstraZeneca, Boehringer Ingelheim, Merck, Medtronic, CSL, and Haemonetics; has received grant support from the NIH,

iichi Sankyo, CSL, AstraZeneca, Coramed, Haemonetics, Medtronic, Harvard Clinical Research Institute, and Duke Clinical

ABBR EV I A T I ON S

AND ACRONYMS

cTn = cardiac troponin

FDA = Food and Drug

Administration

NHLBI = National Heart, Lung,

and Blood Institute

POC = point-of-care

POCT = point-of-care

technology

WG = working group

Research In

interventio

from the N

consultant

GlaxoSmith

for Athera

the conten

Manuscript

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T he prevention and management ofcardiovascular (CV) disease increas-ingly demands effective diagnostic

testing. Consensus defines a diagnostic as amethod and an associated device that per-forms a physical measurement from a patientor associated biological sample and producesa quantitative or descriptive output, knownas a biomarker. The definition of abiomarker, in turn, encompasses “a charac-teristic that is objectively measured andevaluated as an indicator of normal biolog-

ical processes, pathogenic processes, or pharmaco-logic responses to a therapeutic intervention” (1).Diagnostics, because of their strategic position atthe intersection between patients and their clinicallyactionable data, directly affect the patient experienceand the quality of care that individuals receive(Figure 1). They also furnish valuable tools for clinicalinvestigation. Diagnostics enable providers toimprove upon “one-size-fits-all” treatment strategiesand instead provide personalized care on the basis offactors such as genetic makeup, comorbidities, real-time serologic assessments, and responses to therapy.

Historically, during the days of “house calls,” diag-nostic testing relied primarily on physical examinationand bedside analysis of urine (2). As methods forbiochemical and cellular biofluid analysis advanced,the portfolio of available tests expanded and centrallaboratories emerged to standardize sample acquisi-tion and measurement quality while offering econo-mies of scale (3). Today, technology is expanding thenumber of diagnostic tests that can reach beyond thewalls of centralized laboratories and back to the pointof care (POC) for use across a broad range of clinicalsettings. Yet, despite the intuitive appeal of minia-turization and immediate test resulting, point-of-caretechnologies (POCTs) face important practical ques-tions about their integration into clinical workflows,objective measurement of clinical benefit, standardsnecessary to ensure quality despite decentralization,and what reimbursement models will engendermutual enthusiasm by payers and providers.

POCTs promise to provide high-quality biomarkermeasurements optimized for the special constraints

stitute; has been a speaker for Daiichi Sankyo and Merck; and h

nal cardiology. Dr. Weissleder is a founder of and consultant to T2

ational Heart, Lung, and Blood Institute (R01 HL080472); has serv

or involved in clinical trials for Amgen, AstraZeneca, Boehringer

Kline, Kowa, Merck, Novartis, Pfizer, Regeneron-Sanofi, and Take

Biotechnologies and Interleukin Genetics. All other authors have

ts of this paper to disclose. Drs. King and Grazette contributed eq

received January 13, 2016; accepted January 20, 2016.

of diverse clinical settings including acute care,outpatient clinics, clinical research centers, homes,rural areas, and the developing world (Figure 2). Inacute care settings such as the operating room (OR),cardiac catheterization suite, intensive care unit(ICU), or emergency room (ER), physicians seek real-time feedback to optimize care and tailor therapiesto the dynamic circumstances they confront. Inoutpatient clinics, providers look for opportunities toreplace reactive medicine with prevention, and toimplement “precision medicine,” a national initiativethat includes mobile and personal technologies as keycomponents (4). In the home, care teams seek mini-mally invasive devices that seamlessly integratehealth monitoring into daily living. The hope is thatlongitudinal measurements of home health will sup-plement episodic clinic visits and transform outpa-tient care into a data-driven practice. Independent oftheir health care providers, the public is adoptingdiverse POC-like self-tracking devices such as sleepmonitors, Wi-Fi–connected scales, blood pressurecuffs, finger-stick blood tests, and wearable wrist-bands and watches linked to cloud storage, analytics,and opportunities for sharing. The degree to whichsuch technologies will improve health care deliveryand clinical outcomes remains hotly debated. Ulti-mately, only rigorous testing will determine theiractual clinical utility.

In clinical research, POCTs can expand quantitativedata collection to broader populations. By fosteringinclusion of under-represented groups in rural areasand the developing world often beyond the reach oftraditional clinical trials, POCTs promise to improvethe generalizability of study results (5–7).

The National Heart, Lung, and Blood Institute(NHLBI) convened a working group (WG) to examinethe translation of CV POCT to precision medicine andclinical research (8). The meeting aimed to provideguidance to the NHLBI regarding the development,evaluation, and dissemination of high-impact POCTin research and treatment. This report summarizesand expands upon the WG discussions by: 1)describing examples of how POCT can address someof the most commonly faced problems in CV diseasemanagement; 2) identifying barriers and challenges

olds a patent in personalized antiplatelet therapy in

Biosystems. Dr. Libby has received research support

ed as the Chair of this Working Group; is an unpaid

Ingelheim, Bristol-Myers Squibb, DalCor, Genzyme,

da; and is a member of the scientific advisory boards

reported that they have no relationships relevant to

ually to this work.

FIGURE 1 Diagnostics

Diagnostics obtain measurements from a patient or associated

biological sample and produce quantitative or descriptive

outputs known as biomarkers, which enable clinical care, patient

communication, and clinical research.

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to clinical translation; 3) calling for rigorous clinicaltesting and validation before integrating new POCTsinto routine clinical care; and 4) outlining a POCTdevelopment roadmap that articulates specific rec-ommendations to guide NHLBI research priorities.

IPOC EXAMPLES, CHALLENGES,

AND OPPORTUNITIES

POCT IN ACUTE CARE SETTINGS. Practitioners inacute care settings such as the ER, OR, ICU, hemodi-alysis unit, or cardiac catheterization suite face highlydynamic situations. Real-time POCT promise toimprove patient care in these environments by sup-plying data rapidly to support decision-making, asillustrated in the following examples.Example 1: rapid evaluation of ER patients with chestpain—“rule out myocardial infarction”. In ambulancesand ERs, POCT can improve the efficiency of care byenabling rapid assessment and triage of patientswith chest discomfort. Cardiac troponin (cTn), ahighly sensitive and specific biomarker of myocardial

FIGURE 2 Point-of-Care Technologies

Point-of-care technologies (POCTs) are positioned to address the

special constraints of diverse clinical settings including acute

care, outpatient clinics, clinical research centers, homes, rural

areas, and the developing world.

injury, guides triage and management of patientspresenting with symptoms suggestive of acute coro-nary syndrome (9). ERs already use commercial POCcTn assays, but parallel efforts are exploring whethercentral laboratory cTn assays can perform serialmeasurements at progressively shorter intervals todiscriminate cardiac from noncardiac causes of chestdiscomfort and enable rapid patient triage. Histori-cally, stable serial measurements of cTn taken at 6- to12-h intervals served to “rule out” cardiac injury(10,11). More recently, high-sensitivity cTn assays,available only in the central laboratory, permitexclusion of clinically important myocardial injurywith high confidence at initial sampling as well asafter only 2 serial measurements performed at 1- to 2-h intervals (12–15). POC devices that can match thisperformance without sending samples to a centrallaboratory may become mainstream frontline CV di-agnostics (Figure 3A).Example 2: management of bleeding and clottingrisks. The quandary of balancing the risks of bleedingand clotting concerns practitioners of many spe-cialties. Clot formation involves complex interactionsamong coagulation factors, platelets, and tissues(16). Surprisingly, a limited number of coagulationdiagnostics guide routine outpatient and inpatientmanagement (17,18). Central laboratories typicallymeasure 2 key coagulation parameters: prothrombintime and activated prothromboplastin time. Yet,delays of w1 h limit the utility of central laboratorymeasurements for acute care settings such as theICU or OR, where thrombotic risk can vary momentto moment due to administration of anticoagulantboluses and pharmacological reversal agents (19–21).In these settings, activated clotting time (ACT), awhole blood measurement that integrates intrinsicand extrinsic coagulation with platelet function,commonly serves to quantify thrombotic potential(21). In the case of ACT measurements, proceduraltechnicians, within steps of patient and procedur-alist, perform POC testing independent of the centrallaboratory. This example illustrates the feasibilityof integrating real-time POC diagnostics into acuteclinical workflow (Figure 3B).

Platelet function complements coagulation inregulating thrombotic risk. Yet, despite extensivestudies of platelet function assays in both centrallaboratory and POC formats, questions remainregarding their incremental benefits. Measures ofplatelet function do identify populations at higherrisk of thrombotic events, but the demonstration thattherapy guided by such assays improves outcomeshas proven elusive (22–24). This apparent paradoxunderscores the need to subject any POC diagnostic,

FIGURE 3 Dynamic Biomarkers for POCT Measurement

(A) In the emergency room, high-sensitivity troponin assays resolve small differences in troponin levels to rule out clinically important

myocardial injury after serial measurements performed at increasingly short time intervals. (B) In the cardiac catheterization laboratory and the

cardiac surgery operative room, activated clotting time (ACT) measurements are used to follow the dynamics of patient coagulation.

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no matter how plausible, to rigorous research toevaluate its efficacy and added value. Coagulationand platelet function biomarkers exhibit variabilityand context-dependence, adding complexity to theirclinical use (25,26). POC diagnostics offer the poten-tial to capture these variations through more frequentmeasurement, but whether doing so substantially andcost-effectively improves outcomes will requireadditional research (Figure 4).

Exploratory thrombosis assays aim to complementexisting assays of thrombotic risk. Examples includeclot relaxation (27) or thromboelastography (16),which evaluate viscoelastic properties of clot forma-tion. Although such assays were initially consideredto be too complex for routine clinical use, recent POCadaptations of these measurements aim to improveusability (18,28).Example 3: future acute care POC assays. Reliabledetection of thrombosis presents a diagnostic chal-lenge. Available POC devices can measure thrombosisserum biomarkers such as D-dimer, which notori-ously lacks specificity. Often, acute D-dimer eleva-tion due to thrombosis cannot be distinguished fromchronic elevation related to comorbid conditions.Instead, modern diagnosis of deep vein thrombosesand pulmonary emboli relies primarily on imagingmodalities such as ultrasound or contrast chestcomputed tomography, respectively. Recently, exog-enous “synthetic biomarkers” were engineered tosupplement endogenous biomarkers and enablemore flexible remote monitoring of thrombosis. Inconcept, an intravascular nanoparticle-conjugatedpeptide, when cleaved by activated thrombin, liber-ates a peptide fragment that undergoes renal

clearance detectable in the urine centrally or by POCplatforms, such as novel paper-based microfluidicassays (29–31) (Figure 5A). Similar synthetic biomarkerstrategies are under development for a broad rangeof analytes.

In principle, continuous biomarker monitoringwould provide the most complete picture of an in-dividual’s physiological state. Historically, the abilityto measure continuously physicochemical bio-markers such as blood pressure, pulse, electrocar-diogram, respiration rate, and oxygen saturationrevolutionized critical care and substantiallyimproved the safety of general anesthesia. Contin-uous vital sign measurements have become thestandard of care for periprocedural CV monitoring;however, efforts to engineer continuous bloodbiomarker measurement platforms that monitor“biomolecular vital signs” presents more challengingproblems, whose solutions are only nascent (32). Themost notable clinically relevant analyte adapted forcontinuous measurement is glucose. Glucose isreadily detected by diverse electrochemical-sensingplatforms coupled to an immobilized enzyme(glucose oxidase); yet, the lack of broadly availableanalyte-enzyme pairs limits the generalizability ofthis approach. More recently, reversible affinity sen-sors have promised to expand the portfolio of ana-lytes subject to continuous monitoring. For example,a microfluidic device containing a sensing surfacefunctionalized with nucleic acid-based aptamers canreversibly bind corresponding analytes. The fluidicdevice directs blood across the planar sensing surfaceseparated by a layer of buffer solution (Figure 5B)such that only biomolecules below a critical

FIGURE 4 POCT for Antithrombotic Therapy

Many patients have indications for both anticoagulation (e.g.,

atrial fibrillation, venous thromboembolism, mechanical heart

valve) and antiplatelet therapy (e.g., myocardial infarction or

percutaneous coronary intervention). There is limited clinical trial

data to guide the use of these agents in combination therapy.

New diagnostics could aid selection and titration of combination

regimens to personalize care by optimizing the risks of bleeding

and clotting.

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molecular weight can diffuse across the buffer layerand encounter the sensing surface. The reversiblebinding of analytes to their corresponding immobi-lized aptamer then generates an electrochemicalsignal proportional to blood analyte concentration(33). The flexibility of such platforms is expanding asthe number of available analyte-aptamer pairs grows.This example also illustrates the exciting potentialenabled by integrated microfluidic platforms, whichoperate at flow rates less than microliters per minute,and can in theory enable continuous blood drawsover hours and days while keeping total bloodvolumes below that of a single conventional blooddraw.

POCT IN AMBULATORY SETTINGS. In outpatientclinics, the brevity of the patient visit rather than thedynamics of the physiological state provide themotivation for POC diagnostic testing. Patientsfrequently have blood drawn for diagnostic testingafter a clinic visit. Unfortunately, the ad-hocfollow-up discussions of testing results can lead toundesirable breaks in patient-provider communica-tion. A current movement calling for more diagnostictesting in the clinic aims to resolve such in-efficiencies. POC diagnostic platforms in develop-ment aim to answer these challenges by enablingmeasurement of existing biomarkers as well asfundamentally new biomarkers that can enhance theoutpatient practitioner’s diagnostic toolkit.

Example 1: miniaturization and mobilization of existinglaboratory diagnostics. The earliest examples of POCdiagnostics aimed to miniaturize and make portablethe measurement of established biomarkers such asthe complete blood count or basic metabolic panel.Yet, clinical use of such POC diagnostics has notkept pace with the number of commercially availabletesting platforms. Instead, there is continued reli-ance on central laboratories, which likely pointsto challenges presented by new POCT, includingcost, uncertain reimbursement, requirements forcalibration with legacy central laboratories, stan-dardization of testing procedures, verification oftesting expertise, maintenance of the decentralizedtesting equipment and procurement of disposables,and establishment of good data management prac-tices including security and privacy. Despite thesechallenges, miniaturized and mobilized versions ofexisting diagnostic tests, being the first POCTdiagnostics to enter clinical CV care and research,will likely serve as vehicles for addressing thesechallenges.Example 2 : persona l i zed CV care us ing nuc le i cac id assays . Whether nucleic acid-based assaysshould be adapted to POC formats remains an area ofongoing investigation. Deoxyribonucleic acid (DNA)–based diagnostics have enjoyed success in oncologybecause particular DNA mutations inform therapyefficacy. Similarly, in infectious disease, detection ofthe DNA from an invading pathogen carries cleardiagnostic information. Cardiologists, however, haveused DNA diagnostics primarily for monogenic con-ditions. One exception is the assessment of rejectionof transplanted hearts, where cell-free (cf) DNA se-quences can selectively detect donor heart damage.Indeed, circulating donor cfDNA levels correlate withepisodes of acute rejection as determined by inva-sive endomyocardial biopsy (34,35). Detection ofdonor cfDNA enabled prospective noninvasive diag-nosis of acute rejection with sensitivity and speci-ficity comparable to the biopsy alone (35). A similarcfDNA sequencing approach examined the evolvingpathogen landscape in heart transplant recipientsin response to changes in their immunosup-pressant and antiviral regimens (36). Determiningthe utility of POC genomic assays for CV transplantrejection or infection assessment will require addi-tional research.

RNA, in contrast to DNA, can change dynamicallyduring disease, making it an attractive biomarker fornext-generation CV diagnostics. The complex andmultifactorial nature of CV diseases has motivatedexploration of transcriptional profiling. One approachuses a 23-gene expression assay platform on the basis

FIGURE 5 Next-Generation POCT Sensing Strategies

(A) Synthetic urinary biomarkers are being developed to augment endogenous biomarkers and enable noninvasive monitoring of intravascular

thrombosis. A peptide conjugated to a nanoparticle is cleaved in the presence of thrombin and liberates a peptide fragment that is cleared by

the kidney and can be detected in the urine. (B) Microfluidic continuous biomarker monitoring devices allow analytes to diffuse from blood to

an electrochemical sensing surface modified with aptamers that reversibly bind them enabling continuous monitoring.

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of microfluidics and dehydrated primers, whichmeasures gene expression fingerprints from circu-lating cells (37,38) to provide negative predictivepower to limit the need for more elaborate CV testing.The assay, which in its current instantiation is stillfar from POC, requires shipment of samples to acentral facility. Nonetheless, this early exampledemonstrates the feasibility of using gene expressionfingerprinting as a discriminatory CV biomarker.Example 3: next-generation integrated diagnosticsplatforms. In addition to soluble proteins and cell-based or cell-free nucleic acids, emerging biomarkerssuch as rare circulating cells, mRNA, and exosomes,and their contents hold diagnostic promise (39–42).Platforms based on microtechnology and nanotech-nology can capture rare analytes from crude patientsamples, fractionate specimens, and quantify bio-markers using signal amplification and integrateddetection schemes.

Microtechnology uses devices with dimensions onthe order of the thickness of a human hair. Built usingfabrication techniques originally developed for themicroelectronics industry and extended to micro-electromechanical systems, these devices are ideallysuited for POC handling and analysis of small volumesof complex biological fluid specimens such as bloodor urine (43,44). Fabrication in transparent biocom-patible polymers renders these devices compatiblewith conventional optical detectors. Engineers havedeveloped increasingly powerful integrated fluidhandling components that now enable dense arrays of

highly efficient pumps and valves to precisely controlmovement of fluids, solutes, and cells (45,46). Thispowerful toolkit has enabled the design of diagnosticdevices that perform a variety of functions, includingparticle and cell sorting, rare cell capture, andmassively parallel and sequential biochemical re-actions (41). The design flexibility enabled by micro-technologies offers broad utility for the developmentof POCT devices. Defining clear diagnostic problems inCV medicine that can harness the creativity of thiscommunity holds great potential.

Nanoscale devices have a length scale 3 orders ofmagnitude smaller than that of microfabricated de-vices. Nanoparticles are key components of thesetechnologies. Among the many ways to detect nano-particles, strategies on the basis of magnetic proper-ties of the particles or surface plasmon resonancerepresent particularly elegant examples (47–49).Extension of the size scale of particles can allowsensing by commercially available detectors suchas smartphones. For example, in an applicationrequiring counting of cell subsets, investigatorsbathed biological samples in microbeads conjugatedto cell-specific antibodies and used the diffractionpattern of cells decorated with antibody-conjugatedbeads to identify and count the cell population ofinterest using a custom dongle attached to a com-mercially available smartphone (50). Several excel-lent reviews describe these technologies in furtherdetail and describe examples of additional POCapplications (5).

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POCT IN THE HOME. Patients spend <1% of their livesinteracting with the health care system in the tradi-tional sense. They spend the remaining >99% in theoutside world, “at home.” Innovative technologiessuch as the Internet of Things, wearable devices,mobile communication devices, and social networkspromise to improve fundamentally our understand-ing of human health and transform the home into thenext frontier of outpatient medicine.

Outpatient clinical visits frequently begin withopen-ended questions such as “have you been takingcare of yourself at home?” This question calls on pa-tients to summarize months of post-prandial glucoselevels and blood pressure measurements, as well asadherence to recommended exercise, diet, or pre-scription medications. The availability of moreobjective and quantitative data can paint a dynamicand unbiased picture of home health across time.Balancing the desire to inform but not overburdenproviders with extraneous or unactionable informa-tion will require thoughtful data synthesis and ana-lytics to traverse efficiently the voluminous data.Third-party disease management businesses mayserve as intermediates. Nevertheless, successfulnavigation of the “big data” problem will transformthe home into an informative lens through which onecan observe patient health.

The following examples demonstrate the breadthof home health monitoring devices currently avail-able or in development. Together, these technologiespromise to create a more comprehensive picture ofpatient health and behavior that can complementpatient self-reporting during in-person health carevisits.

Example 1: self-testing POC diagnostics. Blood glucosetesting remains one of the oldest and most widelyaccepted POC applications. Yet, despite substantialinvestment and widespread use, few sufficientlypowered studies have examined the clinical utilityand cost-effectiveness of glucose self-monitoring(51,52). Meta-analyses estimate glycated hemoglobindeclines of 0.22% to 0.40% in patients usingblood glucose self-monitoring compared with controlsubjects (52,53). Although these studies did notdirectly evaluate the effect on clinical outcome,this magnitude of reduction associates with a sig-nificantly reduced risk of microvascular complica-tions in other clinical trials (54). Studies that involvedthe inclusion of glucose self-monitoring as a com-ponent of a structured therapeutic managementprogram, including education and follow-up, yieldedthe greatest improvements in outcomes (55).

Monitoring of anticoagulation in warfarin-treatedindividuals with POC international normalized ratio

measurements furnishes another example of self-testing. A meta-analysis of 11 randomized controlledtrials showed significant reductions in the risk forthromboembolic events (hazard ratio: 0.51; 95% con-fidence interval [CI]: 0.31 to 0.85), with no increase inmajor hemorrhagic events or death (hazard ratios:0.88; 95% CI: 0.74 to 1.06; and 0.82; 95% CI: 0.62 to1.09, respectively) in patients who self-monitoredcompared with patients who did not (56). In addi-tion, the coupling of self-monitoring with self-management and dosing was associated with greaterrisk reductions. Thus, although self-monitoring ofthe international normalized ratio may not benefitall patients, wider access and availability of testingin the home can strengthen the effectiveness of care.Example 2: connected diagnostics—wearables, smartphones, and the “Internet of Things.” Wearables. Theability to position sensors onto a patient and into theclothing they wear has powerful potential to trans-form our understanding of CV health and disease.These categories of POC devices, sometimes termed“wearables,” a subset of the “internet of things,” the“Internet of Things,” have captured the imaginationof physicians and patients alike. The earliest versionsof internet-connected home health devices simplyadapted conventional diagnostics previously used inthe clinic or hospital, such as blood pressure cuffs,heart rate monitors, scales, pedometers, oximeters,and positive pressure ventilation controllers.Telehealth programs and chronic diseasemanagement practices developed systems tomonitor data from these sensors, provide feedbackregarding results to providers and/or patients, andencourage compliance using reminders. Morerecently, wearable technologies such as wristbandsand watches equipped with integrated microscaleaccelerometers have enabled activity monitoring,performance feedback, and the ability to annotatedata with subjective measures of health for sharingwith friends, family, health care providers, or theworld.

High-performance electronic circuits play anessential role in home health devices, but rigid circuitboards and wires present a barrier to miniaturizationand integration into ambulatory-sensing solutions.The recent development of a flexible electronicsplatform permits the fabrication of high-functioningelectronic devices into thin flexible tattoo-like trans-parent films that adhere to the skin (57,58,63,64).The durability of initial prototypes underwenttesting in challenging locations such as the elbowwithout signal degradation over days despiterepeated extension and flexion. Transmission ofthe electrocardiogram and electroencephalogram

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confirmed the functional utility of the device. Opti-mization of such technologies should permit con-tinuous remote measurements in outpatients.Monitoring of atrial fibrillation could benefit fromsuch advances. The burden of atrial fibrillation andthe frequency of atrial fibrillation paroxysms likelycorrelate with stroke risk (59,60). The emergence ofminimally invasive heart rate and rhythm-monitoringdevices on the basis of flexible electronics and othertechnologies offers a unique opportunity to docu-ment longitudinally patient rhythms in relation toother life events (61). Such information wouldenhance our understanding of triggers associatedwith arrhythmia onset and termination and aid pa-tient management.Internet of Things. A movement termed the “Internetof Things” aims to convert the home into a denselyinterconnected environment with embedded sensorsin everyday objects that can monitor, communicate,and connect the environments in which we live. As anexample of this technology, bedroom-embeddedsleep monitors aim to optimize rest and detectsleep-disturbed breathing. The embedded sensingconcept, although still in its earliest stages, hasexcited CV care providers with the possibilityof devices that will monitor high-risk patients,identify early warning signs of decline, and promptearly intervention that may avoid more severedecompensation.

Management of heart failure is particularly poisedto benefit from emerging home health technologies(62). Heart failure affects more than 5 millionU.S. patients, triggers >1 million hospitalizationsannually, and associates with remarkably high

FIGURE 6 Management of Patients With Heart Failure Will Benefit

This patient population is benefiting from new point-of-care technologi

decompensation (e.g., symptoms, weight, and ventricular filling pressur

hospitalizations. BBQ ¼ barbecue, a high-salt meal.

rehospitalization rates (w25% at 30 days and w50%by 6 months) (63). Because weight gain often pre-cedes hospitalization by days to weeks, some guide-lines recommend that patients weigh themselvesdaily at home. Unfortunately, adherence to thisrecommendation remains poor; in a recent large-scaleclinical trial, compliance with telemonitoring fellfrom 90% to 55% by 6 months despite implementa-tion of an aggressive reminder system (64). Thisdeficiency challenges disease management teams andpractitioners caring for patients at home. Hence, aneed exists to develop devices that monitor activityand/or weight without proactive patient participa-tion. Doing so should improve the regularity of hometesting and may avert unnecessary hospitalizationsthrough early detection of volume overload(Figure 6).

Medication compliance also received early atten-tion. Adherence to recommended pharmacologicaltherapy remains an important but often unappreci-ated challenge of outpatient CV care. This challengespurred the development of Wi-Fi–connected pillbottle caps and internet-connected sealable blisterpacks, inhalers, or injectables to provide newwindows into patient medication compliance. Thiscapability enables study of whether incentivizationstrategies and gamification can improve adherence todaily medications such as statins. Although recordingpatient medication access times does not directlyreveal ingestion, these data nevertheless providepreviously unobtainable information about patientmedication habits at home. To measure more directlymedication adherence, developers have created amicrochip sensor-enabled pill with Food and Drug

Tremendously From POCT in the Home

es (POCTs) that longitudinally monitor biomarkers of heart failure

es) to guide adjustments in diuretic dosing and avoid unnecessary

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Administration (FDA) clearance that communicateswith an adhesive patch worn on the torso that recordswhen the pill is ingested (65). Early studies using thistechnology reportedly suggest that patients withgreater irregularity in the timing of their morningmedication were more likely to miss doses alto-gether and had lower medication adherence ratesacross time. This result suggested that interventions,such as incorporating therapy into a different facetof a daily routine, might improve compliance.Combining integrated sensing technologies such asthese with behavioral studies is a fertile area forfuture research.

Smartphones. Smartphones serve as powerful plat-forms for software and hardware developersto collect, store, manage, and communicate healthsensor data. In the CV space, a smartphone casewith integrated contact electrodes allows a userto measure continuously an electrocardiographicrhythm strip simply by holding the case with 2 hands.Combined with rhythm detection software and theability to save and share tracings, this technology hasthe potential to expand greatly patient self-recordingof single-lead heart rhythms. For diabetic individuals,an electrochemical blood glucose meter that attachesto commercial smartphones as a dongle can measure,store, and analyze glycemic control. Similarly, fulllaboratory-quality immunoassays have also beenminiaturized and adapted to a custom dongleattached to a commercial smartphone (66).

Smartphones have generated tremendous excite-ment for use in clinical research. Apple’s Research-Kit (Apple, Cupertino, California), which wasdownloaded with great enthusiasm upon its initialrelease, allows users to participate in clinicalresearch via their smartphones and iPads. Applica-tions focusing on CV disease (MyHeart Counts) anddiabetes management (GlucoSuccess) were amongthe initial offerings and feature the ability tomonitor activity, self-record a 6-min walk test, andrecord dietary habits and medication adherence.Google X, Duke, and Stanford also recentlyannounced an ambitious project, the Baseline Study,which aims to understand what keeps peoplehealthy and what determines disease trajectories. Asthe pilot phase of the study gives way to larger co-horts, reports suggest that the study will collectgenomic information and employ more complexhuman phenotyping from the “Study Kit” applica-tion, associated devices, and even wearables such asthe much anticipated “smart” contact lenses. Theseinnovations extend the POC concept to everyday lifeand provide enormous potential for mining “big

data” for health purposes at a population level, butalso enabling precision medicine or personalizedmanagement for the individual.Example 3: invasive outpatient health monitors.Implantable monitors are inherently invasive and,therefore, require careful consideration of safetybefore use. Once placed, however, this class ofmonitoring devices makes several potentiallypowerful biomarkers available to providers longitu-dinally across time. For example, implantable rhythmrecorders as well as conventional pacemakers andimplantable cardiac-defibrillators can detect rare butconcerning paroxysmal ventricular arrhythmias aswell as exhaustively profile the timing and burden ofchronic arrhythmias such as atrial fibrillation. Anambulatory intrathoracic impedance monitor andassociated algorithm attempt to identify thresholdsand temporal signatures of impedance changes thatpredict worsening heart failure (67–69). Another de-vice still in development directly measures leftventricle filling pressures in the left atrial appendage,but requires transseptal puncture for device place-ment. The data, which are transmitted to a hand-heldpatient advisory tool, can then guide medicationdosing changes according to an algorithm. Taking adifferent approach, a new FDA-approved implantablepulmonary artery pressure monitor can be placedduring a right heart catheterization and does notrequire a transseptal puncture. In the COMPASS-HF(Chronicle Offers Management to Patients WithAdvanced Signs and Symptoms of Heart Failure) trialthat evaluated this technology, increases in PA pres-sure were reportedly more sensitive and specific, andthey anticipated weight increase associated withdecompensation (70,71). Support for device approvallargely stems from the CHAMPION (CardioMEMSHeart Sensor Allows Monitoring of Pressure toImprove Outcomes in NYHA Class III Heart FailurePatients) trial, which demonstrated that in New YorkHeart Association functional class III heart failurepatients hospitalized in the past 12 months, manage-ment guided by the pulmonary artery pressuremonitor significantly reduced heart failure admis-sions (72).

PRACTICAL ASPECTS OF

POCT IMPLEMENTATION

CLINICAL TESTING AND VALIDATION OF POCT.

POCT development must balance the enthusiasm forpromising new diagnostic platforms with the need forrigorous validation studies. Adoption of a new deviceshould depend on demonstrated performancecompared with reference standards of care to ensure

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that it provides similar or improved clinical utility.Even if POC diagnostics cannot demonstrably alterhard outcomes such as survival, they may provideadded value by limiting lengths of stay, reducingreadmissions, avoiding unnecessary invasive tests,boosting physician and/or patient satisfaction, im-proving quality of life, or benefiting other aspects ofhealth care delivery, cost, or comparable metrics. Thesuccess or failure of a POC diagnostic depends criti-cally on establishing clearly stated goals and con-ducting rigorous research to evaluate its ability tomeet pre-specified objectives. Anticipating potentialrisks of POCT has equal importance. For example,more diagnostic availability could conceivably in-crease testing volume and cost. More testing mayalso triggermore false positive results and lead tomoreinvasive downstream testing, which would needlesslyalarm patients and practitioners alike. Research thataddresses such health systems and patient-providercommunication issues associated with POCT couldvitally and meaningfully affect patient care.ETHICAL AND REGULATORY CONSIDERATIONS.

Although POC testing offers many advantages as aclinical tool, decentralization of diagnostic testingmay require new regulations to maintain proceduralstandardization, adherence to calibration standards,and maintenance of patient privacy. The FDA, in itsoversight role, has provided related guidance such asthe “regulatory oversight framework for laboratorydeveloped tests” and the “mobile medical applicationpolicy” (73,74). Practitioners should also be awarethat under current regulatory requirements, POC de-vices are not necessarily waived under CLIA (ClinicalLaboratory Improvement Amendments) simplybecause of use at the point of care. The use of POCdevices for clinical research requires development ofa policy regarding sharing of results with participants.

Protecting the health information of patients re-mains fundamental to clinical care by ethics andstatute. The design, ownership, and operation of newPOC devices requires cooperation by multiple part-ners to capitalize on the data collected withoutcompromising patient privacy. These concerns mirrorthose currently encountered with widespread adop-tion of electronic health records. Yet, the mobilenature of POC devices decentralizes privacy preser-vation and entrusts sensitive patient data to a broadrange of individuals spanning health care specialiststo POC data management service providers. Theactive research of the HHS suggests the need toupdate provisions of the Health Insurance Port-ability and Accountability Act of 1996, now influencedby challenges related to the rapid developmentsof health information technology, including

implementation of electronic medical records andmobile technologies for health care (75).

POCT AS A CLINICAL RESEARCH TOOL

POCT have considerable potential to enhance clinicalresearch. Biomarkers can contribute to clinical trialsby complementing clinical endpoints with interimmeasurements that can deepen understanding of in-terventions. In this context, POC diagnostics offerpowerful opportunities to enrich biomarker collectionduring the conduct of well-controlled clinical trialswith carefully adjudicated endpoints. Ambulatorymonitoring devices such as mobile device applica-tions, wearable monitors, and home-based sensorsremain some of the most attractive POCT categoriesas aids to clinical investigation. Unlocking the vastassortment of uncaptured ambulatory data presentsan opportunity for POC devices to enrich substan-tially clinical trial data collection. Similarly, biofluidsampling during clinical trials remains a valuableresource when paired with carefully curated patientpopulations meeting well-defined entry criteria thatcan correlate with carefully adjudicated endpoints.Yet, limits pertain to the number of biofluid bio-markers that conventional assays can measure. POCtechnologies that seek to multiplex biomarker mea-surements have a tremendous potential to maximizethe information yield from these scarce samples andfacilitate biomarker discovery, biomarker validation,and mechanistic insight.

Additional benefits of POCT in clinical researchinclude enabling novel patient recruitment pathwaysby facilitating screening for eligibility criteria withoutrequiring centralized testing or return visits. POCTsalso offer flexible pathways for baseline and follow-up data collection, providing opportunities toimprove clinical trial quality control through longi-tudinal and site-specific monitoring of study protocolcompliance. POC diagnostics could expand opportu-nities for clinical trial participation beyond heavilypopulated urban areas, where trial coordination istypically centered. Doing so will reduce the inherentselection bias associated with existing geographicconstraints and make trial results more relevant to abroader population. The National Institutes of Healthhas initiated funding for several clinical trials to testsuch technologies; continued development of thisapproach will represent an important advance in CVclinical research (see Table 1 for examples).

Clinical research in the developing world oftenfocuses on communicable diseases; however, CVdisease remains the leading cause of death worldwideand does not spare low- and middle-income

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countries (6). In resource-limited environmentswhere geographic and financial constraints limit theavailability of centralized laboratories, catheteriza-tion facilities, and specialty CV care, the relationshipbetween diagnostic testing and CV disease manage-ment differs dramatically from heavily populatedurban centers. Thus, these settings will requirededicated clinical research to understand how POCTcan answer the special needs of these environments.In principle, POCTs that minimize instrumentationand infrastructure demands offer particular promisein these settings. Several platforms in developmentthat use “lab-on-a-chip” technologies featuring inte-grated sample acquisition, processing, and measure-ment may address these needs. Those that interfacewith smart phone technologies are particularlyattractive given the broad availability of cell phonesin rural areas and the developing world (50).

ROADMAP FOR CV CLINICAL RESEARCH

POCT DEVICE DEVELOPMENT

POCTs have tremendous potential to advance CVcare. Realizing this potential will require a fundingenvironment that incentivizes engineering solutionsbeyond mere proof of concept demonstrations andcultivates them throughout the full technologydevelopment life cycle. Through close collaboration,engineers and health care providers must worktogether to ensure that innovative POC devices have apath for clinical testing, regularly undergo quantita-tive comparison to modern standards of care, andrequire careful monitoring to achieve POC goalswithout making excessive performance compromises.The NHLBI occupies an ideal position to incentivizeformation of multidisciplinary teams comprised ofhealth care providers, biomarker scientists, technol-ogists, and clinical trialists to collaborate longitudi-nally throughout the development process. To guidethe activities of these CV POCT teams, the NHLBI WGproposes the following 5-stage CV POCT Devel-opment Roadmap. This approach aims to capitalizeon advances in biomarker science and emergingsensor technologies to create clinically relevant POCdevices with a defined path for rigorous clinicaltesting and validation.

1. Needs identification. Stage 1 goals include theidentification of specific aspects of clinical carethat have potential for substantial improvement byPOCT “clinical needs” and the articulation of (well-posed) clinical problems that carefully describe theprocess of testing a specific POCT solution (whichpatient population, what clinical setting, themethods behind the quantitative measurement of

benefits and risks, and the standard[s] of care thatwill serve as comparison).

2. Biomarker selection and device design specification.Stage 2 will bring biomarker scientists and tech-nologists together to take the “well-posed clinicalproblem” from stage 1 and use it to both select arelevant set of new and/or old biomarker(s) anddefine design criteria for a corresponding POCmeasurement device. Defining the clinical objec-tives early increases the likelihood of success oncethe technology exists.

3. Device development. Stage 3 will focus on devel-opment of component technologies and systemintegration, leading to a functional POC measure-ment device. Guided by the specifications definedin stage 2, an iterative process of design, fabrica-tion, and testing of key technologies and individ-ual components will be undertaken. This willculminate with a system integration process thatwill require additional engineering and perfor-mance characterization using simplified models ofthe relevant human biomarkers.

4. Pilot testing. Stage 4 will use the POC solutiondeveloped in stage 3 to perform pilot testing onclinical samples or small-scale patient populations.This effort will help identify obstacles associatedwith real-world biosamples, identify normalranges and intervention thresholds, highlight datamanagement issues, reveal unanticipated humanfactors, and provide initial data on device usabilityin a real-world clinical setting. An iterative processof device refinement and repeat pilot testing willprepare the technology for rigorous clinical testingin stage 5.

5. Prospective clinical testing. Stage 5 will test andvalidate the technology in “real-world” health caresettings. Assessment of device efficacy as well asliabilities and risks remains the overall goal.Because design tradeoffs are device- andapplication-specific, the criteria for success willneed to be defined on a case-by-case basis (definedduring stages 1 and 2). Acceptance of methodolo-gies and validation studies for all new diagnosticsincluding POC should require transparency andpeer-reviewed publication.

RECOMMENDATIONS FOR

NHLBI CV POCT PRIORITIES

� Support Stage 1 activities with the engagement ofthe broad CV and bioengineering communities inpre-competitive CV POCT needs-assessment ac-tivities. This action would ideally extend beyond a

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single meeting to include the creation of a forumfor an ongoing electronic and living discussionthat encourages broad participation from diversebackgrounds and spans multiple training levels. Amultidisciplinary team of experts can consolidate,curate, and refine contributions to create afocused list of Cardiovascular POCT Grand Chal-lenges that correspond to the most promising“well-posed clinical problems.” The most attractiveChallenges will ideally extend beyond modest re-ductions in assay sample volume or increasedportability of existing biomarker measurements,and instead pursue ambitious goals that ensurethat novel CV POCT can improve dramaticallyCV care. Challenges that offer an opportunity forthe CV POCT community to coalesce around asmall number of high-impact problems are mostlikely to inspire development of high impacttechnologies.

� Support stage 2 activities with the funding ofbiomarker science (basic discovery and validationof novel CV biomarkers) and novel sensing tech-nologies (methods for detecting and quantifying avariety of biomarkers from diverse patient-derivedsamples). This fundamental work will cut acrossindividual clinical POC devices and provide a sci-entific and technological basis for integrated POCsolutions.

� Support stage 3 activities with the funding ofspecific implementations of biomarker-sensing so-lutions that range from individual sensing compo-nents to complex, fully integrated POC sensingplatforms that perform “sample-to-answer” mea-surements from clinically relevant specimens.

� Support stage 4 activities by enabling pilot testingof integrated “sample-to-result” technologiesdeveloped in stage 3 via small-scale, proof-of-concept studies in preparation for larger-scaleprospective POC testing in stage 5. Support couldinclude facilitating access to annotated clinicalspecimens. Such pilot testing can also help deter-mine reference values for POC tests in relevantpopulations, encourage harmonized data stan-dards and reporting of POC tests, and determinethe data and technical integration needs atdifferent levels (e.g., technical, systems, patientdata, and population).

� Support stages 4 and 5 with core data storage, dataprocessing, privacy, and analytics that will permit

the transmittance of POCT results to and from pa-tients and providers to realize their power withoutcompromising patient privacy.

� Integrate stage 4 and 5 POCT activities withongoing or planned clinical studies funded by theNHLBI using funding mechanisms such as ancillarystudies or Small Business Innovation Research/Small Business Technology Transfer grants, andmake existing clinical data and relevant biobanksaccessible to aid validation of POC technologiesagainst established centralized laboratorymeasurements.

� Assess standards for evaluation and clinical useof POC tests through the establishment ofapplication-specific standards of quality, effi-ciency, affordability, accessibility, and safety ofdevices and data (in coordination with otherappropriate agencies.)

� Fund career development activities, program for-mation, and industry surrounding novel biomarkerscience and POC technology development thatprovides the foundation for new POCT opportu-nities on the basis of previously unrecognized orunmeasurable biomarkers.

POCT possess the potential to transform medicalresearch and patient care. Implementation of aresearch and development program as proposed inthe roadmap and recommendations that emergedfrom this WG can accelerate the realization of thispromise.

ACKNOWLEDGMENTS The authors thank thefollowing additional WG participants for their timeand expertise: Robert Califf, MD, Food and DrugAdministration; Paula Caposino, PhD, Food and DrugAdministration; Jonathan Lindner, MD, OregonHealth and Science University; and Shuqui Chen,PhD, IQuum, Inc. National Institutes of Health staffparticipants included: Narasimhan Danthi, PhD, Na-tional Heart, Lung, and Blood Institute; William Riley,PhD, Office of Behavioral and Social SciencesResearch; and Pothur Srinivas, PhD, MPH, NationalHeart, Lung, and Blood Institute.

REPRINT REQUEST AND CORRESPONDENCE: Dr.Peter Libby, Brigham and Women’s Hospital, HarvardMedical School of Medicine, 77 Avenue Louis Pasteur,NRB 741, Boston, Massachusetts 02115-6110. E-mail:plibby@rics.bwh.harvard.edu.

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KEY WORDS biomarkers, clinical trials,precision medicine