Keo et al. BMC Cardiovascular Disorders 2013, 13:120http://www.biomedcentral.com/1471-2261/13/120

STUDY PROTOCOL Open Access

The FReedom from Ischemic Events - NewDimensions for Survival (FRIENDS) registry: designof a prospective cohort study of patients withadvanced peripheral artery diseaseHong H Keo1, Sue Duval2, Iris Baumgartner3, Niki C Oldenburg2, Michael R Jaff4, JoAnne Goldman5,James M Peacock6, Alexander S Tretinyak5, Timothy D Henry5, Russell V Luepker7 and Alan T Hirsch2*

Abstract

Background: Advanced lower extremity peripheral artery disease (PAD), whether presenting as acute limb ischemia(ALI) or chronic critical limb ischemia (CLI), is associated with high rates of cardiovascular ischemic events,amputation, and death. Past research has focused on strategies of revascularization, but few data are available thatprospectively evaluate the impact of key process of care factors (spanning pre-admission, acute hospitalization, andpost-discharge) that might contribute to improving short and long-term health outcomes.

Methods/Design: The FRIENDS registry is designed to prospectively evaluate a range of patient and health systemcare delivery factors that might serve as future targets for efforts to improve limb and systemic outcomes for patientswith ALI or CLI. This hypothesis-driven registry was designed to evaluate the contributions of: (i) pre-hospital limbischemia symptom duration, (ii) use of leg revascularization strategies, and (iii) use of risk-reduction pharmacotherapies,as pre-specified factors that may affect amputation-free survival. Sequential patients would be included at an index“vascular specialist-defined” ALI or CLI episode, and patients excluded only for non-vascular etiologies of limb threat.Data including baseline demographics, functional status, co-morbidities, pre-hospital time segments, and use of medicaltherapies; hospital-based use of revascularization strategies, time segments, and pharmacotherapies; and rates ofsystemic ischemic events (e.g., myocardial infarction, stroke, hospitalization, and death) and limb ischemic events(e.g., hospitalization for revascularization or amputation) will be recorded during a minimum of one year follow-up.

Discussion: The FRIENDS registry is designed to evaluate the potential impact of key factors that may contribute toadverse outcomes for patients with ALI or CLI. Definition of new “health system-based” therapeutic targets could thenbecome the focus of future interventional clinical trials for individuals with advanced PAD.

Keywords: Peripheral artery disease, Amputation, Atherosclerosis, Health service research, Outcomes research

BackgroundAdvanced lower extremity peripheral artery disease(PAD) represents a relatively uncommon, but excep-tionally high-risk, manifestation of systemic atheroscler-osis. Both traditional PAD classification systems andrecent evidence-based PAD care guidelines have em-phasized the potential benefit of more consistent case

* Correspondence: hirsc005@umn.edu2Vascular Medicine Program, Lillehei Heart Institute and CardiovascularDivision, University of Minnesota Medical School, Minneapolis, MN, USAFull list of author information is available at the end of the article

© 2013 Keo et al.; licensee BioMed Central LtdCommons Attribution License (http://creativecreproduction in any medium, provided the orwaiver (http://creativecommons.org/publicdomstated.

classification of advanced PAD into two distinct clinicalsyndromes, denoted as acute limb ischemia (ALI) orchronic critical limb ischemia (CLI). Both PAD syn-dromes represent manifestations of a severe comprom-ise of arterial blood flow to the affected lower extremity,with the acuity of onset of ischemia and specific clinicalsigns used to distinguish between these syndromes [1].In contrast to comparable acute coronary disease syn-dromes (such as the acute coronary syndromes [ACS]of non-ST segment myocardial infarction (MI) andST-elevation MI), the epidemiology of ALI and CLI is

. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited. The Creative Commons Public Domain Dedicationain/zero/1.0/) applies to the data made available in this article, unless otherwise

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much less well defined in the absence of population-based surveillance. Current evidence suggests an inci-dence of approximately 430 to 1160 cases per millionindividuals annually [2-4]. Although ALI and CLI repre-sent the primary etiology of most lower-limb amputa-tions [5] and are associated with high short-term ratesof systemic and limb ischemic events [6,7], uncertaintyregarding the incidence, prevalence, and outcomes ofthe ALI and CLI syndromes is, in part, based on the lackof a uniform and applicable definition used in eitherfield studies or in clinical practice outside of specializedvascular centers.Improvements in coronary ischemic syndrome health

outcomes have been facilitated by consistent use of ACSdefinitions and subsequent evaluation of health systemfactors that contribute to cardiovascular risk. For example,improved outcomes for patients with ST-elevation MI andacute stroke were achieved by evaluation of methods toshorten end-organ ischemia time (including patient recog-nition of heart attack symptoms and creation of expeditedreferral systems) and this knowledge has been success-fully encompassed in cardiac and stroke care guidelines[8,9]. In contrast, little data exist to define the contribu-tion of limb ischemia time to adverse limb or systemicoutcomes for individuals with ALI and CLI. Similarly,whereas the impact of pharmacological and behavioralrisk-reduction interventions (e.g., use of antiplatelet andstatin medications) is well-defined for patients withACS, a knowledge gap exists regarding the potentialimpact of these systemic treatments after successful legarterial revascularization. This knowledge gap is centralfor patients with advanced PAD as recent data do-cument that both endovascular and open surgical ap-proaches, while effective in improving limb outcomesfor individuals with CLI [10], are still associated withvery high rates of heart attack, stroke, and cardiovascu-lar death within one year of an index CLI presentation.Randomized clinical trials (RCTs) provide the most ro-

bust methodological approach to determining the effi-cacy, harm, and net impact of potential treatments forindividuals with advanced PAD. Nevertheless, recentexperience has demonstrated the challenges and costsassociated with recruitment of individuals with ALI andCLI into prospective RCTs. As for coronary disease orheart failure clinical research, there are potential ad-vantages to the study of outcome determinants from aprospective disease registry. These advantages include:enrollment of the full patient cohort with minimal exclu-sion criteria, the use of a multicenter design that is oftenmore broadly representative of the ALI and CLI popula-tion than might be recruited from specialized centersthat participate in sponsored RCTs, the potential to cap-ture longer-term outcomes data, the ability to pre hoc de-fine outcome determinants (e.g., pre-hospital leg ischemia

time) that are not easily evaluated in a RCT context, andoften the ability to collect such data at lower cost [11-13].In this context, specific knowledge gaps regarding de-

terminants of adverse health outcomes for individualswith ALI and CLI were used to design a hypothesis-driven clinical registry. The primary aim of the FRIENDSregistry is to evaluate a pre-defined set of patient andhealth system factors on one-year rates of systemic andlimb ischemic events, and thus on amputation-free sur-vival. These factors included: (i) pre-hospital limb ische-mia symptom duration, (ii) use of leg revascularizationstrategies, and (iii) use of risk-reduction pharmacother-apies. Outcome events (rates of non-fatal MI, stroke,amputation, and death) will be collected at one month, sixmonths, and one year. Secondary study aims are to assess:(a) the relative frequency and etiology of the ALI and CLIdiagnoses in a large community-derived population, (b)the frequency of use of evidence-based risk-reductionmedication in this high-risk population at baseline andduring follow-up, (c) predictors of functional status, and(d) rates of systemic ischemic events. The FRIENDS regis-try structure was pre hoc designed to serve as a pilot studyfor future implementation of a multicenter registry toprospectively evaluate the impact of standards of care onhealth outcomes for all individuals with ALI and CLI.

Methods/DesignStudy designThe registry is designed as a prospective cohort evalu-ation of individuals with advanced PAD, defined as in-clusive of the ALI and CLI syndromes.

EnrollmentWe defined the index hospitalization as the first presenta-tion for ALI or CLI, since a hospital admission serves asan easily identified site for detection of such cases. Use ofan index hospitalization is also advantageous (as comparedto recruitment from vascular specialty clinics or woundcenters) since it defines a population in whom health careresource utilization is high and in which quality outcomesstaff now exist to facilitate initial and subsequent out-comes data collection. Patient enrollment is intended tobe sequential and fully inclusive, with exclusions limitedto non-provision of informed consent that are docu-mented by a screening log.

Definition of advanced PAD syndromesThe registry was designed to utilize definitions of ad-vanced PAD (ALI and CLI) that are encompassed in theintersocietal “ACC/AHA Guidelines for the Managementof Patients with PAD” [1] and concordant TASC-II [2]PAD guidelines. As such, ALI is clinically defined by theadmitting vascular specialist in patients who experiencethe clinical stigmata associated with acute ischemia and a

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potential threat to limb viability of less than or equal to14 days in duration. Using this guideline-derived ALI caseclassification, enrollment of patients is achieved via docu-mentation of acute limb ischemic symptoms and signs(the 6 “Ps”) (Table 1). CLI will be defined, per these PADclinical care guidelines, in patients with Rutherford class 4,5, or 6 manifestations such as ischemic rest pain, andminor or major tissue loss of greater than two weeks dur-ation. At enrollment, patients with ALI and CLI willundergo evaluation of an objective pedal or toe pressuremeasurement when this is feasible pre-revascularization.Source documents have been created so that collection ofthese entry criteria, as applied by participating clinicians,will be uniformly obtained.

Use of source documents and data abstractionThis is a prospective registry, and as such all sequentialeligible patients with ALI or CLI who are hospitalized(defined as requiring an index leg revascularization pro-cedure or overnight stay) will be entered into the registry.Medical record documentation will be required immedi-ately on admission (not retrospectively) for establishmentof the presence of ALI or CLI. Vascular specialty and hos-pitalist staff will receive instruction on: (a) the clinical defi-nitions of ALI and CLI, (b) how to complete a sourcedocument on patient admission that includes the time ofonset of symptoms, and (c) the use of health system tools(e.g., standardized order sets) to facilitate prompt meas-urement of pedal or great toe pressures (Table 1).A documented medical history of coronary artery disease

(CAD) will consist of 1 or more of any of the followingchart documented conditions or procedures: stable angina,previous myocardial infarction, history of percutaneous cor-onary intervention or history of coronary artery bypass graftsurgery. Documented cerebrovascular disease (CVD) willbe defined by a history of transient ischemic attack (TIA),ischemic or hemorrhagic stroke, carotid stenting or carotidendarterectomy. Documented prior PAD will be defined by1 or more of the following criteria: symptomatic PADdefined by history of claudication, asymptomatic PAD doc-umented in the medical records, or history of ALI or CLI.

Table 1 Inclusion criteria: Ischemic symptoms and signs, and

For all patients: Clinicalsymptoms and signs

For ALI patientsof any of the

Ischemic rest pain Pain

Ulcer Pale

Gangrene Pulseles

Paresthe

Paralys

Poikilothe

Abbreviations: ABI Ankle-brachial index, TBI toe-brachial index.

Baseline height and weight will be obtained from themedical records, and body mass index (BMI) calculated.Patients will be considered overweight if they have aBMI of 25 kg/m2 to less than 30 kg/m2 or obese if theyhave a BMI ≥30 kg/m2. Atherosclerosis risk factors will bedefined as present: if documented in the medical record, ifthe patient is receiving treatment for the risk factor at thetime of study enrollment, or if there are supporting labora-tory test data proximal to the index hospitalization. Dia-betes will be considered present when there is chartdocumentation, regardless of type (I or II), or when useof an anti-diabetic medication or dietary intervention isdocumented. As well, the documentation of fastingblood glucose ≥7 mmol/l (126 mg/dl) will be consideredevidence of diabetes when these laboratory data areavailable. Hypertension will be defined when chart doc-umented or when there is evidence of treatment withany antihypertensive medication or behavioral inter-vention (e.g., use of calcium channel blockers, ACE-inhibitors, beta blockers, diuretics or diet/exercise).Dyslipidemia is considered present when there is chartdocumentation or use of any lipid-lowering or choles-terol modifying medication (e.g., statin, niacin, fibrates,or bile acid binding resin agents). Dyslipidemia is alsoconsidered to be present if, per the National CholesterolEducation Program (NCEP) guidelines, the total choles-terol concentration is >200 mg/dl (5.18 mmol/l), LDLconcentration is >130 mg/dl (3.37 mmol/l), and/or HDLconcentration is <40 mg/dl (1.04 mmol/l). Other criteriafor establishment of dyslipidemia include a fasting triglycer-ide concentration of ≥200 mg/dl, or total cholesterol/HDLratio ≥5.0. Smoking status is recorded as “current” if anycigarettes were used within one month of the encounter,“former” if smoking had ceased more than one month priorto the encounter, and “never” if there is no history of to-bacco use. A family history of premature CAD consists ofany chart documentation of a family history of prematureCAD or any myocardial infarction (MI) in a first-degreerelative (men <55 years or women <65 years). The etiologyof ALI or CLI is coded from data obtained in the medicalrecord.

objective limb pressure measurements at enrollment

: Presence“6 Ps”

For all patients: Objectivepressure measurements

Pedal pressures

Great toe pressures

s Ankle-brachial index

sia Toe-brachial index

is

rmia

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Ambulatory status on admission and discharge will beobtained from patient self-report and supplemented byabstracted medical record reports of treating clinicians.There is at present no single well-accepted format forrecording ambulatory status in individuals with ALI andCLI. Ambulatory status therefore will be categorized intofive groups and assigned ordinal values of 1 to 5, with 5representing the best, and 1 the lowest, ambulatory status.The highest class (5), “fully ambulatory”, is defined as theability to independently ambulate and fully interact in thecommunity. “Minimal ambulation” (4) is defined as ambu-lation limited to within the house/hospital, around thehouse/hospital, and to the mail box. “Ambulation withassistance” (3) is defined by ambulation requiring anotherperson’s help for mobility. “Wheelchair bound” (2) isdefined by dependency on a wheelchair for all mobility.“Bed bound” (1) is defined when the patient is not mobileat all, is fully restricted, and non-ambulatory. Ambulatorystatus at baseline is the level of function after onset of ALIor CLI and within one week prior to admission. Data willbe abstracted by trained research staff and reviewed byvascular physicians.All data will be collected via a standardized case report

form and then entered into a password-protected data-base. Data will be collected consistent with the intersoci-etal “2012 ACCF/AHA/ACR/SCAI/SIR/STS/SVM/SVNKey Data Elements and Definition for Peripheral Athero-sclerotic Vascular Disease” standards [14]. Outcome eventswill be reviewed and adjudicated by a clinical event com-mittee consisting of individuals with expertise in vascularsurgery and vascular medicine. The registry design hasbeen approved by the local institutional review board atthe University of Minnesota and Allina Health System. Allincluded patients will provide written informed consent.Patients screened for entry who do not offer informed con-sent will be entered into a screening log.

Key time segmentsThe symptom onset of an initial episode of ALI/CLI isdefined by the patient’s self-report provided to the vas-cular specialist at hospital admission, is dictated into theencounter note, and this note (date and time) is later ab-stracted from the medical records. Vascular specialists(vascular surgeons, vascular medicine specialists, andinterventional radiologists) are instructed to documentthe patient-reported index limb symptom onset withinpre-specified time parameters: within one hour for pa-tients presenting within 3 days, within one day for pa-tients presenting within 3 to 30 days, and within oneweek for patients presenting greater than one monthsince symptom onset. For CLI patients who cannot statean exact time of leg symptom onset, it will be assumedthat the onset time is 12 noon on the day specified. Inas-much as ALI or CLI is known to recur (repeat episodes

are common), the index leg symptom is arbitrarily de-fined as that which is temporally closest to the indexhospitalization. This approach is similar to that used forACS or stroke health services research.While the pre-admission symptom duration serves as

the primary pre-defined hypothesized predictor of ad-vanced PAD health outcomes, a number of other clinicalcare time segments are considered of potential utility inevaluation of the efficiency of hospital-based PAD care,as it is known that CLI hospitalizations are lengthy(greater than seven days) and expensive [15]. The“admission to ABI/TBI” time segment is defined as thetime from hospital arrival to initiation of the firsthospital-based pedal or toe pressure measurement. The“admission to heparin” time is defined as the time fromhospital arrival to the chart-documented initiation of atherapeutic intravenous heparin infusion for patients sotreated. The “admission to vascular specialist at bedside”time segment is defined as the time from hospital arrivaluntil the patient is evaluated by a vascular specialist, andthis is set by the time of the dictated note. The “admis-sion to revascularization” time segment is defined as thetime from hospital arrival until the patient enters theoperating room or catheterization laboratory, and includesonly the use of an endovascular procedure, surgical pro-cedure or primary amputation (medical treatment alone isnot included in this definition). Hospital length of stay isdefined as the number of days of hospitalization fromadmission to discharge.

List of pre-specified “key time segments” for patients withadvanced peripheral artery disease

Symptom onset to admissionAdmission to ABI/TBI measurementAdmission to IV heparin administrationAdmission to vascular specialist at bedsideAdmission to revascularizationLength of stay (days)

Study outcomesThe study outcomes that will be evaluated are summarizedin Table 2. The systemic ischemic risk clinical outcomes in-clude: nonfatal MI, nonfatal stroke, cardiovascular (CV)death, all-cause death, and cardiovascular re-hospitalizationevent rates. The limb ischemic risk clinical outcomesinclude: ALI or CLI recurrence, minor or major ampu-tation, and total amputation event rates. These individ-ual outcomes will be used to derive a composite tripleendpoint (defined as any nonfatal MI, stroke or amputa-tion) and quadruple endpoint (defined as any non-fatalMI, stroke, amputation or death). As well, the relevantclinical outcome of “amputation-free survival” time willbe calculated at one year.

Table 2 Clinical evaluations on admission and at 1-, 6- and 12-month follow-up

Admission Hospital discharge 1 month 6 month 12 month

Demographic, clinical and functional characteristics, and key time segments

Demographic variables

Race, gender, education X

Marital and employment status X X X X X

Physical examination (weight, height, blood pressure, heart rate and rhythm) X

Laboratory values (serum creatinine, hemoglobin, fasting lipid profile) X

Etiology of ALI-CLI X

Key time segments (see ‘List of key time segments’) X X

Length of hospital stay X

Endovascular and open surgical procedures X

Ambulatory status X X X X X

Risk factors and risk-reduction therapies

Historical risk factors X

Use of risk-reduction pharmacotherapies X X X X X

Smoking status X X X X X

Outcome events

Amputation (major or minor) X X X X

Cardiovascular ischemic events (non-fatal MI and stroke), death X X X X

Recurrence of ALI-CLI X X X X

Other causes of hospitalization X X X

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“Minor amputation” is defined as removal of any part ofthe lower limb below the ankle and “major amputation” isdefined as removal of part of the lower limb above theankle. All-cause death is ascertained via the social securitydeath index (SSDI) in the USA or via other national deathregistry systems using a combination of the social securitynumber (SSN), name and birth date to identify cases.Searching the online SSDI, with a correct SSN provides anaccurate method to determine death as an outcome in clin-ical research studies. A majority of subjects ordinarily lostto followup including those with sudden death outside thehospital can thus have their vital status accurately deter-mined [16]. Cardiovascular death includes fatal stroke, fatalMI, and other cardiovascular death. Other cardiovasculardeath includes deaths of cardiac origin: death associatedwith pulmonary embolism, vascular operation or proced-ure, amputation (except for trauma or malignancy), heartfailure and visceral or limb infarction. Re-hospitalizationfor CV events is defined as hospitalization for transient is-chemic attack, unstable angina, worsening of PAD, CHF,other ischemic arterial event or bleeding leading to bothhospitalization and transfusion. Recurrence of ALI/CLI isdefined as occurrence of any second episode of clinically di-agnosed ALI/CLI and ascertained by medical chart reviewat follow-up.Follow-up will be performed primarily by phone calls

at 1 month (with a one week window), 6 months (with a

one month window), and 12 months (with a two monthwindow) after hospital discharge using a phone script con-taining standardized questions. The occurrence of non-fatal MI, non-fatal stroke, amputation, re-hospitalization,recurrence of ALI/CLI are ascertained by medical records,all cause death by social security death index website [17],and CV death by medical record review. Ambulatory sta-tus will be ascertained by self-report during follow-up callsand at return visits.

Determination of sample sizeThis is a hypothesis-generating registry from which pre-liminary data will be obtained that will be key to refiningvalues used for estimating statistical power for futuremulticenter clinical trials. It is anticipated that these datamay be useful in identifying medical, endovascular, andhealth system interventions that could be tested in afuture randomized clinical trial, providing more accurateestimates of expected detectable differences and theirstandard deviations. Therefore, a formal power analysiswas not undertaken in the design of this pilot registry.

Statistical analysisDescriptive statistics will be presented as means andstandard deviations for continuous variables, and fre-quencies and percentages for categorical data. Conti-nuous data that are not normally distributed will be

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analyzed by nonparametric methods. Key time variableswill be analyzed as continuous variables, and also cate-gorized to allow assessment of dose–response patterns.Univariate models for all outcome variables with demo-graphic, clinical and risk factor variables will be used toelucidate potential confounding variables. Multivariablelogistic regression models will be used to assess the as-sociation between key time variables and short-term bin-ary outcomes (amputation, MI, stroke and death), withadjustment for confounders. Survival analysis will beperformed using Kaplan-Meier methods for preliminaryanalyses, and Cox proportional hazards models withadjustment for confounders. Multiple linear regressionmodels will be used to assess the associations betweentime segment variables and length of stay, with adjustmentfor confounders. A two-sided p-value of <0.05 will be con-sidered statistically significant. Data analysis will be per-formed using Stata (Stata Inc, College Station, TX, USA).

DiscussionIt is well-known that patients presenting with advancedPAD bear a high burden of systemic ischemic events andsuffer an adverse limb prognosis, with very high healtheconomic impact [18]. Thus, care for patients with ad-vanced PAD is a critical public health issue in the USAand internationally [19]. Current epidemiological datasuggest that the incidence of ALI is 130 to 160 per mil-lion per year [3,7] and the incidence of CLI is approxi-mately 340 to 1000 per million per year [2,4]. Majoramputation rates at 30 days after clinical presentationhave been reported to be 10-30%, and death at one yearis reported to range from 16-42% for ALI patients [7,20].Patients with CLI face a comparably dismal prognosisand the annual amputation rate has been reported tovary between 10% and 40% after a first diagnosis of CLI[21]. Overall, one- and five-year mortality rates of pa-tients with CLI are reported to be 20-25% and 40-70%,respectively [22-24]. There are few cardiovascular dis-eases with such adverse short-term outcomes. However,diseases with high rates of adverse short term outcomesare favorable for study within a disease registry frame.The FRIENDS Registry was designed to enroll a high

volume of sequential patients with advanced PAD in orderto collect an adequate sample to permit evaluation ofthe contributions of patient demographics, PAD etiology(e.g., cardioembolism vs. graft failure), key time segments,use of risk-reduction medications, and revascularizationstrategies on functional status, rates of revascularization,amputation, systemic ischemic event rates, and death.These data will also provide the opportunity to determinehow clinicians in practice assess patients with advancedPAD in real world (not clinical trial) settings, includingdata that might define rates of adherence to currentevidence-based clinical care guidelines.

We hypothesize that the current arbitrary 14 day diag-nostic “time-based syndrome definition” that is oftenused to differentiate ALI and CLI (beyond use of the 6“Ps”) may not adequately discriminate these two syn-dromes. The rationale for use of the 14-day timeframeto define ALI has not been based on evidence as robustas the data used to define the efficacy of acute MI orstroke treatments. While there was a biological rationalefor setting an objective 14-day, time-based inclusioncriteria for study of catheter-directed thrombolysis inindividuals with acute arterial occlusion [20,25], thistime-based definition has been carried forward into sub-sequent PAD care guidelines without corroborating theutility of this approach for endovascular and open surgi-cal techniques.This registry provides an opportunity to assess whether

ALI or CLI are indeed two distinct clinical syndromes withdifferent etiologies and outcomes, or whether these trad-itional clinical distinctions alternatively represent a time-dependent continuum of advanced PAD.More than 20 years ago, Panetta et al. [26] observed

that a longer duration of ischemia was associated withincreased amputation rates in ALI patients, and a morerecent study suggested that an increased duration oflimb ischemia was associated with more extensive gan-grene [27]. Nevertheless, these observations were de-rived from small cohorts, did not clarify a precisevulnerable period, nor elucidate other factors that mightaffect limb outcomes. This registry may provide insightsinto factors that, along with prolonged pre-admissionlimb ischemia, worsen prospects for limb survival. Theregistry will also provide a contemporary description ofcurrent etiologies of limb ischemia. For example, doesatrial fibrillation contribute to limb ischemic events at arate documented a decade ago, now that antithrombotictherapies are more widely used? Is graft surveillanceused, per current national care guidelines, at ratesadequate to protect individuals who have undergoneprior successful limb revascularization?During the last decade, cardiovascular care guidelines

have become an important cornerstone of the manage-ment of heart disease and the positive impact of guidelinesis known [28]. In contrast, the development and dissemin-ation of PAD care guidelines, including recommendationsregarding the ideal management of ALI and CLI, are rarelyevaluated prospectively [1,2]. These guidelines have re-cognized that appropriate use of evidence-based risk-reduction medication represents a major opportunity forreducing future myocardial infarction, stroke, and death ifused in individuals with recognized PAD. However, recentdata have shown poor rates of use of evidence-basedrisk-reduction medication on admission or discharge inpatients with CLI [10,29,30]. The registry will providean opportunity to evaluate the contemporary use of

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risk-reduction medications to prevent these majorischemic events in the PAD population at highest short-term risk. We hypothesize that higher use of these med-ications would offer a potentially major contribution toimprovement in rates of amputation-free survival; onlya prospective registry with an adequate cohort sample islikely to provide such data, as a prospective RCT toevaluate this hypothesis is currently unlikely. Datafurther demonstrating such benefits of risk-reductionmedication use might then be considered for futureguideline inclusion, or within future PAD performancestandards [31].Currently there are no standardized quality-of-life

instruments that are widely applied in populations ofindividuals with critical limb ischemia. This registry of-fers an opportunity to evaluate functional status onadmission, at discharge and at follow-up, as well as otherpredictors of functional status at follow-up. While it isknown that poor ambulatory status on presentation isassociated with loss of primary patency and higher ratesof amputation at six months follow-up, other factorsbeyond patency (e.g., avoidance of readmission, socialsupport, etc.) may contribute to the achievement ofimproved functional outcomes [32].Several limitations are inherent to this (or any) regis-

try. First, the enrollment of patients is intended to beconsecutive, but this is never fully achieved for anyregistry. Nevertheless, the majority of the patients whopresent for hospital care may be enrolled if, as planned,both hospitalists and vascular specialists are engaged atregistry launch. Second, as for any registry, selection forinclusion of a wide array of hospitals and health systemscan facilitate accrual of a representative cohort. Third,any PAD registry is encumbered – in contrast to CADor stroke registries – by the inconsistent use of objectivediagnostic criteria in real world clinical practice (in con-trast to RCTs). Whereas all individuals with an acute MIundergo an ECG, it is not now clear whether individualswith advanced PAD undergo consistent vascular labora-tory testing. Thus, we have elected to initially permit theinclusion of all “clinically diagnosed” ALI and CLI with-out the requirement of pedal or toe pressure measure-ments. Analysis of cohorts who have, or have not,undergone such testing can demonstrate the utility ofthis diagnostic approach. We note that the past diagnos-tic inclusion criteria of an ankle pressure of ≤50 mmHg[33] would potentially exclude two-thirds of patientswith CLI, as only 30% would fulfill the European Con-sensus Guideline pedal pressure criteria, as observed inthe BASIL trial [34]. Thus, the registry will provide valu-able information in a “real-world” setting by usingbroader inclusion criteria. Pre hoc defined subgroupanalysis of the “clinical diagnosis” and “objective diagno-sis” groups will provide insight regarding the value of

current diagnostic pathways on choice of therapy andachievement of positive outcomes.In conclusion, a multicenter advanced PAD registry

may represent a significant opportunity to assess a seriesof hypothesis-based factors that may modify systemic orlimb outcomes. In a manner analogous to methods usedto better understand the natural history and impactof treatments for acute MI, stroke and heart failure,advanced PAD registry data that includes pre-hospitalfactors, revascularization strategies used during an indexhospitalization, and that evaluates long-term use of riskmodifying pharmacotherapies may provide new insightsto help the design of future PAD clinical trials.

Trial statusRecruitment for a multi-center CLI and ALI registrybegan in February 2007 at a single center and willcontinue at other centers, dependent upon funding.

AbbreviationsABI: Ankle-brachial index; ACS: Acute coronary syndromes; ALI: Acute limbischemia BMI, body mass index; CAD: Coronary artery disease; CLI: Criticallimb ischemia; CV: Cardiovascular; CVD: Cerebrovascular disease; MI: Myocardialinfarction; NCEP: National Cholesterol Education Program; PAD: Peripheral arterydisease; RCTs: Randomized clinical trials; TBI: Toe-brachial index; TIA: Transientischemic attack; SSDI: Social security death index; SSN: Social security number.

Competing interestsThe authors have no financial or non-financial competing interests.

Authors’ contributionsHHK, SD and ATH made substantial contributions to study concept anddesign; ATH and HHK acquired funding for the study; IB, NCO, MRJ, JG, JMP,AST, TDH, RVL participated in its design and helped to draft the manuscript.All authors read and approved the final manuscript.

AcknowledgmentsDr. Keo received a grant (PBBEB-121067) from the Swiss National ScienceFoundation and a research grant from Abbott Vascular, Switzerland. Dr.Hirsch received a grant from Abbott Vascular, USA, to support registrydevelopment.

Author details1Division of Angiology, Kantonsspital Aarau AG, Aarau, Switzerland. 2VascularMedicine Program, Lillehei Heart Institute and Cardiovascular Division,University of Minnesota Medical School, Minneapolis, MN, USA. 3SwissCardiovascular Center, Division of Angiology, University Hospital Bern, Bern,Switzerland. 4Massachusetts General Hospital and Harvard Medical School,Boston, MA, USA. 5Minneapolis Heart Institute Foundation at AbbottNorthwestern Hospital, Minneapolis, MN, USA. 6Minnesota Department ofHealth, Heart Disease and Stroke Prevention Unit, Saint Paul, MN, USA.7Division of Epidemiology and Community Health, University of MinnesotaSchool of Public Health, Minneapolis, MN, USA.

Received: 24 September 2013 Accepted: 2 December 2013Published: 19 December 2013

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doi:10.1186/1471-2261-13-120Cite this article as: Keo et al.: The FReedom from Ischemic Events - NewDimensions for Survival (FRIENDS) registry: design of a prospectivecohort study of patients with advanced peripheral artery disease. BMCCardiovascular Disorders 2013 13:120.

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