Background: Clinical trials do not represent community settings,making widespread implementation of evidence-based medicineproblematic. New heart failure treatments are an example, asresults comparable to those of clinical trials have not beenobserved in the community. Alternatives to clinical trials couldprovide useful complementary information.
Objectives and Methods: To review the clinical trials and communityexperiences in heart failure management by searchingPubmed with key words "observational studies," "clinical trials,"and "heart failure," to present the preliminary results of a community-based heart failure registry as a complementary database, andto assess the potential value and limitations of the registryapproach.
Results: Recent advances in the treatment of heart failure led toguidelines using clinical trial evidence as the rationale for transferringnewer therapeutic technologies to the community practice setting.Implementation of such guidelines is slow, reflecting concernsover applicability of clinical trial results to the community setting.A community-based registry of β-blocker treatment for heart failureshowed outcomes comparable to those of clinical trials, despitesignificant differences between physicians and their patients inthese settings.
Conclusion: Registries can complement clinical trials to expeditetechnology transfer to the community setting.
(Am J Manag Care. 2004;10:487-492)
Evidence-based medicine relies on results of clinicaltrials, which may be problematic as clinicaltrials often do not represent patients or careproviders from the broad community practice setting.Clinical trials are carried out by investigators who areusually based in academic centers and have a highdegree of experience, specialized training, or interest inthe particular clinical problem being investigated.Patients enrolled into these trials are selected by criteriathat tend to optimize their responsiveness to thequestion being investigated. Therefore, the results ofclinical trials may not be applicable to the communitysetting.
The transfer of technology from clinical trials to thecommunity setting occurs slowly, as the "evidence" forevidence-based medicine derives from sources not readilyapplicable to the community setting. The usualapproach for expediting the transfer of new technologyto the community setting is to expand efforts aimed ateducating about the results of clinical trials and urgingtheir rapid and broad adoption. Inherent in thisapproach is the assumption that clinical trials aloneoffer sufficient supportive evidence and rationale. Thecalls for increased educational efforts often emanatefrom the clinical trialists, who may have biased confidencein their findings. Therefore, this approach maynot consider the shortcomings of clinical trials. Anotherinterpretation of the slow transfer of technology is thatthe community practitioner has been educated but isskeptical about the applicability of clinical trials resultsto his or her practice setting. In that case, further educationabout clinical trial results would likely have littleeffect.
The objective of this article is to examine the potentialrole of alternative means, especially registries, as investigativetools for collecting valid and useful information tocomplement clinical trial data and to expedite the transferof technology from the clinical trial to the communitysetting. There exists a so-called efficacy-effectivenessgap in the applicability of clinical trial results, especiallyin the contexts of managed care, disease managementprograms, and pharmacoeconomics.1-3 The limitedamount of reliable effectiveness data affects healthcareproviders and health policy makers in their ability tomake well-informed decisions and formulate recommendations.1 Heart failure represents an area in which anefficacy-effectiveness gap has been recognized. Therefore,we used heart failure as a model for reviewing theroles of clinical trials and registries. The preliminaryresults of a registry of patients beginning treatment withβ-blockers for heart failure are reviewed as an exampleof these methods.
CLINICAL TRIALS AND COMMUNITYEXPERIENCES IN HEART FAILURE
There have been great advances in our understandingof the pathophysiology of heart failure and its management.The favorable results of new treatments, suchas vasodilators, angiotensin-converting enzyme (ACE)inhibitors, and β-blockers, on clinical outcomes haveled to the development of heart failure management andtreatment guidelines that are being updated at shorterintervals.4-6 The latest guidelines rely on evidence-basedmedicine as the rationale for transferring these newerdiagnostic and therapeutic technologies from the realmof clinical research to the community setting of practicingcardiologists and primary care providers, neither ofwhom necessarily has specialized interest or expertisein heart failure. Therefore, the rate and extent of implementationof the latest technologies in the communitysetting appear limited. The scientific basis for and clinicalapplication of β-blockers in heart failure were thesubjects of recent reviews that concluded that "[t]hescience supporting β-blockers must be translated intopractice safely and rationally if the agents are to achievetheir full potential."7(p883),8
The concerns in heart failure are that clinical trialsare usually carried out by experts in the field andinclude patients who are predominantly younger whitemen, selected to have stable symptoms, little comorbidity,and rigidly defined criteria for heart failure (eg,reduced left ventricular ejection fraction). Large-scalecommunity observations indicate that the general populationwith heart failure contains significantly morewomen, African Americans, and older patients thanthose included in clinical trials.9-11 In addition, almosthalf of the patients in the community setting have normalsystolic function, with possible diastolic dysfunction.12-14 Furthermore, most of these patients aremanaged by primary care providers who are not cardiologistsor do not have specialized expertise or interestin heart failure. In fact, the ability to replicate theapparent improvements in the management and outcomesof heart failure outside the clinical trial settinghas been questioned, as results comparable to thosereported from clinical trials have not been observed inthe broad community, especially among groups inadequatelyrepresented in the clinical trials.15-19 The mostrecent heart failure management guidelines recognizethis problem and call for further investigation in sub-populationswith heart failure.6
A β-BLOCKER HEART FAILURE REGISTRY
When carvedilol became the first β-blocker approvedfor use in heart failure in the United States, there was areluctance among practitioners to use it in the communitysetting, because β-blockers were previouslythought to be contraindicated in heart failure and it wasperceived as difficult to apply this new therapeutic technologysafely and effectively. Therefore, a β-blockerheart failure registry was designed and implemented toenroll patients starting a regimen of carvedilol for heartfailure in the usual care setting and to follow them withprospective longitudinal observations.
Complete details of the registry design have beenpublished elsewhere.20 Specific objectives were to collectoutcomes data and to observe the experience usinga β-blocker, carvedilol, in unselected patients with heartfailure managed by community physicians in their usualpractice without a structured protocol. There were nopatient selection criteria other than that patients mustbe adults starting a regimen of carvedilol for heart failure.The decision to prescribe carvedilol was at the discretionof the participant physician, without applyingany prespecified eligibility criteria. The physicians participatingin the registry were selected to be representativeof community practitioners in the United Statesand Canada. They included cardiologists and primarycare physicians, and special care was taken to minimizethe inclusion of physicians from academic settings orwith a special interest in heart failure. There was noprespecified schedule of visits or procedures to be followed,as patients were seen according to the usualpractice of the participant physician, who performedonly those procedures or assessments (eg, echocardiogramsand laboratory tests) per his or her usual practice.Information about patient status was recorded atbaseline, at the end of carvedilol titration, and as closeas possible to 6 and 12 months after completing titration.It is assumed, although not specified, that patientswith heart failure would be seen at least at these intervalsper standards of good clinical practice. The informationrecorded included survival status, New YorkHeart Association (NYHA) class, current medications,clinical or adverse events, and other relevant assessmentsthe physician may have made. Detailed informationon the carvedilol dose titration experience wascollected.
The registry was completed and analyzed. Characteristicsof patients and physicians in the registry andthe primary results have been preliminarily reported,comparing groups within the registry and examining registryresults relative to those of the carvedilol clinical trialsexperience in the United States.21-24 There were 4280patients enrolled, with 259 cardiologists enrolling 3121patients and 129 primary care physicians enrolling 1159patients. Both physician groups had prior experiencewith use of β-blockers in the treatment of heart failure,but that experience was considered extensive by morecardiologists than primary care physicians. The primarycare physicians enrolled more women, AfricanAmericans, patients with diabetes mellitus or hypertension,and patients who were older. Their patients alsohad higher left ventricular ejection fractions. Thepatients of cardiologists were more likely to be receivingbackground therapy with a combination of ACE inhibitors,diuretics, and digitalis. The duration of carvediloltitration and the reported degree of difficulty with titrationwere similar in both groups. Fewer patients managedby primary care physicians achieved recommended maximaltarget maintenance doses of carvedilol (25 or 50 mgtwice daily), but they were less likely to discontinuecarvedilol. Therefore, there were significant differencesbetween physician profiles, the baseline characteristicsof their patients, and their titration experience withcarvedilol in the setting of this β-blocker registry. Thesedifferences may reflect heart failure management in generalin the community and might be expected to affectthe overall results of the registry.
Important differences were also observed when thesesame types of characteristics were compared betweenthe registry and the carvedilol clinical trials experience.Physicians in the registry were less likely to have an academicaffiliation, be hospital-based, or be cardiologists.Patients in the registry were significantly older, includedmore women, had higher left ventricular ejection fractions,and were less likely to have NYHA class III or IVsymptoms. Fewer registry patients were receiving ACEinhibitors, digoxin, or diuretics at baseline comparedwith those in clinical trials in which background therapywas prespecified per protocol. Although no or little difficultywith carvedilol titration was reported in 83% ofpatients in the registry, registry patients took longer tocomplete titration than those in clinical trials. In addition,fewer registry patients achieved the maximal targetmaintenance doses of carvedilol compared with patientsin clinical trials, and more patients in the registry discontinuedcarvedilol.
Despite the observed differences within the registrybetween physician profiles, the characteristics of theirpatients, and the dosing of carvedilol, there was no significantdifference in 1-year all-cause mortality betweenpatients treated by cardiologists vs primary care physicians(6.5% vs 7.5%, = .33). In addition, in both groupsof patients, hospitalizations for heart failure werereduced by 42% from the year before entering the registry.
In summary, these preliminary results suggest thatthis β-blocker registry recruited physicians and patientgroups who differ significantly from each other and fromclinical investigators and patients in heart failure clinicaltrials. Despite such differences, the all-cause mortalityand heart failure hospitalization rates werecomparable between patient groups within the registryand were in the same range as those observed incarvedilol clinical trials.24 Therefore, the differences inpatient populations and their risk factors were unimportantprognosticators, or they tended to cancel eachother out. This registry provides a large prospectivedatabase evaluating a recently approved heart failuretreatment (at the time of registry development) in thecommunity setting and demonstrates the key role thatcommunity-based healthcare providers can fulfill asclinical investigators outside the traditional clinical trialssetting.
ALTERNATIVES TO CLINICAL TRIALS
Whereas the preliminary results of the registrydescribed in the previous section appear to bolster thoseof clinical trials by confirming them in the different setting,such may not always be the case, as other community-based observations may not replicate clinical trialresults (eg, spironolactone treatment of heart failure wasmore problematic in the community setting than in clinicaltrials25). Therefore, it is imperative to evaluate theadvantages and disadvantages of clinical trials and otherapproaches for providing the most reliable and applicableinformation for patients and healthcare providers.
The intent is not to challenge the role of clinical trialsand the educational activities they generate, asthese are well-established important and desirableactivities. However, they could be complemented byother initiatives aimed at helping to "fill in the gaps"with additional data that appropriately address thecommunity setting. Therefore, alternative means ofcollecting more representative data are needed andhave been called for.1,6-11,15-18
Alternative means include the use of subset analyses,targeted clinical trials, observational studies, and registries.It has become commonplace to report subsetanalyses from large clinical trials. Examples of thisinclude trial results among heart failure subpopulations,defined by ethnicity, sex, comorbidity, and age.26-30Whereas this information may be of some value, itremains a subset of the overall clinical trial results and,therefore, has the same limitations as clinical trials.Furthermore, the overall limitations may be magnifiedin these subset analyses because the sample sizes aresmaller, the question being asked was not prospectivelyformulated, and randomization may not be balanced forthe subset in question. Given these limitations, theresults of these subset analyses can be used, at best, togenerate hypotheses for testing in subsequent studiesand cannot be considered conclusive. Therefore, a newclinical trial targeted at a previously identified subsetcould be designed. An example of such a targeted clinicaltrial deriving from subset analyses is the recentlyannounced African American Heart Failure Trial (AHeFT),31designed to prospectively address issues recognizedduring earlier trials among small numbers ofAfrican American patients who appeared to respond differentlyto treatment.26-28 However, this approach is stilla clinical trial, with the associated limitations of patientand physician selectivity, as well as protocol rigidity.
Observational studies use existing databases to providelarge experiences, but are limited by their retrospectivenature and the inherent design of theparticular database. For example, health claims databasescontain coded information, and the accuracy orcompleteness of coded diagnoses may not meet standardsof practice. In addition, much demographic andcomorbidity information may be missing. Prescriptiondatabases are confined largely to types of drugs prescribed,with limited information about the patient orthe indication for the drugs. Therefore, such studiesoften include inaccuracies of diagnosis and rely onassumptions about the reasons for patient managementdecisions. These, too, are probably best used forhypothesis generation.
RATIONALE FOR REGISTRIES
Registries are another means of collecting complementarydata from the community setting. Comparedwith a clinical trial, a registry is a database created froma broader source, using flexibly applied means of datacollection. Registries may be designed to acquire newinformation not yet available in any organized fashion.For example, the Coronary Artery Surgery Study32 registrywas begun with the introduction of coronary arterybypass grafting to learn more about the natural historyof medically treated coronary artery disease to evaluatethe role of the new surgical technology. Registries alsoprovide preliminary data for use in designing clinical trialsand comparing patients in a clinical trial with similarpatients observed outside the protocol setting.33,34
Registries have limitations. They are usually uncontrolledand lack provisions to assure the quality, accuracy,and completeness of data. Furthermore, participationof investigators and patients involves some selectionprocess. Although the β-blocker heart failure registrydescribed herein was designed to simulate the communitysetting and be less like the clinical trials setting, ithad to recruit physicians and patients and ended upwith a preponderance of cardiologists. Therefore, thesephysicians and their patients were selected, at least inpart. Nevertheless, this registry may reflect the naturalhistory and management of heart failure in the "realworld." That such is the case is suggested by the similarityof the registry's patient characteristics and outcomesto those reported from large databases ofcommunity patients with heart failure.9-19,35-37
Registries constructed from clinical data are limitedby often being retrospective and examining 1 or a fewfixed points in time. For example, there is limited informationon the natural history of heart failure in thebroad population, as the observations derive largely fromlocalized databases examining retrospective data.9,15Registries have not been widely used in a prospectivemanner (as was done in the registry described herein) tocollect information longitudinally while the actual dataof interest are generated, as is commonly done in a clinicaltrial. There is a role for prospective collection of datafrom the community setting to assess the effect of newtreatments. To provide a more valid interpretation relativeto the clinical trials experience, such community-deriveddata should include information about thepatients and the care providers involved in that setting.Some of these kinds of limitations are exemplified by theStudies of Left Ventricular Dysfunction (SOLVD)34 multicenterregistry, which enrolled patients who were ineligiblefor the clinical trial and, thus, represented selectedpatients. In addition, the data were derived from retrospectivereview, and some registry patients entered asubstudy protocol. Finally, the care providers were thesame clinical trialists, largely heart failure experts.
That registries are subject to patient and physicianselection biases is further exemplified by some recentheart failure registries that have noted important differencesbetween their observations and results from clinicaltrials. The Management to Improve Survival inCongestive Heart Failure registry noted higher mortalityand rehospitalization rates in a community setting, alongwith reduced use of recommended medications after hospitaldischarge for heart failure, compared with thereported results of similar clinical trials.18 The registrypatients were predominantly older white women, amarked difference from most clinical trial populations.The Italian Network on Congestive Heart FailureRegistry19 recruited outpatients with heart failure from acommunity setting and also noted a higher than expectedrate of short-term heart failure decompensation, aswell as frequent unexplained withdrawal of medicationsthat are routinely recommended for heart failure. Thisregistry is limited in its generalizability, as the patientswere followed up by expert cardiologists in specializedcenters and their demographic characteristics were similarto those of patients in clinical trials. The RochesterEpidemiology Project recently compared incidence andsurvival of heart failure measured a decade apart in theOlmstead County, Minnesota, community.17 The incidenceof heart failure did not change significantly inpatient cohorts enrolled in 1981 or 1991, and the survivalrate failed to change during that decade of markedadvances in heart failure management. The patients inthis registry were typical of the community population inthat they were older, included more women, and had significantcomorbidity, but differed by coming from a predominantlywhite population of middle to uppersocioeconomic class that received much of its healthcarefrom a prestigious tertiary care provider.
Other registries and observational studies havefocused on differences in quality of care and outcomesaccording to type of healthcare providers and havenoted differences in patient characteristics, medicationuse, and use of procedures among patients managed bycardiologists or primary care physicians, while clinicaloutcomes have been mixed.36-38 A limitation of most ofthese other registries is their use of hospitalizedpatients to find index cases, rather than recruiting fromoutpatients, who constitute the much larger and morerepresentative population of heart failure patients.Identifying patients at hospital discharge tends toinclude a population that is at increased risk of mortalityand readmission, whereas most patients with heartfailure are ambulatory and have a lower incidence ofprior hospitalizations and lower risk of subsequent mortalityand hospitalization.15,18,35 The limitations of thisapproach have been the subject of recent comment thathas called for the establishment of community-basedregistries for longitudinal observations.39
CLINICAL TRIALS VS REGISTRIES
Although the methods of randomized, controlledclinical trials limit the general applicability of theirresults because of investigator and patient selectionbiases and adherence to a rigid protocol, they remainthe cornerstone for establishing proof of concept anddemonstrating efficacy within the populations studiedand the particular research environment. It is more difficultand costly to use these same methods to demonstratecomparable results in larger diverse patientpopulations managed in the usual community care setting.It is not uncommon for new treatments to fail andfor new drugs to be recalled by regulatory authoritiesshortly after their approval and widespread use in thecommunity setting. Regulatory agencies recognize theselimitations of small clinical trials and have urged inclusionof broader, more representative patient populationsand investigators during the early development ofnew therapeutic approaches.40 Therefore, a role formethods other than the randomized, controlled trialmay exist.
The heart failure registry experience described hereinreinforces the potential value and role of observationalstudies to assess experience with and outcomes of newtreatments outside the clinical trial setting. Like a clinicaltrial and unlike most registries, the data in this exampleregistry were collected in a longitudinal prospectivemanner. This should permit interpretation of the resultsin juxtaposition to those of a clinical trial, with a greaterdegree of validity than most registry-type data, which areretrospective or point estimates. As already described,registries have limitations. Without an appropriate controlgroup, a registry cannot evaluate efficacy. Therefore,we cautiously interpret the general experience of this β-blocker registry as demonstrating the value of a prospectiveregistry as a tool for collecting data to complementthose obtained from more structured clinical trials.
In summary, the relatively small randomized, controlledclinical trial should probably still be used toestablish proof of concept and efficacy in the idealpatient population. Other techniques, such as prospectiveregistries, may be more suited to assessing the efficacyand broad applicability of new therapeutictechnologies to the real-world community setting.Combining the 2 methods might be a better approachand be more cost effective by limiting the clinical trials(with their high per patient costs) to small numbers ofpatients and using the low per patient costs of a registryfor the large observational studies. The "practical clinicaltrial" has been suggested as a way of combining theseapproaches to broaden the diversity of patients andinvestigators, rendering them more representative ofcommunity settings, while maintaining controlled conditionsand validity of observations.1
Alternatives to clinical trials, such as registry data,can be used to fill in the gaps left by clinical trials and toprovide experience in patient and physician populationsthat more closely reflects the real world. The registryapproach also emphasizes an important role for communityphysicians as investigators, a role they can fulfillwith fewer disruptions to their usual practice than mightbe demanded by involvement in clinical trials. A registrycan provide community physicians with firsthand experiencein using a new treatment modality to confirm orallay their concerns and possible misconceptions aboutusing that new treatment. If the clinical outcomes of aregistry parallel the benefits observed in clinical trials,important new therapeutic technologies might be transferredmore widely and expeditiously to the communitysetting. Therefore, the registry experience describedherein may serve as an important model for future applicationsand merit consideration for earlier inclusion indevelopment programs. Successful implementation ofdifferent approaches to clinical investigation, such asregistries and practical clinical trials, will require governmentagencies and private industry sectors that supporthealthcare research to rethink and reprioritize theirgoals and resource allocation.1
From the Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School ofMedicine, New York, and the Weill Medical College of Cornell University, Ithaca, NY.
Dr Franciosa is a paid consultant to GlaxoSmithKline Pharmaceuticals, ResearchTriangle Park, NC.
Address correspondence to: Joseph A. Franciosa, MD, Zena and Michael A. WienerCardiovascular Institute, Mount Sinai School of Medicine, 209 West 86th Street, ApartmentM-17, New York, NY 10024. E-mail: email@example.com.
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