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Multicenter research in adult congenital heart disease
International Journal of Cardiology 129 (2008) 155 – 159 www.elsevier.com/locate/ijcard
Editorial
Multicenter research in adult congenital heart disease Paul Khairy ⁎, Jamil Aboul Hosn, Craig Broberg, Stephen Cook, Michael Earing, Deborah Gersony, Joseph Kay, Michael J. Landzberg, Michelle J. Nickolaus, Sasha Opotowsky, Anne Marie Valente, Carole Warnes, Gary Webb, Michelle Z. Gurvitz The Alliance for Adult Research in Congenital Cardiology (AARCC) Received 22 November 2007; received in revised form 24 January 2008; accepted 1 March 2008 Available online 24 June 2008
Keywords: Adult congenital heart disease; Multicenter research; Alliance for Adult Research in Congenital Cardiology (AARCC)
The care of patients with congenital heart disease has evolved over the past half century largely through an iterative paradigm combining creative innovations and astute observations with some early failures and great successes. Extraordinary triumphs have given rise to a rapidly expanding population of adults with congenital heart disease (ACHD) [1–3]. Although it was once true that adult survivors with congenital heart defects had predominantly simple lesions in comparison to children, the spectrum of complexity has progressively transitioned [4]. The number of adults now exceeds children with moderate or severe defects [4,5]. As the burden of disease shifts from the child to the young and older adult with congenital heart disease, research efforts must reflect this changing reality. ACHD caregivers face the challenge of meeting this need in a thoughtful and organized fashion, through carefully designed and orchestrated studies. The collaborative multicenter research study is pivotal in this regard. Herein, we present our perspectives regarding trends and evolution towards multicenter research in ACHD, discuss benefits of collaborative research, and highlight particular challenges. It is our hope that this viewpoint will sensitize the ACHD community to the value of multicenter research in further advancing our field and encourage active participation in these endeavors. ⁎ Corresponding author. Adult Congenital Heart Center, Montreal Heart Institute, University of Montreal, 5000 Bélanger Street, Montreal, Quebec, Canada, H1T 1C8; Boston Adult Congenital Heart (BACH) Service, Children's Hospital Boston, Boston, Massachusetts. Tel.: +1 514 3763330x3800; fax: +1 514 3761355. E-mail address: [email protected] (P. Khairy). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.03.014
1. Evolution of research in ACHD Historically, the field of ACHD was born out of successes in pediatric cardiology [6,7] and was much later recognized as a unique subspecialty [8,9]. Advances in congenital heart disease progressed through an unfolding, incremental, and logical process with occasional radical changes in approach. The ACHD literature initially and appropriately focused on case reports, small case series, and guiding expert commentaries [10–12]. Paralleling the growth of the population of patients with ACHD and strategies implementing centralized care, research emerged as observational single-center cross-sectional and retrospective cohort studies. Survival patterns and risk factors for adverse outcomes in patients with and without surgical or catheter interventions were increasingly defined, leading to a better understanding of health needs in ACHD. With continued growth in the field of ACHD, the critical mass of patients, dedicated facilities, and committed investigators allowed new opportunities, with stimulating and valuable interdisciplinary exchanges. Within this context, multicenter research in ACHD emerged. A systematic electronic search of the MEDLINE database from January 1966 through October 2007, with manual retrieval of primary sources and inclusion of all languages, revealed that over 50 multicenter studies pertaining predominantly to ACHD have thus far been published. More specifically, the following criteria were mandated: 1) study undertaken at two or more institutions with different university affiliations, if applicable; 2) inclusion of at least 10 patients; 3) congenital heart disease documented in over 50% of the study cohort;
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P. Khairy et al. / International Journal of Cardiology 129 (2008) 155–159
Fig. 1. Multicenter research publications in ACHD.
and 4) mean age of the study population 18 years or older. All such studies were reported in the past 15 years. As depicted in Fig. 1, the number of published multicenter studies has markedly increased over the past decade. To date, multicenter studies in ACHD have been largely limited to observational cohort studies [13–19], with a few case– control studies [20], cross-sectional studies [21,22], and small prospective randomized clinical trials [23,24]. 2. NHLBI recommendations on research in ACHD In 2004, the National Heart, Lung, and Blood Institute (NHLBI) and Office of Rare Diseases, both components of the National Institutes of Health (NIH), convened a Working Group on research in ACHD. Among its summary statements, the group recommended that a network of specialized ACHD centers be formed to design and conduct multicenter research on pressing clinical issues. “These include but are not limited to natural history of specific conditions, interaction of ACHD with adult cardiovascular risk factors, assessment and treatment of ventricular dysfunction, understanding of ventricular–vascular interactions and their role in circulatory failure, predictors of risk for sudden death and serious arrhythmias, understanding of genetic factors influencing outcome, and improved pregnancy management” [25]. The group also recommended that a database be developed to track outcomes, formulate best practices, and foster continuous quality improvement based on these practices [25]. 3. Benefits of multicenter research in ACHD In general, multicenter research affords the following major advantages: firstly, with a cooperative effort involving many centers, studies may be large enough to meet more stringent requirements for statistical analyses. This advantage cannot be
over-stated, as study power is fundamental to any quantitative analysis. A common misinterpretation of inferential statistics is that failure to demonstrate a significant difference between two variables implies that no such difference exists. Equivalency cannot be inferred from most reported negative findings due to insufficient statistical power [26]. Secondly, by virtue of combining several patient populations, multicenter research may minimize or overcome information biases. In some cases, multicenter studies may reduce systematic differences in characteristics between ACHD patients who are selected for study and those who are not. Internal validity may be favorably impacted by reducing selection bias at entry. In other situations, such as potential referral bias, combining patient populations may improve external validity, i.e. generalizability, with little impact on internal validity. Other practical advantages include collaborative sharing of particular expertise and skills regarding specific aspects of research, especially considering the relatively small total number of trained caregivers dispersed across centers [27]. Individual teams, particularly from smaller and medium-size centers, may not have the required patient numbers and/or infrastructures to tackle studies on their own. Multicenter research allows these centers to actively participate, pool resources, and share information. The prototype of the multicenter study is the randomized controlled trial. Benefits of this rigorous study design are widely accepted and include random allocation to prevent known and unknown systematic differences between study groups; blinding to avoid preconceived views from biasing results; standardization of inclusion criteria, definitions, and outcomes assessment; and ease of interpretability of findings. Although randomized controlled trials are powerful tools and rightfully considered the gold-standard for therapeutic interventions, other multicenter study designs may be more aptly suited to address particular study questions of interest. In some situations, observational studies may be the only means of assessing an intervention as a result of ethical and/or practical concerns [28]. Prospective multicenter cohort studies with “hard” clinical end-points generally require large sample sizes and incur high costs for all but the commonest of outcomes. They are often initiated after obtaining sufficient evidence from less expensive case–control, cross-sectional, retrospective cohort, or prospective cohort studies with surrogate end-points. Advantages of these study designs include considerably less cost, completion in a more timely fashion, and possibility of excluding latency periods. Features common to prospective and retrospective cohort studies include the ability to address rare exposures, directly measure risk, calculate incidencedensity rates, and assess multiple outcomes. In contrast, the multicenter case–control study may be better suited for rare outcomes. It is, however, a misconception that case–control studies offer a level of evidence superior to cohort studies as a result of their “controlled” nature. Although case–control studies have their merits, risk estimates are indirect and generally approximate more conclusive direct measurements
P. Khairy et al. / International Journal of Cardiology 129 (2008) 155–159 Table 1 Challenges to multicenter research in ACHD Complexity and heterogeneity of the patient population Divergences in nomenclature and classification Institutional variations in treatment strategies Identification of appropriate clinically relevant end-points Paucity of preliminary data for sample size estimates Recruitment of a sufficiently large number of patients Issues regarding patient safety and confidentiality Research infrastructure for efficient implementation Limited funding opportunities
157
AARCC exists as a research group to foster collaborative relationships between programs and investigators, to further and sustain research efforts, and to include the goals of innovative investigations, advancing knowledge, and improving outcomes. AARCC's first multicenter research studies are currently underway on such diverse topics as exercise stress testing in pregnant women with congenital heart disease, the aortic root and left ventricle in tetralogy of Fallot, and systemic venous anomalies in the univentricular heart. 5. Unique challenges
from cohort studies. Challenges in designing multicenter case–control studies in ACHD include assembly of a case group representative of the target population, identification of a suitable control group, availability of accurate information on potential risk factors and confounders, and inferences regarding cause–effect relationships. Cost-effectiveness analyses [29,30] and alternate study designs such as case–cohort [31], nested case–control [32], and case-crossover [33] studies have yet to be explored in multicenter ACHD research. 4. Research infrastructures Over the past few years, several networks and organizations have made inroads into multicenter research in ACHD. Some have focused on multicenter research as their main objective, whereas others provide a supportive environment that facilitates such research. These networks include, but are not limited to, the International Society for Adult Congenital Cardiac Disease (ISACCD), Canadian Adult Congenital Heart (CACH) network, Congenital Heart Information Network (CHIN), European Society of Cardiology (ESC), Japanese Circulation Society, Alliance for Congenital Quebec Interinstitutional Research (ACQUIRE), Surgical Thoracic Society (STS), and Congenital Heart Surgeon's Society (CHSS). Patient advocacy organizations, such as the Adult Congenital Heart Association (ACHA), are contributing their valuable perspectives and resources towards furthering multicenter research in the field. Nursing groups are also creating alliances, such as the International Adult Congenital Heart Disease Nursing Network (IACHDNN) [34]. As an example of a well-orchestrated and productive infrastructure in children, the Pediatric Heart Network (PHN) is a collaboration of clinical sites, with a designated data coordinating center, that conducts research on pediatric congenital or acquired heart disease [35]. It was created and funded in 2001 by the NHLBI. In the Netherlands, the Interuniversity Cardiology Institute and Heart Foundation developed a national registry and DNA-bank of patients with congenital heart disease, named CONCOR. Objectives are to facilitate investigation of prevalence and long-term outcomes of specific congenital heart defects and their treatment, develop an efficient organizational structure to improve healthcare, and investigate the molecular basis of congenital heart defects [36]. In the United States, an Alliance for Adult Research in Congenital Cardiology (AARCC) was formed in 2006.
Several unique challenges to multicenter research in ACHD are summarized in Table 1. Congenital heart disease is arguably one of the most complex, clinically and morphologically heterogeneous disease states. For research purposes, this may considerably complicate attempts to isolate specific exposure– outcome associations. In some forms of congenital heart disease, nomenclature and classification issues remain a subject of intense debate. Diverse coding and classification schemes between centers may obscure efforts to reliably identify eligible patients and provide a uniform study population for multicenter research. Fortunately, substantial progress has been made towards standardizing nomenclature classification schemes and creating an international coding system [37,38]. Selection of appropriate and relevant primary end-points for multicenter research in ACHD may be challenging. For a given magnitude of effect, sample size requirements to assess such discrete end-points as total mortality or major adverse events may be prohibitive. Consequently, primary end-points are often relegated to surrogate markers. Examples in multicenter ACHD research include appropriate defibrillator shocks to approximate sudden death [18,39] and hemodynamic parameters to assess benefits of pharmacological therapy [24]. Even parameters that have been wellstudied in non-congenital populations, such as echocardiographic Doppler indices of diastolic function, may not be generalizable to patients with ACHD. Moreover, although quality of life metrics are important components of multicenter research in ACHD, few have been validated in this patient population. A situation may also arise where a given therapy or approach becomes a de facto standard of care, in the absence of any real evidence. When the perception that therapeutic equipoise is disrupted, whether well founded or not, ethical concerns must be addressed. Since ACHD encompasses a conglomerate of orphan diseases, assembling a sufficient number of patients for any one study may be challenging. In our experience, initial estimates provided by cursory database searches tend to overestimate the number of patients that ultimately qualify for enrollment. Reasons are likely multifactorial, but may include practical issues related to the follow-up of patients living at a distance from their regional ACHD center of excellence, physician reticence based on prior beliefs, intricacies of informed consent procedures, inaccuracies of diagnostic labels, and patient concerns. Moreover, lack of preliminary
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data on which to base sample size calculations may hinder development of multicenter research protocols. In some situations, sample size estimates have been based on case series or systematic reviews with no formal intra-study comparisons [40]. Although this may represent the best available option, potential inaccuracies are substantial. Multicenter clinical trials in ACHD must carefully address patient safety concerns. The level of complexity involved in scrutinizing adverse events is dependant, in part, on the study population. In patients with tenuous physiology, such as Eisenmenger or single ventricle physiology, it may be difficult to detect increases in adverse events from already high baseline rates, particularly in smaller populations. With the convenience of electronic and internet-based data transfer capabilities, particular care is required to maximize data security and protect the confidentiality of participants. This entails a comprehensive understanding of national and/ or state protections applicable to medical research; strict adherence to rules or guidelines to ensure appropriate collection, use, and sharing of data; and secure systems for storing both paper and electronic records [41]. Other obstacles to multicenter research in ACHD include the lack of resources required to provide state-of-the-art coordination of collaborative efforts and solid infrastructures for efficient orchestration. As discussed above, in recent years, remarkable progress has been achieved towards this end. 6. Conclusion In order to advance the care of patients with ACHD, evidence-based approaches are critically needed through welldesigned research. The majority of contemporary diagnostic and management strategies in patients with ACHD are based on extrapolations from other patient populations, expert opinion, and single-institutional observational studies. However, significant strides have been achieved over the past few years towards coordinating research efforts and creating dedicated infrastructures. Internationally, a sizeable clinical research workforce is emerging. A critical mass of patients and investigators now permits a new era of multicenter research, with higher and more rigorous standards. Many barriers to collaborative, efficient, and cost-effective studies may be overcome by solidifying existing frameworks, elaborating common goals, and pooling resources and expertise. With these nascent efforts, early successes, and availability of refined resources for data sharing, a solid foundation now exists for a paradigm shift in ACHD research. References [1] Perloff JK, Warnes CA. Challenges posed by adults with repaired congenital heart disease. Circulation 2001;103:2637–43. [2] Gatzoulis MA, Hechter S, Siu SC, Webb GD. Outpatient clinics for adults with congenital heart disease: increasing workload and evolving patterns of referral. Heart 1999;81:57–61. [3] Khairy P, Poirier N, Mercier LA. Univentricular heart. Circulation 2007;115(6):800–12.
[4] Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation 2007;115:163–72. [5] Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. First of two parts. N Engl J Med 2000;342:256–63. [6] Perloff JK. Pediatric congenital cardiac becomes a postoperative adult. The changing population of congenital heart disease. Circulation 1973;47: 606–19. [7] Mark H, Young D. Congenital heart disease in the adult. Am J Cardiol 1965;15:293–302. [8] Perloff JK. Congenital heart disease in adults. A new cardiovascular subspecialty. Circulation 1991;84:1881–90. [9] Ritchie JL, Cheitlin MD, Hlatky MA, Ryan TJ, Williams RG. Task Force 5: Profile of the cardiovascular specialist: trends in needs and supply and implications for the future. J Am Coll Cardiol 1994;24: 313–21. [10] Khoury GH, Marshall RJ. A report on 101 adults with congenital heart disease. Med Times 1971;99:119–25. [11] Cundey Jr PE, Edmonds Jr JH. Adult congenital heart disease analysis of 206 patients. J Med Assoc Ga 1968;57:20–4. [12] Coles JC, Gergely NF, Buttigliero JB. Congenital Heart Disease In The Adult. Surgical Treatment. Arch Surg 1964;89:130–3. [13] Gatzoulis MA, Balaji S, Webber SA, et al. Risk factors for arrhythmia and sudden cardiac death late after repair of tetralogy of Fallot: a multicentre study. Lancet 2000;356:975–81. [14] Siu SC, Sermer M, Colman JM, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001;104: 515–21. [15] Khairy P, Landzberg MJ, Gatzoulis MA, et al. Value of programmed ventricular stimulation after tetralogy of Fallot repair: a multicenter study. Circulation 2004;109:1994–2000. [16] Oosterhof T, van Straten A, Vliegen HW, et al. Preoperative thresholds for pulmonary valve replacement in patients with corrected tetralogy of Fallot using cardiovascular magnetic resonance. Circulation 2007;116:545–51. [17] Khairy P, Landzberg MJ, Gatzoulis MA, et al. Transvenous pacing leads and systemic thromboemboli in patients with intracardiac shunts: a multicenter study. Circulation 2006;113:2391–7. [18] Yap SC, Roos-Hesselink JW, Hoendermis ES, et al. Outcome of implantable cardioverter defibrillators in adults with congenital heart disease: a multi-centre study. Eur Heart J 2007;28:1854–61. [19] Sakazaki H, Niwa K, Echigo S, Akagi T, Nakazawa M. Predictive factors for long-term prognosis in adults with cyanotic congenital heart disease—Japanese multi-center study. Int J Cardiol 2007;120:72–8. [20] Kammeraad JA, van Deurzen CH, Sreeram N, et al. Predictors of sudden cardiac death after Mustard or Senning repair for transposition of the great arteries. J Am Coll Cardiol 2004;44:1095–102. [21] Moons P, Engelfriet P, Kaemmerer H, Meijboom FJ, Oechslin E, Mulder BJ. Delivery of care for adult patients with congenital heart disease in Europe: results from the Euro Heart Survey. Eur Heart J 2006;27: 1324–30. [22] Moons P, Van Deyk K, Marquet K, et al. Individual quality of life in adults with congenital heart disease: a paradigm shift. Eur Heart J 2005;26: 298–307. [23] Dore A, Houde C, Chan KL, et al. Angiotensin receptor blockade and exercise capacity in adults with systemic right ventricles: a multicenter, randomized, placebo-controlled clinical trial. Circulation 2005;112: 2411–6. [24] Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48–54. [25] Williams RG, Pearson GD, Barst RJ, et al. Report of the National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease. J Am Coll Cardiol 2006;47:701–7. [26] Williams JL, Hathaway CA, Kloster KL, Layne BH. Low power, type II errors, and other statistical problems in recent cardiovascular research. Am J Physiol 1997;273:H487–493. [27] Gurvitz MZ, Chang RK, Ramos FJ, Allada V, Child JS, Klitzner TS. Variations in adult congenital heart disease training in adult and pediatric cardiology fellowship programs. J Am Coll Cardiol 2005;46:893–8.
P. Khairy et al. / International Journal of Cardiology 129 (2008) 155–159 [28] Kelsey JL, Whittemore AS, Evans AS, Thompson WD. Methods in Observational Epidemiology. Second edn. Oxford: Oxford University Press; 1996. [29] Hlatky MA, Owens DK, Sanders GD. Cost-effectiveness as an outcome in randomized clinical trials. Clin Trials 2006;3:543–51. [30] Mark DB, Hlatky MA. Medical economics and the assessment of value in cardiovascular medicine: Part I. Circulation 2002;106:516–20. [31] Kulathinal S, Karvanen J, Saarela O, Kuulasmaa K, Project FT. Case– cohort design in practice — experiences from the MORGAM Project. Epidemiol Perspect Innov 2007;4:15. [32] Essebag V, Genest Jr J, Suissa S, Pilote L. The nested case–control study in cardiology. Am Heart J 2003;146:581–90. [33] Wang PS, Schneeweiss S, Glynn RJ, Mogun H, Avorn J. Use of the case-crossover design to study prolonged drug exposures and insidious outcomes. Ann Epidemiol 2004;14:296–303. [34] Moons P, Canobbio MM, Harrison J. The International Adult Congenital Heart Disease Nursing Network: coming together for the future. Prog Cardiovasc Nurs 2006;21:94–6. [35] Mahony L, Sleeper LA, Anderson PA, et al. The Pediatric Heart Network: a primer for the conduct of multicenter studies in children with congenital and acquired heart disease. Pediatr Cardiol 2006;27:191–8.
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[36] van der Velde ET, Vriend JW, Mannens MM, Uiterwaal CS, Brand R, Mulder BJ. CONCOR, an initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: rationale, design, and first results. Eur J Epidemiol 2005;20:549–57. [37] Jacobs JP, Mavroudis C, Jacobs ML, et al. Nomenclature and databases — the past, the present, and the future: a primer for the congenital heart surgeon. Pediatr Cardiol 2007;28:105–15. [38] Franklin RC, Anderson RH, Daniels O, et al. Report of the Coding Committee of the Association for European Paediatric Cardiology. Cardiol Young 2002;12:611–8. [39] Khairy P, Harris L, Landzberg MJ, et al. Implantable cardioverterdefibrillators in tetralogy of Fallot. Circulation 2008;117:363–70. [40] Khairy P, O'Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003;139:753–60. [41] Carney PA, Geller BM, Moffett H, et al. Current medicolegal and confidentiality issues in large, multicenter research programs. Am J Epidemiol 2000;152:371–8.
Editorial
Multicenter research in adult congenital heart disease Paul Khairy ⁎, Jamil Aboul Hosn, Craig Broberg, Stephen Cook, Michael Earing, Deborah Gersony, Joseph Kay, Michael J. Landzberg, Michelle J. Nickolaus, Sasha Opotowsky, Anne Marie Valente, Carole Warnes, Gary Webb, Michelle Z. Gurvitz The Alliance for Adult Research in Congenital Cardiology (AARCC) Received 22 November 2007; received in revised form 24 January 2008; accepted 1 March 2008 Available online 24 June 2008
Keywords: Adult congenital heart disease; Multicenter research; Alliance for Adult Research in Congenital Cardiology (AARCC)
The care of patients with congenital heart disease has evolved over the past half century largely through an iterative paradigm combining creative innovations and astute observations with some early failures and great successes. Extraordinary triumphs have given rise to a rapidly expanding population of adults with congenital heart disease (ACHD) [1–3]. Although it was once true that adult survivors with congenital heart defects had predominantly simple lesions in comparison to children, the spectrum of complexity has progressively transitioned [4]. The number of adults now exceeds children with moderate or severe defects [4,5]. As the burden of disease shifts from the child to the young and older adult with congenital heart disease, research efforts must reflect this changing reality. ACHD caregivers face the challenge of meeting this need in a thoughtful and organized fashion, through carefully designed and orchestrated studies. The collaborative multicenter research study is pivotal in this regard. Herein, we present our perspectives regarding trends and evolution towards multicenter research in ACHD, discuss benefits of collaborative research, and highlight particular challenges. It is our hope that this viewpoint will sensitize the ACHD community to the value of multicenter research in further advancing our field and encourage active participation in these endeavors. ⁎ Corresponding author. Adult Congenital Heart Center, Montreal Heart Institute, University of Montreal, 5000 Bélanger Street, Montreal, Quebec, Canada, H1T 1C8; Boston Adult Congenital Heart (BACH) Service, Children's Hospital Boston, Boston, Massachusetts. Tel.: +1 514 3763330x3800; fax: +1 514 3761355. E-mail address: [email protected] (P. Khairy). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.03.014
1. Evolution of research in ACHD Historically, the field of ACHD was born out of successes in pediatric cardiology [6,7] and was much later recognized as a unique subspecialty [8,9]. Advances in congenital heart disease progressed through an unfolding, incremental, and logical process with occasional radical changes in approach. The ACHD literature initially and appropriately focused on case reports, small case series, and guiding expert commentaries [10–12]. Paralleling the growth of the population of patients with ACHD and strategies implementing centralized care, research emerged as observational single-center cross-sectional and retrospective cohort studies. Survival patterns and risk factors for adverse outcomes in patients with and without surgical or catheter interventions were increasingly defined, leading to a better understanding of health needs in ACHD. With continued growth in the field of ACHD, the critical mass of patients, dedicated facilities, and committed investigators allowed new opportunities, with stimulating and valuable interdisciplinary exchanges. Within this context, multicenter research in ACHD emerged. A systematic electronic search of the MEDLINE database from January 1966 through October 2007, with manual retrieval of primary sources and inclusion of all languages, revealed that over 50 multicenter studies pertaining predominantly to ACHD have thus far been published. More specifically, the following criteria were mandated: 1) study undertaken at two or more institutions with different university affiliations, if applicable; 2) inclusion of at least 10 patients; 3) congenital heart disease documented in over 50% of the study cohort;
156
P. Khairy et al. / International Journal of Cardiology 129 (2008) 155–159
Fig. 1. Multicenter research publications in ACHD.
and 4) mean age of the study population 18 years or older. All such studies were reported in the past 15 years. As depicted in Fig. 1, the number of published multicenter studies has markedly increased over the past decade. To date, multicenter studies in ACHD have been largely limited to observational cohort studies [13–19], with a few case– control studies [20], cross-sectional studies [21,22], and small prospective randomized clinical trials [23,24]. 2. NHLBI recommendations on research in ACHD In 2004, the National Heart, Lung, and Blood Institute (NHLBI) and Office of Rare Diseases, both components of the National Institutes of Health (NIH), convened a Working Group on research in ACHD. Among its summary statements, the group recommended that a network of specialized ACHD centers be formed to design and conduct multicenter research on pressing clinical issues. “These include but are not limited to natural history of specific conditions, interaction of ACHD with adult cardiovascular risk factors, assessment and treatment of ventricular dysfunction, understanding of ventricular–vascular interactions and their role in circulatory failure, predictors of risk for sudden death and serious arrhythmias, understanding of genetic factors influencing outcome, and improved pregnancy management” [25]. The group also recommended that a database be developed to track outcomes, formulate best practices, and foster continuous quality improvement based on these practices [25]. 3. Benefits of multicenter research in ACHD In general, multicenter research affords the following major advantages: firstly, with a cooperative effort involving many centers, studies may be large enough to meet more stringent requirements for statistical analyses. This advantage cannot be
over-stated, as study power is fundamental to any quantitative analysis. A common misinterpretation of inferential statistics is that failure to demonstrate a significant difference between two variables implies that no such difference exists. Equivalency cannot be inferred from most reported negative findings due to insufficient statistical power [26]. Secondly, by virtue of combining several patient populations, multicenter research may minimize or overcome information biases. In some cases, multicenter studies may reduce systematic differences in characteristics between ACHD patients who are selected for study and those who are not. Internal validity may be favorably impacted by reducing selection bias at entry. In other situations, such as potential referral bias, combining patient populations may improve external validity, i.e. generalizability, with little impact on internal validity. Other practical advantages include collaborative sharing of particular expertise and skills regarding specific aspects of research, especially considering the relatively small total number of trained caregivers dispersed across centers [27]. Individual teams, particularly from smaller and medium-size centers, may not have the required patient numbers and/or infrastructures to tackle studies on their own. Multicenter research allows these centers to actively participate, pool resources, and share information. The prototype of the multicenter study is the randomized controlled trial. Benefits of this rigorous study design are widely accepted and include random allocation to prevent known and unknown systematic differences between study groups; blinding to avoid preconceived views from biasing results; standardization of inclusion criteria, definitions, and outcomes assessment; and ease of interpretability of findings. Although randomized controlled trials are powerful tools and rightfully considered the gold-standard for therapeutic interventions, other multicenter study designs may be more aptly suited to address particular study questions of interest. In some situations, observational studies may be the only means of assessing an intervention as a result of ethical and/or practical concerns [28]. Prospective multicenter cohort studies with “hard” clinical end-points generally require large sample sizes and incur high costs for all but the commonest of outcomes. They are often initiated after obtaining sufficient evidence from less expensive case–control, cross-sectional, retrospective cohort, or prospective cohort studies with surrogate end-points. Advantages of these study designs include considerably less cost, completion in a more timely fashion, and possibility of excluding latency periods. Features common to prospective and retrospective cohort studies include the ability to address rare exposures, directly measure risk, calculate incidencedensity rates, and assess multiple outcomes. In contrast, the multicenter case–control study may be better suited for rare outcomes. It is, however, a misconception that case–control studies offer a level of evidence superior to cohort studies as a result of their “controlled” nature. Although case–control studies have their merits, risk estimates are indirect and generally approximate more conclusive direct measurements
P. Khairy et al. / International Journal of Cardiology 129 (2008) 155–159 Table 1 Challenges to multicenter research in ACHD Complexity and heterogeneity of the patient population Divergences in nomenclature and classification Institutional variations in treatment strategies Identification of appropriate clinically relevant end-points Paucity of preliminary data for sample size estimates Recruitment of a sufficiently large number of patients Issues regarding patient safety and confidentiality Research infrastructure for efficient implementation Limited funding opportunities
157
AARCC exists as a research group to foster collaborative relationships between programs and investigators, to further and sustain research efforts, and to include the goals of innovative investigations, advancing knowledge, and improving outcomes. AARCC's first multicenter research studies are currently underway on such diverse topics as exercise stress testing in pregnant women with congenital heart disease, the aortic root and left ventricle in tetralogy of Fallot, and systemic venous anomalies in the univentricular heart. 5. Unique challenges
from cohort studies. Challenges in designing multicenter case–control studies in ACHD include assembly of a case group representative of the target population, identification of a suitable control group, availability of accurate information on potential risk factors and confounders, and inferences regarding cause–effect relationships. Cost-effectiveness analyses [29,30] and alternate study designs such as case–cohort [31], nested case–control [32], and case-crossover [33] studies have yet to be explored in multicenter ACHD research. 4. Research infrastructures Over the past few years, several networks and organizations have made inroads into multicenter research in ACHD. Some have focused on multicenter research as their main objective, whereas others provide a supportive environment that facilitates such research. These networks include, but are not limited to, the International Society for Adult Congenital Cardiac Disease (ISACCD), Canadian Adult Congenital Heart (CACH) network, Congenital Heart Information Network (CHIN), European Society of Cardiology (ESC), Japanese Circulation Society, Alliance for Congenital Quebec Interinstitutional Research (ACQUIRE), Surgical Thoracic Society (STS), and Congenital Heart Surgeon's Society (CHSS). Patient advocacy organizations, such as the Adult Congenital Heart Association (ACHA), are contributing their valuable perspectives and resources towards furthering multicenter research in the field. Nursing groups are also creating alliances, such as the International Adult Congenital Heart Disease Nursing Network (IACHDNN) [34]. As an example of a well-orchestrated and productive infrastructure in children, the Pediatric Heart Network (PHN) is a collaboration of clinical sites, with a designated data coordinating center, that conducts research on pediatric congenital or acquired heart disease [35]. It was created and funded in 2001 by the NHLBI. In the Netherlands, the Interuniversity Cardiology Institute and Heart Foundation developed a national registry and DNA-bank of patients with congenital heart disease, named CONCOR. Objectives are to facilitate investigation of prevalence and long-term outcomes of specific congenital heart defects and their treatment, develop an efficient organizational structure to improve healthcare, and investigate the molecular basis of congenital heart defects [36]. In the United States, an Alliance for Adult Research in Congenital Cardiology (AARCC) was formed in 2006.
Several unique challenges to multicenter research in ACHD are summarized in Table 1. Congenital heart disease is arguably one of the most complex, clinically and morphologically heterogeneous disease states. For research purposes, this may considerably complicate attempts to isolate specific exposure– outcome associations. In some forms of congenital heart disease, nomenclature and classification issues remain a subject of intense debate. Diverse coding and classification schemes between centers may obscure efforts to reliably identify eligible patients and provide a uniform study population for multicenter research. Fortunately, substantial progress has been made towards standardizing nomenclature classification schemes and creating an international coding system [37,38]. Selection of appropriate and relevant primary end-points for multicenter research in ACHD may be challenging. For a given magnitude of effect, sample size requirements to assess such discrete end-points as total mortality or major adverse events may be prohibitive. Consequently, primary end-points are often relegated to surrogate markers. Examples in multicenter ACHD research include appropriate defibrillator shocks to approximate sudden death [18,39] and hemodynamic parameters to assess benefits of pharmacological therapy [24]. Even parameters that have been wellstudied in non-congenital populations, such as echocardiographic Doppler indices of diastolic function, may not be generalizable to patients with ACHD. Moreover, although quality of life metrics are important components of multicenter research in ACHD, few have been validated in this patient population. A situation may also arise where a given therapy or approach becomes a de facto standard of care, in the absence of any real evidence. When the perception that therapeutic equipoise is disrupted, whether well founded or not, ethical concerns must be addressed. Since ACHD encompasses a conglomerate of orphan diseases, assembling a sufficient number of patients for any one study may be challenging. In our experience, initial estimates provided by cursory database searches tend to overestimate the number of patients that ultimately qualify for enrollment. Reasons are likely multifactorial, but may include practical issues related to the follow-up of patients living at a distance from their regional ACHD center of excellence, physician reticence based on prior beliefs, intricacies of informed consent procedures, inaccuracies of diagnostic labels, and patient concerns. Moreover, lack of preliminary
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data on which to base sample size calculations may hinder development of multicenter research protocols. In some situations, sample size estimates have been based on case series or systematic reviews with no formal intra-study comparisons [40]. Although this may represent the best available option, potential inaccuracies are substantial. Multicenter clinical trials in ACHD must carefully address patient safety concerns. The level of complexity involved in scrutinizing adverse events is dependant, in part, on the study population. In patients with tenuous physiology, such as Eisenmenger or single ventricle physiology, it may be difficult to detect increases in adverse events from already high baseline rates, particularly in smaller populations. With the convenience of electronic and internet-based data transfer capabilities, particular care is required to maximize data security and protect the confidentiality of participants. This entails a comprehensive understanding of national and/ or state protections applicable to medical research; strict adherence to rules or guidelines to ensure appropriate collection, use, and sharing of data; and secure systems for storing both paper and electronic records [41]. Other obstacles to multicenter research in ACHD include the lack of resources required to provide state-of-the-art coordination of collaborative efforts and solid infrastructures for efficient orchestration. As discussed above, in recent years, remarkable progress has been achieved towards this end. 6. Conclusion In order to advance the care of patients with ACHD, evidence-based approaches are critically needed through welldesigned research. The majority of contemporary diagnostic and management strategies in patients with ACHD are based on extrapolations from other patient populations, expert opinion, and single-institutional observational studies. However, significant strides have been achieved over the past few years towards coordinating research efforts and creating dedicated infrastructures. Internationally, a sizeable clinical research workforce is emerging. A critical mass of patients and investigators now permits a new era of multicenter research, with higher and more rigorous standards. Many barriers to collaborative, efficient, and cost-effective studies may be overcome by solidifying existing frameworks, elaborating common goals, and pooling resources and expertise. With these nascent efforts, early successes, and availability of refined resources for data sharing, a solid foundation now exists for a paradigm shift in ACHD research. References [1] Perloff JK, Warnes CA. Challenges posed by adults with repaired congenital heart disease. Circulation 2001;103:2637–43. [2] Gatzoulis MA, Hechter S, Siu SC, Webb GD. Outpatient clinics for adults with congenital heart disease: increasing workload and evolving patterns of referral. Heart 1999;81:57–61. [3] Khairy P, Poirier N, Mercier LA. Univentricular heart. Circulation 2007;115(6):800–12.
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