.
`(cid:14)
`Progress in Pediatric Cardiology 12 2000 1]28
`
`Ventricular dysfunction clinical research in infants, children
`and adolescents
`
`Steven E. LipshultzU
`Di¤ision of Pediatric Cardiology, Uni¤ersity of Rochester Medical Center and Children’s Hospital at Strong, and Department of
`Pediatrics, Uni¤ersity of Rochester School of Medicine and Dentistry, 601 Elmwood A¤enue, Box 631, Rochester, NY 14642, USA
`
`Abstract
`
`These two issues of Progress in Pediatric Cardiology comprehensively illustrate the wealth of currently available information
`on the pathophysiology of heart failure, age-related myocardial responsiveness, energy metabolism, cardiopulmonary interac-
`tions, the pressure-volume relationship, the systemic inflammatory response, the management of heart failure, pediatric
`pharmacology, the use of heart failure therapies including digoxin, ACE inhibitors, beta-adrenergic blockers, inotropic agents,
`diuretics, vasodilators, calcium sensitizers, angiotensin and aldosterone receptor blockers, growth hormone, and future gene
`therapy. The etiology and course of ventricular dysfunction in children is poorly characterized. Furthermore, many changing
`developmental properties of the pediatric myocardium and differences in the etiologies of ventricular dysfunction in children
`compared with adults are illustrated in these articles, invalidating the concept that children can safely be considered small
`adults for the purpose of understanding heart failure pathophysiology and treatment. However, these articles reveal that
`strikingly little research in children with ventricular dysfunction exists in terms of well-designed large-scale studies of the
`epidemiology or multicenter controlled clinical
`therapeutic trials. A future research agenda is proposed to improve
`understanding etiologies, course and treatment of ventricular dysfunction in children that is based on organized and funded
`cooperative groups since no one pediatric cardiac center treats enough children with a particular etiology of ventricular
`dysfunction. In conclusion, significant understanding of basic mechanisms of pediatric ventricular dysfunction and effective
`therapies for adults with ventricular dysfunction exist. A multicenter pediatric cardiac ventricular dysfunction network would
`allow improved understanding of diseases and treatments, and result in evidence-based medicine for pediatric patients with
`ventricular dysfunction. Q 2000 Elsevier Science Ireland Ltd. All rights reserved.
`
`Keywords: Congestive heart failure; Pediatrics; Ventricular function; Cardiomyopathy; Clinical trials
`
`1. Introduction
`
`The pathophysiology and pharmacologic treatment
`of ventricular dysfunction in infants, children, and
`adolescents have been reviewed in these two issues of
`Progress in Pediatric Cardiology. The large amount of
`work by contributors to highlight pediatric issues de-
`monstrates many unique and potentially important
`aspects of ventricular dysfunction related to children.
`
`These articles, however, also illustrate how little has
`been done thus far to understand the pathophysiology
`and pharmacotherapy of ventricular dysfunction in
`this population. This summary of where the field of
`pediatric ventricular dysfunction stands will review
`unique aspects of pediatric research, challenges in the
`study of children with ventricular dysfunction, and
`principles of pediatric ventricular dysfunction. Tre-
`mendous opportunities exist to advance our under-
`standing in this area at an unprecedented pace. How-
`ever, many obstacles need to be overcome, including
`ourselves. I was recently approached by a respected
`colleague who explained at great length why he could
`not participate in an active double-blinded, placebo-
`1058-9813r00r$ - see front matter Q 2000 Elsevier Science Ireland Ltd. All rights reserved.
`(cid:14)
`.
`PII: S 1 0 5 8 - 9 8 1 3 0 0 0 0 0 7 6 - X
`
`U Tel.: q1-716-275-6096; fax: q1-716-275-7436.
`(cid:14)
`E-mail address: steve lipshultz@urmc.rochester.edu S.E. Lip-
`]
`.
`shultz .
`
`IKARIA EXHIBIT 2006
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`1
`
`

`

`S.E. Lipshultz r Progress in Pediatric Cardiology 12 2000 1]28
`)
`(
`
`quently in adults and is extremely rare in childhood.
`Yet, for children there are greater productive years
`saved by preventing symptomatic ventricular dysfunc-
`tion. There may be a higher potential for cure from
`ventricular dysfunction in children than in adults. As
`a result, the potential goal of pediatric therapy for
`ventricular dysfunction is more likely to be curative in
`intent,
`in contrast to the palliative intent of most
`adult therapies. Ventricular dysfunction in children is
`more likely to be due to genetic factors while in
`adults exogenous exposures predominate. At this time
`adult causes of ventricular dysfunction may be more
`amenable to prevention than pediatric causes.
`
`2.2. Reliance on anecdotal experience
`
`The art of learning medicine as a series of clinical
`anecdotes is important but an over reliance on anec-
`dotal experience, to the exclusion of clinical research,
`w x
`has pitfalls as well 3 .
`
`2.3. A lack of appreciation for the need to consider the
`length of subsequent sur¤i¤al to understand disease
`process and therapeutic response
`
`The longer a patient remains with LV dysfunction
`the worse the LV dysfunction becomes. Snapshot
`studies examining a high-risk population for LV dys-
`function at a single point in time are inadequate to
`state that the population is normal or non-progres-
`sive. Natural history studies of LV dysfunction are
`particularly important
`in children where we have
`found that the long length of subsequent survival
`coupled with the need of the pediatric myocardium to
`grow in response to increasing somatic growth may
`result in accelerated progressive LV dysfunction. A
`small amount of LV dysfunction early in childhood
`w
`x
`may be particularly problematic later in life 4]40 .
`
`2.4. Paucity of data
`
`(cid:14)
`The risk factors for e.g. age, sex, ethnic origin and
`.
`geographic differences and course of myocardial dys-
`function in infants, children, and adolescents have
`also been studied in a very limited fashion. Conse-
`quently, the results of studies to examine the effec-
`tiveness of therapies for the prevention, treatment, or
`beneficial alteration of the subsequent course of pedi-
`atric myocardial dysfunction are scarce. This is espe-
`cially relevant for pediatric congestive heart failure
`where essentially no prospective multicenter con-
`trolled clinical trials have occurred. Yet, the conse-
`quences of mild left ventricular dysfunction may be
`more significant than in adults and due to growth and
`length of future survival. Heart disease remains the
`leading cause of death in the United States with
`
`2 c
`
`ontrolled clinical trial of therapy for asymptomatic
`LV dysfunction in children because he just knew,
`without the benefit of a controlled clinical trial, that
`this was an effective therapy for his patients. Other
`pediatric cardiologists have lectured at national meet-
`ings stating it is sufficient
`to study, for example,
`pharmacologic agents for ventricular dysfunction in
`adults and, if benefit is found, use the drugs in chil-
`dren with the same illness without clinical trials in
`this age group. Some of the problems with this ap-
`proach are that the disease processes resulting in
`ventricular dysfunction are often different in children
`than adults. Many pediatric conditions have no close
`analogies in the adult. Secondly, the effects of the
`intervention may be unlike those seen in adults. The
`pharmacokinetics of many drugs vary with age and
`their beneficial or adverse effects are different in
`children and adults. Thirdly, children differ from
`adults. Some therapies may not be tolerated by young
`children because they are unpalatable or difficult to
`administer. A final point is that, because the an-
`tecedents of many adult diseases are thought to have
`their origins in early life, studies in very young chil-
`dren, and even antenatally, may identify strategies for
`preventing diseases which have important public
`w x
`health consequences 1 .
`Tremendous advances in pediatric cardiology with
`catheter, surgical, and diagnostic procedures have oc-
`w x
`curred during the past four decades 2 . Unfortu-
`nately, the fields of prevention, therapeutics, and de-
`cision analysis based on very limited or biased data
`for all pediatric ventricular dysfunction have not kept
`pace. A network of cardiologists willing to participate
`and adequate funding for an infrastructural network
`would facilitate research in this area.
`
`2. The current status of clinical research in pediatric
`ventricular dysfunction
`
`2.1. Reliance on data from studies in adults
`
`In many areas of pediatric practice, therapies have
`been studied only in adults, and pediatricians must
`consider whether it is appropriate to generalize from
`adult to child. Although some pediatric cardiologists
`have advocated that treatments proved effective for
`adults with myocardial dysfunction be used in pedi-
`atric patients based on data from adults this may not
`be prudent without further testing.
`There appears to be real differences in incidence,
`implications, expectations, causes, treatment styles,
`and prevention between children and adults with ven-
`tricular dysfunction suggesting that for ventricular
`dysfunction, children should not be considered ‘small
`adults’. Known ventricular dysfunction occurs fre-
`
`IKARIA EXHIBIT 2006
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`

`

`S.E. Lipshultz r Progress in Pediatric Cardiology 12 2000 1]28
`)
`(
`
`3
`
`deaths from congestive heart failure on a steadily
`upward course.
`
`2.5. Lack of e¤idence-based medicine
`
`(cid:14)
`The emerging discipline of research synthesis evi-
`.
`dence-based healthcare has led to greater awareness
`of the need to evaluate critically what is already
`known before either making recommendations for
`clinical practice or embarking on further research
`
`w x41 . Evidence-based medicine is defined as the con-
`scientious, explicit, and judicious use of current best
`evidence in making decisions about the care of indi-
`vidual patients. By highlighting the strengths and
`weaknesses of clinical research in different speciali-
`ties, this process of critical appraisal has shown that,
`by comparison with situations in adults, research
`questions relevant to the health of children may have
`been addressed not at all or only by small, poorly
`w
`x
`designed studies 42 . Reviews of randomized trials
`published during a 15-year period in one specialist
`pediatric journal showed that sample sizes were gen-
`(cid:14)
`erally small
`less than 20 in approx. one-half of the
`.
`studies , only a small proportion were multicenter,
`and reporting of key quality indices was inadequate.
`When subspecialty areas have been reviewed, the
`conclusions have been similar. For example, one re-
`view characterized recent advances in pediatric cardi-
`ology that have led to improved outcomes for surgical
`repair of complex cardiac malformations to clinical
`trial-and-error and the common sense and accumu-
`lated wisdom of astute clinicians, rather than to basic
`w
`x
`science or epidemiology 42 . Clinical trial-and-error
`can occasionally lead to serious errors.
`The four steps involved in translating research into
`(cid:14) .
`practice include: 1 creating evidence through basic
`science research, phenotype]genotype correlations
`since different etiologies may lead to different pheno-
`typic outcomes and a heterogeneous population is of
`limited value, randomized controlled trials, and obser-
`(cid:14) .
`vational studies; 2 summarizing evidence by pub-
`(cid:14) .
`lished meta-analyses; 3 disseminating evidence by
`(cid:14) .
`clinical practice guidelines; and 4 implementing evi-
`w
`x
`dence by clinical pathways 41 .
`The clinical effectiveness of therapy comes from
`w
`x
`randomized controlled trials 43]45 . Observational
`studies have several advantages over randomized,
`controlled trials, including lower cost, greater timeli-
`ness, and a broader range of patients. Although non-
`randomized or observational studies have in the past
`been criticized for bias related to overestimating the
`true efficacy of a given therapy or leading to erro-
`neous
`conclusions,
`recent
`comparisons
`to ran-
`domized, controlled trials suggest little evidence that
`estimates of treatment effects in well-designed obser-
`(cid:14)
`vational studies with either a cohort or a case]con-
`
`.
`trol design are either consistently larger than or
`qualitatively different from those obtained in ran-
`w
`x
`43]45 . These prior
`domized,
`controlled trials
`concerns led observational studies to be limited in
`their use to the identification of risk factors and
`prognostic indicators and to situations in which ran-
`domized, controlled trials would be impossible or
`unethical.
`The clinical data for non-therapeutic questions can
`be derived from observational studies with long fol-
`low-up periods to assess prognosis and from large
`cross-sectional or cohort studies to evaluate the valid-
`w
`x
`ity and importance of diagnostic tests 41 . The valid-
`ity of a diagnostic test frequently relies on surrogate
`endpoints rather than actual patient outcomes and its
`utility is its ability to meaningfully effect patient out-
`comes. Diagnostic tests are rarely evaluated in this
`manner.
`Problems encountered in translating research into
`pediatric practice include a paucity of pediatric clini-
`cal trials, underfunding of pediatric research, lack of
`trained pediatric clinical
`investigators, frequency of
`small underpowered studies, heterogeneity of studies,
`inconsistency between meta-analyses and large ran-
`domized, controlled trials, lack of awareness of exist-
`ing efforts, access to evidence, information overload,
`format not helpful,
`labor-intensive, expensive, and
`x
`w
`waning effectiveness 41 .
`A schism exists between laboratory-based medical
`(cid:14)
`scientists who attempt to understand the biologic and
`.
`molecular processes underlying health and disease
`(cid:14)
`and epidemiologists who try to assess health and
`w
`x
`disease states outcomes in groups of human subjects,
`exposure to factors that may increase or reduce the
`likelihood of health or disease, and the causal rela-
`.
`tionship between these outcomes and exposures , as
`(cid:14)
`.
`well as between classical population-based and clini-
`.
`(cid:14)
`cal patient- and clinical intervention-based epidemi-
`w
`x
`ologists 42 .
`including cardi-
`subspecialists,
`Most pediatric
`ologists, have not acquired the methodologic skills in
`research design and statistical analysis required to
`conduct fundable, hypothesis-driven research. Good
`science requires focus, depth, and a good question.
`Rigorous methods should be coupled to substantive
`expertise to ensure that the hypothesis tested is a
`useful one. Good epidemiologic science is time-con-
`suming and often quite expensive, especially when it
`requires long-term follow-up. There are currently 1470
`US board-certified pediatric cardiologists with approx-
`imately 38 new members each year that trained in the
`w
`x
`46 certified US centers 46 . Most centers graduate
`1]2 physicians each year and over the past decade the
`percentage of all pediatric cardiology graduates
`choosing careers in full-time academic medicine has
`fallen from nearly 65 to 40%, making it more
`
`IKARIA EXHIBIT 2006
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`

`

`S.E. Lipshultz r Progress in Pediatric Cardiology 12 2000 1]28
`)
`(
`
`cardiovascular research. A paucity of funding for such
`research, including cardiomyopathy, is related in part
`to the small number of pediatric cardiovascular scien-
`tists. According to the Manpower Advisory and Pedi-
`atric Cardiology Committees of the American College
`of Cardiology, there were -1000 certified specialists
`in pediatric cardiology in the United States in 1994,
`almost all of whom were centered on patient care and
`w
`x
`diagnostic or interventional techniques 52 . Only a
`limited number of them devoted a substantial effort
`to either clinical or basic biomedical research; fur-
`thermore, such research was largely retrospective, de-
`scriptive, and not controlled. Only 3% of responding
`certified pediatric cardiologists had completed G22
`months of research training, suggesting that
`the
`growth of basic and clinical sciences within the field is
`limited. This was similar to a prior manpower study of
`pediatric cardiology that demonstrated that 20 years
`earlier only 6% of professional activities were devoted
`w
`x
`to research 53 .
`Cooperative groups in pediatric cardiology have
`been helpful at achieving research goals. The Pedi-
`atric Cardiomyopathy Registry, for example, has in-
`creased the likelihood of collaboration and research,
`since it allows prospective capture of cases and, in this
`era of molecular biology, permits new techniques to
`be applied to the study of pediatric cardiomyopathy
`
`w x54 . It is hoped that many advances in the prevention,
`diagnosis, and treatment of cardiomyopathy in the
`young will be realized by the Registry. The field of
`pediatric cardiology has always worked well together
`on multicenter studies and registries. As evidenced by
`their publications, many of the most important clini-
`cal advances in pediatric cardiology have been done
`in the setting of multicenter studies, such as the New
`England Regional Infant Cardiac Program, the United
`States Multicenter Kawasaki Study Group, the Pedi-
`atric Cardiac Surgical Registry, the Northern Great
`Plains Regional Cardiac Program,
`the Balti-
`more]Washington Infant Study,
`the Electrophysi-
`ology Study Group, the Valvuloplasty and Angioplasty
`of Congenital Anomalies Registry, and the Pediatric
`Heart Transplantation Study Group.
`Decoding the human genome will trigger develop-
`w
`x
`ments that will change our daily lives 55]57 . The
`finding of genes responsible for diseases will require
`phenotypically well characterized populations of af-
`fected patients to determine patients whose genotypes
`reveal homogenous defects at high risk of disease and
`then to test etiology-specific therapies on these popu-
`lations. Indeed, even at this time single-nucleotide
`polymorphisms of different genes can be studied by
`CHIP technology and determine, for example, whether
`a patient with ventricular dysfunction is likely to
`decline rapidly on standard drugs for the condition,
`and hence might need more aggressive treatment.
`
`4 c
`
`oncerning whether research in pediatric cardiology
`will expand in the coming years without an organized
`w
`x
`research infrastructure 47 . An annual account of
`research grants funded by the NIH in 1998 showed
`that the number awarded on topics related to pedi-
`w
`x
`atric cardiology to be 117 48 . Yet, only nine of them
`involved a pediatric cardiologist as the project’s prin-
`w
`x
`cipal
`investigator 48 . This is occurring at a time
`when laboratory-based discoveries of new preventive
`or therapeutic interventions will continue to require
`demonstration of efficacy and safety in randomized
`trials. Although more and better epidemiologic stud-
`ies are needed, so too are laboratory investigations
`that can confirm or undermine the associations
`observed in human populations, and explain the
`biochemical and cellular processes underlying them.
`Kramer points out that the future of pediatric re-
`search will depend on the collaboration of basic scien-
`w
`x
`tists and epidemiologists 42 . He cites as an example
`the use of molecular and other biologic markers that
`cannot only provide more valid and precise measure-
`ments of potentially causal exposures and disease
`outcomes but can also be used to assess causal mech-
`w
`x
`anisms and pathways 42 .
`The 1990 US Department of Health and Human
`Services report entitled ‘Healthy People 2000’ noted
`that heart disease was among the five most common
`w
`x
`causes of death in childhood at any age 49 . An
`official policy report approved by the Board of Direc-
`tors of the American Heart Association and written
`by the Task Force on Children and Youth of the
`American Heart Association noted that cardiovascu-
`lar disease occurs more often in children than is
`w
`x
`generally appreciated 50,51 . More than 600 000 chil-
`dren in the United States have an abnormality of the
`cardiovascular system, including at least 40 000 whose
`life expectancy is shortened by an acquired disease
`such as cardiomyopathy. The annual cost of pediatric
`cardiovascular disease is )$8 billion in medical ex-
`penses and lost contributions to the gross national
`product. Cardiomyopathy accounts for an increasing
`number of the pediatric cardiac transplants. Genetic
`abnormalities in contractile proteins or energy-pro-
`ducing enzymes, among others, cause cardiomyopathy
`that becomes manifest in adulthood. Recent advances
`in genetics allow molecular diagnoses in fetal
`life.
`This report acknowledges that cardiomyopathy in
`children is increasing, and while the prevalence is
`unknown,
`‘Eventually more precise classification
`based on genetic advances will allow detection of
`people at risk and provide information about the basis
`of the disease.... With improved understanding of
`precise etiology, more effective and specific treatment
`w
`x
`can be developed’ 50,51 .
`Children represent one-third of the United States
`population, yet they are virtually unrepresented in
`
`IKARIA EXHIBIT 2006
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`

`

`S.E. Lipshultz r Progress in Pediatric Cardiology 12 2000 1]28
`)
`(
`
`5
`
`Dr Francis Collins, director of the Human Genome
`Research Institute, recently said at the 2000 AAP
`meeting that understanding the human genome will
`result in routinely predicting and preventing diseases,
`and treating patients with highly potent designer drugs
`tailored to their own genes. Collins said ‘It’s going to
`have a profound impact on the practice of medicine
`and probably nowhere more so than in pediatrics.
`Virtually all diseases have a genetic component and
`having the genome will accelerate finding genes for
`varied diseases.’ Collins predicted that by 2010 there
`will be predictive genetic tests available for at least 10
`disorders and treatments to lower risks for several
`conditions. By 2020 he predicted gene-based designer
`drugs targeted to the molecular fingerprint of the
`patient’s problem will be available and doctors will be
`ordering genotype tests on patients before writing
`prescriptions. By 2030 Collins stated that individual-
`ized preventive medicine keyed to a person’s genetic
`profile will be routine, infants will be tested at birth,
`and gene therapy and gene-based drug therapy will be
`available.
`
`2.6. Lack of well-designed pharmaceutical industry
`sponsored studies
`
`Pharmaceutical company placebo-controlled trials
`have been inadequately performed in children in the
`(cid:14)
`.
`past. Prescriptions 25% in pediatric wards were for
`drug courses that were either unlicensed or for off-
`label uses. In neonates, only 35% of prescription
`w x
`episodes were licensed 1 . Industry objectives are
`frequently more short-term in duration or low cost
`(cid:14)
`.
`e.g. survey data assembly if possible to meet FDA
`requirements. However, a large increase in industry-
`sponsored pediatric drug trials is currently underway
`due to a new federal law and new FDA regulations
`that 2 years ago began requiring the pharmaceutical
`industry to test the effects of many adult products on
`(cid:14)
`children pediatric drug-study proposals filed with
`FDA, 1999]2000: 184, expected number completed:
`.150 . In December 2000 the FDA will require pedi-
`
`atric study of any adult disease-fighting drug that
`could be prescribed for children with the same dis-
`ease. This is expected to increase the number of US
`children in clinical drug trials from -1000 in 1990 to
`18 000 by 2002. Prior to this legislation there were
`very few pediatric drug-study proposals filed with the
`x
`. w
`(cid:14)
`FDA 1991]1997: 70, number completed: 11 58]62 .
`
`3. The necessary clinical research agenda in pediatric
`ventricular dysfunction
`
`3.1. Understanding heterogeneous etiologies in children
`
`When trying to understand the proper therapy for
`children with ventricular dysfunction it is usually im-
`portant not to view the child as a small adult and
`extrapolate the effects of ventricular dysfunction ther-
`apy for adult ischemia or post-infarction patients to
`the child where a multitude of non-ischemic, non-
`post-infarction etiologies exist. For example, in the
`article on angiotensin-converting enzyme inhibitors in
`this issue we reviewed the effects of this therapy
`based on the pathophysiology of the condition and
`w
`x
`found different reported effects of this therapy 63 . A
`is to have effective individualized, etiology-
`goal
`specific therapeutics. An individualized therapeutic
`approach, based on the etiology of ventricular dys-
`function and possibly other factors, such as drug
`levels or the levels of neurohormones, could result in
`major progress in treating these patients. We have
`examined the effect of growth hormone replacement
`therapy in pediatric LV dysfunction following anthra-
`cycline therapy over a 10-year period and found that,
`unlike adults with LV dysfunction from other etiolo-
`gies, there was not an improvement in LV dysfunction
`on growth hormone therapy compared to controls
`
`w x64 . This suggests that the etiology is extremely im-
`portant in determining whether the therapy will work.
`Similar to etiology-specific therapies for children with
`ventricular dysfunction we have utilized a similar eti-
`ology-specific preventive approach for pediatric
`
`Table 1
`Detection of doxorubicin cardiotoxicity during therapy by cause and comparison to late cardiotoxicity
`
`Cause of
`cardiotoxicity
`
`Depressed energetic
`(cid:14)
`.
`mitochondrial
`Cytokine myocardial
`depressant
`Apoptosis
`Free radical injury
`Myocarditis
`acTnT, cardiac troponin T.
`
`During therapy
`echocardiogram
`y2
`
`y2
`
`"
`y1
`y2
`
`During therapy
`a
`serum cTnT
`
`Late
`echocardiogram
`
`0
`
`0
`
`"
`Gq1
`q2
`
`"
`
`]
`
`y1
`Gy1
`Gy1
`
`IKARIA EXHIBIT 2006
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`

`

`S.E. Lipshultz r Progress in Pediatric Cardiology 12 2000 1]28
`)
`(
`
`rate approaching 50%, suggesting that an aggressive
`approach to the diagnosis and treatment of asympto-
`(cid:14)
`.
`matic patients with DCM is clearly warranted Fig. 1 .
`Small single center series of pediatric DCM ranging
`from 24 to 81 children have suggested 14 factors
`predictive of poor outcomes: decreased LV systolic
`performance at presentation, persistent decreased LV
`systolic performance, a more spherical LV shape, an
`elevated LV end-diastolic pressure,
`increased LV
`mass, increased cardiothoracic ratio on chest radio-
`graph, mural thrombi, age )2 years, no LV hypertro-
`(cid:14)
`.
`phy by electrocardiogram EKG , endocardial fi-
`complex atrial or
`broelastosis,
`ventricular ar-
`rhythmias, persistent CHF, ST and T wave changes on
`EKG, a family history of cardiomyopathy. Most of
`these factors varied or were in conflict between these
`different studies making it impossible to understand
`risk factors for a poor prognosis in children with
`cardiomyopathy at this time. A report of 137 children
`with cardiomyopathy in Turkey from 1984 to 1989
`noted that DCM improved or normalized for 38.5%,
`
`6 p
`
`atients about to receive multiagent chemotherapy
`that includes doxorubicin. Current protocols employ
`multiagent cardioprotection targeted against specific
`etiologies of cardiotoxicity with the goal of no cardiac
`(cid:14)
`.
`injury Table 1 .
`.
`(cid:14)
`Although dilated cardiomyopathy DCM may be
`caused by )75 different disorders, the etiology in
`(cid:14)
`.
`most cases is unknown idiopathic . The course of
`DCM, almost regardless of etiology, is usually pro-
`(cid:14)
`.
`gressive Fig. 1 , with approximately 75% of these
`children dying within 5 years after the onset of symp-
`toms. Most reports give 1- and 2-year mortality esti-
`mates of 25 and 40%, respectively. The cause of death
`in approximately 80% of cases is evenly divided
`between sudden cardiac death and congestive heart
`(cid:14)
`.
`failure CHF . Some authors believe that adults who
`survive more than 2 or 3 years have relatively good
`long-term survival, but no data have been reported in
`children. However, the natural history of incidentally
`discovered, asymptomatic DCM in adults cannot be
`considered a benign diagnosis, with a 7-year mortality
`
`Fig. 1. Stages in the course of pediatric ventricular dysfunction. The identification of risk factors and high risk populations for ventricular
`dysfunction are highlighted where their use may lead to preventive or early therapeutic strategies. The determination of etiology may lead to
`etiology-specific therapies. The numbers 1]5 indicate stage-related points of intervention for preventive and therapeutic strategies and where
`biomarkers and surrogate markers may be used.
`
`IKARIA EXHIBIT 2006
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`

`

`S.E. Lipshultz r Progress in Pediatric Cardiology 12 2000 1]28
`)
`(
`
`7
`
`DCM remained stable or worsened for 50%, and
`11.5% of children died; numbers that are virtually
`identical to the mean values for these parameters
`from all studies from more developed countries such
`as the United States, Canada, and England during
`similar time periods. This suggests that the enormous
`intensive and invasive resources spent on the treat-
`ment of children with DCM in more developed na-
`tions may not have had a significant impact on the
`morbidity or mortality of pediatric DCM, mandating
`the need to more completely understand the course,
`causes, factors predictive of adverse clinical outcomes,
`and newer etiology-specific therapeutics.
`We have found that, in spite of large resources and
`advanced technology, the prognosis of DCM in devel-
`oped nations is no better than in developing nations
`
`w x65 . Furthermore, there has not been a significant
`improvement in outcome for DCM in children in
`published studies over the past four decades. We have
`been involved with studies of the myocardium from
`children with idiopathic dilated cardiomyopathy that
`specifically investigated disturbed myocardial energet-
`ics. We found a high percentage of these patients had
`abnormal mitochondrial enzyme function, mitochon-
`w
`x
`drial deletions, or mitochondrial mutations 66,67 .
`This suggests that treating all children with sympto-
`matic ventricular dysfunction in a similar fashion,
`regardless of etiology, may be detrimental since in-
`otropes, for example, may not be the most efficacious
`therapy for a child with disturbed myocardial energet-
`ics
`from mitochondrial genetic or environmental
`abnormalities.
`
`3.2. Understanding de¤elopmental differences in
`pharmacokinetics
`
`cardiovascular drug
`is known about
`Little
`metabolism in children and this has implications for
`predicting clinically important drug interactions with
`the potential for either excessive drug exposure, ef-
`fect, and toxicity or decreased drug exposure and loss
`w
`x
`of drug effect 58]62 . Historically this has been due
`to ethical, economic, regulatory, and technical issues.
`Dosing children by scaling adult doses based on body
`weight or surface area does not account for develop-
`(cid:14)
`mental changes that affect drug disposition phar-
`macokinetics or tissuerorgan sensitivity to a drug
`.
`(cid:14)
`.
`pharmacodynamics . The pharmacologic impact of
`these developmental changes is uncovered when un-
`expected or severe toxicity leads to pharmacologic
`w
`x
`studies 68,69 . Children metabolize drugs differently
`than adults. Therefore, drugs must be assessed in
`children in terms of increased risk of toxicity and
`reduced efficacy because they may act differently in
`children than in adults. We need earlier evaluation of
`
`drugs and approaches to make access available as
`soon as possible. In oncology, for example, in the past
`20 years there have been 34 new drugs approved for
`use in adult cancers, but only one new drug approved
`w
`x
`to treat cancer in children 58 . Most FDA-approved
`drugs simply state ‘safety and effectiveness in pedi-
`atric patients have not been established.’
`Some of the goals of using combination therapy in
`(cid:14) .
`children with ventricular dysfunction include: 1 To
`reduce morbidity and mortality with improved quality-
`(cid:14) .
`of-life; 2 To treat different mechanisms contributing
`(cid:14) .
`to ventricular dysfunction; 3 To treat for different
`(cid:14)
`effects e.g. drugs to prevent functional deterioration,
`drugs to reduce mortality, and drugs to control symp-
`.
`(cid:14) .
`toms ; 4 To decrease underlying disease complica-
`(cid:14) .
`tions; 5 To reduce treatment toxicity by using lower
`(cid:14) .
`(cid:14) .
`doses; 6 To increase patient compliance; 7 To
`(cid:14) .
`reduce drug dosage or dosing interval; and 8 To
`(cid:14)
`fewest drugs, fewest
`provide rational prescriptions
`.
`side effects, maximal compliance, and minimal cost .
`
`3.3. Understanding unique aspects of pediatric
`recruitment, retention, compliance, and adherence with
`clinical studies
`
`Children and their families h