EDITORIALS
`
`52 000 participants (32 000 with prior cardiovascular dis-
`ease in unfortified populations, 14 000 with prior cardio-
`vascular disease in fortified populations, and 6000 with
`renal disease in fortified populations); thus, the meta-
`analysis should be sufficiently powered to detect a 10%
`reduction in rates of major vascular events, major coronary
`events, and stroke.
`In the meantime, based on existing data, including the
`findings of the HOST trial by Jamison et al, there is insuf-
`ficient evidence to justify routine use of homocysteine-
`lowering vitamin supplements for the prevention of vascu-
`lar events among individuals at high risk for vascular disease.
`Financial Disclosures: None reported.
`
`REFERENCES
`
`1. McCully KS. Homocysteine and vascular disease. Nat Med. 1996;2(4):386-
`389.
`2. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assess-
`ment of plasma homocysteine as a risk factor for vascular disease: probable ben-
`efits of increasing folic acid intakes. JAMA. 1995;274(13):1049-1057.
`3. Danesh J, Lewington S. Plasma homocysteine and coronary heart disease: sys-
`tematic review of the published epidemiological studies. J Cardiovasc Risk. 1998;
`5(4):229-232.
`4. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart
`disease and stroke. JAMA. 2002;288(16):2015-2022.
`5. Klerk M, Verhoef P, Clarke R, et al. MTHFR 677C→T polymorphism and risk
`of coronary heart disease: a meta-analysis. JAMA. 2002;288(16):2023-2031.
`
`6. Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C→T poly-
`morphism and coronary heart disease: does totality of evidence support causal role
`for homocysteine and preventive potential of folate? BMJ. 2005;331(7524):
`1053.
`7. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evi-
`dence on causality from a meta-analysis. BMJ. 2002;325(7374):1202.
`8. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and
`stroke: evidence on a causal link from mendelian randomisation. Lancet. 2005;
`365(9455):224-232.
`9. Wald DS, Morris JK, Law M, Wald NJ. Folic acid, homocysteine, and cardio-
`vascular disease: judging causality in the face of inconclusive trial evidence. BMJ.
`2006;333(7578):1114-1117.
`10. Baker F, Picton D, Blackwood S, et al. Blinded comparison of folic acid and
`placebo in patients with ischaemic heart disease: an outcome trial. Circulation.
`2002;106(1)(suppl II):2-741.
`11. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in pa-
`tients with ischemic stroke to prevent recurrent stroke, myocardial infarction and
`death. JAMA. 2004;291(5):565-575.
`12. Bønaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardio-
`vascular events after acute myocardial infarction. N Engl J Med. 2006;354(15):
`1578-1588.
`13. Lonn E, Yusuf S, Arnold MJ, et al; Heart Outcomes Prevention Evaluation (HOPE)
`2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular
`disease. N Engl J Med. 2006;354(15):1567-1577.
`14. Jamison RL, Hartigan P, Kaufman JS, et al; Veterans Affairs Site Investigators.
`Effect of homocysteine lowering on mortality and vascular disease in advanced
`chronic kidney disease and end-stage renal disease: a randomized controlled trial.
`JAMA. 2007;298(10):1163-1170.
`15. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementa-
`tion on risk of cardiovascular diseases: a meta-analysis of randomized controlled
`trials. JAMA. 2006;296(22):2720-2726.
`16. B-Vitamin Treatment Trialists’ Collaboration. Homocysteine-lowering trials for
`prevention of cardiovascular events: a review of the design and power of the large
`randomized trials. Am Heart J. 2006;151(2):282-287.
`
`The Importance of Randomized Controlled
`Trials in Pediatric Cardiology
`
`Samuel S. Gidding, MD
`
`EXPERIENCE WITH RANDOMIZED CONTROLLED CLINI-
`
`cal trials in pediatric cardiology is limited. Perhaps
`the most cited article in the field had a sample size
`of 1, a baby with transposition of the great arteries
`who successfully underwent balloon dilation of a patent fo-
`ramen ovale.1 When this procedure was found to improve
`survival from a median of less than a week to several years,
`the immediate challenge to clinicians was not to replicate
`the finding by a randomized trial but to determine how best
`to manage a living child with an oxygen saturation of 60%
`to 70% and persistent complex anatomical defects.
`Within 25 years and incorporating many technical inno-
`vations into diagnosis and management, more than 95% of
`children born with this defect survived an arterial switch
`procedure with little morbidity until adulthood.2,3 Along the
`path to these results, many treatment centers simply con-
`verted from performing the conventional “venous switch”
`procedure to an arterial switch procedure because of the high
`
`See also p 1171.
`
`prevalence of right ventricular dysfunction and atrial dys-
`rhythmias associated with the older procedure.2,3 This
`achievement best exemplifies the “craft” era, when indi-
`vidual skill combined with rapidly improving technology
`substantially improved long-term survival for most congen-
`ital heart defects.
`An important question is why, when a successful surgi-
`cal procedure, the “venous switch,” was widely accepted,
`did cardiologists and surgeons completely convert to a tech-
`nically more difficult, completely different procedure, the
`arterial switch? How could such a radical change in therapy
`be advocated and accepted without the type of “gold stan-
`dard” evidence provided by a randomized trial? Arguably,
`there were 2 reasons. One is that the success of the inter-
`vention relied on the skills of a complex multidisciplinary
`team repeatedly performing the same task; randomization
`either within or by treatment center seemed both inappro-
`priate, impractical, and perhaps even unethical3 A second,
`and perhaps more compelling reason relates to a fundamen-
`
`Author Affiliations: Nemours Cardiac Center, A. I. duPont Hospital for Children,
`Wilmington, Delaware; Jefferson Medical College, Philadelphia, Pennsylvania.
`Corresponding Author: Samuel S. Gidding, Nemours Cardiac Center, 1600 Rock-
`land Rd, Wilmington, DE 19803 (sgidding@nemours.org).
`
`1214 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
`
`©2007 American Medical Association. All rights reserved.
`
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`
`tal difference between pediatric and adult medicine. A pal-
`liated infant living with substantial morbidity as an adoles-
`cent and young adult is an unsatisfactory result. Just as the
`“venous switch” performed at younger ages eliminated the
`morbidity of chronic hypoxemia in infants, the arterial switch
`held out the hope that an affected infant’s future would not
`include right ventricular failure and chronic untreatable dys-
`rhythmias. Return to near normal life expectancy after treat-
`ment measured in decades rather than months or years as
`in adult trials was the goal.
`There are several other possible reasons for the limited
`use of randomized clinical trials in pediatric cardiology: the
`relative rarity of individual diseases, the heterogeneity of pre-
`sentation, rapid changes in technology making older diag-
`nostic and therapeutic techniques obsolete, the impor-
`tance of individual physician skill to outcome, difficulties
`in subject recruitment, etc. Nevertheless, when clinical trials
`have been performed, their effect has been substantial. Ma-
`jor trials performed in the 1980s and early 1990s initiated
`the pharmacological treatment for patent ductus arterio-
`sus,4 defined optimal treatment for Kawasaki disease,5 and
`made rigorous the search for optimal cerebral protection dur-
`ing cardiopulmonary bypass in infants.6
`During the last decade, because of US Food and Drug Ad-
`ministration requirements for licensing of devices and the
`mandate to collect data in pediatric patients to obtain indi-
`cations for use of new pharmaceutical agents in children,
`many randomized trials in children have been financed by
`industry. In cardiology, important information has been ac-
`quired about the safety and efficacy of different catheter-
`based interventions as have medications for hypertension
`and dyslipidemia. These studies have been mutually ben-
`eficial for drug companies and pediatric research even though
`results have not been sufficiently published.7-9 For ex-
`ample, a table providing doses of antihypertensive medica-
`tions validated from clinical trials has been published as part
`of an evidence-based clinical guideline.10 A critical out-
`come of such studies is the recognition that results in chil-
`dren and adults are not necessarily the same.
`In this issue of JAMA, Shaddy and colleagues11 report some-
`what disappointing results from a randomized trial of carve-
`dilol use for children with heart failure; study participants
`surprisingly did not seem to benefit from treatment. These
`findings stand in stark contrast to results from randomized
`trials involving adults and also anecdotal reports of suc-
`cessful experience in small uncontrolled studies.
`Despite the findings, the study by Shaddy et al is not the
`final word in pediatric heart failure research but, rather, is
`a first and important step in a new era for the field. The les-
`sons learned in the conduct of this trial were considerable.
`First, within the context of randomized trials, the out-
`comes of children with heart failure are different from adults,
`particularly in young children. This finding suggests that
`the study was significantly underpowered. Second, in at-
`tempting to recruit a sufficient sample size, the investiga-
`
`EDITORIALS
`
`tors combined patients with single ventricle physiology and
`those with conventional left ventricular systolic dysfunc-
`tion into 1 group. The outcomes were significantly poorer
`for those with systemic right ventricle. Third, carvedilol is
`metabolized more rapidly in children than in adults, and,
`therefore, dosing may need to be different. Fourth, there is
`greater etiologic heterogeneity of disorders causing dilated
`cardiomyopathy in childhood, another possible factor lead-
`ing to the negative result.12 Fifth, in the absence of consen-
`sus criteria for the diagnosis of congestive heart failure in
`infants and children, Shaddy et al were forced to rely on a
`composite subjective end point related to assessment of clini-
`cal improvement by parents and clinicians.11 And sixth, an
`important reassuring finding is that carvedilol did not ap-
`pear to cause harm, paving the way for more ambitious fu-
`ture trials.
`Recruitment has been a significant problem for conduct-
`ing randomized trials in pediatric cardiology. The study by
`Shaddy et al has a sample size an order of magnitude (160
`rather than ⬎1000) less than comparable adult studies .11,13
`The same sense of urgency that inspired efforts to convert
`from the “venous switch” to the arterial switch for trans-
`position of great arteries must inform current relationships
`with patients to improve recruitment into clinical trials. Much
`more needs to be learned about pediatric heart failure and
`the long-term care of congenital heart disease survivors. For
`example, a survey of those who care for patients with a single
`ventricle revealed that the most important factor predict-
`ing prescribing practice of digoxin, diuretics, angiotensin-
`converting enzyme inhibitors, and anticoagulation was not
`by clinical profile but by medical center submitting data to
`the registry.14 These data provide the ethical rationale for a
`new effort at defining optimal cardiovascular therapy by re-
`cruiting patients into trials rather than continuing to treat
`patients using agents without proven efficacy. The Na-
`tional Heart, Lung, and Blood Institute–funded Pediatric
`Heart Network and registries devoted to specific pediatric
`cardiac problems have initiated multicenter randomized stud-
`ies with these objectives in mind.15
`A subtle but important difference between pediatric and
`adult research relates to goals. Adult cardiac trials, whether
`related to heart failure or prevention of recurrent myocar-
`dial infarction, are considered successful when the inevi-
`table is delayed. For most adults, the inevitable still occurs.
`For children with heart disease, the goals are different: to
`treat pediatric patients effectively so that they can experi-
`ence decades of as normal a quality of life as possible. This
`difference provides the ethical rationale for independent pe-
`diatric clinical research and rigorous clinical trials in pedi-
`atric patients as opposed to a reliance on adult outcomes,
`which often are not generalizable to children. After all, and
`especially in pediatric cardiology research and treatment,
`children are not simply little adults.
`
`Financial Disclosures: None reported.
`
`©2007 American Medical Association. All rights reserved.
`
`(Reprinted) JAMA, September 12, 2007—Vol 298, No. 10 1215
`
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`
`IKARIA EXHIBIT 2009
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`

`
`EDITORIALS
`
`REFERENCES
`
`1. Rashkind WJ, Miller WW. Creation of an atrial septal defect without thora-
`cotomy: a palliative approach to complete transposition of the great arteries. JAMA.
`1966;196(11):991-992.
`2. Mahony L, Turley K, Ebert P, Heymann MA. Long-term results after atrial re-
`pair of transposition of the great arteries in early infancy. Circulation. 1982;66
`(2):253-258.
`3. Kirklin JW, Blackstone EH, Tchervenkov CI, Castaneda AR. Clinical outcomes
`after the arterial switch operation for transposition: patient, support, procedural,
`and institutional risk factors. Circulation. 1992;86(5):1501-1515.
`4. Peckham GJ, Miettinen OS, Ellison RC, et al. Clinical course to 1 year of age in
`premature infants with patent ductus arteriosus: results of a multicenter random-
`ized trial of indomethacin. J Pediatr. 1984;105(2):285-291.
`5. Newburger JW, Takahashi M, Burns JC, et al. The treatment of Kawasaki
`syndrome with intravenous gamma globulin. N Engl J Med. 1986;315(6):341-
`347.
`6. Bellinger DC, Wypij D, Kuban KC, et al. Developmental and neurological
`status of children at 4 years of age after heart surgery with hypothermic
`circulatory arrest or low-flow cardiopulmonary bypass. Circulation. 1999;100
`(5):526-532.
`7. Lock JE. Device availability for the child with heart disease. J Am Coll Cardiol.
`2007;49(22):2222.
`
`8. Li JS, Eisenstein EL, Grabowski HG, et al. Economic return of clinical trials
`performed under the pediatric exclusivity program. JAMA. 2007;297(5):
`480-488.
`9. Benjamin DK Jr, Smith PB, Murphy MD, et al. Peer-reviewed publication of clini-
`cal trials completed for pediatric exclusivity. JAMA. 2006;296(10):1266-1273.
`10. National High Blood Pressure Education Program Working Group on High Blood
`Pressure in Children and Adolescents. The fourth report on the diagnosis, evalu-
`ation, and treatment of high blood pressure in children and adolescents. Pediatrics.
`2004;114(2 suppl 4th rep):555-576.
`11. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adoles-
`cents with heart failure: a randomized controlled trial. JAMA. 2007;298(10):
`1171-1179.
`12. Towbin JA, Lowe AM, Colan SD, et al. Incidence, causes, and outcomes of
`dilated cardiomyopathy in children. JAMA. 2006;296(15):1867-1876.
`13. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity
`and mortality in patients with chronic heart failure. US Carvedilol Heart Failure
`Study Group. N Engl J Med. 1996;334(21):1349-1355.
`14. Anderson PA, Atz AM, Breibart RE, et al. The Fontan Patient: present medical
`therapy at seven pediatric cardiology centers. Circulation. 2005;112(17)(suppl 3):
`420.
`15. 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 ac-
`quired heart disease. Pediatr Cardiol. 2006;27(2):191-198.
`
`Cardiovascular Risk
`and the Thiazolidinediones
`De´ jà Vu All Over Again?
`
`Daniel H. Solomon, MD, MPH
`Wolfgang C. Winkelmayer, MD, ScD
`
`IN 2005, THE US FOOD AND DRUG ADMINISTRATION (FDA)
`
`held an advisory committee meeting to help determine
`the safety of selective cyclooxygenase 2 (COX-2) in-
`hibitors, a popular group of drugs with a novel mecha-
`nism of action but with incompletely understood effects on
`the cardiovascular system. Although these drugs have some
`potential benefits with respect to gastrointestinal toxic ef-
`fects, their benefit-risk ratio was and is still unclear. Fast
`forward 2 years to 2007, and the FDA held a similar advi-
`sory committee meeting about the safety of rosiglitazone, a
`widely used thiazolidinedione (TZD) with known benefits
`on glycemic control but potential cardiovascular toxic ef-
`fects. What have clinicians, patients, and the public learned
`through these recent events?
`The TZDs sensitize end organs to insulin through their
`effect on the peroxisome proliferation–activated receptor ␥
`(PPAR-␥). The PPAR system is a group of nuclear recep-
`tors (␣, ␥, and ␦) that serve as transcription factors for genes
`important in glucose, lipid, and bone metabolism.1 The var-
`ied actions of the PPAR system fueled enthusiasm for the
`potential benefits of TZDs, even beyond their effects on hy-
`perglycemia. However, early toxic effects observed with these
`agents, such as hepatic and heart failure,2 should have fueled
`
`See also pp 1180 and 1189.
`
`equal levels of caution. The heart failure observed with rosi-
`glitazone and pioglitazone prompted changes in the warn-
`ing section of the package inserts but no “black box” warn-
`ing until very recently.3
`Approval of the TZDs was based on their ability to re-
`duce blood glucose levels and glycated hemoglobin levels.
`Little information was available on their effects on the mac-
`rovascular complications of diabetes before these agents were
`approved. Since their marketing, few adequately powered
`randomized controlled trials have been conducted in mod-
`erate- or high-risk patients to definitively determine the true
`benefits of these agents on macrovascular complications. The
`only completed trial that was specifically designed and pow-
`ered to evaluate the efficacy of a TZD in reducing hard car-
`diovascular outcomes was the Prospective Pioglitazone Clini-
`cal Trial in Macrovascular Events (PROactive), a placebo-
`controlled randomized trial in patients with evidence of
`existing macrovascular disease who otherwise received usual
`diabetes care.4 The study failed to show a significant ben-
`efit of pioglitazone treatment on the primary composite end
`point of cardiovascular, cerebrovascular, and peripheral vas-
`cular outcomes. However, pioglitazone reduced by 16% a
`secondary composite end point including death from any
`
`Author Affiliations: Division of Pharmacoepidemiology (Drs Solomon and Winkel-
`mayer) and Rheumatology, Immunology, and Allergy (Dr Solomon), and Renal
`Division (Dr Winkelmayer), Department of Medicine, Brigham and Women’s Hos-
`pital, Harvard Medical School, Boston, Massachusetts.
`Corresponding Author: Daniel H. Solomon, MD, MPH, Division of Rheumatol-
`ogy, 75 Francis St, Boston, MA 02115 (dhsolomon@partners.org).
`
`1216 JAMA, September 12, 2007—Vol 298, No. 10 (Reprinted)
`
`©2007 American Medical Association. All rights reserved.
`
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