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• W2054687535 abstract "HomeCirculationVol. 129, No. 19A New START for Sildenafil in Pediatric Pulmonary Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBA New START for Sildenafil in Pediatric Pulmonary HypertensionReframing the Dose–Survival Relationship in the STARTS-2 Trial Doff B. McElhinney, MD Doff B. McElhinneyDoff B. McElhinney From the NYU School of Medicine, Departments of Pediatrics, Cardiothoracic Surgery, and Medicine, New York, NY. Search for more papers by this author Originally published17 Mar 2014https://doi.org/10.1161/CIRCULATIONAHA.114.009584Circulation. 2014;129:1905–1908Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 13, 2014: Previous Version 1 Pharmacotherapy for pulmonary arterial hypertension (PAH) has evolved dramatically over the past decade. One of the agents at the vanguard of this evolution was sildenafil, which was reported in 2005 to improve exercise capacity, functional status, and hemodynamics in a large randomized, controlled trial (RCT) of adults with PAH (Sildenafil Use in Pulmonary Arterial Hypertension-1 [SUPER-1])1 and has since become a therapeutic mainstay.2 On the basis of in part the promising early findings of SUPER-1, sildenafil was studied in treatment-naïve children and adolescents as part of the first ever RCT for pediatric PAH, Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension (STARTS-1), which randomized patients to placebo or 1 of 3 dose ranges of sildenafil.3 After the 16-week evaluation, patients were allowed to remain on therapy in the extension trial, STARTS-2, which continued sildenafil in treated patients and randomized those in the placebo arm to one of the sildenafil doses. STARTS-1 enrolled 234 patients over 4.5 years at 32 centers, the vast majority of whom continued in STARTS-2.Article see p 1914Results of STARTS-1 and survival data from the extension study were published in this journal in 2012.3 The most notable findings were that (1) the prespecified primary outcome (placebo-corrected change in peak oxygen consumption [PVO2] on exercise testing for the combined sildenafil-treated cohort) was not met, although post hoc analysis showed a significant improvement in the medium- and combined medium-/high-dose groups but not the low- or high-dose groups; (2) relevant secondary outcomes, including functional class, pulmonary vascular resistance, and pulmonary artery pressure, improved in high- and medium-dose patients but not in low-dose patients; and (3) survival over time was worse among patients randomized to high- than to low-dose sildenafil.3In August 2012, 7 months after that article was published, the US Food and Drug Administration (FDA) posted a Drug Safety Communication recommending against the use of sildenafil in children with PAH, specifying that its decision was “based on a recent long-term clinical pediatric trial showing that: (1) children taking a high dose of Revatio had a higher risk of death than children taking a low dose and (2) the low doses of Revatio are not effective in improving exercise ability.”4 In other words, the agency inferred an excessive risk of therapy with higher doses and minimal benefit with lower doses and consequently an unfavorable risk-benefit balance across the range of doses studied.By this time, sildenafil, which was approved by the FDA for PAH in adults in 2005, had become a common off-label agent for treating PAH of various origins in children; it had also been approved by the European Medicines Agency for the treatment of pediatric PAH on the basis of the same data available to the FDA.5,6 Needless to say, the FDA’s warning forced the pediatric PAH and cardiology communities in the United States, not to mention the many children who were receiving sildenafil and their parents, into a quandary. Within months of the FDA communication, members of the Pediatric Pulmonary Hypertension Network published a response in which they acknowledged the limitations of the STARTS trial and offered a series of recommendations about the use of sildenafil in children.7 Although diplomatic in tone and prudent in its guidance, the statement could be read as a preliminary refutation of the FDA’s decision.It has now been >1½ years since the FDA issued its warning, which remains in place and is featured in the instructions for use of sildenafil. In that time, several investigators have followed Abman et al7 in working to show that the Drug Safety Communication was overly conservative in its conclusions about both the effectiveness and mortality risk of sildenafil. This effort to set the record straight has included a more nuanced assertion of the benefits of sildenafil in children7–9 and now, in this issue of Circulation, a deeper examination of the mortality data from STARTS-2 that aims to reframe the previously reported dose–mortality relationship.10Arguably, STARTS was a failed trial, but not necessarily because sildenafil was ineffective or unsafe in children or because the trial was misbegotten. Rather, STARTS was a victim of chance, circumstance, miscalculation, and scientific and regulatory ideology. It was designed as and intended to carry the authority of an RCT, but a series of confounders undermined the tenets of this framework, and ultimately, multiple methodological heuristics did not pan out. Thus, before addressing the implications of the present report, it may be useful to consider some of problems and assumptions from which STARTS suffered (along with caveats reflecting reasons they might have been difficult to anticipate or avoid):Given the heterogeneity of patients enrolled (ie, wide age range, PAH of differing origins, variable functional status), STARTS was configured with several potentially incongruous aims—dose finding, clinical efficacy, and long-term survival—and inadequate statistical power to support them all. Thus, there was a lot riding on the assumption that stratified randomization would effectively distribute risk for all of the outcomes assessed across the many potentially relevant covariates. (Caveat: Enrollment for pediatric trials, particularly for rare and heterogeneous conditions, is difficult, and the chosen design was likely the most efficient in a variety of ways.)Survival in the treatment arms was not compared with survival in a placebo group or with prespecified objective performance criteria. (Caveat: There were few contemporary data on outcomes of comparable treatment-naïve patients, and long-term randomization to placebo alone would have been ethically and practically impossible.)Dose ranges were defined on the basis of predicted plasma concentrations derived by scaling adult pharmacokinetic data. Actual plasma concentrations were later found to be lower than predicted in patients who received low-dose sildenafil and were likely higher than expected in medium- and high-dose patients >30 kg.10,11 (Caveat: Pediatric pharmacokinetic data for sildenafil did not exist when the study was designed, and in any event, available formulations limited flexibility in dosing.)From SUPER-1, it was assumed that there would be a similar treatment effect across the dosing ranges, but this assumption proved to be erroneous in that primary and secondary outcomes did not improve in the low-dose group. (Caveat: There was no basis to assume that efficacy would differ according to dose, and estimation of appropriate dose ranges was inaccurate, as discussed above.)The effect size used for power calculations in STARTS-1 was overly generous. A 15% placebo-corrected improvement in PVO2 was estimated for the combined sildenafil group, similar to the increase in the 6-minute walk distance in SUPER-1.1 However, extrapolating from plots in the study cited to support the correlation between PVO2 and 6-minute walk distance in adults,12 a 15% increase in 6-minute walk distance for SUPER-1 patients would have corresponded to a 10% to 11% change in PVO2.1 (Caveat: Powering STARTS-1 to a smaller effect size would have required substantial increases in sample size, time, and cost.)These are just a few of the limitations specific to STARTS that may have contributed to its ambiguous efficacy and survival findings. In addition to contextualizing the legacy of STARTS, enumerating them here should serve as a reminder of the difficulties inherent in undertaking a groundbreaking study under the RCT rubric in a patient population that may not have been suited to such a rigidly conventional approach. The complexities of performing drug or device trials for pediatric cardiovascular conditions, including PAH, are well documented.13–15 PAH in children is a heterogeneous disease that spans the spectrum of childhood, and appropriate clinical and study end points are unclear. It is managed variably and often off-label with agents that are approved for adults, thus making it difficult to find treatment-naïve patients, complicating randomization to a placebo, and precluding an understanding of the contemporary natural history of the various subtypes of PAH. Even when the disease and population are amenable to more robust sampling, RCTs are inherently limited, but for conditions such as pediatric PAH, the foundations of the method are even less stable.16 This is not to suggest that the RCT approach is a priori inappropriate to study pediatric PAH and similarly rare and heterogeneous diseases, but if such patients are to be served effectively, the regulatory paradigm must incorporate a more expansive vision of drug and device evaluation and approval.13,17–19To their credit, the authors of the present article did not cry foul and rely on that line of defense. Rather, they followed a judicious but demanding strategy of remaining true to the ideal of the RCT method while simultaneously implying what they believed to be the deeper truth, that the dose–mortality association was a stochastic aberration. To be sure, the task of this report was uniquely awkward in that it pursued the dissonant objectives of upholding the RCT method, clarifying the problematic dose–survival data without adequate statistical power to do so authoritatively, and advancing the justifiable agenda of reframing the implications of the 2012 article.3 This is a challenging course to navigate, and the care the authors took was evident. For instance, even as they insinuated the flaws in the prior prespecified analyses by summarizing aggregate data for several subgroups of patients, they resorted to post hoc analyses only sparingly and without appending P values, in effect affirming the validity of the RCT dogma vis-à-vis STARTS. Along the same lines, their observation that multivariable modeling with clinically relevant covariates lowered the hazard ratio for the high-dose sildenafil group supported the contention that other factors predominated in explaining survival, but these analyses were not overwrought or overemphasized. Given the delicacy of the task, the article was understandably tentative in places. On occasion, this reticence could leave the impression that prior and newly presented data were not synthesized cogently in support of the case that mortality and high-dose sildenafil in STARTS-2 were not causally related. In particular, a more decisive position and committed dissection of the data such as revealing the distributions of weight range, diagnostic category, functional status, and hemodynamic parameters across one another might have helped identify whether and how failed randomization contributed to the erroneous association between dose and survival, which would have been a convincing revelation.A valuable complement to the glimpse of complexity offered by the limited multivariable modeling was the disclosure of multiple lines of evidence that patients who died in STARTS-2 were sicker at enrollment and more likely to have idiopathic or heritable PAH than survivors. Of course, the preponderance of deaths in these patients would be expected from registry data, and although confirmation of this bias may not speak to the mortality-treatment relationship per se, given that such patients were not clearly overrepresented in the high-risk dose group, it reinforces normative assumptions about the study population and, as a result, indirectly attenuates the dose–survival finding.There are at least 2 good reasons to doubt the dose–survival relationship found in the original STARTS report3: (1) The purported relationship lacks face validity, and (2) the survival analysis was seriously confounded and was not adequately adjusted. With increasingly detailed data, including the information presented in the present report, it has become apparent that the particular dose–survival relationship documented in STARTS was likely a statistical artifact. For example, as the authors pointed out, the relationship between high-dose sildenafil and poorer survival in STARTS-2 was largely accounted for by mortality among patients in the middle of 3 weight groups, which is inconsistent with a primary dose–effect relationship. However, they did not broach the equally pertinent question of how, mechanistically, higher-dose sildenafil might accelerate or cause death in patients with pediatric PAH. Although there is some evidence of rare but real concerns about heart failure and arrhythmia with sildenafil, there are insufficient data to support a plausible mechanism.20Aside from the aforementioned data that helped illustrate the texture of the group of patients who died, another important contribution of the present report was its elucidation of the extensive confounding that compromised the survival analysis, some inevitable and some potentially avoidable. In addition to the factors discussed earlier, an important confounder that was revealed only in the present analysis was the fact that, in STARTS-2, physicians had the option of titrating the sildenafil dose. Among patients who continued in the extension study, 22% had an uptitration, including 51% of those initially randomized to low-dose sildenafil. Moreover, at the time of death or censoring, 30% of patients were “off treatment” (no longer on sildenafil within the trial), but no information was available about therapy or functional outcomes in these patients. Altogether, only 27%, 55%, and 68% of patients randomized to the low-, medium-, and high-dose groups remained on the same dose throughout. At its inception, the study was not powered to assess relative survival between dosing groups, and with the inevitable confounding that the extensive changes in therapy during START-2 imparted to an intention-to-treat dose–survival analysis, the ground was even less firm.Although the data and analyses in the present article do not clear the air completely, they help to reframe the discussion, illuminating a number of pertinent factors that should be considered in interpreting the risk-benefit balance of sildenafil in this population. Although ambivalent at times, the message of this report can be distilled down to a simple resounding thesis, that the risk of therapy-related mortality in children treated with sildenafil for PAH is lower than the FDA inferred. It seems that most stakeholders agree. What is done is done, and at this point, the important thing is how the data, as problematic as they may be, are integrated into the rapidly evolving narrative of pediatric PAH. The present report should influence this process, and to the extent that it does, it will serve as a valuable addition to the field.It has now been more than a decade since STARTS-1 began and almost 10 years since sildenafil was approved for treatment of PAH in adults, and the landscape has only become more complicated: Pfizer’s patents on sildenafil have expired, a growing number of PAH therapies are entering the market and preclinical investigation, and there is a growing trend toward combination regimens that act on multiple pathophysiological pathways. In this environment, it is unlikely that another RCT of sildenafil monotherapy in children will be performed in the United States, and it is difficult to imagine a pathway to pediatric approval. However, it is reasonable to hope that the FDA will reconsider its warning, that is, to hope for a new start for sildenafil in pediatric PAH.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Doff B. McElhinney, MD, NYU School of Medicine, Departments of Pediatrics, Cardiothoracic Surgery, and Medicine, 403 E 34th St, 4th Floor, New York, NY 10016. E-mail [email protected]References1. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension.N Engl J Med. 2005; 353:2148–2157.CrossrefMedlineGoogle Scholar2. Galiè N, Corris PA, Frost A, Girgis RE, Granton J, Jing ZC, Klepetko W, McGoon MD, McLaughlin VV, Preston IR, Rubin LJ, Sandoval J, Seeger W, Keogh A. 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Beghetti M, Wacker Bou Puigdefabregas J and Merali S (2014) Sildenafil for the treatment of pulmonary hypertension in children, Expert Review of Cardiovascular Therapy, 10.1586/14779072.2014.958077, 12:10, (1157-1184), Online publication date: 1-Oct-2014. Butrous G (2014) The role of phosphodiesterase inhibitors in the management of pulmonary vascular diseases, Global Cardiology Science and Practice, 10.5339/gcsp.2014.42, 2014:3, (42), Online publication date: 1-Oct-2014. May 13, 2014Vol 129, Issue 19 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.114.009584PMID: 24637560 Originally publishedMarch 17, 2014 KeywordsUnited States Food and Drug Administrationhypertension, pulmonaryEditorialsrandomized controlled trialheart diseasesPDF download Advertisement SubjectsCongenital Heart DiseasePulmonary Hypertension" @default.
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