Planning and Conducting the ISCHEMIA Trial
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 14 Linguagem: Inglês
10.1161/circulationaha.118.036904
ISSN1524-4539
AutoresDavid J. Maron, Robert A. Harrington, Judith S. Hochman,
Tópico(s)Advanced MRI Techniques and Applications
ResumoHomeCirculationVol. 138, No. 14Planning and Conducting the ISCHEMIA Trial Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBPlanning and Conducting the ISCHEMIA TrialSetting the Record Straight David J. Maron, MD, Robert A. Harrington, MD and Judith S. Hochman, MD David J. MaronDavid J. Maron David J. Maron, MD, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Falk CVRC 265, Stanford, CA 94305–5406. Email E-mail Address: [email protected] Department of Medicine, Stanford University School of Medicine, CA (D.J.M., R.A.H.). , Robert A. HarringtonRobert A. Harrington Department of Medicine, Stanford University School of Medicine, CA (D.J.M., R.A.H.). and Judith S. HochmanJudith S. Hochman Department of Medicine, New York University School of Medicine, New York, NY (J.S.H.). Originally published16 Aug 2018https://doi.org/10.1161/CIRCULATIONAHA.118.036904Circulation. 2018;138:1384–1386Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 16, 2018: Ahead of Print As members of the leadership of the ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches),1 a large, international, ongoing National Institutes of Health–funded clinical trial, we write to provide insight into why the study group made certain trial design decisions after the trial started enrolling patients. These decisions were made to preserve the trial's ability to address the primary aim in our grant proposal to the National Heart, Lung, and Blood Institute (NHLBI): "The primary aim of the ISCHEMIA trial is to test the hypothesis that in patients with moderate-severe ischemia on stress imaging, a routine early invasive strategy (INV) with cath followed by optimal revascularization plus OMT [optimal medical therapy] is superior to a conservative strategy (CON) of OMT, with cath and revascularization reserved for those with refractory symptoms or deterioration in clinical status for reducing the incidence of cardiovascular death, MI [myocardial infarction], or hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure (acute cardiac event) in patients with moderate-severe myocardial ischemia and left ventricular ejection fraction ≥35% over an average 3.7 years of follow-up." The grant to conduct the trial with that primary aim was awarded by NHLBI in 2011.2When designing and conducting a large randomized clinical trial, after settling on the primary hypothesis and target patient population, choices must be made early in the process that may subsequently impact the ability of the trial to achieve its specific aim. These decisions are based on several assumptions, including importance to patients, anticipated event rate and effect size used to calculate an adequately powered sample size, and potential for bias in event ascertainment and reporting. Often there is limited evidence during the planning phase of a trial on which to base these assumptions. Investigators must estimate the number of sites required to meet recruitment milestones, determine an adequate period of follow-up for events to accrue, and consider rates of nonadherence to the protocol and potential loss to follow-up. Investigators must decide whether the design should be a pragmatic effectiveness trial, mimicking routine clinical practice as closely as possible, or an efficacy trial, with core laboratory review of entry criteria and central monitoring of protocol adherence. The drivers of these decisions are clinical, statistical, operational, financial, and sociocultural factors that may only emerge after the study transitions from the theoretical phase (grant application process) to the applied phase (grant award). As the trial progresses, factors such as actual recruitment rates, aggregate event rates, and external evidence from other published research may provide insights to investigators, leading to modification of design elements to preserve the ability of the trial to answer the primary research question. It is the trial leadership's responsibility to anticipate these challenges, make decisions based on the best available information, and adjust as challenges arise in accordance with accepted clinical trial standards. What is sacrosanct in the conduct of a trial, and what can be modified? What are valid reasons for making modifications, what should be the process of making changes, and when and how should the community outside of the trial group be informed? In the following sections, we describe how the ISCHEMIA investigators have addressed some of these issues in the trial. As is readily apparent from the long list of ISCHEMIA trial committee members,1 a wide spectrum of experts offered extensive input into the design and execution of the trial.Eligibility CriteriaDuring the design phase, ISCHEMIA investigators debated whether the qualifying stress test should reflect clinical practice (eg, read by sites without core laboratories—pragmatic design), include all stress imaging modalities and nonimaging exercise tolerance testing (ETT), or be limited to nuclear myocardial perfusion imaging with core laboratory readings of all studies. The original ISCHEMIA protocol entry criteria allowed only stress imaging tests demonstrating moderate or severe ischemia. After starting the trial, we discovered that the prevalence of at least moderate ischemia on stress tests as interpreted by local laboratories was less than the reported prevalence of ≈15% to 20%.3,4 This finding had a negative effect on recruitment, and we needed to make an adjustment to meet our projected recruitment milestones without harming the trial's integrity. We reconsidered ETT as a qualifying test. To reduce the risk of false-positive stress tests and less than moderate ischemia, we proposed the requirement of stable angina, an interpretable resting ECG, evidence of core laboratory-confirmed major ischemic ST depression occurring at an early stage, and ≥70% stenosis in a major epicardial coronary artery on coronary computed tomography angiography. This deviation from the original design was hotly debated by the steering committee, with opponents arguing that severity of ischemia cannot be measured without imaging, ETT cannot be equated to stress imaging tests, and we could potentially dilute study power by allowing ETT to qualify. Proponents of the change argued that ETT is the most common form of stress testing globally, is recommended by guidelines for patients with an interpretable ECG,5 has the potential to improve the trial's relevance to practice, and could improve recruitment. In January 2014, the trial-independent Data and Safety Monitoring Board recommended approval of the protocol amendment to allow ETT as a method to determine participant eligibility, and NHLBI concurred with this recommendation.Sample SizeThe original estimated sample size was 8000, with projected power ≥90% if the 4-year event rate in the conservative strategy group was 20%, assuming a 15% risk reduction of the primary end point. Nonadherent cardiac catheterization rates in the conservative strategy in the absence of an end point event ranging from 30% to 70% were considered during study planning. By 2015, it was clear that we would not be able to randomize 8000 participants even with an extended recruitment period allowable by the available funding. On the positive side, with regard to power, the observed rate of nonadherent cardiac catheterization in the conservative strategy was much lower than projected. We proposed a plan to reduce the sample size from 8000 to 5000, extend recruitment by 6 months, and extend follow-up by 6 months. This proposal was approved by the NHLBI in 2016.Primary End PointWhen writing the original grant application, we proposed and were approved for the previous 5-component primary end point. All-cause mortality would have been a preferable primary end point, but it would have required a sample size >11 000 and was not considered feasible. Cognizant that unstable angina and heart failure are more susceptible to bias in diagnosis and reporting, we proposed in the early postaward period to change the primary end point to the 2-component end point of cardiovascular death or myocardial infarction. We were aware that it is common for event rates (and consequently statistical power) in clinical trials to be lower than initially projected. We therefore prospectively developed a contingency plan that was written into the original protocol to revert to the original 5-component end point to retain power if a sufficient number of primary end point events had not accrued by a designated time point. To mitigate potential bias, we developed rigorous mechanisms to capture all events and stringent objective criteria to define unstable angina and heart failure end points reviewed by an independent blinded adjudication committee. In 2017, before accrual of 50% of projected end point events, the NHLBI convened an independent panel that recommended reversion to the 5-component end point to achieve adequate statistical power under a range of clinically important and plausible between-group differences. The NHLBI approved the panel's recommendation, retaining the 2-component end point as the key secondary end point. No one with access to unblinded end point data participated in the decision to change the end point.Although it is not desirable to modify fundamental design elements of a clinical trial, sometimes it is necessary to adjust to postaward realities so that the aim of the trial can be preserved. Design changes after the trial is in progress should be carried out in a transparent manner that minimizes bias and is well justified by information coming from both external data sources and within the trial. This is especially critical in the case of the primary end point: the criteria and process should be prespecified in the protocol, including the condition that it is done before unblinding of events by treatment group.As a research community, we have made great progress with the use of clinicaltrials.gov to post an overview of design features at the start and protocols and statistical analysis plans when trial results are published. Perhaps the best time for broad comment is before the design is finalized (between award and sponsor/funding agency approval of the protocol) or when results are presented (the historical model) to aid in trial interpretation. A model has not been established for the communication of important revisions to trial design while a trial is in progress. In the era of social media with rapidly spread sound bites based on incomplete information about ongoing trials, the risk of misinformation is high and could adversely affect participant recruitment and retention, undermining the trial's integrity. Rather, the best approach may be to update clinicaltrials.gov within a few months of the change to inform the research community. We trust this perspective will provide the community with further generalizable insights into the complexities of designing and executing trials that go well beyond hypotheticals and speculations. There is no such thing as a perfect trial design that can be implemented under the budgetary, regulatory, healthcare system, and time constraints that exist in the real world, in addition to satisfying the preferences of patients and physicians. The critical test is whether the trial can provide meaningful data for patients and physicians to aid in making clinical decisions. We believe the ISCHEMIA trial meets that criterion.Sources of FundingThis work was supported by National Institutes of Health grants U01HL105907, U01HL105462, U01HL105561, and U01HL10556; in-kind donations from Abbott Vascular, Medtronic, Inc, St Jude Medical, Inc, Volcano Corp, and Omron Healthcare, Inc; medications provided by Arbor Pharmaceuticals, LLC, AstraZeneca Pharmaceuticals, LP, Merck Sharp & Dohme Corp, and Amgen Inc; and financial donations from Arbor Pharmaceuticals, LLC, and AstraZeneca Pharmaceuticals, LP.DisclosuresDr Maron receives funding from National Institutes of Health grant U01HL105907. Dr Harrington receives funding from the National Heart, Lung, and Blood Institute, AstraZeneca Pharmaceuticals, LP, Janssen, Bristol-Myers Squibb, and The Medicines Company. Dr Hochman receives funding from National Institutes of Health grant U01HL105907.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the US Department of Health and Human Services.https://www.ahajournals.org/journal/circDavid J. Maron, MD, Department of Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Falk CVRC 265, Stanford, CA 94305–5406. Email david.[email protected]eduReferences1. Maron DJ, Hochman JS, O'Brien SM, Reynolds HR, Boden WE, Stone GW, Bangalore S, Spertus JA, Mark DB, Alexander KP, Shaw L, Berger JS, Ferguson TB, Williams DO, Harrington RA, Rosenberg Y; ISCHEMIA Trial Research Group. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: rationale and design.Am Heart J. 2018; 201:124–135. doi: 10.1016/j.ahj.2018.04.011.CrossrefMedlineGoogle Scholar2. Anonymous. NIH RePORT-THE ISCHEMIA TRIAL-CCC.Project Information. https://projectreporter.nih.gov/project_info_description.cfm?aid=9265117&icde=38661984&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC&pball=. Accessed July 2, 2018.Google Scholar3. Shaw LJ, Hendel RC, Cerquiera M, Mieres JH, Alazraki N, Krawczynska E, Borges-Neto S, Maddahi J, Bairey Merz CN. Ethnic differences in the prognostic value of stress technetium-99m tetrofosmin gated single-photon emission computed tomography myocardial perfusion imaging.J Am Coll Cardiol. 2005; 45:1494–1504. doi: 10.1016/j.jacc.2005.01.036CrossrefMedlineGoogle Scholar4. Hachamovitch R, Rozanski A, Shaw LJ, Stone GW, Thomson LE, Friedman JD, Hayes SW, Cohen I, Germano G, Berman DS. Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy.Eur Heart J. 2011; 32:1012–1024. doi: 10.1093/eurheartj/ehq500CrossrefMedlineGoogle Scholar5. Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, Douglas PS, Foody JM, Gerber TC, Hinderliter AL, King SB, Kligfield PD, Krumholz HM, Kwong RY, Lim MJ, Linderbaum JA, Mack MJ, Munger MA, Prager RL, Sabik JF, Shaw LJ, Sikkema JD, Smith CR, Smith SC, Spertus JA, Williams SV, Anderson JL; American College of Cardiology Foundation/American Heart Association Task Force. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.Circulation. 2012; 126:e354–e471. doi: 10.1161/CIR.0b013e318277d6a0LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By De Martino A, Del Re F, Gregori D, Azzolina D, Pascarella C, Falcetta G, Ravenni G, Celiento M, Morganti R and Colli A (2022) Surgical revascularization for stable coronary syndrome: the ISCHEMIA trial versus a single-centre matched population—a real-world analysis of patients undergoing surgical revascularization, European Journal of Cardio-Thoracic Surgery, 10.1093/ejcts/ezac068, 61:5, (1155-1161), Online publication date: 2-May-2022. 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Jafary F and Jafary A (2022) Ischemia Trial: Does the Cardiology Community Need to Pivot or Continue Current Practices?, Current Cardiology Reports, 10.1007/s11886-022-01725-1 Avanzas P and Kaski J (2021) The ISCHEMIA Trial: And the Winner Is… the Patient, European Cardiology Review, 10.15420/ecr.2021.03, 16 Lopez-Sendon J, Moreno R and Tamargo J (2021) ISCHEMIA Trial: Key Questions and Answers, European Cardiology Review, 10.15420/ecr.2021.16, 16 Gabaldon-Perez A, Marcos-Garces V, Gavara J, Rios-Navarro C, Miñana G, Bayes-Genis A, Husser O, Sanchis J, Nunez J, Chorro F and Bodi V (2021) Coronary Revascularization and Long-Term Survivorship in Chronic Coronary Syndrome, Journal of Clinical Medicine, 10.3390/jcm10040610, 10:4, (610) October 2, 2018Vol 138, Issue 14 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.036904PMID: 30354348 Originally publishedAugust 16, 2018 Keywordscoronary artery diseaseresearch designsecondary preventionrandomized controlled trialsrevascularizationischemiaPDF download Advertisement SubjectsCardiovascular SurgeryIschemiaPercutaneous Coronary InterventionRevascularizationSecondary Prevention
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