ISCHEMIA Main Trial SAP (Aug.14.2018)

ISCHEMIA Protocol, Version 1.0 (Jan.18.2012)

ISCHEMIA Protocol, Version 2.0 (Jan.06.2014)

ISCHEMIA Protocol v2.0 Clarification Memos

ISCHEMIA Protocol Addendum (Sep.22.2016)

Protocol Summary of Changes, Version 2.0 (Jan.06.2014)

Protocol Guidance for LTFU (Dec.03.2018)

ISCHEMIA Protocol v2.0 Clarification Memo 1 (Feb.04.2014)

ISCHEMIA Protocol v2.0 Clarification Memo 2 (Jul.22.2014)

ISCHEMIA Protocol v2.0 Clarification Memo 3 (Nov.05.2014)

ISCHEMIA Protocol, Version 1.0 (Jan.18.2012)

ISCHEMIA Protocol, Version 2.0 (Jan.06.2014)

ISCHEMIA Protocol v2.0 Clarification Memos

ISCHEMIA Protocol Addendum (Sep.22.2016)

Protocol Summary of Changes, Version 2.0 (Jan.06.2014)

Protocol Guidance for LTFU (Dec.03.2018)

ISCHEMIA Main Trial SAP (Aug.14.2018)

Why is there discussion on social media about CABG in the ISCHEMIA trial?

The ACC/AHA (and other societies) 2021 guideline writing committee for revascularization of patients with stable coronary disease revised the recommendation for CABG to improve overall survival in patients with 3-vessel disease and preserved ejection fraction from Class 1 to Class 2b. This significant change in guidelines sparked a controversy. AATS and STS withdrew their support of the guidelines.

According to the process for development of guideline recommendations, the totality of evidence is considered when a recommendation is created or revised. ISCHEMIA was included as evidence cited to support the revised recommendation for CABG.

Understandably, controversy surrounding the guidelines has led to more intensive scrutiny of ISCHEMIA data. Questions have been raised online about data accuracy across ISCHEMIA manuscripts. We communicated with investigators about this separately. That communication, and additional details addressing concerns raised about concordance of results between the primary report and secondary analyses are available here on the ISCHEMIA website.

Is it true that one of the ISCHEMIA Steering Committee members recently resigned?

Yes. Dr. Bruce Ferguson, who served on the Leadership and Steering Committees and chaired the CABG Subcommittee of the ISCHEMIA Optimal Revascularization Planning Committee from trial inception, announced his resignation.

What was the process for developing CABG site certification and selecting sites to perform CABG for trial participants?

Comments were made online about the quality of CABG in the trial. The process was rigorous. The site and operator selection criteria were developed by the CABG Subcommittee of the ISCHEMIA Optimal Revascularization Planning Committee. The ISCHEMIA Optimal Revascularization Planning Committee, the Steering Committee and the Leadership Committee approved site qualification criteria for performance of revascularization procedures, including requirements for cardiac surgeon participation and site selection with respect to CABG performance. The same committee defined optimal anatomic and functional revascularization with CABG for the trial.  They may be found in Table S2 of the ISCHEMIA design paper, here. The membership of ISCHEMIA committees appears here.

Who serves as the Statistical and Data Coordinating Center for ISCHEMIA?

The Duke Clinical Research Institute (DCRI) has served as the Statistical and Data Coordinating Center. DCRI has done a remarkable job ensuring data integrity. Academic statisticians at Duke, NYU and Mid-America Heart Institute have analyzed study data and have performed sophisticated statistical analyses. These analyses are undertaken after thorough discussion of a statistical analysis plan with the ISCHEMIA Publications Committee. Manuscripts are approved by the ISCHEMIA Publications Committee. This process helps assure the integrity of the data and analyses.

We are steadfast in our commitment to analyze and publish ISCHEMIA data while adhering to the highest scientific standards, whether the results are consistent with or are counter to our hypothesis and expectations.

Can other research groups verify ISCHEMIA data reports?

Yes. The data sharing platform is NHLBI BioData Catalyst. It is open to all researchers. The process of making ISCHEMIA data, including data on coronary vessel disease severity, available within BioData Catalyst is underway.

FAQ about corrections to “Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity” by Reynolds et al. Circulation September 2021

Two correction notices were recently issued about “Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity” in Circulation. Why were they needed? 

• The first corrected typographical errors in the number of participants in various CAD categories within two tables in the supplement. The data were correct in the manuscript and in the rest of the supplement. The error occurred during copying and pasting of data from a statistical report into the supplement. The correction notice appears here.
• The second clarified how the analytic cohort was derived (n=2475). We excluded from the analysis 43 randomized participants with CCTA showing left main disease (protected or unprotected) or showing no obstructive CAD. The correction notice appears here.

The Circulation readers who identified the errors leading to these corrections asked additional questions online. These additional questions did not require correction or clarification in the article. However, we provide additional clarifications here: https://ischemiatrial.org/.

We are grateful to the readers for calling our attention to the errors in the supplement and we regret having made these errors. We appreciate the opportunity offered by Circulation to provide corrections to the article.

Did the published corrections change the interpretation of the data?

No. They did not change the results or their interpretation. We only corrected typographical errors and clarified how the cohort was selected. 

Why is there so much controversy on social media, especially Twitter, about these corrections?

ISCHEMIA is a high profile trial, with major implications for clinical practice, and accordingly is subject to intense scrutiny. ISCHEMIA has published over 30 peer-reviewed articles to date, and you should be proud of your contribution. We stand by the integrity of the data we have published. We will continue to adhere to the highest scientific standards.

Will ISCHEMIA data be shared with the public?

Yes. The data sharing platform is NHLBI BioData Catalyst. It is open to all researchers. The process of making ISCHEMIA data available within BioData Catalyst is underway.

Response to questions asked online about: “Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity” by Reynolds et al. Circulation September 2021

Some of the questions below relate to differences in various CCTA data across manuscripts. Differences may be due to varying selection criteria across secondary analyses, as is typical in secondary analyses of large trials. Exclusion criteria pertinent to one analysis may not be necessary in another. Also, there are different numbers of CCTA images that are evaluable for specific analyses, leading to different denominators. For example, as outlined in the manuscript, some CCTA images could not be evaluated for the number of diseased vessels because one or more vessels could not be scored for percent stenosis due to artifact.

Reader Comment: In supplement Tables 1 and 2, only 40 patients are in the modified Duke Prognostic Index Group 6 (3-vessel severe stenosis (>70%) or 2-vessel severe stenosis with proximal LAD), not 659 as in the paper. In addition, in the supplement Tables 1 and 2, there are 659 patients in modified Duke Prognostic Index group 5, not 894 as in the manuscript; there are 894 patients in modified Duke prognostic index group 4, not 743; and, there are 743 patients in modified Duke Prognostic Index group 3, not 179. It appears that there may have been an upgrading of 1 grade in the modified Duke Prognostic Index from the Supplemental Tables to the actual manuscript in all categories of coronary artery disease analyzed. We ask the authors to clarify if our observations are correct and if there is a discrepancy between the Supplemental Tables and the manuscript, which is correct.

• ISCHEMIA Clarification: The numbers in the manuscript were correct and the indicated Supplemental Tables were incorrect. The error occurred when cutting and pasting data from a statistical report into the Supplement. We are grateful that Circulation has allowed us to make necessary updates to Supplemental Tables 1 and 2.(https://www.ahajournals.org/doi/10.1161/CIR.0000000000001080)

Reader Comment: Careful examination of the corrected numbers in the context of the totality of the published ISCHEMIA data identifies significant discrepancies that persist. For example, in the corrected Supplemental Tables I and II (pages 3 and 5), the number of patients with left main (LM) stenosis ≥50% is 40. This number (40) is surprisingly identical to the number cited for LM ≥50% stenosis in the Supplement (Table S5, page 107) of the primary ISCHEMIA manuscript published in the New England Journal of Medicine (NEJM). Logically, one would expect a drop-off in the number of patients with LM≥50% when moving from a denominator of 3845 participants (Table S5, primary NEJM manuscript) to 2475 in participants with evaluable modified Duke Prognostic Score Index in the Reynolds et al. manuscript.

• ISCHEMIA Clarification: Both publications are counting the same 40 participants with left main ≥50% stenosis. The NEJM left main calculation is based on participants who have CCTA scans that are interpretable for presence/absence of left main ≥50% stenosis whereas Reynolds et al. is based on participants who have CCTA scans that are interpretable for the Duke score. The latter is a relatively smaller subset. The number of left main cases is the same because, by definition, patients with left main stenosis ≥50% have an interpretable Duke score, i.e., category 7.

Reader Comment: If 2475 is the correct number as stated in the abstract and body of the manuscript, then why is it different from the 2518 in the corresponding Supplemental Figure I, page 35, of the corrected manuscript?

• ISCHEMIA Clarification: 2518 is the number of participants with an evaluable stress test result and evaluable Duke score. 2475 is the number remaining after restricting to Duke scores 3 thru 6. As noted in the revised manuscript: "Duke categories 1 and 2 (nonobstructive coronary artery disease or normal arteries) and 7 (left main stenosis ≥50%) were excluded from analysis because these subgroups were small."
• Additional detail: The 40 randomized participants with CCTA core laboratory confirmed left main stenosis ≥50% in general had a) protected left main with prior CABG; b) pre-randomization invasive coronary angiography documenting <50% stenosis in the left main; or c) a non-study CCTA transferred to the core laboratory near the end of the study that was interpreted by the core laboratory as showing stenosis ≥50% but interpreted locally before randomization as showing <50% left main stenosis. The 4 randomized participants who had CCTA interpreted by the core laboratory as showing no obstructive CAD had pre-randomization invasive coronary angiography documenting obstructive CAD; 1 of these was excluded from the Reynolds et al. analysis because stress data were not interpretable.

Reader Comment: In addition, the percentage of participants with one coronary vessel having at least moderate (≥50%) stenosis is 7.2% (179/2475) in the corrected manuscript (Supplemental Tables I and II) vs. 23.3% (697/2986) in the primary NEJM manuscript (Table S5).

• ISCHEMIA Clarification: Duke score categories are assigned hierarchically, meaning that participants are assigned to the highest category for which criteria are met. Among 697 participants randomized with only one vessel exhibiting stenosis ≥50% as reported in NEJM Table S5, 135 met criteria for single vessel stenosis ≥70% affecting the proximal LAD (Duke category 5), 359 met criteria for single vessel stenosis ≥70% not affecting the proximal LAD (Duke category 4), and 24 did not have an interpretable Duke score. The remaining 179 participants were assigned to Duke category 3 (1 vessel with at least ≥50% stenosis).

Clinical Coordinating Center

Sripal Bangalore, MD, Principal Investigator

Statistical and Data Coordinating Center, Duke Clinical Research Institute

Sean O’ Brien, Ph.D, Principal Investigator

National Heart, Lung, and Blood Institute

Jerome L. Fleg, MD, Project Officer

Steering Committee

Sripal Bangalore, MD, Principal Investigator

Judith Hochman, MD, ISCHEMIA trial Chair

David Maron, MD, ISCHEMIA trial Co-Chair

Glenn Chertow, MD, Nephrologist

William Boden, MD, ISCHEMIA trial Co-PI

Bruce Ferguson, MD, ISCHEMIA trial Co-PI

Robert Harrington, MD, ISCHEMIA trial Co-PI

Gregg Stone, MD, ISCHEMIA trial Co-PI

David O. Williams, MD, ISCHEMIA trial Co-PI

Renal Committee

Charles Herzog, MD, Committee Chair

David Charytan, MD, Committee Co-Chair

Glenn Chertow, MD, Member

Peter McCullough, MD, Member

Roxana Mehran, MD, CIN subcommittee Chair

Carlo Briguori, MD, CIN subcommittee Co-Chair

Angiographic Core Laboratory, Cardiovascular Research Foundation

Ziad Ali, MD, Director

Gregg Stone, MD

ECG Core Laboratory

Bernard Chaitman, MD, Director

Clinical Events Committee

Bernard Chaitman, MD, Committee Chair

Country Leaders

Clinical Coordinating Center

Sripal Bangalore, MD, Principal Investigator

Statistical and Data Coordinating Center, Duke Clinical Research Institute

Sean O’ Brien, Ph.D, Principal Investigator

National Heart, Lung, and Blood Institute

Jerome L. Fleg, MD, Project Officer

Steering Committee

Sripal Bangalore, MD, Principal Investigator

Judith Hochman, MD, ISCHEMIA trial Chair

David Maron, MD, ISCHEMIA trial Co-Chair

Glenn Chertow, MD, Nephrologist

William Boden, MD, ISCHEMIA trial Co-PI

Bruce Ferguson, MD, ISCHEMIA trial Co-PI

Robert Harrington, MD, ISCHEMIA trial Co-PI

Gregg Stone, MD, ISCHEMIA trial Co-PI

David O. Williams, MD, ISCHEMIA trial Co-PI

Renal Committee

Charles Herzog, MD, Committee Chair

David Charytan, MD, Committee Co-Chair

Glenn Chertow, MD, Member

Peter McCullough, MD, Member

Roxana Mehran, MD, CIN subcommittee Chair

Carlo Briguori, MD, CIN subcommittee Co-Chair

Angiographic Core Laboratory, Cardiovascular Research Foundation

Ziad Ali, MD, Director

Gregg Stone, MD

ECG Core Laboratory

Bernard Chaitman, MD, Director

Clinical Events Committee

Bernard Chaitman, MD, Committee Chair

Country Leaders