ISCHEMIA-EXTEND (Extended Follow-up)

• ClinicalTrials.gov Identifier: NCT04894877
• Recruitment Status: Active, not recruiting
• First Posted: May 20, 2021
• Last Update Posted: September 21, 2022
• Sponsor: NYU Langone Health
• Collaborators: New York University; Stanford University; National Heart, Lung, and Blood Institute (NHLBI); Duke University
• Information provided by (Responsible Party): NYU Langone Health

Tracking Information

• First Submitted Date: May 18, 2021
• First Posted Date: May 20, 2021
• Last Update Posted Date: September 21, 2022
• Actual Study Start Date: July 2012
• Estimated Primary Completion Date: March 31, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 16, 2022)

• Cumulative Event Rate of Death: All-Cause [ Time Frame: Year 10 (Range: 6-13 years) ]
  Cumulative event rate of death from all causes.
• Cumulative Event Rate of Cardiovascular (CV) Death [ Time Frame: Year 10 (Range 6-13 years) ]
  Cumulative event rate of death from cardiovascular causes.
• Cumulative Event Rate of Non-CV Death [ Time Frame: Year 10 (Range: 6-13 years) ]
  Cumulative event rate of death from non-cardiovascular causes.

Original Primary Outcome Measures (submitted: May 18, 2021)

Cumulative Event Rate of Death From Cardiovascular Causes [ Time Frame: 13 years ]

median of 10 years; years (range 7.5-13 years)

Current Secondary Outcome Measures (submitted: September 16, 2022)

Cumulative Event Rate of Death by High Risk Subgroups [ Time Frame: Year 10 (Range 6-13 years) ]

Angiographic and clinical risk variables.

• Original Secondary Outcome Measures (submitted: May 18, 2021): Cumulative Event Rate of Death From Any Cause [ Time Frame: 5 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ISCHEMIA-EXTEND (Extended Follow-up)
• Official Title: International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) Extended Follow-up

Brief Summary

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Extended Follow-up (ISCHEMIA-EXTEND) is the long-term follow-up of randomized, surviving participants in ISCHEMIA. ISCHEMIA was an NHLBI-supported trial that randomized 5,179 participants with stable ischemic heart disease to two different management strategies: 1) an initial invasive strategy (INV) of cardiac catheterization and revascularization when feasible plus guideline-directed medical therapy (GDMT), or 2) an initial conservative strategy (CON) of GDMT. The trial did not demonstrate a reduction in the primary endpoint with an initial invasive strategy. There was an excess of procedural myocardial infarction (MI) and a reduction in spontaneous MI in the INV group. Prior evidence suggests that spontaneous MI carries a higher risk of subsequent death than procedural MI. There was a late separation in the cardiovascular (CV) mortality curves over a median of 3.2 years follow-up in ISCHEMIA. The MI incidence curves crossed at approximately 2 years. However, during the trial follow-up phase there were excess non-CV deaths in the invasive strategy. Therefore, it is imperative to ascertain long-term vital status to provide patients and clinicians with robust evidence on whether there are differences between management strategies and to increase precision around the treatment effect estimates for risk of all-cause, CV and non-CV death over the long-term.

Overarching Goal:

To assess the effect of an initial invasive strategy on long-term all-cause, CV and non-CV mortality compared with an initial conservative strategy in SIHD patients with at least moderate ischemia on stress testing, over 10 years median follow-up.

Condition: Coronary Disease Procedure: Observational Phase: Phase III per NIH Condition: Cardiovascular Diseases Procedure: Observational Phase: Phase III per NIH Condition: Heart Diseases Procedure: Observational Phase: Phase III per NIH

Detailed Description

The primary goals of all therapies are to enable patients to feel better and/or live longer. ISCHEMIA provided definitive data on the benefit of INV on quality of life. However, mortality is the most objective and compelling clinical outcome. Strategies that reduce deaths over the long term are of greatest interest to patients and physicians. Long-term follow-up of the ISCHEMIA trial cohort to assess all-cause, CV and non-CV mortality by treatment group is particularly important given that the primary results show relatively late crossing of the event curves, an overall reduction in spontaneous MI with INV, and late divergence of CV death curves in favor of the INV strategy but with an excess of non-CV deaths.

DESIGN NARRATIVE, INCLUDING MODIFICATIONS DURING THE TRIAL:

The investigators will conduct a long-term ascertainment of all-cause, CV and non-CV mortality for surviving ISCHEMIA participants. The limited follow-up after the observed reduction in spontaneous MI events may not have been long enough to observe a mortality benefit, and this makes it imperative to assess long-term all-cause, CV and non-CV mortality to determine whether an initial invasive strategy reduces the risk of death years later, as seen in other trials with crossing curves, e.g., STICH, a randomized trial comparing a strategy of surgical revascularization to GDMT alone in patients with SIHD and LVEF <35%.

Furthermore, with additional accrual of deaths, the investigators will provide estimates on the impact of INV in the highest risk subgroup, those with coronary artery anatomy for whom practice guidelines have recommended CABG to improve survival (3-vessel CAD and 2-vessel CAD with proximal LAD stenosis). Equally important is to improve precision around the point estimates of the treatment effect for all-cause, CV and non-CV mortality for the trial overall and in important subgroups to efficiently maximize the substantial investment by of NHLBI, patients, and study teams.

Vital status data will be collected in a rigorous manner from high-quality vital statistics registries, medical records, or by contacting participants and their next of kin.

ISCHEMIA-EXTEND will also follow eligible participants from the NHLBI-funded ISCHEMIA-CKD trial with the same methodology as for the main trial with separate analyses. They will be referred to as ISCHEMIA-EXTEND for the main trial and ISCHEMIA-CKD EXTEND for the CKD trial.

PARTICIPATING COUNTRIES:

North America: Canada; Mexico; USA South America: Argentina; Brazil; Peru Asia: China; India; Japan; Malaysia; Singapore; Thailand; Russian Federation Pacifica: Australia; New Zealand Europe: Austria; Belgium; France; Germany; Hungary; Italy; Lithuania; Macedonia; Netherlands; Poland; Portugal; Romania; Serbia; Spain; Sweden; Switzerland; UK Middle East: Egypt; Israel; Saudi Arabia Africa: South Africa

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: Participants of the ISCHEMIA main trial that meet the EXTEND inclusion criteria

Condition

• Cardiovascular Diseases
• Coronary Disease
• Coronary Artery Disease
• Heart Diseases
• Myocardial Ischemia

Intervention

• Procedure: cardiac catheterization
  Narrowed blood vessels can be opened without surgery using stents or can be bypassed with surgery. To determine which is the best approach for you the doctor needs to look at your blood vessels to see where the narrowings are and how much narrowing there is. This is done by a procedure known as a cardiac catheterization.
  Other Name: Cath
• Procedure: coronary artery bypass graft surgery
  Artery narrowing is bypassed during surgery with a healthy artery or vein from another part of the body. This is known as coronary artery bypass grafting, or CABG (said, "cabbage"). The surgery creates new routes around narrowed and blocked heart arteries. This allows more blood flow to the heart.
  Other Name: CABG
• Procedure: percutaneous coronary intervention
  Percutaneous coronary intervention may be done as part of the cardiac catheterization procedure. With this procedure a small, hollow, mesh tube (stent) is inserted into the narrowed part of the artery. The stent pushes the plaque against the artery wall, and opens the vessel to allow better blood flow.
  Other Name: PCI
• Behavioral: Lifestyle
  diet, physical activity, smoking cessation
  Other Name: Behavior change
• Drug: Medication
  antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies
  Other Name: Pharmacologic Therapy

Study Groups/Cohorts

• Active Comparator: Invasive Strategy (INV)
  Routine invasive strategy with cardiac catheterization followed by revascularization plus optimal medical therapy.
  Interventions:

  • Procedure: cardiac catheterization
  • Procedure: coronary artery bypass graft surgery
  • Procedure: percutaneous coronary intervention
• Active Comparator: Conservative Strategy
  Optimal medical therapy with cardiac catheterization and revascularization reserved for patients with acute coronary syndrome, ischemic heart failure, resuscitated cardiac arrest or refractory symptoms.
  Interventions:

  • Behavioral: Lifestyle
  • Drug: Medication

• Publications *: Hochman JS, Anthopolos R, Reynolds HR, Bangalore S, Xu Y, O'Brien SM, Mavromichalis S, Chang M, Contreras A, Rosenberg Y, Kirby R, Bhargava B, Senior R, Banfield A, Goodman SG, Lopes RD, Pracon R, Lopez-Sendon J, Maggioni AP, Newman JD, Berger JS, Sidhu MS, White HD, Troxel AB, Harrington RA, Boden WE, Stone GW, Mark DB, Spertus JA, Maron DJ; ISCHEMIA-EXTEND Research Group. Survival After Invasive or Conservative Management of Stable Coronary Disease. Circulation. 2023 Jan 3;147(1):8-19. doi: 10.1161/CIRCULATIONAHA.122.062714. Epub 2022 Nov 6.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 16, 2022): 4825
• Original Actual Enrollment (submitted: May 18, 2021): 4844
• Estimated Study Completion Date: March 31, 2026
• Estimated Primary Completion Date: March 31, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Alive at the end of the initial follow-up period for ISCHEMIA

Exclusion Criteria:

• Participants who withdrew consent during initial trial phase
• Participants who declined participation in long-term follow-up

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 21 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04894877
• Other Study ID Numbers: 11-00498-2; 1R01HL149888 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Data from the follow-up analysis will be made available 2 years after the main results paper is published.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: Beginning 9 months and ending 36 months following article
• URL: http://www.ischemiatrial.org/

• Current Responsible Party: NYU Langone Health
• Original Responsible Party: Same as current
• Current Study Sponsor: NYU Langone Health
• Original Study Sponsor: Same as current

Collaborators

• New York University
• Stanford University
• National Heart, Lung, and Blood Institute (NHLBI)
• Duke University

Investigators

• Study Chair: Judith S Hochman, MD; New York University
• Principal Investigator: David J Maron, MD; Stanford University

• PRS Account: NYU Langone Health
• Verification Date: September 2022