ISCHEMIA-EXTEND evaluates initial invasive versus conservative management for long-term survival in stable coronary disease.
AHR 0.97
95% CI 0.86-1.09
n=5,179
Key points
Context & question:ISCHEMIA-EXTEND was conducted because it remained unknown whether adding routine invasive management to guideline-directed medical therapy improves long-term survival in patients with chronic coronary disease. The study aimed to compare the effects of initial invasive versus conservative treatment strategies on long-term mortality in this population.
Methods & population:Study design, patient population, and sample size are not yet reported.
Finding & limits:In patients with chronic coronary disease, an initial invasive strategy did not significantly reduce 11-year all-cause mortality compared with a conservative strategy (25.8% vs 26.9%; adjusted HR 0.97, 95% CI 0.86-1.09). Trial leaders say they do not know why non-cardiovascular deaths were higher with the invasive strategy, naming chance or differences in death reporting as possibilities. The extension collected only mortality, so it cannot show whether the earlier reduction in spontaneous heart attacks persisted.
Endpoint critique·General / Preventive / Lipids · Cedars-Sinai Medical Center
Drawing firm conclusions from an unplanned interim look at cardiovascular death is a slippery slope.
Read full perspective
Kaul contrasted the non-prespecified 5.7-year look, where CV deaths favored the invasive arm (0.78) but nonCV deaths rose (1.44), with the prespecified 9-year analysis, where ACM was 0.97 and neither cause-specific death was significant. He argues all-cause mortality is the most relevant outcome and PCI did not move it at early or extended follow-up.
“ISCHEMIA-EXTEND trial reported in @JAMANetwork An initial invasive approach involving routine cardiac catheterization and revascularization is no better than a conservative approach in stable coronary artery disease. All-cause mortality is the most reliable end point when”
Patients with stable coronary artery disease have different needs and treatment considerations than people experiencing a heart attack or another urgent heart problem. Long-term follow-up from ISCHEMIA will help patients and their clinicians weigh the potential benefits and trade-offs of different treatment strategies.
🫀 ISCHEMIA-EXTEND at #ScientificSessions26
⏳ The estimated difference in mean survival over 11 years in OMT vs. the invasive arm?
+14 days with invasive management, with a 95% CI spanning −41 to +70 days.
Longer follow-up, still no demonstrated survival advantage from routine initial invasive management.
N=5,179 patients with stable coronary disease and moderate–severe ischemia
Median follow-up: 9 years, maximum 13.4 years.
📊 Estimated 11-year mortality, invasive vs conservative:
▪️ All-cause, CV or non-CV death didn't reach statistical significance.
🔬 The earlier CV mortality signal did not translate into a demonstrated overall survival benefit.
The trial collected mortality, not long-term nonfatal MI, revascularization, or health-status outcomes. It cannot establish whether the original reduction in spontaneous MI persisted.
#ISCHEMIA #AHA26 #Cardiox
If this were a competing risk issue, with that timing and that low death rate, you'd have to hypothesize that every patient saved from a cardiovascular death went on in short order to die of cancer, but that is pretty unlikely. So we don't think it's a competing risk issue. Maybe it's chance. It would be odd to have differences in the way deaths are reported, but that's a possibility. We don't know the answer.
These longer-term results build on our original findings, which is that patients with daily or even weekly angina will likely see improved quality of life, but we have more robust data that an invasive approach is not going to prolong life. Although cardiovascular mortality was reduced, with an invasive approach it was offset by higher non-cardiovascular mortality, so all-cause mortality is the same over time in both groups. Either strategy is acceptable, which is good news for patients, who have different preferences.
LIVE from #ScientificSessions26 @AHAScience ISCHEMIA-EXTEND at 9 years: invasive-first did not prolong life in stable CAD (HR 0.97). A small CV-death signal remains, partly offset by non-CV deaths.
My take: revascularize for angina, not for survival. @ACCinTouch @JACCJournals
When we look at the results and we put them into perspective, we see that the findings of all-cause mortality in the ISCHEMIA-EXTEND report are comparable to other previously recorded trials of revascularisation versus medical therapy
Just published at #AHA26: ISCHEMIA-EXTEND, 11-year follow-up (JAMA)
5,179 patients, chronic coronary disease + moderate/severe ischemia
Invasive vs conservative strategy
All-cause death at 11 y: 25.8% vs 26.9%
Diff −1.0 pp (95% CI −4.2 to 2.1)
aHR 0.97 (0.86–1.09)
Notably, the pattern of contributions of cardiovascular and noncardiovascular mortality differed between the 2 strategies. Cardiovascular mortality favored the invasive strategy with cumulative incidence curves diverging after 2.5 years (cumulative incidence at 11 years (15.8% vs 17.1%).
An early invasive strategy for patients with moderate to severe ischemic heart disease does not reduce mortality; at best, it shifts mortality from cardiovascular to noncardiovascular causes for those with multivessel disease.
When the ISCHEMIA trial was first designed, the idea of the trial was to determine whether a cath-based strategy could ultimately reduce cardiovascular events like cardiovascular mortality and MI. And what I think we're starting to see with these data is that when one looks at those endpoints, certainly MI at the earlier [time point] and now cardiovascular death being reduced by this strategy, that's kind of novel to me and pretty interesting. I think the absolute magnitude of reduction is not huge, but it's not small given how prevalent coronary disease is.
Really the most important thing to a patient is being alive, their overall survival. I don't think the cause of death is as important as whether or not someone is alive or dead. So the major detail that I go over when I'm with patients is overall survival, then if somebody has a particular preference to undergo revascularization to reduce their risk of cardiovascular death, then I try to respect that preference.
@SripalBangalore discussing invasive strategies and reduction in hard endpoints in Stable CAD.
Revasc ⬇️ cv mortality but not overall mortality (ischemia extend)
Also covers reasons for revasc @summitmd_cvrf @dukwoo_park @SVRaoMD @Hragy @jgranadacrf @gbiondizoccai
Open questions from this trial that would benefit from expert input.
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Full evidence
Why the trial, key points, tables, limitations, PICO, abstract, media & sources
Why the trial?
ISCHEMIA-EXTEND was conducted because it remained unknown whether adding routine invasive management to guideline-directed medical therapy improves long-term survival in patients with chronic coronary disease. The study aimed to compare the effects of initial invasive versus conservative treatment strategies on long-term mortality in this population.
Does an initial invasive strategy coupled with guideline-directed medical therapy reduce long-term all-cause mortality compared with an initial conservative strategy in patients with chronic coronary disease and moderate or severe ischemia?
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Key Points
To compare the effects of an initial invasive strategy versus an initial conservative strategy on long-term all-cause, cardiovascular, and noncardiovascular mortality in patients with chronic coronary disease.
Extended follow-up of the ISCHEMIA randomized trial (NCT04894877) conducted across 320 sites in 37 countries including 5,179 patients with chronic coronary disease, moderate or severe ischemia, and ejection fraction of 35% or higher.
Participants were randomized to an initial invasive strategy of guideline-directed medical therapy plus coronary angiography and revascularization or an initial conservative strategy of guideline-directed medical therapy alone.
Follow-up continued through December 2025 for a median of 9 years (range, 1 day to 13.4 years), analyzing mortality by intention-to-treat using Cox models, Fine-Gray models, and bayesian analyses.
Eleven-year all-cause mortality was not significantly different between the invasive and conservative groups (25.8% vs 26.9%; adjusted HR, 0.97 [95% CI, 0.86-1.09]; difference, −1.0 percentage point [95% CI, −4.2 to 2.1]).
Eleven-year cardiovascular mortality was 15.8% in the invasive arm vs 17.1% in the conservative arm (adjusted HR, 0.88 [95% CI, 0.75-1.02]), while noncardiovascular mortality was 9.1% vs 8.1% (adjusted HR, 1.18 [95% CI, 0.96-1.45]).
Eleven-year restricted mean survival time showed no significant difference between treatment strategies (estimated difference, 14 days [95% CI, −41 to 70 days]), with an 18% bayesian posterior probability of achieving greater than a 1 percentage-point survival benefit.
Structured PICO
Does an initial invasive strategy coupled with guideline-directed medical therapy reduce long-term all-cause mortality compared with an initial conservative strategy in patients with chronic coronary disease and moderate or severe ischemia?
PPopulation
5,179 patients (median age 64 years, 23% female, 42% diabetes) with chronic coronary disease, moderate or severe ischemia, and LVEF ≥35% across 320 sites in 37 countries followed for a median of 9 years.
IIntervention
Initial invasive strategy of guideline-directed medical therapy plus coronary angiography and revascularization (when feasible)
CComparator
Initial conservative strategy with guideline-directed medical therapy alone, with invasive management reserved for failure of medical therapy
OOutcome
All-cause mortality at 11 years (during 9-year median follow-up, range 1 day to 13.4 years)hard clinical endpoint
Main Result
Hazard Ratio0.97 (95% CI 0.86–1.09)
Absolute Event Rate25.8% vs 26.9%
Absolute Risk Reduction1%
In patients with chronic coronary disease and moderate-to-severe ischemia, an initial routine invasive strategy did not improve long-term all-cause survival over a median 9-year follow-up compared with initial conservative medical management.
Where experts stand
Coronary artery disease evidence still forming
Experts read ISCHEMIA-EXTEND as a firm null for survival: routine early invasive treatment of stable coronary disease does not help patients live longer, so revascularization remains a tool for symptoms and patient preference.
Most experts agree that longer follow-up confirms what the original trial suggested: an invasive-first strategy does not prolong life, and either approach is acceptable. Where they part ways is the lower rate of cardiovascular death with the invasive strategy, which some find novel and meaningful while others say only overall survival matters. The open question is why non-cardiovascular deaths ran higher in the invasive group, and whether the cardiovascular signal is real.
Agreement
Several clinicians state directly that an initial invasive strategy did not improve overall survival, even with extended follow-up. They read the earlier cardiovascular death signal as not translating into a longer life.
4 clinicians say this directly
Main debate
Is the cardiovascular death reduction meaningful, or does only overall survival count?
CV death signal matters1
The reduction in cardiovascular death is novel and not small given how common coronary disease is.
vs
Overall survival is what counts3
All-cause mortality did not move, and the cause of death matters less than whether patients are alive.
Not placed2 reporting, watching, or context only
What they’re arguing about
supportiveneutralcautiouscritical
Counts are expert takes we classified by axis. Tap a row to see the takes behind its count.
Still unclear
Trial leaders say they do not know why non-cardiovascular deaths were higher with the invasive strategy, naming chance or differences in death reporting as possibilities. The extension collected only mortality, so it cannot show whether the earlier reduction in spontaneous heart attacks persisted.
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Peer votes count verified clinicians only (n=0).
Implication
Initial invasive management does not improve long-term survival in stable coronary disease; confirms no mortality benefit over conservative care.
Abstract
Importance
It is unknown whether routine invasive management of chronic coronary disease improves long-term survival when added to guideline-directed medical therapy.
Objective
To compare the effects of initial invasive and conservative strategies on long-term mortality in patients with chronic coronary disease.
Design, Setting, and Participants
In this long-term follow-up study of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), an international trial of patients with chronic coronary disease, moderate or severe ischemia, left ventricular ejection fraction of 35% or more, and no left main coronary artery disease, unacceptable angina, or recent acute coronary syndrome, participants were randomized at 320 sites in 37 countries beginning August 2012 and followed up through December 2025. Data were analyzed using the intention-to-treat principle.
Intervention
ISCHEMIA randomized patients to an initial invasive strategy of guideline-directed medical therapy plus coronary angiography and revascularization (when feasible) or an initial conservative strategy with guideline-directed medical therapy alone, with invasive management for failure of medical therapy.
Main Outcomes and Measures
All-cause, cardiovascular, and noncardiovascular mortality were analyzed using cumulative incidence estimates, Cox and Fine-Gray models, bayesian analysis, and restricted mean survival time.
Results
Among 5179 participants, median age was 64 (IQR, 58-70) years; 23% were female, 42% had diabetes, and median ejection fraction was 60% (IQR, 55%-65%). During 9-year median follow-up (range, 1 day to 13.4 years), 1071 deaths occurred (782 during extended follow-up): 672 cardiovascular, 359 noncardiovascular, and 40 unclassified. All-cause 11-year mortality was not significantly different between groups (25.8% invasive vs 26.9% conservative; estimated difference, −1.0 percentage point [95% CI, −4.2 to 2.1 percentage points]; adjusted hazard ratio [AHR], 0.97 [95% CI, 0.86-1.09]). By bayesian analysis, the posterior probability of more than 1 percentage-point survival benefit to invasive vs conservative was low (18%). Cardiovascular mortality at 11 years was 15.8% in the invasive group vs 17.1% in the conservative group (estimated difference, −1.4 percentage points [95% CI, −4.0 to 1.3 percentage points]; AHR, 0.88 [95% CI, 0.75-1.02]). Noncardiovascular mortality at 11 years was 9.1% in the invasive group vs 8.1% in the conservative group (estimated difference, 1.0 percentage point [95% CI, −0.9 to 2.9 percentage points]; AHR, 1.18 [95% CI, 0.96-1.45]). Eleven-year restricted mean survival was not significantly different (estimated difference, 14 days [95% CI, −41 to 70 days]).
Conclusions and Relevance
In this study, long-term all-cause mortality in patients with high-risk chronic coronary disease was not significantly different after routine invasive vs initial conservative management.
Trial Registration
ClinicalTrials.gov Identifier:
NCT04894877
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Hochman et al. (2026) conducted an RCT in Chronic coronary disease with moderate or severe ischemia (n=5,179). Initial invasive strategy (guideline-directed medical therapy plus coronary angiography and revascularization when feasible) vs. Initial conservative strategy (guideline-directed medical therapy alone, with invasive management for failure of medical therapy) was evaluated on All-cause 11-year mortality (AHR 0.97, 95% CI 0.86-1.09). Initial invasive management did not significantly reduce 11-year all-cause mortality vs conservative management in chronic coronary disease (25.8% vs 26.9%; AHR 0.97; 95% CI, 0.86-1.09).
