August 16, 2021European Heart Journal
Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial
José López‐SendónDerek D. CyrDaniel B. MarkSripal BangaloreZhen HuangHarvey D. WhiteKaren P. AlexanderJianghao LiGopalan Nair RajeshMarcin DemkowJesús PeteiroGurpreet Singh WanderЕ. А. ДемченкоReto GammaMilind GadkariKian Keong PohThuraia NagehPeter H. StoneMátyás KeltaiMandeep S. SidhuJonathan NewmanWilliam E. BodenHarmony R. ReynoldsBernard ChaitmanJudith S. HochmanDavid J. MaronSean M. O’Brien
Key result
Initial invasive strategy shows no benefit over conservative management for total cardiovascular events.
- difference -1.5
- 95% CI -5.0 to 2.0
- P=0.398
- n=5,179
Why the study?
The ISCHEMIA trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of treatment effects.
Does initial invasive management reduce recurrent and total cardiovascular events compared to initial conservative management in patients with stable CAD and moderate or severe ischaemia?
Key Points
- This study aims to understand if initial invasive or conservative treatment affects recurrent cardiovascular events in stable coronary artery disease.
- Patients with stable coronary artery disease were randomized to either initial invasive or initial conservative management.
- The primary outcome was a composite of cardiovascular death, myocardial infarction, and hospitalization for cardiac-related issues.
- The mean cumulative incidence of total events was estimated using the Ghosh-Lin method.
- A total of 670 index events and 203 recurrent events were reported among 5179 patients.
- The average number of primary events per 100 patients was 18.2 in the invasive group and 19.7 in the conservative group, with no significant difference (P = 0.398).
- There was no significant difference in recurrent or total cardiovascular events between the two treatment strategies.
Study Design
Type
RCT (n=5,179)
Randomization
randomized
Multicenter
Yes
Structured PICO
Does initial invasive management reduce recurrent and total cardiovascular events compared to initial conservative management in patients with stable CAD and moderate or severe ischaemia?
P
Population
5,179 patients with stable coronary artery disease and moderate or severe ischaemia on stress testing, followed over 4 years.
I
Intervention
Initial invasive (INV) management
C
Comparator
Initial conservative (CON) management
O
Outcome
Composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest (analyzed for recurrent and total events)composite
Main Result
Mean Difference: -1.5 (95% CI -5–2)
Absolute Event Rate: 18.2% vs 19.7%
p-value: p=0.398
In patients with stable CAD and moderate or severe ischemia, an initial invasive strategy does not significantly reduce recurrent or total cardiovascular events compared to a conservative strategy over 4 years.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Initial results from ISCHEMIA showed durable improvements in angina control and quality of life with initial invasive management—but no differences in major adverse cardiac events and mortality.”
“survival is not improved by an invasive approach. 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.”
“The ISCHEMIA main trial results apply to all ischemia and anatomic subgroups. There was no statistically significant evidence of a benefit from the invasive strategy on 4-year event rates for any level of ischemic or anatomic burden. Although more severe and extensive coronary disease increased risk for death and MI, an invasive strategy did not significantly lower that risk at 4 years.”
Implication
Does not support routine invasive strategy in stable CAD; reinforces conservative management as noninferior for total events.
Abstract
AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.
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Cite This Study
López‐Sendón et al. (2021) conducted an RCT in stable coronary artery disease (CAD) and moderate or severe ischaemia (n=5,179). initial invasive (INV) management vs. initial conservative (CON) management was evaluated on composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest (difference -1.5, 95% CI -5.0 to 2.0, p=0.398). An initial invasive strategy did not significantly reduce total cardiovascular events over 4 years compared to a conservative strategy (difference -1.5 events per 100 patients; P=0.398).