Lancet August 15, 2015

Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial

Thomas Engstrøm, Henning Kelbæk, Steffen Helqvist, Dan Eik Høfsten, Lene Kløvgaard, Lene Holmvang et al.

Bottom Line

In patients with STEMI and multivessel coronary artery disease, fractional flow reserve (FFR)-guided complete revascularization prior to hospital discharge significantly reduced the composite risk of death, myocardial infarction, or ischemia-driven revascularization compared to culprit-lesion-only PCI.

Key Findings

1. The primary composite endpoint (all-cause mortality, non-fatal MI, or ischemia-driven revascularization of non-infarct-related arteries) occurred in 13% of patients in the complete revascularization group compared to 22% in the culprit-only group (HR 0.56; 95% CI, 0.38-0.83; p=0.004).

2. The benefit was driven predominantly by a significant reduction in the need for subsequent ischemia-driven revascularization, which occurred in 5% of the complete revascularization group versus 17% of the culprit-only group (p<0.001).

3. There were no significant differences between the two groups regarding hard clinical endpoints, including all-cause mortality (5% vs. 4%; p=0.43) and non-fatal myocardial infarction (5% vs. 5%).

4. Staged complete revascularization was performed safely during the index admission (median 2 days after primary PCI), without increasing the rate of periprocedural complications.

Study Design

Design

RCT

Open-Label

Sample

627

Patients

Duration

27 mo

Median

Setting

Multicenter, Denmark

Population Patients presenting with STEMI within 12 hours of symptom onset who underwent successful primary PCI of the infarct-related artery and had at least one angiographically significant non-infarct-related coronary stenosis (>50% diameter stenosis in a vessel >2.0 mm in diameter).

Intervention Fractional flow reserve (FFR)-guided complete revascularization of non-culprit lesions, performed as a staged procedure prior to hospital discharge (median 2 days). Lesions were treated if FFR was ≤0.80 or diameter stenosis was >90%.

Comparator No further revascularization (culprit-lesion-only PCI), with medical therapy for non-culprit lesions.

Outcome A composite of all-cause mortality, non-fatal myocardial infarction, or ischemia-driven revascularization of lesions in non-infarct-related arteries.

Study Limitations

• The open-label study design may have introduced reporting or ascertainment bias, particularly influencing the decision to pursue the subjective endpoint of ischemia-driven revascularization in the culprit-only arm.

• With a sample size of 627 patients, the trial was underpowered to detect potential differences in individual hard clinical outcomes such as mortality or recurrent myocardial infarction.

• The protocol mandated staged revascularization (median 2 days post-index procedure), meaning the trial does not provide evidence regarding the safety or efficacy of immediate complete revascularization at the time of the primary PCI.

• The study was conducted at only two university hospitals in Denmark, potentially limiting the generalizability of the workflow and outcomes to other healthcare settings.

Clinical Significance

The DANAMI-3-PRIMULTI trial established that for hemodynamically stable STEMI patients with multivessel disease, FFR-guided staged complete revascularization during the index admission is safe and superior to a culprit-only approach. By significantly reducing the need for future revascularization procedures, the study provided vital evidence that shifted international guidelines away from culprit-only PCI toward routine complete revascularization strategies.

Historical Context

Historically, major cardiology guidelines recommended against intervening on non-culprit lesions during the setting of an acute STEMI (a Class III recommendation) due to concerns over extended procedure times, contrast-induced nephropathy, and the pro-thrombotic acute inflammatory state. Trials like PRAMI (2013) and CvLPRIT (2015) challenged this paradigm by demonstrating improved outcomes with complete angiography-guided revascularization. Published in 2015, DANAMI-3-PRIMULTI advanced this evolving standard by proving the efficacy of a physiology-guided (FFR) approach to non-culprit lesions performed as a staged, in-hospital procedure. This set the stage for subsequent mega-trials, such as the COMPLETE trial (2019), which ultimately solidified complete revascularization as the standard of care.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale behind using Fractional Flow Reserve (FFR) to evaluate non-culprit lesions in a STEMI patient, and how does FFR differ from standard coronary angiography?

Key Response

FFR measures the pressure difference across a stenosis during maximal hyperemia to determine its true hemodynamic significance, whereas angiography only provides a 2-dimensional visual estimate. In the setting of STEMI, visual estimation of non-culprit lesions might be confounded by systemic catecholamine surge, coronary spasm, and adjacent microvascular dysfunction, making physiologic assessment crucial for accurate decision-making.

Resident

Based on the DANAMI-3-PRIMULTI trial, if a patient presents with an inferior STEMI and a 70% lesion in the LAD is incidentally found, what is the recommended timing and approach for managing the LAD lesion?

Key Response

The trial supports performing an FFR-guided assessment and staged PCI of the non-culprit LAD prior to hospital discharge. This strategy significantly reduces the risk of future ischemia-driven revascularization compared to treating only the culprit right coronary artery and managing the rest medically.

Fellow

The primary composite endpoint in DANAMI-3-PRIMULTI was significantly reduced by FFR-guided complete revascularization, but which specific component drove this benefit, and how should this influence patient counseling regarding mortality and future MI?

Key Response

The benefit was driven almost entirely by a 69% reduction in repeat ischemia-driven revascularization, with no significant differences in all-cause mortality or non-fatal MI. Fellows must counsel patients that while staged FFR-guided PCI reduces recurrent angina and the need for future procedures, it did not demonstrate a survival or hard ischemic event advantage in this specific trial.

Attending

Given that the reduction in the primary endpoint was driven by repeat revascularizations rather than hard endpoints, how do you balance the procedural risk of non-culprit PCI, contrast nephropathy, and resource utilization when deciding whether to pursue staged complete revascularization for an older, frail patient?

Key Response

Attendings must weigh the soft endpoint benefit (fewer repeat hospitalizations for angina or PCI) against the upfront risks of a second procedure (bleeding, stroke, contrast-induced nephropathy) and the patient's overall life expectancy. In highly frail patients with limited lifespan, a conservative symptom-guided approach post-discharge might still be a reasonable, individualized choice despite trial results favoring routine staged PCI.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

DANAMI-3-PRIMULTI was an open-label trial with a primary endpoint that included ischemia-driven revascularization. How does the lack of blinding introduce potential performance and detection bias in this specific composite endpoint, and how could future trial designs mitigate this?

Key Response

In an open-label trial, both patients and physicians know who received complete revascularization. This knowledge lowers the threshold to perform repeat revascularization in the culprit-only arm if the patient reports atypical chest pain, thereby artificially inflating the event rate for the soft endpoint. A sham-controlled design or strictly blinded endpoint adjudication with rigorous, objective criteria for ischemia (e.g., positive stress test required) could mitigate this bias.

Journal Editor

As a peer reviewer, what concerns would you raise regarding the reliability of FFR measurements taken just days after a STEMI, and how does the exclusion of cardiogenic shock patients affect the trial's external validity?

Key Response

Staged procedures were performed a median of 2 days after the index PCI. Reviewers would flag whether the microvascular dysfunction and systemic inflammation immediately post-STEMI alter maximal hyperemia, potentially affecting FFR accuracy for non-culprit vessels. Furthermore, excluding cardiogenic shock patients limits applicability to the highest-risk multivessel STEMI population, an important caveat that requires explicit acknowledgment in the limitations section.

Guideline Committee

Considering DANAMI-3-PRIMULTI alongside subsequent trials like COMPLETE, should guidelines upgrade the recommendation for routine staged non-culprit revascularization in STEMI to a Class 1 recommendation, and should they specifically mandate FFR guidance over angiography alone?

Key Response

DANAMI-3-PRIMULTI showed soft-endpoint benefits for FFR-guided staged PCI, while the COMPLETE trial later showed hard-endpoint benefits (reduced CV death/MI) for angio-guided complete revascularization. Current ACC/AHA and ESC guidelines give complete revascularization a Class 1 recommendation, but the strict mandate for FFR over angio-guidance is not absolute, as visual estimation also proved effective in COMPLETE. Guidelines must reflect that complete revascularization is the standard of care, but the specific modality (FFR vs. angio) can depend on lesion severity, timing, and operator discretion.

Clinical Landscape

Noteworthy Related Trials

2013

PRAMI Trial

n = 465 · NEJM

Tested

Preventive PCI of non-culprit lesions

Population

STEMI patients with multivessel coronary artery disease

Comparator

Culprit-lesion-only PCI

Endpoint

Composite of cardiovascular death, nonfatal MI, or refractory angina

Key result: Preventive PCI significantly reduced the risk of adverse cardiovascular events by 65% compared to culprit-only PCI.

2015

CvLPRIT Trial

n = 296 · JACC

Tested

Complete revascularization during index admission

Population

STEMI patients with multivessel disease undergoing primary PCI

Comparator

Culprit-lesion-only PCI

Endpoint

Composite of all-cause death, recurrent MI, heart failure, or ischemia-driven revascularization at 12 months

Key result: Complete revascularization significantly reduced the primary composite endpoint compared to culprit-only treatment at 12 months.

2019

COMPLETE Trial

n = 4,041 · NEJM

Tested

Routine staged complete revascularization of non-culprit lesions

Population

STEMI patients with multivessel coronary artery disease who had successful culprit-lesion PCI

Comparator

Culprit-lesion-only PCI

Endpoint

Composite of cardiovascular death or new myocardial infarction

Key result: Complete revascularization was superior to culprit-lesion-only PCI in reducing the hard clinical endpoints of cardiovascular death or myocardial infarction.

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