DANAMI-3 PRIMULTI

Published

Engstrom T, et al. "Complete Revascularization Versus Treatment of the Culprit Lesion Only in Patients with ST-segment Elevation Myocardial Infarction and Multivessel Disease". The Lancet. 2015. 386:665-71.
PubMed • Full text • PDF

Clinical Question

Among patients undergoing percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) found to have multivessel disease on angiography, is culprit lesion-only revascularization superior to fractional flow reserve (FFR) guided complete revascularization with regard to a primary composite outcome of death, nonfatal MI, or ischemia-driven revascularization?

Bottom Line

In patients undergoing PCI for STEMI found to have multivessel CAD, FFR-guided complete revascularization is associated with a 9% absolute reduction in major cardiovascular adverse events (death, MI, revascularization) at 27 months. This was driven primarily by an 12% absolute reduction in ischemia-driven revascularization.

Major Points

PCI is standard of care for STEMI and treatment of the infarct-related artery (IRA) has an established mortality benefit in this disease. However, up to 30% of patients presenting with STEMI are found to have multivessel CAD with significant stenosis seen in one or more non-infarct-related arteries (N-IRA). It is unclear whether these lesions are simply incidental, in which the risks of intervening upon them after culprit vessel revascularization may outweigh the benefits, or whether these N-IRA lesions contribute to a pro-thrombotic milieu, for which intervention may reduce the risk of recurrent events. Older observational and registry studies suggested that multivessel revascularization either at the time of index PCI or within a short interval lead to either similar or worse outcomes. However, these retrospective analyses are limited by confounding, as sicker patients may be more likely to undergo more aggressive intervention at the time of PCI. In addition, PCI technology has improved significantly since the time of these analyses and thus the risk profile of more complex intervention may be lower than previously suggested.

As a result, the role of upfront or staged complete revascularization using multivessel PCI has been the subject of multiple RCTs including CvLPRIT and PRAMI, which have demonstrated that complete revascularization results in fewer adverse cardiovascular events, particularly need for urgent revascularization. It is thought that intervention even upon non-culprit lesions may lead to pacification of an inflammatory milieu in the peri-STEMI anatomy that may lead to decreased risk of recurrent thrombosis and possible salutary effects on ischemic/stunned myocardium. A limitation of CvLPRIT and PRAMI was the use of angiographic severity in order to determine whether treatment of a lesion is indicated. When compared to angiographic severity, functional significance as measured using fractional flow reserve (FFR, a method of determining physiologically significant coronary stenoses by objectively measuring flow reduction caused by an atheroma) has been associated with improved outcomes in stable coronary disease (see FAME 2). Whether FFR-guidance has a role in guiding multivessel PCI in the setting of STEMI required further study.

The 2015 Complete Revascularization Versus Treatment of the Culprit Lesion Only in Patients with ST-segment Elevation Myocardial Infarction and Multivessel Disease (DANAMI-3 PRIMULTI) trial randomized 627 patients presenting with acute STEMI found to have multivessel disease on angiography to IRA only PCI or FFR-guided revascularization of N-IRAs and assessed for a primary outcome of death, nonfatal MI, or ischemia-driven revascularization. Patients randomized to the FFR-guided complete revascularization group underwent FFR measurement and PCI of all FFR positive lesions two days after the index PCI. At 27 months, there was a 9% absolute reduction in the primary outcome in patients randomized to FFR-guided PCI of N-IRAs. This was driven primarily by 12% absolute reduction in ischemia-driven revascularizations, with no difference in mortality or nonfatal MI.

In summary, the DANAMI-3 PRIMULTI trial provides further evidence that treatment of non-infarct related arteries discovered during STEMI is beneficial, and suggests that the use of FFR-guidance remains beneficial even in the recent ACS setting. The subsequent Compare-Acute trial showed similar findings. On the strength of DANAMI-3 PRIMULTI as well as CvLPRIT and PRAMI, the 2015 ACC/AHA/SCAI guidelines on primary PCI for STEMI now include PCI of N-IRAs in "selected patients with STEMI and multivessel disease who are hemodynamically stable, either at the time of primary PCI or as a planned staged procedure" as a class IIb recommendation. The optimal timing of N-IRA PCI (whether upfront at the time of index PCI versus staged after a short period) remains unclear and is the subject of ongoing investigation.

Guidelines

Adapted from the 2015 Focused Update of the ACC/AHA/SCAI guidelines on primary PCI for STEMI

• PCI of a non-infarct artery may be considered in selected patients with STEMI and multivessel disease who are hemodynamically stable, either at the time of primary PCI or as a planned staged procedure (Class IIb, Level of Evidence B-R)

Design

• Multicenter, open-label, randomized, controlled trial
• N=627
  • FFR-guided complete revascularization (N=314)
  • Infarct-related artery only PCI (N=313)
• Setting: 4 sites in Denmark
• Enrollment: March 2011 - February 2014
• Median follow-up: 27 months
• Analysis: Intention-to-treat
• Primary Outcome: Death, nonfatal MI, ischemia-driven revascularization

Population

Inclusion Criteria

• Presenting with STEMI within 12 hours after the onset of symptoms and eligible for primary PCI
• Successful treatment of the culprit lesion (defined as TIMI flow ≥ 2 and residual stenosis < 30%)
• At least one stenosis ≥ 50% in a non-infarct related artery

Exclusion Criteria

• Intolerance of contrast media
• Intolerance of relevant antiplatelet or anticoagulant drugs
• Unconsciousness or cardiogenic shock
• Stent thrombosis
• Indication for CABG
• Increased bleeding risk

Baseline Characteristics

From the infarct-related artery only group.

• Demographics: age 63, male 81%
• Comorbidities: DM 13%, HTN 47%, smoking 48%, previous MI 9%
• Infarct: posterior 6%, anterior 36%, inferior 57%
• Heart failure: LVEF 50%, Killip class II-IV 6%
• Medications (discharge): ASA 98%, clopidogrel 12%, prasugrel 65%, ticagrelor 21%, statin 98%, beta blocker 91%, ACEi/ARB 44%, CCB 12%

Interventions

• Patients randomized 1:1
  • Complete revascularization using FFR guidance (N=314)
  • IRA only PCI (N=313)
• Patients randomized in open-label manner after successful treatment of the culprit lesion
• For patients randomized to FFR-guided complete revascularization, additional PCI procedures with FFR-guidance were performed two days after index PCI
  • All lesions ≥ 50% angiographic severity were measured using FFR
  • PCI was performed if FFR ≤ 0.80 or angiographic severity was ≥ 90%
• Patients were followed at their local hospitals with a general policy of encouraging them to participate in rehabilitation programs
• All other medical management at the discretion of treating physician

Outcomes

Comparisons are FFR-guided complete revascularization vs. infarct-related artery only treatment

Primary Outcomes

Death, nonfatal MI, ischemia-driven revascularization

68 (22%) vs. 40 (13%); HR 0.56 (95% CI 0.38-0.83); p = 0.004

Secondary Outcomes

Death

11 (4%) vs. 15 (5%); HR 1.40 (95% CI 0.63-3.00); p = 0.43

Nonfatal MI

16 (5%) vs. 15 (5%); HR 0.94 (95% CI 0.47-1.90); p = 0.87

Revascularization

52 (17%) vs. 17 (5%); HR 0.31 (95% CI 0.18-0.53); p < 0.0001

Urgent revascularization

18 (6%) vs. 7 (2%); HR 0.38 (95% CI 0.16-0.92); p = 0.03

Adverse Events

Periprocedural MI

0 vs. 2 (1%); p = 0.20

Bleeding requiring transfusion or surgery

4 (1%) vs. 1 (<1%); p = 0.20

Contrast nephropathy

7 (2%) vs. 6 (2%); p = 0.8

Stroke

1 (<1%) vs. 4 (1%); p = 0.20

Subgroup Analysis

• There was a greater reduction in the primary outcome in patients aged < 65% versus those aged ≥ 65 (interaction p = 0.02)

Age < 65%

HR 0.33 (95% CI 0.18-0.60)

Age &ge 65%

HR 0.89 (95% CI 0.52-1.50)

Criticisms

• Open label design may lead to bias, particularly in which patients randomized to IRA only revascularization may be more likely to undergo subsequent revascularization due to providers knowing that lesions were not treated previously.
• Trial was underpowered to detect reductions in death or nonfatal MI
• Optimal timing of N-IRA PCI (upfront vs. staged vs. delayed) remains unclear

Funding

• Funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report