Editor's Note: This is Part II of a two-part Expert Analysis. Go to Part I.

It is well known that multivessel (MVD) coronary artery disease (CAD) is associated with a worse prognosis in the ST elevation myocardial infarction (STEMI) patient, and that some of these lesions may contain unstable plaque. However, performing acute multivessel PCI during the hypercoagulable, inflammatory state of a STEMI, when antiplatelet therapy may not be optimal, as it results in longer procedures using more contrast and radiation, more stents and higher cost. Furthermore, non-culprit lesion severity is often exaggerated during STEMI and large definitive trials have not yet been performed to prove that routine multivessel revascularization can improve hard clinical events such as death, MI or stroke.

Non-culprit vessels may have abnormal flow, spasm and exaggeration of the coronary stenosis in the midst of a STEMI. One study of STEMI patients with "significant" multivessel disease found at follow-up catheterization non-culprit vessel MLD and percent stenosis was significantly improved¹. Another study found that 40% of non-culprit lesions thought to be significant during the acute catheterization had negative fractional flow reserve (FFR) at follow-up². Similarly, Smits et. al. reported FFR in 1000 non-infarct related arteries with stenosis >50%, as part of the COMPARE ACUTE trial and found that only 40% of lesions were hemodynamically significant³. Thus routine PCI of diseased non-infarct vessels may not be appropriate in a large number of patients.

Several retrospective trials have found that multivessel PCI during the acute STEMI setting is associated with worse outcome. Multivariate analysis of the NCDR data in 32,682 STEMI patients with multivessel disease showed a higher mortality if multivessel PCI was performed⁴. In the HORIZONS trial, acute multivessel PCI was associated with increased mortality, stent thrombosis and bleeding compared to staged PCI of the non-culprit vessel⁵. Similarly, a pairwise and network meta-analysis of 40,280 patients reported that multivessel PCI during the STEMI procedure was associated with the highest mortality rates at both short- and long-term follow-up⁶. Staged PCI was associated with lower mortality.

There have been several recent randomized trials in STEMI patients with MVD⁷. The PRAMI trial randomized 465 patients (planned enrollment of 600) and found the primary endpoint of cardiac death, nonfatal MI or refractory angina was markedly reduced in patients who received complete revascularization (9% versus 23%, p<.001) The CvLPRIT trial randomized 297 STEMI patients with multivessel disease to culprit vessel only versus complete revascularization (either acutely or prior to discharge)⁸. At one year, the primary endpoint of death, recurrent MI, CHF or ischemia driven revascularization occurred in 10% of patients with complete revascularization versus 21.2% of patients with culprit PCI only. Although these trials were reassuring, they were not powered to detect differences in death or MI. Furthermore, more recent trials have not shown any benefit in hard endpoints. The DANAMI 3 PRIMULTI randomized 627 STEMI patients with successful primary PCI and multivessel disease to conservative care versus FFR guided complete revascularization two days later. Even in the complete revascularization group, 31% of the patients had negative FFR in all "multivessel" lesions and were treated medically⁹. Although the primary endpoint of death, reinfarction and revascularization of non-infarct lesions favored complete revascularization (13% versus 22%, p=.004), it was driven entirely by reduction in revascularization.

PRAGUE-13 randomized 214 STEMI patients with multivessel disease to culprit PCI only versus staged PCI at 3-40 days¹⁰. There was no difference in the primary endpoint of death, non-fatal reinfarction or stroke at a mean follow-up of 38 months. Although there was a significant reduction in cross-over treatment of the non-infarct artery, there was no difference in hard endpoints or rehospitalization.

Finally, it is thought that much of the prognostic importance of multivessel disease is due to the presence of a chronic total occlusion. Several studies have shown among STEMI patients with multivessel disease that mortality is increased two-to-three fold in patients with a non-infarct CTO. Accordingly, the EXPLORE trial randomized 300 STEMI patients with non-infarct CTO to conservative care versus PCI of the CTO within seven days of successful primary PCI¹¹. Angioplasty success in the CTO occurred in 72% of cases, but there was no apparent benefit with similar ejection fraction and end diastolic volume at four months and similar clinical outcomes.

In conclusion, there are now ample data to suggest that PCI of the non-culprit vessel during or shortly after successful primary PCI is safe. But is it effective? To date, none of the trials have been adequately powered to determine clinical endpoints. Benefit appears to be confined to reduction in ischemia, rather than improved hard endpoints such as death, MI or stroke. Moreover, it is uncertain what lesions may benefit, and the appropriate timing of PCI. Although in the recent STEMI guidelines, complete revascularization has moved from Class 3 to 2b, it is important to "first do no harm." A prudent interventionalist may wait for the results of the ongoing COMPARE ACUTE which randomized 885 patients and the ongoing COMPLETE trial, which will randomize 3900 STEMI patients with multivessel disease to PCI of culprit only versus staged complete revascularization, with primary endpoint of cardiovascular death or MI. Stay tuned for further updates in this exciting area!

Randomized Trials of Complete Revascularization in STEMI Patients with Multivessel Disease

	PRAMI (n=465)	CvLPRIT (n=297)	DANAMI-3 PRIMULTI (n=627)	PRAGUE-13 (n=214)	EXPLORE (n=302) ongoing	COMPLETE (n=3900) ongoing	COMPARE ACUTE (n=885)
Non-culprit criteria	>50%	>70% or >50% in 2 views	>50% and FFR <80%	>70%	100% - CTO	>70% or >50% with FFR<0.80	>50%
Strategy for non-culprit lesions	Immediate	Immediate (64%) or staged within index admission	Staged within index admission (median 2d)	Staged 3-40	Staged <7 days	Staged 72 hrs	Immediate FFR guided PCI
Primary endpoint	D/MI/ ischemia	D/MI/HF/isch Revasc	D/MI/isch Revasc	D/MI/Stroke	CV death/MI	CV death/MI	D/MI/ Revasc/CVA
Results	23% reduced to 9% (65% Rx effect)	21% reduced to 10% (55% Rx effect)	22% reduced to 13% (44% Rx effect)	13.9% vs 16.0% p=NS	no diff in EF, LVED by MRI at 4 mos	n/a	n/a
Early Benefit	Yes	Yes	Safe to postpone	No benefit	No benefit	n/a	n/a
Effect on hard endpoints	Yes	No	No	No	No	n/a	n/a

References

1. Hanratty CG, Koyama Y, Rasmussen HH, Nelson GI, Hansen PS, Ward MR. Exaggeration of nonculprit stenosis severity during acute myocardial infarction: implications for immediate multivessel revascularization. J Am Coll Cardiol 2002;40:911–916
2. Dambrink JH, Debrauwere JP, Van 't Hof AW, et al. Non-culprit lesions detected during primary PCI: treat invasively or follow the guidelines? Eurointervention 2010;5:968–75.
3. Smits PC, et al. TCT-1 High number of angiographic significant lesions are FFR negative in STEMI patients with multi-vessel disease: preliminary insight into the COMPARE-ACUTE trial. J Am Coll Cardiol 2015;66(15_S)
4. Cavender MA, Milford-Beland S, Roe MT, Peterson ED, Weintraub WS, Rao SV. Prevalence, predictors, and in-hospital outcomes of non-infarct artery intervention during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (from the National Cardiovascular Data Registry). Am J Cardiol 2009;104:507-13
5. Kornowski et al. Prognostic impact of staged versus "one-time" multivessel percutaneous intervention in acute myocardial infarction. J Am Coll Cardiol 2011;58:704-11
6. Vlaar PJ, Mahmoud KD, Holmes DR et al. Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction. A pairwise and network meta-analysis. J Am Coll Cardiol 2011;58:692-703
7. Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry C, Oldroyd KG. Randomized Trial of Preventive Angioplasty in Myocardial infarction. N Engl J Med 2013;369:1115-1123
8. Gershlick AH, et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease. The CvLPRIT Trial. J Am Coll Cardiol 2015;65:963-972.
9. Engstrom T, et al. Complete revascularization versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomized controlled trial. Lancet 2015;386:665-671
10. Hlinomaz O. Multivessel coronary disease diagnosed at the time of primary PPCI for STEMI: Complete revascularization versus conservative strategy: the PRAGUE -13 trial. Presented at EurPCR May 19, 2015
11. Henriques JPS. EXPLORE: A prospective, randomized trial of chronic total occlusion intervention versus medical therapy after successful primary angioplasty in patients with ST-segment elevation myocardial infarction. Presented at TCT October 2015.

Keywords: Acute Coronary Syndrome, Angioplasty, Arteries, Catheterization, Constriction, Pathologic, Coronary Artery Disease, Coronary Disease, Coronary Stenosis, Follow-Up Studies, Hirudins, Multivariate Analysis, Myocardial Infarction, Prognosis, Randomized Controlled Trials as Topic, Retrospective Studies, Spasm, Stents, Stroke, Thrombosis

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