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

Background statement of the problem

Multivessel coronary artery disease (MVD) is usually an unheralded but common finding during emergency percutaneous coronary intervention (PCI) for acute ST-elevation myocardial infarction (STEMI). National registry data indicate MVD complicates STEMI in approximately 50% of all-comers¹. Compared to patients with acute STEMI and single vessel coronary disease, patients with an acute STEMI and 'bystander' MVD have an adverse prognosis early post-MI^2,3. These patients have an increased risk of spontaneous cardiac events, and in particular, recurrent MI. However, despite the high prevalence of bystander MVD, only a small minority of affected patients (≤10%) is treated acutely¹.

Summary of treatment options and contemporary clinical guidelines

The management options to prevent further cardiac events include medical therapy with or without coronary revascularization that typically involves PCI, or rarely, CABG. Management by medical therapy alone may involve clinical review during follow-up with or without a plan for provocative stress testing for ischemia. There are several approaches to PCI in STEMI patients with bystander MVD, however, to-date, the evidence-base to inform the use of each strategy is recognized as incomplete with further research warranted⁴.

PCI of coronary lesions that are >50% narrowing of the lumen diameter may be immediate, staged, or ischemia-driven. The evaluation of lesion severity may involve visual assessment alone, or may include adjunctive diagnostic testing, such as with fractional flow reserve (FFR) to assess lesion-level ischemia. Two randomized trials of PCI strategies have been published (PRAMI⁵ and CULPRIT⁶), two others have been recently reported (DANAMI-3-DEFER⁷ and PRAGUE 13⁸), and two other large trials are currently on-going (COMPARE-ACUTE⁹ and COMPLETE¹⁰). However, in the absence of conclusive evidence to inform treatment, contemporary guideline recommendations state for PCI of a Noninfarct Artery Before Hospital Discharge: Recommendations⁴:

CLASS 1 "PCI is indicated in a noninfarct artery at a time separate from primary PCI in patients who have spontaneous symptoms of myocardial ischemia. (Level of Evidence: C)."

CLASS IIa
PCI is reasonable in a noninfarct artery at a time separate from primary PCI in patients with intermediate- or high-risk findings on noninvasive testing (Level of Evidence: B)

Recent clinical trials

The randomized trial of PReventative Angioplasty in Myocardial Infarction (PRAMI) trial tested the hypothesis that in STEMI patients with MVD, immediate preventive PCI would improve health outcomes compared to medical therapy alone⁵. Patients were considered for eligibility immediately after primary PCI while they were in the catheterization laboratory. The inclusion criterion was successful PCI of the infarct artery, and a stenosis of 50% or more in one or more non-culprit arteries amenable to PCI. The exclusion criteria were 1) cardiogenic shock, 2) lack of informed consent, 3) previous CABG, 4) presence of a non-infarct-artery stenosis of 50% or more in the left main stem or the ostia of both the left anterior descending and circumflex arteries, or 5) if the only non-infarct stenosis was a chronic total occlusion. The primary outcome was a composite of death from cardiac causes, non-fatal MI, or refractory angina.

Of the 465 patients randomized, during a mean follow-up of 23 months, the primary outcome occurred in 21 patients assigned to preventive PCI and in 53 patients assigned to no preventive PCI (infarct artery-only PCI) (hazard ratio (HR) in the preventive-PCI group, 0.35; 95% confidence interval [CI], 0.21 to 0.58; p<0.001). Importantly, there were directionally consistent findings between the groups for each of the components of the primary outcome, implying a uniform treatment effect. The trial was stopped prematurely by the data and safety monitoring committee because of a between-group difference (P<0.001) in the incidence of the primary outcome favoring preventive PCI. The committee concluded that further enrollment would have been highly unlikely to result in a change in this difference.

In PRAMI, the performance of additional preventive PCI had to be "an acceptable treatment option" and successful infarct-artery PCI was an eligibility requirement. Therefore, participants were randomized during emergency care in the catheterization laboratory when these circumstances were fulfilled. In other words, preventive PCI was not performed in lesions that were not deemed treatable at that time. The procedure duration in the preventive PCI group was 18 minutes longer and an additional 100 ml of radiographic contrast median was used supporting the conclusion that the PCI was not complex (mean lesion length 19.4 ± 5.8 mm, no. of stents per artery 1.29 ± 5.3). We would argue that although this design may have resulted in a degree of patient selection, it also reflects what might be anticipated in real-world practice. Primary PCI occurs 24/7, and interventional cardiologists and staff in the catheterization laboratory should not undertake procedures in which success is not anticipated or when circumstances are not conducive to procedure success.

PRAMI included an MRI sub-study with imaging performed early post-MI (~1 week, 1 year) in a sub-set of participants from two of the centers¹¹. Reflecting the safety concern of additional preventive PCI in the acute setting, one of the main aims in the MRI sub-study was to assess for procedure-related MI using late gadolinium enhancement and edema imaging. Indeed, new MI territories treated by non-infarct artery PCI was rare implying that preventive PCI as performed in this trial was safe. Considering the relevance of this result for clinical practice, immediate preventive PCI should be considered as a plausible strategy by the attending cardiologist for lesions that are amenable to treatment when the circumstances permit.

The PRAMI trial was 'first-in-class'⁵. The next trial to be reported on this subject was the Randomized Trial of Complete Versus Lesion-Only Revascularization in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI and Multivessel Disease (CvLPRIT)⁶. This trial had similarities and differences with respect to PRAMI. The trial shared a common aim to test immediate complete revascularization vs. medical therapy only. The study population in CvLPRIT was smaller (n=296 patients), and staged PCI during the index admission was permitted. In CvLPRIT, all patients were scheduled for myocardial perfusion scintigraphy at 6 weeks to assess for residual ischemia. The primary endpoint was a composite of all-cause death, recurrent myocardial infarction (MI), heart failure, and ischemia-driven revascularization within 12 months. The primary endpoint occurred in 10.0% of the complete revascularization group versus 21.2% in the infarct-only PCI group (HR: 0.45; 95% CI: 0.24 to 0.84; p=0.009). There were no differences observed in ischemic burden on myocardial perfusion scintigraphy or in the safety endpoints of major bleeding, contrast-induced nephropathy, or stroke between the groups⁶.

PRAMI⁵ and CvLPRIT⁶ are two independent clinical trials performed in the UK with broadly similar design and results. The other trials, DANAMI-3-PRIMULTI⁷ and PRAGUE 13⁸ have important differences in design. DANAMI-3-PRIMULTI involved the use of FFR as an adjunctive test to guide the decision for preventive PCI during staged procedures vs. infarct only PCI in 650 STEMI patients with MVD⁹. PRAGUE 13 included 106 patients who underwent complete revascularization of all significant stenoses in non-infarct coronary arteries with staged PCI from day 3 to 40 after the index procedure, compared to 108 patients who received conservative management based on guideline-recommended treatment⁸. The publications of both of these trials are eagerly anticipated. Clearly, larger clinical trials that are appropriately designed and powered to address the questions of (1) whether or not to perform additional preventive PCI, and if so, (2) when, and, (3) should adjunctive diagnostic tests to test for ischemia (FFR) or rupture-prone plaque (intravascular imaging) be used to inform this decision.

Conclusions in favor of multivessel PCI, where appropriate

At this time, we would argue that based on the results of PRAMI⁵ and CvLPRIT⁶, which were randomized controlled trials with similar designs and findings, the balance has tipped in favor of angiographically-guided preventive PCI in lesions that are amenable to treatment and to take place either immediately in the catheterization laboratory after successful culprit-artery PCI, or staged subsequently in a second procedure during the index admission. We conclude that the COURAGE approach¹² as applied to STEMI with PCI performed in response to spontaneous ischemia post-discharge, exposes STEMI patients with MVD to an avoidable risk of early recurrent adverse cardiac events.

References

1. British Cardiovascular Intervention Society (BCIS) Audit Returns for Adult Interventional Procedures, January 2013 to December 2013. Peter F Ludman, BCIS National Audit Lead on behalf of BCIS. October 2014 http://www.bcis.org.uk/documents/E15_BCIS_Audit_2013_for_web_no_track_Version_03-11-2014.pdf
2. Sorajja P, Gersh BJ, Cox DA, McLaughlin MG, Zimetbaum P, Costantini C, Stuckey T, Tcheng JE, Mehran R, Lansky AJ, Grines CL, Stone GW. Impact of multivessel disease on reperfusion success and clinical outcomes in patients undergoing primary percutaneous coronary intervention for acute myocardial infarction. Eur Heart J 2007;28(14):17091716.
3. Park DW, Clare RM, Schulte PJ, Pieper KS, Shaw LK, Califf RM, Ohman EM, Van de Werf F, Hirji S, Harrington RA, Armstrong PW, Granger CB, Jeong MH, Patel MR. Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA. 2014 Nov 19;312(19):2019-27. doi: 10.1001/jama.2014.15095. PubMed PMID: 25399277.
4. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78140.
5. Wald DS, Morris JK, Wald NJ, Chase AJ, Edwards RJ, Hughes LO, Berry C, Oldroyd KG; PRAMI Investigators. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013 Sep 19;369(12):1115-23. doi: 10.1056/NEJMoa1305520. Epub 2013 Sep 1. PubMed PMID: 23991625.
6. Gershlick AH, Khan JN, Kelly DJ, Greenwood JP, Sasikaran T, Curzen N, Blackman DJ, Dalby M, Fairbrother KL, Banya W, Wang D, Flather M, Hetherington SL, Kelion AD, Talwar S, Gunning M, Hall R, Swanton H, McCann GP. 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 Mar 17;65(10):963-72. doi: 10.1016/j.jacc.2014.12.038. PubMed PMID: 25766941; PubMed Central PMCID: PMC4359051.
7. Høfsten DE, Kelbæk H, Helqvist S, Kløvgaard L, Holmvang L, Clemmensen P, Torp-Pedersen C, Tilsted HH, Bøtker HE, Jensen LO, Køber L, Engstrøm T; DANAMI 3 Investigators. The Third DANish Study of Optimal Acute Treatment of Patients with ST-segment Elevation Myocardial Infarction: Ischemic postconditioning or deferred stent implantation versus conventional primary angioplasty and complete revascularization versus treatment of culprit lesion only: Rationale and design of the DANAMI 3 trial program. Am Heart J. 2015 May;169(5):613-21. doi: 10.1016/j.ahj.2015.02.004. Epub 2015 Feb 14. PubMed PMID: 25965708.
8. Hlinomaz O et al. Multivessel Coronary Disease Diagnosed at the Time of Primary PCI for STEMI: Complete Revascularization Versus Conservative Strategy. PRAGUE - 13 Trial. https://clinicaltrials.gov/ct2/show/NCT01332591
9. Smits P et al. Fractional Flow Reserve Guided Primary Multivessel Percutaneous Coronary Intervention to Improve Guideline Indexed Actual Standard of Care for Treatment of ST-elevation Myocardial Infarction in Patients With Multivessel Coronary Disease. https://clinicaltrials.gov/ct2/show/NCT01399736
10. Mehta S et al. Randomized Comparative Effectiveness Study of Complete vs Culprit-only Revascularization Strategies to Treat Multi-vessel Disease After Primary Percutaneous Coronary Intervention (PCI) for ST-segment Elevation Myocardial (STEMI) Infarction. https://clinicaltrials.gov/ct2/show/NCT01740479
11. Mangion K, Carrick D, Payne AR, McClure J, Mason M, Petrie MC, McEntegart M, Eteiba H, Oldroyd KG, Berry C. Left ventricular outcomes following multivessel pci versus infarct-only pci in patients with acute stemi: the Glasgow PRAMI-CMR sub-study. J Am Coll Cardiol. 2015;65(10_S):. doi:10.1016/S0735-1097(15)61937-4.
12. Boden WE, O'Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS; COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. Epub 2007 Mar 26. PubMed PMID: 17387127.

Keywords: Acute Coronary Syndrome, Angina Pectoris, Angioplasty, Catheterization, Confidence Intervals, Constriction, Pathologic, Coronary Artery Disease, Cost of Illness, Diagnostic Tests, Routine, Edema, Emergency Medical Services, Follow-Up Studies, Gadolinium, Heart Failure, Incidence, Informed Consent, Myocardial Infarction, Patient Selection, Percutaneous Coronary Intervention, Perfusion Imaging, Prevalence, Prognosis, Registries, Shock, Cardiogenic, Stents, Stroke

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