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

Delineation of strategies for the treatment of multivessel disease in the setting of primary PCI (P-PCI) for STEMI continues to evolve with new data. Multiple studies, both registry and now smaller, randomized clinical trials, have been published and then have formed the basis for multiple meta-analyses. Within this current year, at least five meta-analyses have already been published with variable conclusions.

There are substantial issues in the field related to:

1. Conflicting results of small randomized clinical trials vs large registries;
2. Multiple meta-analyses with multiple blends of data
3. The use of composite endpoints, often without hierarchical consideration in terms of clinical importance
4. Different strategies, e.g. complete revascularization at the time of the index procedure vs staged PCI during the index hospitalization
5. Variable patient populations described.

In the cardiovascular disease field, not all things may be as they seem. This has important implications in the field of P-PCI in high-risk patients. In the past, in patients with multi-vessel disease and cardiogenic shock related to STEMI, immediate multi-vessel PCI was thought to be important to improve hemodynamic stability and optimize outcome.^1,2 However, subsequent studies have not found uniform benefit. The ALKK-PCI registry evaluated this in 735 consecutive patients who were seen for AMI complicated by cardiogenic shock in the presence of multi-vessel disease who underwent PCI.³ In this registry, 173 (23.5%) had immediate multi-vessel PCI while the remainder – 562 patients (26.5%) – had culprit-only PCI. In the group of patients who underwent immediate multi-vessel PCI, in-hospital mortality was increased (46.8%) compared with culprit-lesion PCI (35.8%). Using multi-variate analysis, multi-vessel PCI was associated with increased mortality (OR 1.5; 95% CI 1.15-1.84). Similar findings have been found in multiple other registry experiences.^4,5 Accordingly, the role of multi-vessel PCI during cardiogenic shock remains undetermined despite the fact that it would make intuitive sense. There is, however, no current randomized clinical trial data.

Another important issue in the field of multivessel disease, STEMI and P-PCI relates to whether the non-culprit lesions are responsible for ischemia.⁶ The application of FFR in assessing ischemia in lesions of undetermined severity is well established. The role of FFR for non-culprit lesions during P-PCI is relatively controversial and deemed by some to be either not feasible or practical or reliable. This has been studied in a small group of 101 patients undergoing P-PCI for both STEMI and NSTEMI, who had 112 non-culprit lesions.⁷ After PCI of the culprit lesion, FFR was then performed in non-culprit lesions. These measurements were then repeated 35±4 days later. The FFR of these non-culprit stenoses was 0.77±0.13 during the index procedure and was identical 0.77±0.13 at the time of follow-up. Such data would indicate that FFR at the time of P-PCI is valid for assessing the degree of ischemia potentially associated with non-culprit lesions. Accordingly, it could be used to guide multivessel intervention, although the practicalities of assessing FFR during STEMI are problematic.

The preliminary data from the COMPARE-ACUTE trial have been presented.⁸ This multicenter trial included 408 patients with multi-vessel disease and STEMI undergoing P-PCI. A total of 613 FFR measurements were made in non-culprit lesions, which included all coronary vessels. Using a positive FFR, defined as an FFR ≤0.80 under conditions of maximal hyperemia, the authors found that FFR measurement in a non-culprit lesion was negative in 56.5% (>0.80) and positive in the remainder (43.5%). These findings underscore the fact that non-culprit lesions identified during P-PCI may be innocent bystanders and may not need to be treated.

Against these considerations is the issue that the two recent studies, PRAMI⁹ and CvLPRIT¹⁰, found that multivessel PCI during STEMI is associated with improved outcomes, and in one study the impact was found to be so important that the randomized clinical trial was stopped early by the Data Safety Monitoring Board.

Both trials are small in comparison with the aggregate experience from registries and both used a composite endpoint. Mortality was not different in the CvLPRIT and specific cardiac death was not statistically different between the two groups in PRAMI, although there was a trend towards lower mortality (p=0.07). The total composite MACE rate was markedly improved with multivessel intervention: in CvLPRIT, MACE (defined as mortality, recurrent myocardial infarction, heart failure and repeat revascularization) was significantly reduced (HR 0.45, 95% CI 0.24-0.88; p=0.009) although no individual endpoint was statistically significant; in PRAMI, the composite MACE rate (cardiac death, nonfatal MI, or refractory angina) was also markedly reduced (HR 0.35, 95%CI 0.21-0.58, p<0.001). In this study, individual endpoints of nonfatal myocardial infarction and refractory angina were both significantly reduced. Trial design varied somewhat in the two studies. PRAMI discouraged staged PCI during the index hospitalization while CvLPRIT allowed it if clinically indicated.

What then are we to make of the issue of the treatment of multi-vessel disease during P-PCI, which is a common finding? The field is complex – variable data sets, variable definitions, and variable outcomes. It is an attractive option to treat all lesions during P-PCI and this option is well favored by interventional cardiologists; however, the bottom line is not as clear as it might seem to be. As authors from the CvLPRIT trial concluded¹⁰, 'In-patient total revascularization may be considered in multi-vessel disease patients but larger clinical trials are required to confirm this result and specifically address whether this strategy is associated with improved survival.' Or as the most recent state of the art review concluded¹¹, "Thus the question remains – which patients with significant residual disease should have additional interventions on an elective basis? Larger randomized clinical trials are needed to further address the question of the timing of non-culprit PCI in this clinical context and help clarify which patients may derive the most benefit."

A final comment that can be attributed to Henry, Lord Cohen of Birkenhead seems to be appropriate for this situation: "The feasibility of an operation is not the best indication for its performance."

References

1. Steg PG, James SK, Atar D et al: Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33:2569-619
2. Wijns W, Kolh P, Danchin N et al: Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); European Association for Percutaneous Cardiovascular Interventions (EAPCI): Guidelines on myocardial revascularization. Eur Heart J 2010; 31;2501-55
3. Zeymer U, Hochadel M, Thiele H et al: Immediate multivessel percutaneous coronary intervention versus culprit lesion intervention in patients with acute myocardial infarction complicated by cardiogenic shock: results of the ALKK-PCI registry. Euro Intervention 2014; 10-online published ahead of print, August 2014
4. Van der Schaaf RJ, Claessen BE, Vis MM et al: Effect of multivessel coronary disease with or without concurrent chronic total occlusion on one-year mortality in patients treated with primary percutaneous coronary intervention of cardiogenic shock. Am J Cardiol 2010, 105:955-9
5. Cavender MA, Milford-Beland S, Roe MT et al: 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
6. Sulimov DS, Abdel-Wahab M, Richardt G: Fractional flow reserve in acute myocardial infarction: a guide for non-culprit lesions? Cardiol Ther 2015; 4:39-46
7. Ntalianis A, Sels JW, Davidavicius G et al: Fractional flow reserve for the assessment of nonculprit coronary artery stenoses in patients with acute myocardial infarction. J Am Coll Cardiol Intv 2010; 3:1274-81
8. Smits PC, Vlachojannis GJ, Lunde K et al: TCT-328 FFR-guided complete revascularization during primary PCI: Preliminary data from the COMPARE ACUTE trial. J Am Coll Cardiol 2014; 64:doi: 10.1016/j.jacc2014.07.374
9. Wald DS, Morris JK, Wald NJ et al: Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med 2013; 369:1115-23
10. Gershlick AH, Khan JN, Kelly DJ 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: 65:963-72
11. Pollack A, Mohanty BD, Handa R et al: Preventive stenting in acute myocardial infarction. J Am Coll Cardiol Intv 2015- 8:131-8

Keywords: Acute Coronary Syndrome, Constriction, Pathologic, Coronary Vessels, Follow-Up Studies, Heart Failure, Hemodynamics, Hospital Mortality, Hospitalization, Hyperemia, Myocardial Infarction, Registries, Shock, Cardiogenic, Stents, omega-Chloroacetophenone

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