CVIT expert consensus document on primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in 2018

Specific differences between Japan and Europe (Table 1)

For example, glycoprotein (GP) IIb/IIIa inhibitors are not available in Japan, where thrombus aspiration is still a first choice of strategy of treatment of AMI.

Currently preferred oral P2Y12 inhibitors in acute coronary syndrome (ACS) in Europe are prasugrel and ticagrelor. Although ticagrelor became available recently in Japan, it was approved in 2016 and put on the market in February 2017, with a 7-year lag from the approval in Europe. In addition, dose difference in P2Y12 inhibitors between Japan and Europe may cause different anti-thrombotic benefit/bleeding risk profile. Intravenous cangrelor is not approved in Japan, while its use may be considered in patients not pre-treated with oral P2Y12 inhibitors at the time of PCI or in those who are considered unable to absorb oral agents in Europe.

LV assist devices and ECMO are increasingly popular managing patients with cardiogenic shock in Europe although they have not been sufficiently evaluated in clinical trials, while the use of IABP has not met prior expectations of benefit [22, 23]. In contrast, left ventricular assist devices (LVADs, i.e. intra-cardiac axial flow pumps and arterial-venous extracorporeal membrane oxygenation) are not widely available in Japanese institutions, while percutaneous ventricular assist devices (Impella) has recently been approved in limited institution in Japan where we largely rely on intra-aortic balloon pump as a mechanical support.

Regarding intravascular imaging devices, intravascular ultrasound and optical coherence tomography during PCI are routinely reimbursed in Japan. On the contrary to the situation in Europe and United States of America, its use is not restricted in selected cases such as unprotected left main lesions or stent failure.

Recommendations

Loading dose DAPT

Prasugrel and ticagrelor reduce ischemic events and mortality in ACS patients compared to clopidogrel and are recommended by current guidelines [20, 36].

In TRITON-TIMI 38, 13608 patients with acute coronary syndromes with scheduled percutaneous coronary intervention were randomized to either prasugrel or clopidogrel. Prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups [36]. In Japanese population, the PRASFIT-ACS study was conducted to confirm the efficacy and safety of prasugrel at loading/maintenance doses of 20/3.75 mg [37]. Japanese patients (n = 1363) with acute coronary syndrome undergoing percutaneous coronary intervention were randomized to either prasugrel (20 mg for loading/3.75 mg for maintenance) or clopidogrel (300 mg for loading/75 mg for maintenance). The incidence of MACE at 24 weeks was 9.4% in the prasugrel group and 11.8% in the clopidogrel group (risk reduction 23%, hazard ratio 0.77, 95% confidence interval 0.56–1.07). The incidence of non-coronary artery bypass graft-related major bleeding was similar in both groups (1.9 vs. 2.2%). The results were similar to TRITON-TIMI 38 with a low risk of clinically serious bleeding in Japanese ACS patients.

Regarding ticagrelor, clinical outcomes in a large real-world post-ACS population was studied in a Swedish prospective cohort study in 45073 ACS patients who were discharged on ticagrelor (N = 11954) or clopidogrel (N = 33119) [38]. The risk of the primary outcome (i.e. composite of all-cause death, re-admission with Ml or stroke) with ticagrelor vs. clopidogrel was 11.7 vs. 22.3% [adjusted HR (HR) 0.85 (95% CI 0.78–0.93)], risk of death 5.8 vs. 12.9% [adjusted HR 0.83 (0.75–0.921)], and risk of Ml 6.1 vs. 10.8% [adjusted HR 0.89 (0.78–1.011)] at 24 months. Re-admission for bleeding with ticagrelor versus clopidogrel was similar. Ticagrelor versus clopidogrel post-ACS was associated with a lower risk of death, Ml, or stroke, as well as death alone. Risk of bleeding was higher with ticagrelor [38]. These real-world outcomes are consistent with the results of the landmark Platelet Inhibition and Patient Outcomes (PLATO) trial [39].

Both prasugrel and ticagrelor are available for clinical use in Japan as well. While the recommended dose of prasugrel is the same as in Europe and United States of America, the Japanese dose of prasugrel was reduced according to the PLASFIT-ACS study [37] (EU: 60 mg loading dose and 10 mg maintenance dose once daily; Japan: 20 mg loading dose and 3.75 mg maintenance dose once daily) (Table 1).

Anticoagulation during PCI

According to the 2017 ESC STEMI Guidelines, routine use of unfractionated heparin (UFH) is recommended as a Class I recommendation and routine use of enoxaparin or bivalirudin during primary PCI is a Class IIa recommendation [20].

There has been no placebo-controlled trial evaluating UFH in primary PCI, but there is a large body of experience with this agent. Dosage should follow standard recommendations for PCI (i.e. initial bolus 70–100 U/kg). There are no robust data recommending the use of activated clotting time to tailor dose or monitor UFH, and if activated clotting time is used, it should not delay recanalization of the IRA.

An i.v. bolus of enoxaparin 0.5 mg/kg was compared with UFH in the ATOLL randomized trial including 910 STEMI patients [40]. The primary composite endpoint of 30 day death, MI, procedural failure, or major bleeding was not significantly reduced by enoxaparin (17% relative risk reduction, P = 0.063), but there was a reduction in the composite main secondary endpoint of death, recurrent MI or ACS, or urgent revascularization. Importantly, there was no evidence of increased bleeding following the use of enoxaparin over UFH. In a meta-analysis of 23 PCI trials (30966 patients, 33% primary PCI), enoxaparin was associated with a significant reduction in death compared to UFH. This effect was particularly significant in the primary PCI context and was associated with a reduction in major bleeding [41]. In Japan, enoxaparin is approved only for subcutaneous and is practically difficult to use during PCI.

A meta-analysis comparing bivalirudin with unfractionated heparin (UFH) with or without planned use of GP IIb/IIIa inhibitors in patients with STEMI showed no mortality advantage with bivalirudin and a reduction in the risk of major bleeding, but at the cost of an increased risk of acute stent thrombosis [42]. In the recent MATRIX trial including 7213 ACS patients (56% with STEMI), bivalirudin did not reduce the incidence of the primary endpoint (composite of death, MI, or stroke) compared to UFH. Bivalirudin was associated with lower total and cardiovascular mortality, lower bleeding, and more definite stent thrombosis [43]. A post hoc analysis suggested that prolonging bivalirudin with a full-PCI dose after PCI was associated with the lowest risk of ischemic and bleeding events, which is in accordance with the current label of the drug [43]. Bivalirudin could be considered in STEMI, especially in patients at high bleeding risk [44, 45, 46]. Bivalirudin is recommended for patients with heparin-induced thrombocytopenia.

After the publication of the 2017 ESC guidelines, the VALIDATE-SWEDEHEART (Bivalirudin versus Heparin in ST-Segment and Non-ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial) multicenter, randomized, registry-based trial was published [47]. Patients with either ST-segment elevation Ml (N = 3005) or non ST-segment elevation Ml (N = 3001) undergoing PCI and receiving a potent P2Y12 inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors were randomly assigned to receive bivalirudin or heparin during PCI performed predominantly with the use of radial artery access. The primary composite end point (death from any cause, Ml, or major bleeding during 180 days of follow-up) occurred in 12.3% of the patients in the bivalirudin group and in 12.8% in the heparin group (HR 0.96; 95% CI 0.83–1.10; P = 0.54). The results were consistent between patients with ST-segment elevation Ml and those with non ST-segment elevation Ml and across other major subgroups. There was no difference between groups in Ml, major bleeding, definite stent thrombosis or mortality. This study shows overall clinical non-inferiority for use of bivalirudin or heparin during PCI for ACS, along with increased cost with use of bivalirudin. Consistently with these findings, the current uptake of bivalirudin in Europe is very low. Bivalirudin remains unavailable in Japan with no evaluation by clinical trials.

Glycoprotein (GP) IIb/IIIa inhibitors are the strongest antiplatelet agents currently available in Europe and in the US, but are not available in Japan. There are three different compounds, namely abciximab, tirofiban, and eptifibatide. However, procedural use of abciximab plus unfractionated heparin (UFH) showed no benefit compared to bivalirudin [44]. In Japan, JEPPORT randomized, placebo-controlled trial (n = 973) did not show efficacy of abciximab in reducing the primary endpoint (30-day post-PCI coronary events: death, MI or urgent revascularization) [48]. However, using GP IIb/IIIa inhibitors as bailout therapy in the event of angiographic evidence of a large thrombus, slow- or no-reflow, and other thrombotic complications is reasonable, as recommended in 2017 ESC guidelines [20], although this strategy has not been tested in a randomized trial. Overall, there is no evidence to recommend the routine use of GP IIb/IIIa inhibitors for primary PCI.

Approach (femoral vs. radial)

Over recent years, several studies have provided robust evidence in favor of the radial approach as the default access site in ACS patients undergoing primary PCI by experienced radial operators [49, 50]. In the Minimizing Adverse Hemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) programme patients were randomized to radial or femoral access, stratified by STEMI (2001 radial, 2009 femoral) and NSTE-ACS (2196 radial, 2198 femoral). MACE occurred in 121 (6.1%) STEMI patients with radial access vs. 126 (6.3%) patients with femoral access [rate ratio (RR) 0.96, 95% CI 0.75–1.24; P = 0.76] and in 248 (11.3%) NSTE-ACS patients with radial access vs. 303 (13.9%) with femoral access (RR 0.80, 95% CI 0.67–0.96; P = 0.016) (P_int = 0.25). NACE occurred in 142 (7.2%) STEMI patients with radial access and in 165 (8.3%) patients with femoral access (RR 0.86, 95% CI 0.68–1.08; P = 0.18) and in 268 (12.2%) NSTE-ACS patients with radial access compared with 321 (14.7%) with femoral access (RR 0.82, 95% CI 0.69–0.97; P = 0.023) (P_int = 0.76). All-cause mortality and access site-actionable bleeding favored radial access irrespective of ACS type (P_interaction = 0.11 and P_interaction = 0.36, respectively) [51]. Radial as compared with femoral access was shown to have consistent benefit across the whole spectrum of patients with ACS, resulting in upgrading recommendation as Class I in 2017 ESC guidelines.

In Japan, the TEMPURA trial randomized patients with AMI undergoing primary PCI to transradial coronary intervention (TRI) group (n = 77) and transfemoral coronary intervention (TFI) group (n = 72) [52]. The success rate of reperfusion and the incidence of in-hospital MACE were similar in both groups (96.1 and 5.2 vs. 97.1 and 8.3% in TRI and TFI groups, respectively). In a sub-study of PRASFIT-ACS including ACS patients with prasugrel, rates of periprocedural bleeding, bleeding not related to CABG, and puncture site bleeding were consistently lower in the TRI group than in the TFI group [53]. More recently, in a report from the CREDO-Kyoto AMI registry was published [54]. 3662 STEMI patients who had primary PCI by TRI (N = 471) or TFI (N = 3191) were analyzed. The prevalence of hemodynamically compromised patients (Killip II–IV) was significantly less in TRI group than in TFI group (19 vs. 25%, P = 0.002). Cumulative 5-year incidences of death/MI/stroke, and major bleeding were not significantly different between the TRI and TFI groups (26.7 vs. 25.9%, log-rank P = 0.91, and 11.3 vs. 11.5%, log-rank P = 0.71, respectively). After adjustment for confounders, the risks of the TRI or TFI group were not significant for both death/MI/stroke [hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.83–1.59, P = 0.41] and major bleeding (HR 1.29, 95% CI 0.77–2.15, P = 0.34), leading to the conclusion that clinical outcomes of transradial approach were not different from those of transfemoral approach in primary PCI for STEMI in the real-world practice.

Thrombus aspiration

In the new guidelines released by the European Society of Cardiology in 2017 on the management of patients with ST-segment elevation Ml, routine thrombus aspiration was downgraded from IIa to III.

A pooled analysis of individual patient data from three large randomized trials [Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction (TAPAS), Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE), and Trial of Routine Aspiration Thrombectomy with PCI Versus PCI Alone in Patients with STEMI (TOTAL)] provided novel insights about thrombus aspiration for ST-elevation MI [55]. By including 18306 patients, the study did not show a significant reduction in cardiovascular death when thrombus aspiration was compared with standard therapy. There were also no differences between thrombus aspiration and no thrombus aspiration with respect to stroke or transient ischemic attack, recurrent Ml, stent thrombosis, heart failure or target vessel revascularization [56]. Although routine use of mechanical thrombus aspiration is no longer recommended, prior safety concerns regarding the risk of stroke could not be confirmed. Because a trend toward reduced cardiovascular death and increased stroke or transient ischemic attack was found in the subgroup of patients with high thrombus burden, future studies may want to investigate improved thrombus aspiration technologies in this high-risk subgroup.

In contrast to the studies mentioned above, earlier studies have shown the benefit of thrombus aspiration in primary PCI [57, 58].

Distal protection

The benefit of distal protection using filter device or occlusion balloon has not been confirmed [63, 64]. However, the use of distal protection devices can be considered when plaque burden is large and there is a high possibility of distal embolism or no reflow.

Pharmacological intervention for no reflow

In 2017 ESC guidelines [20], using GP IIb/IIIa inhibitors as bailout therapy is considered as Class IIa in the event of angiographic evidence of a large thrombus, slow- or no-reflow, although this strategy has not been tested in a randomized trial.

Direct stenting

Evidence in favor of direct stenting (stenting without predilation) in patients with STEMI comes from several studies [71]. Loubeyre et al. [72] randomized 206 patients with STEMI to direct stenting or stent implantation after balloon predilation. The composite angiographic [corrected thrombolysis in myocardial infarction (TIMI) frame count, slow-flow/no-reflow or distal embolization] endpoint (11.7 vs. 26.9%; P = 0.01) and ST-segment resolution (79.8 vs. 61.9%; P = 0.01) were better among patients randomized to direct stenting than among those randomized to stent implantation after predilation [72]. In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI), direct stenting (n = 698) compared with conventional stenting after predilation (n = 1830) was associated with better ST-segment resolution at 60 min after the procedure (median: 74.8 vs. 68.9%; P = 0.01) and lower 1-year rates of all-cause mortality (1.6 vs. 3.8%; P = 0.01) and stroke (0.3 vs. 1.1%; P = 0.049) [73]. The EUROTRANSFER Registry that included 1419 patients showed that direct stenting (n = 276) was superior to stenting after predilation in terms of post-procedural TIMI flow grade of 3 (94.9 vs. 91.5%; P = 0.02), no-reflow (1.4 vs. 3.4%; P = 0.035), ST-segment resolution of > 50% (86.2 vs. 76.3%; P = 0.016) and 1-year mortality (2.9 vs. 6.5%; P = 0.047 after adjustment for propensity score) [74]. Direct stenting may be advantageous over stenting after predilation in several aspects including the use of fewer and shorter stents, shorter fluoroscopy time and less use of contrast media and reduced microvascular dysfunction/obstruction and no-reflow by reduced distal embolization. Potential disadvantages of direct stenting may include: failure to reach and/or to cross the lesion, stent loss, erroneous estimation of stent length, difficulty with stent positioning (especially in case of persistent TIMI flow 0–1), underexpansion of the stent in an undilatable (i.e., calcified) lesion and stent undersizing due to underestimation of vessel diameter because of reduced flow [75]. Notwithstanding these disadvantages, direct stenting is considered almost as a default strategy during primary PCI.

Balloon angioplasty

The clinical efficacy of balloon angioplasty for STEMI is limited due to the relatively high percentage of restenosis caused by elastic recoil and late negative remodeling [76]. Several studies showed the need for repeat revascularization was significantly reduced by the use of coronary stents [77, 78, 79]. There are also Japanese evidences supporting this fact in patients with AMI [80, 81]. Nonetheless, stent implantation did not result in lower rates of recurrent myocardial infarction (MI) or death, when compared with balloon angioplasty alone. Subsequently, numerous randomized trials demonstrated a further reduction in target lesion revascularization (TLR) could be achieved when using drug-eluting stents (DES) as opposed to bare-metal stents (BMS). Equivalent to studies comparing balloon angioplasty with stenting, though, none of these studies demonstrated a reduction in recurrent MI or death [82, 83, 84]. An important limitation of stent usage is a persistent risk of stent thrombosis and/or in-stent restenosis even years after implantation, particularly in patient subsets as STEMI [85, 86, 87, 88, 89, 90].

Considering stent implantation may even induce no-reflow and thereby expand infarct size [91, 92, 93], it may be reasonable to refrain from stenting if coronary flow is restored and no significant stenosis persists after thrombus aspiration and balloon dilatation. Indeed, recent studies have demonstrated it is safe to defer stent implantation in the acute phase of STEMI [94, 95]. Considering the absence of superiority with regard to hard clinical end points and the potential short- and long-term disadvantages of stent implantation, angioplasty with a drug coated balloon (DCB) without stenting may well serve as a therapeutic strategy of choice in STEMI.

The PAPPA pilot study was the first prospective clinical trial studying the efficacy and safety of a DCB only strategy in primary PCI for STEMI [96]. Additional stenting was allowed only in case of type C–F coronary dissection or residual stenosis > 50%. All patients were treated with i.v. bivalirudin. Of 100 consecutive STEMI patients, 59 patients were treated with a DCB only strategy, whereas bail-out stenting was required in 41 patients. At 1-year, a total of five major adverse cardiac events were reported (5%). Cardiac death was seen in two patients, while three patients underwent TLR. Although in this pilot study the rate of bail-out stenting was relatively high, the use of a DCB angioplasty-only strategy in the setting of primary PCI seems to be a safe and feasible treatment modality. Thus far, no angiographic data are available for the use of a DCB only strategy in STEMI.

In the INNOVATION study, 114 patients receiving primary PCI for STEMI were randomized into deferred stenting (DS) or immediate stenting (IS) [97]. In the DS group, the primary procedures included thrombus aspiration and balloon angioplasty and the second-stage stenting procedure was scheduled to be performed at 3–7 days after primary reperfusion procedure. DS did not significantly reduce infarct size (15.0 versus 19.4%; P = 0.112) and the incidence of microvascular obstruction (42.6 versus 57.4%; P = 0.196), compared with IS. However, in anterior wall myocardial infarction, infarct size (16.1 versus 22.7%; P = 0.017) and the incidence of microvascular obstruction (43.8 versus 70.3%; P = 0.047) were significantly reduced in the DS group.

The REVELATION trial plans to randomize 120 patients presenting with STEMI either to treatment with a DCB or DES [98] (NCT02219802). The primary endpoint is non-inferiority of the functional assessment of the infarct-related lesion by FFR at 9 months after initial treatment.

Pre-procedural IVUS/OCT

In ESC guideline of myocardial revascularization [99], intravascular imaging is recommended only in case of restenosis and stent thrombosis to detect stent-related mechanical problems and to assess and guide PCI in left main stem (IIa).

Stent

Post-procedural IVUS/OCT

Post-procedural IVUS/OCT is used to evaluate stent under-expansion, malapposition, tissue protrusion, dissection, geographic miss and thrombus.

In the IVUS-XPL trial [125], 1400 patients with long lesions were randomized to IVUS versus angiographic guidance. IVUS guidance was associated with a lower MACE rate of 2.9 versus 5.8% (P = 0.007). In CLI-OPCI observational study (n = 670), OCT guidance was associated with a significantly lower risk of cardiac death or MI as compared to angiographic only guidance [adjusted OR = 0.49 (0.25–0.96), P = 0.037]. Intravascular imaging-guided PCI has a potential to reduce cardiac death, major adverse cardiac events, stent-thrombosis, and target lesion revascularization as compared with angiography-guided PCI [126]. OCT-guided PCI is non-inferior to IVUS-guided PCI in terms of stent expansion in the ILUMIEN III trial [127] and clinical outcome in the OPINION trial [128] from Japan.

In general, a small edge dissection found on OCT which is undetected on angiography most likely does not have a clinical impact [129, 130, 131, 132]. However, the following factors need to be considered: longitudinal and circumferential extension of dissection, and the depth of dissection (intima, media or even adventitia). In the ILUMIEN III [127], edge dissections were categorized as major if they constituted ≥ 60° of the circumference of the vessel at the site of dissection and/or were ≥ 3 mm in length. In this trial, when the intra-dissection lumen area is < 90% of the respective reference area, additional stent implantation was considered. In CLI-OPCI-II trial [133], dissection was defined on OCT as a linear rim of tissue with a width of ≥ 0.2 mm and a clear separation from the vessel wall or underlying plaque. In this retrospective multicenter registry, the acute dissection in the distal stent edge was an independent predictor for major adverse cardiac events.

If the malapposition distance from the endoluminal lining of strut to the vessel wall is < 250 µm, such struts likely become in contact with vessel wall at follow-up. Therefore, such small malapposition may be less relevant [134, 135]. The clinical relevance of acute malapposition on stent failure is not yet fully established [133, 136, 137, 138]. Ozaki et al. reported the fate of stent malapposition with serial (post and 10 months follow-up) OCT examinations [139]. They found that of the 4320 struts in 616 slices in 32 patients with sirolimus eluting stent (SES), persistent malapposition (incomplete stent apposition; ISA) was observed in 4.67%, resolved/healed malapposition was 2.48%, late acquired malapposition was 0.37% and most of them was well apposed with neointimal coverage in 84.89% and without coverage in 7.59% [139]. More interestingly, thrombus was visualised in 20.6% of struts with ISA at follow-up and in 2.0% of struts with good apposition (P < 0.001) [139]. The temporal evolution and disappearance of malapposition made the investigation of clinical relevance of strut malapposition more complicated.

Mechanical hemodynamic support

IABP counterpulsation is the most widely used mechanical support for the treatment of cardiogenic shock, based on the beneficial effect of aortic diastolic inflation and rapid systolic deflation, improving myocardial and peripheral perfusion and reducing afterload and myocardial oxygen consumption.

The previous ESC guidelines stated that intra-aortic balloon pumping may be considered in cardiogenic shock after STEMI (IIb) [21]. However, IABP counterpulsation does not improve outcomes in patients with STEMI and cardiogenic shock without mechanical complications [23, 140], nor does it significantly limit infarct size in those with potentially large anterior MIs [22]. The latest ESC guidelines no longer recommend routine IABP counterpulsation in cardiogenic shock except selected patients (i.e. severe mitral insufficiency or ventricular septal defect).

In other countries, mechanical LV assist devices (LVADs), including percutaneous short-term mechanical circulatory support devices (i.e. intra-cardiac axial flow pumps and arterial-venous extracorporeal membrane oxygenation), have been used in patients not responding to standard therapy, including inotropes, fluids, and IABP, but evidence regarding their benefits is limited [141]. A small exploratory trial studying the Impella CP percutaneous circulatory support device did not find any benefit compared with IABP in AMI complicated by cardiogenic shock [142]. Therefore, short-term mechanical circulatory support may be considered as a rescue therapy to stabilize the patients and preserve organ perfusion (oxygenation) as a bridge to recovery of myocardial function, cardiac transplantation, or even LV assist device destination therapy on an individual basis [143, 144].

There have been several clinical reports suggesting the combined use of Impella with IABP [147, 148]. However, this combination may decrease Impella forward flow during diastole due to diastolic pressure augmentation from the IABP [149].

The latest guidelines for STEMI from Japanese Circulation Society recommended IABP use as Class I with level of evidence B, considering the percutaneous LVADs were not broadly available in Japan. However, the Impella 2.5 and Impella 5.0 heart pumps received Pharmaceuticals and Medical Devices Agency (PMDA) approval from the Japanese Ministry of Health, Labor and Welfare (MHLW) in September 2016 and received reimbursement, effective as of September 2017. Proper selection of patients, institutional criteria are being reviewed in J-PVAD (http://j-pvad.jp).

DAPT in maintenance phase

DAPT duration

Recommendations on duration of DAPT in patients with ACS and after elective stenting have been given in the ESC/EACTS focused update on DAPT (Fig. 1) [151]. Recently, the 2 year follow-up report of the Is There a Life for DES After Discontinuation of Clopidogrel (ITALIC) study (N = 2031) confirmed the 1-year results and showed that patients receiving 6-month DAPT after PCI with second-generation DES have similar outcomes to those receiving 24-month DAPT [153].

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Another study pooled patient-level data from 6 randomized controlled trials and investigated the efficacy and safety of long-term (≥ 12 months) versus short-term (3 or 6 months) DAPT with aspirin and clopidogrel after PCl [154]. Of 9577 patients included in the pooled dataset for whom procedural variables were available, 1680 (17.5%) underwent complex PCI. Overall, 85% of patients received new-generation DES. At a median follow-up time of 392 days, patients who underwent complex PCI had a higher risk of MACE [(HR) 1.98; 95% (CI) 1.50–2.60; P < 0.0001]. Compared with short-term DAPT, long-term DAPT yielded significant reductions in MACE in the complex PCI group (adjusted HR 0.56; 95% CI 0.35–0.89) versus the noncomplex PCI group (adjusted HR 1.01; 95% CI 0.75–1.35; P for interaction = 0.01). The magnitude of the benefit with long-term DAPT was progressively greater per increase in procedural complexity. Long-term DAPT was associated with increased risk for major bleeding, which was similar between groups [154]. Results were consistent by per-treatment landmark analysis and further establish procedural complexity is an important parameter to take into account in tailoring upfront duration of DAPT [151].

A large individual patient data pairwise and network meta-analysis comparing short-term (≤ 6 months) versus long-term (1-year) DAPT as well as 3 versus 6-month versus 1-year DAPT included 11473 patients [155]. The primary study outcome was the 1-year composite risk of Ml or definite/probable stent thrombosis. Six trials including 11473 randomized patients in which DAPT after DES consisted of aspirin and clopidogrel: 6714 (58.5%) had stable CAD and 4758 (41.5%) presented with ACS, the majority of whom (67.0%) had unstable angina. In ACS patients, ≤ 6-month DAPT was associated with non-significantly higher 1-year rates of Ml or stent thrombosis compared with 1-year DAPT (HR 1.48, 95% CI 0.98–2.22), whereas in stable patients, the rates of Ml and stent thrombosis were similar between the two DAPT strategies (HR 0.93, 95% CI 0.65–1.35). By network meta-analysis, 3-month DAPT, but not 6-month DAPT, was associated with higher rates of Ml or stent thrombosis in ACS, whereas no significant differences were apparent in stable patients. Short DAPT was associated with lower rates of major bleeding compared with 1-year DAPT, irrespective of clinical presentation. All-cause mortality was not significantly different with short versus long DAPT in both patients with stable CAD and ACS [155].

Regarding long-term antiplatelet therapy, the PEGASUS-TIMI 54 trial examined two doses of ticagrelor (60 and 90 mg b.i.d.) vs. placebo in patients with a history of MI 1–3 years previously. The two ticagrelor doses each reduced, as compared with placebo, the rate of the efficacy endpoint (cardiovascular death, myocardial infarction, or stroke) with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor b.i.d, 7.77% in the group that received 60 mg of ticagrelor b.i.d., and 9.04% in the placebo group [hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval (CI) 0.75–0.96; P = 0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI 0.74–0.95; P = 0.004]. The 60 mg (but not the 90 mg) ticagrelor (plus aspirin) regimen also significantly reduced the stroke risk compared with aspirin monotherapy. The ticagrelor regimen was associated with a significantly increased bleeding risk. Patients with previous STEMI comprised more than 50% of the overall PEGASUS-TIMI 54 population, and subgroup analysis has shown consistent results in patients with previous STEMI vs. NSTEMI. Extension of DAPT beyond 1 year (up to 3 years) in the form of aspirin plus ticagrelor 60 mg b.i.d. may be considered in patients who have tolerated DAPT without a bleeding complication [156].

The studies mentioned above support the concept that duration of DAPT should be individualized as discussed in detail in the ESC/EACTS DAPT Consensus document [151].

General recommendation in revascularization of non-infarct-related artery in acute MI

Management of non-infarct-related coronary arteries after primary PCI for ST-segment elevation Ml remains controversial. In the new guidelines released by the European Society of Cardiology in 2017 on the management of patients with ST-segment elevation Ml, complete revascularization for ST-segment elevation Ml patients with multivessel disease (MVD) was upgraded from III to IIa with level of evidence A.

In the Compare-Acute trial, 885 patients with ST-segment elevation Ml and MVD who underwent primary PCI were randomized in a 1:2 fashion to complete revascularization of non-infarct-related coronary arteries guided by FFR or no revascularization of non-infarct-related coronary arteries [159]. There was a significant reduction in MACCE at 1 year with FFR-guided complete revascularization (8 vs. 21%; P < 0.001). The benefit was mostly driven by a reduced risk of revascularization. Meta-analyses published so far on the topic do not incorporate the results of this study. In one of them focusing on the issue of timing for PCI of non-culprit artery lesions, which encompassed a total of 10 trials with 2285 patients, the reduction in the risk of cardiovascular events was observed irrespective of the timing of non-infarct-related coronary artery revascularization [160]. These results are thus in line with the 2017 ESC guidelines on ST-elevation Ml recommending ischemia-guided full revascularization [20].

In the setting of cardiogenic shock, the efficacy and safety of treating non-infarct-related coronary arteries in the context of primary PCI has been a matter of debate. In the Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial (N = 706), the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower in patients who underwent initial PCI of the culprit lesion only compared with those who underwent immediate multivessel PCI [161]. In 2017 ESC guidelines, published 2 months before the publication of CULPRIT-SHOCK trial, Grade IIa recommendation with level of evidence C was applied for complete revascularization in ST-segment elevation Ml at patients with MVD who present with cardiogenic shock.

Recommendations

Physiological assessment of non-infarct-related artery

FFR has been documented as a valuable tool to guide coronary intervention. The adenosine-free index, iFR, has emerged as a potential alternative to FFR. The Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation (DEFINE-FLAIR) [162] (N = 2492) and Instantaneous Wave-free Ratio versus Fractional Flow Reserve in Patients with Stable Angina Pectoris or Acute Coronary Syndrome (iFR-Swedeheart) [163] (N = 2038) clinical trials both examined if iFR was non-inferior to FFR for PCI guidance. The primary end point in both studies was a composite of death from any cause, nonfatal Ml or unplanned revascularization at 1-year follow-up. In the DEFINE-FLAIR study, the primary end point occurred in 6.8% in the iFR group and in 7.0% in the FFR group (P < 0.001 for non-inferiority) [162]. In the iFR-Swedeheart study, the primary end point occurred in 6.7% in the iFR group as compared to 6.1% in the FFR group (P = 0.007 for non-inferiority). Moreover, iFR was associated with shorter procedural time and less procedural discomfort [163].

Recently, Quantitative flow ratio (QFR) was developed as an image-based index for estimating fractional flow reserve (FFR). In a retrospective, observational study conducted in Japan (n = 142) [164], QFR had good correlation (r = 0.80, P < 0.0001) and agreement (mean difference: 0.01 ± 0.05) with FFR. After applying the FFR cut-off ≤ 0.8, the overall accuracy rate of QFR ≤ 0.8 was 88.0%. On receiver-operating characteristics analysis, the area under the curve was 0.93 for QFR. In contrast, 3-D QCA-derived anatomical indices had insufficient correlation with FFR and diagnostic performance compared with QFR. An observational study to investigate diagnostic performance of QFR in comparison to FFR in intermediate stenosis in STEMI patients is on-going (NCT02998853).

In addition to FFR, iFR, QFR and CT-FFR could be useful tools to decide the treatment indication of non-infarct-related artery.

Recommendations