The Year in Cardiology 2018: Acute Coronary Syndromes

Petr Widimsky; Filippo Crea; Ronald K. Binder; Thomas F. Lüscher

Disclosures

Eur Heart J. 2019;40(3):271-282. 

In This Article

Medical Treatment

Antithrombotic Therapy

Anti-platelet drugs. After an ACS dual anti-platelet therapy for 12 months is the default anti-thrombotic regimen irrespective of treatment modality. Whether a shorted period of 6 months dual antiplatelet therapy (DAPT) may be non-inferior to 12 or more months was investigated in the SMART-DATE trial.[41] A total of 2712 ACS patients undergoing PCI were randomly assigned to 6 months DAPT or 12 months (or longer). The primary endpoint was a composite of all-cause death, MI, or stroke at 18 months. While the non-inferiority margin was met (cumulative event rate 4.7% vs. 4.2%; absolute risk difference 0·5%; upper limit of one-sided 95% CI 1.8%; P non-inferiority = 0.03 with a predefined non-inferiority margin of 2.0%), MI occurred more frequently in the 6-month DAPT group (24 [1.8%] patients vs. 10 [0.8%]; 2.41 [1.15–5.05]; P = 0.02). Furthermore, there were numerically more stent thrombosis in the 6-month DAPT group [15 (1.1%) patients in the 6-months DAPT group vs. 10 (0.7%) patients in the 12-month or longer DAPT group; P = 0.32]. Therefore, the safety of a shortened DAPT duration after ACS cannot be proclaimed.

The two potent P2Y12 inhibitors ticagrelor and prasugrel were compared in ACS patients in the PRAGUE-18 trial.[42] A total of 1230 ACS patients were randomized to either treatment option on the background of continued ASA use. The combined endpoint was cardiovascular death, MI, or stroke at 1 year. No significant differences were observed for the primary endpoint (6.6% of prasugrel patients vs. 5.7% of ticagrelor patients; HR 1.167, 95% CI 0.742–1.835; P = 0.503), cardiovascular death (3.3% vs. 3.0%; P = 0.769), MI (3.0% vs. 2.5%; P = 0.611), stroke (1.1% vs. 0.7%; P = 0.423), all-cause death (4.7% vs. 4.2%; P = 0.654), definite stent thrombosis (1.1% vs. 1.5%; P = 0.535), and all bleeding (10.9% vs. 11.1%; P = 0.999). Thus, it appears that both potent P2Y12 inhibitors are similar in their effectivity.

De-escalation from a potent of P2Y12 inhibitor to clopidogrel is an alternative treatment strategy in ACS patients especially in cost sensitive environments. In the TROPICAL ACS trial[43] patients were randomly assigned to either standard treatment with prasugrel for 12 months (control group) or to a guided de-escalation regimen (1 week prasugrel followed by 1 week clopidogrel and platelet function testing guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). When the impact of age, as a continuous variable, was analysed on the primary endpoint (cardiovascular death, MI, stroke, or bleeding ≥ Grade 2 according to Bleeding Academic Research Consortium criteria) after guided de-escalation vs. control treatment, an increasing relative risk reduction was observed by decreasing age (P = 0.02), due to significant reductions in bleeding. In elderly patients (age >70, n = 370), the absolute risk of events was higher without significant differences between guided de-escalation vs. control group (15.5% vs. 13.6%; HR 1.17, 95% CI 0.69–2.01; P = 0.56). Guided de-escalation for P2Y12 inhibitors depend on patient's age with younger patients deriving a significant net clinical benefit.

The GLOBAL LEADERS trial[44] included 15991 all-comer PCI patients [ACS including STEMI or stable coronary artery disease (CAD)] and compared short dual antiplatelet regimen (DAPT) with ASA plus ticagrelor given only during the first month and followed by ticagrelor 90 mg bid monotherapy vs. guideline-recommended therapy (1-year DAPT, followed by ASA monotherapy). The primary endpoint of all-cause mortality or new Q-wave MI at 2 years displayed a statistical trend: 3.8% ticagrelor monotherapy vs. 4.4% 1 year DAPT (RR 0.87, 95% CI 0.75–1.01; P = 0.073). All-cause mortality at 2 years was not different: 2.81% ticagrelor monotherapy vs. 3.17% one year DAPT (P = 0.182). Interestingly, the results were almost exactly the same among ACS and among stable CAD patients.

Oral anticoagulants. Oral anticoagulation (OAC) is indicated in patients with atrial fibrillation (AF) at increased risk for stroke. After an ACS a combination of OAC with antiplatelet therapy is warranted in AF patients. Four randomized trials have compared anti-thrombotic regimens including the combination of DAPT with OAC or a single antiplatelet with OAC in this scenario. In a meta-analysis,[45] the safety and efficacy of dual vs. triple antithrombotic therapy was studied (Figure 5). Compared with the triple therapy arm, thrombolysis in myocardial infarction (TIMI) major or minor bleeding showed a reduction by 47% in the dual therapy arm [4.3% vs. 9.0%; HR 0.53, 95% credible interval (CrI) 0.36–0.85, I2 = 42.9%]. There was no difference in the trial-defined major adverse cardiac events (MACE) (10.4% vs. 10.0%, HR 0.85, 95% CrI 0.48–1.29, I2 = 58.4%), or in individual outcomes of all-cause mortality, cardiac death, MI, stent thrombosis, or stroke between the two arms. These findings support the concept that dual therapy (one anticoagulant + one antiplatelet drug) may be a better option than triple therapy (one anticoagulant + two antiplatelet drugs) in many patients with AF following PCI.

Figure 5.

Summary of bleeding risks and ischaemic risks with dual vs. triple antithrombotic therapy (from Golwala et al. 45). All the four trials have demonstrated a reduction in bleeding with dual therapy compared with triple therapy, but dual therapy may not only reduce bleeding events but is comparable to triple antithrombotic therapy for the reduction of major adverse cardiovascular events.

The important yet not definitely resolved question whether triple or dual antithrombotic therapy after MI should be used in patients with AF undergoing PCI was further investigated in a study based on the Swedish registries.[46] The study included n = 7116 patients with AF undergoing PCI during AMI. Landmark analysis was done for the first 3 months (0–90 days) and for 91–365 days. At discharge, 16.2% received triple therapy (ASA, clopidogrel, and warfarin), 1.9% ASA plus warfarin, 7.3% clopidogrel plus warfarin, and 60.8% dual antiplatelets (Table 3).

Besides AF, the detection of a LV thrombus warrants initiation of OAC in ACS patients because of an increased risk of systemic embolism (SE). Such an event occurred in 16.3% of patients with LV thrfombus and 2.9% of patients without LV thrombus in a study by Maniwa.[47] A multivariate analysis showed that LV thrombus was an independent predictor for SE in ACS patients. Among 84 patients treated with vitamin K antagonists, 34 patients within the therapeutic range ≥50% of time were compared with 50 within TTR <50% of time. Only one embolic event (2.9%) developed in those within the therapeutic range ≥50% of time, while nine embolic events (19%) developed in the <50% group (P = 0.036). While patients with LV thrombus seem to benefit from OAC, the optimal duration of OAC for this indication is still uncertain and would need interpretation in the context of the neutral COMMANDER trial (with rivaroxaban[48]) and possibly further trials.

The addition of OAC with rivaroxaban 2.5 mg orally twice daily to DAPT with ASA and clopidogrel was investigated in the ATLAS ACS-2 TIMI 51 trial. In a post hoc analysis[49] fatal and irreversible efficacy events including non-bleeding cardiovascular death, MI, and ischaemic stroke were compared with fatal or irreversible safety events, including fatal and intracranial bleeding. The addition of low dose rivaroxaban to DAPT was associated with 115 (95% CI 18–212) fewer fatal or irreversible ischaemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI −11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10 000 patient-years of exposure. The authors conclude that there was a net reduction in fatal or irreversible events for ACS patients when low dose rivaroxaban is added to DAPT.

Periprocedural Anticoagulation

The latest ESC guidelines on revascularization[50] have downgraded the recommendation for bivalirudin as anticoagulant during primary PCI. In the VALIDATE-SWEDEHEART trial[51] with 6006 ACS patients [3005 with STEMI and 3001 with ST-segment elevation myocardial infarction (NSTEMI)] randomized to bivalirudin or heparin during primary PCI at 180 days, a primary Endpoint event occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (HR 0.96, 95% CI 0.83–1.10; P = 0.54). Definite stent thrombosis was observed in 0.4% patients with bivalirudin and 0.7% patients with heparin, (HR 0.54, 95% CI 0.27–1.10; P = 0.09).

In the MATRIX trial,[52] 7213 patients were randomly assigned to receive either bivalirudin or heparin with or without GPIs at discretion of the operator. Thus also here the rates of MACE (a composite of death, MI, or stroke) were not significantly lower in ACS patients receiving bivalirudin than in those receiving heparin, irrespective of GPI use.

Lipid Lowering Agents

ODYSSEY OUTCOMES trial enrolled 18 924 patients after an ACS with low-density lipoprotein cholesterol level of at least 1.8 mmol per liter in spite of statins at the maximal tolerated dose. Patients were randomized to alirocumab or placebo. The median duration of follow-up was 2.8 years. A primary endpoint event occurred in 903 (9.5%) patients in the alirocumab group and in 1052 (11.1%) patients in the placebo group (HR 0.85, 95% CI 0.78–0.93; P < 0.001). Mortality was lower after alirocumab [3.5% (334 patients) vs. 4.1% (392 patients), HR 0.85; 95% CI 0.73–0.98]. There was no difference in safety measures.[53]

The US authors reviewed the new data for the 2018 guidelines on the management of blood cholesterol.[54] The use of ezetimibe/simvastatin vs. simvastatin in IMPROVE-IT trial reduced the primary outcome by 1.8% over 7 years (HR 0.90; 95% CI 0.84–0.96, 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study decreased the primary outcome by 1.5% over 2.2 years (HR 0.80; 95% CI 0.73–0.88; 2.2 = year number needed to treat: 67). The ODYSSEY OUTCOMES trial is described above. For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups.

Oxygen Therapy

Whether supplemental oxygen in patients with STEMI impacts on procedure-related and clinical outcomes was studied in a pre-specified Subgroup analysis of the DETO2X-AMI trial.[55] A total of 1361 STEMI patients were assigned to receive oxygen, and 1446 assigned to ambient air. The pre-specified primary composite endpoint of all-cause death, rehospitalization with MI, cardiogenic shock, or stent thrombosis at 1 year occurred in 6.3% (86 of 1361) of patients allocated to oxygen compared with 7.5% (108 of 1446) allocated to ambient air (HR 0.85, 95% CI 0.64–1.13; P = 0.27). In accordance with current guidelines the routine use of supplemental oxygen in normoxemic patients with STEMI undergoing primary PCI was not beneficial (Figure 6).

Figure 6.

The Kaplan–Meier curves for the composite of all-cause death, rehospitalization with myocardial infarction, cardiogenic shock, or stent thrombosis major adverse cardiac event up to 365 days. Enrolled ST-elevation myocardial infarction patients were randomized to either oxygen therapy at a moderate flowrate of 6 L/min for a median of 10.36 h or ambient air (from Wilson et al. 54).

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