Guidelines SCA 2023

Question 1

ATOLL

Answer 1

STEMI < 12 H
HNF EV vs Enoxaparina EV (0-5 mg/Kg)
Farmacos concomitantes a descrição dos clínicos
900 doentes
Redução EP primario a 30 dias
Morte, complicação EAM, falência procedimento ou hemorragia Major

Question 2

BRIGHT-4

Answer 2

AHA 2022
Open-Label, China
PCI primária, via radial (93%)
Sem fibrinoliticos, anticoagulantes ou Inibidores GpIIbIIIA
HNF vs Bivalirudina (bolus + perfusao 2-4H pos PCI)
6000 doentes
Gp IIb-IIIA limitado a doentes com complicações trombóticas
Bivaluridina mostrou superioridade
EP: morte por todas as causas, hemorragia major a 30 dias
RRA : 1.33%; RRR: HR 0.69
Hemorragia BARC 3-5 (HR 0.21; 0.08 - 0.54)
Trombose stent : 11 vs 22

Question 3

OASIS-6

Answer 3

Effects of Fondaparinux on Mortality
and Reinfarction in Patients With Acute
ST-Segment Elevation Myocardial Infarction

Context Despite many therapeutic advances, mortality in patients with acute ST- segment elevation myocardial infarction (STEMI) remains high. The role of additional an- tithrombotic agents is unclear, especially among patients not receiving reperfusion therapy.
Objective To evaluate the effect of fondaparinux, a factor Xa inhibitor, when initi- ated early and given for up to 8 days vs usual care (placebo in those in whom unfrac- tionated heparin [UFH] is not indicated [stratum 1] or unfractionated heparin for up to 48 hours followed by placebo for up to 8 days [stratum 2]) in patients with STEMI.
Design, Setting, and Participants Randomized double-blind comparison of fondaparinux 2.5 mg once daily or control for up to 8 days in 12 092 patients with STEMI from 447 hospitals in 41 countries (September 2003-January 2006). From day 3 through day 9, all patients received either fondaparinux or placebo according to the original randomized assignment.
Main Outcome Measures Composite of death or reinfarction at 30 days (pri- mary) with secondary assessments at 9 days and at final follow-up (3 or 6 months).
Results Deathorreinfarctionat30dayswassignificantlyreducedfrom677(11.2%) of 6056 patients in the control group to 585 (9.7%) of 6036 patients in the fondaparinux group (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.96; P = .008); ab- solute risk reduction, 1.5%; 95% CI, 0.4%-2.6%). These benefits were observed at 9 days (537 [8.9%] placebo vs 444 [7.4%] fondaparinux; HR, 0.83; 95% CI, 0.73- 0.94; P = .003, and at study end (857 [14.8%] placebo vs 756 [13.4%] fondaparinux; HR, 0.88; 95% CI, 0.79-0.97; P=.008). Mortality was significantly reduced through- out the study. There was no heterogeneity of the effects of fondaparinux in the 2 strata by planned heparin use. However, there was no benefit in those undergoing primary percutaneous coronary intervention. In other patients in stratum 2, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days (HR, 0.82; 95% CI, 0.66-1.02; P=.08) and at study end (HR, 0.77; 95% CI, 0.64-0.93; P=.008). Significant benefits were observed in those receiving thrombolytic therapy (HR, 0.79; P = .003) and those not receiving any reperfusion therapy (HR, 0.80; P = .03). There was a tendency to fewer severe bleeds (79 for placebo vs 61 for fondaparinux; P = .13), with significantly fewer cardiac tamponade (48 vs 28; P = .02) with fondaparinux at 9 days.
Conclusion InpatientswithSTEMI,particularlythosenotundergoingprimaryper- cutaneous coronary intervention, fondaparinux significantly reduces mortality and re- infarction without increasing bleeding and strokes.

Question 4

OASIS-5

Answer 4

Background
The combined use of anticoagulants, antiplatelet agents, and invasive coronary proce- dures reduces ischemic coronary events but also increases bleeding in patients with acute coronary syndromes. We therefore assessed whether fondaparinux would pre- serve the anti-ischemic benefits of enoxaparin while reducing bleeding.
Methods
We randomly assigned 20,078 patients with acute coronary syndromes to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg per kilogram of body weight twice daily) for a mean of six days and evaluated death, myocardial infarction, or refractory ischemia at nine days (the primary outcome); major bleeding; and their combination. Patients were followed for up to six months.
Results
The number of patients with primary-outcome events was similar in the two groups (579 with fondaparinux [5.8 percent] vs. 573 with enoxaparin [5.7 percent]; hazard ratio in the fondaparinux group, 1.01; 95 percent confidence interval, 0.90 to 1.13), satisfying the noninferiority criteria. The number of events meeting this combined outcome showed a nonsignificant trend toward a lower value in the fondaparinux group at 30 days (805 vs. 864, P=0.13) and at the end of the study (1222 vs. 1308, P=0.06). The rate of major bleeding at nine days was markedly lower with fonda- parinux than with enoxaparin (217 events [2.2 percent] vs. 412 events [4.1 percent]; hazard ratio, 0.52; P<0.001). The composite of the primary outcome and major bleeding at nine days favored fondaparinux (737 events [7.3 percent] vs. 905 events [9.0 percent]; hazard ratio, 0.81; P<0.001). Fondaparinux was associated with a sig- nificantly reduced number of deaths at 30 days (295 vs. 352, P=0.02) and at 180 days (574 vs. 638, P=0.05).
Conclusions
Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long term mor- tality and morbidity. (ClinicalTrials.gov number, NCT00139815.)

Question 5

Classe de recomendação para anticoagulação no NSTEMI:
1) HNF
2) Enoxaparina
3) Fondaparinux

Answer 5

1) Classe I se angio < 24 H
2) Classe IIa se angio < 24 H
3) Classe I se angio > 24 H

Question 6

PLATO

Answer 6

2019, NEJM

Ticagrelor versus clopidogrel SCA
> 15% 75 anos
38% STEMI, 42% NSTEMI
80% CAT, 60% PCI
Menos EAM, mortalidade por causa vascular e por todas as causas e menos trombose stent
Aumento da hemorragia não relacionada com o procedimento

BACKGROUND
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.

METHODS
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.

RESULTS
At 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.

CONCLUSIONS
In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding.

Question 7

TRITON TIMI 38

Answer 7

Prasugrel versus clopidogrel SCA
Doentes com SCA para PCI (13.600)
Morte por todas as causas, enfarte e AVC
Hemorragia major
Exclusão: antecedentes AVC, anemia, trombocitopenia
75% NSTEMI, 25% STEMI
13 % > 75 anos
12.1 vs 9.9%
EAM 9.7 vs 7.4%, Trombose stent 2.4 vs 1.1%
Hemorragia 2.4 vs 1.8%

3 grupos de interesse:
- > 75 anos - sem benificio
- < 60 Kg - sem benificio
- AIT previo - harm

Question 8

ISAR-REACT 5

Answer 8

Prasugrel versus Ticagrelor
NEJM, 2019

BACKGROUND
The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain.

METHODS
In this multicenter, randomized, open-label trial, we randomly assigned patients who presented with acute coronary syndromes and for whom invasive evaluation was planned to receive either ticagrelor or prasugrel. The primary end point was the composite of death, myocardial infarction, or stroke at 1 year. A major secondary end point (the safety end point) was bleeding.

RESULTS
A total of 4018 patients underwent randomization. A primary end-point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9%) in the prasugrel group (hazard ratio, 1.36; 95% confidence interval [CI], 1.09 to 1.70; P=0.006). The respective incidences of the individual components of the primary end point in the ticagrelor group and the prasugrel group were as follows: death, 4.5% and 3.7%; myocardial infarction, 4.8% and 3.0%; and stroke, 1.1% and 1.0%. Definite or probable stent thrombosis occurred in 1.3% of patients assigned to ticagrelor and 1.0% of patients assigned to prasugrel, and definite stent thrombosis occurred in 1.1% and 0.6%, respectively. Major bleeding (as defined by the Bleeding Academic Research Consortium scale) was observed in 5.4% of patients in the ticagrelor group and in 4.8% of patients in the prasugrel group (hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P=0.46).

CONCLUSIONS
Among patients who presented with acute coronary syndromes with or without ST-segment elevation, the incidence of death, myocardial infarction, or stroke was significantly lower among those who received prasugrel than among those who received ticagrelor, and the incidence of major bleeding was not significantly different between the two groups.

Question 9

ACCOAST

Answer 9

NEJM, 2013

BACKGROUND
Although P2Y12 antagonists are effective in patients with non–ST-segment elevation (NSTE) acute coronary syndromes, the effect of the timing of administration — before or after coronary angiography — is not known.

We evaluated the effect of administering the P2Y12 antagonist prasugrel at the time of diagnosis versus administering it after the coronary angiography if percutaneous coronary intervention (PCI) was indicated.

METHODS
We enrolled 4033 patients with NSTE acute coronary syndromes and a positive troponin level who were scheduled to undergo coronary angiography within 2 to 48 hours after randomization. Patients were randomly assigned to receive prasugrel (a 30-mg loading dose) before the angiography (pretreatment group) or placebo (control group). When PCI was indicated, an additional 30 mg of prasugrel was given in the pretreatment group at the time of PCI and 60 mg of prasugrel was given in the control group.

RESULTS
The rate of the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout) through day 7, did not differ significantly between the two groups (hazard ratio with pretreatment, 1.02; 95% confidence interval [CI], 0.84 to 1.25; P=0.81). T

he rate of the key safety end point of all Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, whether related or not related to coronary-artery bypass grafting (CABG), through day 7 was increased with pretreatment (hazard ratio, 1.90; 95% CI, 1.19 to 3.02; P=0.006).

The rates of TIMI major bleeding and life-threatening bleeding not related to CABG were increased by a factor of 3 and 6, respectively.

Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI (69% of the patients) but increased the rate of TIMI major bleeding at 7 days. All the results were confirmed at 30 days and in prespecified subgroups.

CONCLUSIONS
Among patients with NSTE acute coronary syndromes who were scheduled to undergo catheterization, pretreatment with prasugrel did not reduce the rate of major ischemic events up to 30 days but increased the rate of major bleeding complications.

Question 9

ATLANTIC

Answer 9

NEJM, 2014

BACKGROUND
The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.

METHODS
We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours’ duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days.

RESULTS
The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used.

CONCLUSIONS
Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion.

Explorou o conceito de pré-tratamento com ticagrelor no STEMI

Question 10

Classe de recomendação do pre tratamento com:
1) AAS
2) P2Y12 STEMI
3) P2Y12 NSTEMI

Answer 10

1) Classe I
2) Classe IIb (ATLANTIC)
3) Classe III (ACCOAST)

Question 11

Escolha do P2Y12 nos doentes submetidos a PCI em contexto de SCA

Answer 11

Prasugrel > Ticagrelor (ISAR-REACT 5)

Question 12

Estudos da angiografia no pós paragem em doentes sem supra (5)

Answer 12

Principais: COACT, TOMAHAWK

Secundários: EMERGE, PEARL, COUPE

Question 13

SHOCK Trial

Answer 13

Revascularização vs TMO no AMI-CS

Question 14

IABP-SHOCK 2

Answer 14

IABP + PCI vs PCI only
AMI-CS
Sem melhoria mortalidade por todas as causas aos 3o dias
Não está recomendado por rotina

Question 15

ECMO-CS Trial

Answer 15

ECMO-VA + PCI vs PCI only AMI-CS
Negativo

Question 16

RIVAL Trial

Answer 16

Lancet, 2011
Objetivo: determinar qual o melhor acesso para coronariografia e PCI no que respeita a segurança e eficácia

7021 doentes com SCA

Primary outcome: a composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft (non-CABG)-related major bleeding at 30 days.
Patients and investigators were not masked to treatment allocation.

Resultados
EP: 128 (3·7%) of 3507 in the radial vs 139 (4·0%) of 3514 in the femoral (hazard ratio [HR] 0·92, 95% CI 0·72–1·17; p=0·50).

Non-CABG-related major bleeding at 30 days was 24 (0·7%) vs (0·9%), (HR 0·73, 95% CI 0·43–1·23; p=0·23).

At 30 days, 42 of 3507 patients in the radial group had large haematoma compared with 106 of 3514 in the femoral group (HR 0·40, 95% CI 0·28–0·57; p<0·0001).

Pseudoaneurysm needing closure occurred in seven of 3507 patients in the radial group compared with 23 of 3514 in the femoral group (HR 0·30, 95% CI 0·13–0·71; p=0·006).

Interpretation: Radial and femoral approaches are both safe and effective for PCI. However, the lower rate of local vascular complications may be a reason to use the radial approach.

Question 17

MATRIX Trial

Answer 17

Acesso Femoral vs Radial
Menos hemorragia acesso
Menos reparaçao cirurgica acesso
Menos transfusões

Question 18

NORSTENT

Answer 18

2016, NEJM

Introduction:

Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and stent thrombosis and on quality of life.

9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents

In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents.

The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up.

Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life.

At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome.

The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498).

Quality-of-life measures did not differ significantly between the two groups.

In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents.

BMS vs DES nova geraçao
Menos trombose de stent
Menos target lesion revascularization (TLR)

Question 19

COMFORTABLE-AMI

Answer 19

2012, JAMA

Context: The efficacy and safety of drug-eluting stents compared with bare-metal stents remains controversial in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).

Objective: To compare stents eluting biolimus from a biodegradable polymer with bare-metal stents in primary PCI.

Design, Setting, and Patients:

A prospective, randomized, single-blinded, controlled trial of 1161 patients presenting with STEMI at 11 sites in Europe and Israel between September 19, 2009, and January 25, 2011.

Clinical follow-up was performed at 1 and 12 months.

Intervention Patients were randomized 1:1 to receive the biolimus-eluting stent (n = 575) or the bare-metal stent (n = 582).

Main Outcome Measures

Primary end point was the rate of major adverse cardiac events, a composite of cardiac death, target vessel–related reinfarction, and ischemia-driven target-lesion revascularization at 1 year.

Results

Major adverse cardiac events at 1 year occurred in 24 patients (4.3%) receiving biolimus-eluting stents with biodegradable polymer and 49 patients (8.7%) receiving bare-metal stents (hazard ratio [HR], 0.49; 95% CI, 0.30-0.80; P = .004).

The difference was driven by a lower risk of target vessel–related reinfarction (3 [0.5%] vs 15 [2.7%]; HR, 0.20; 95% CI, 0.06-0.69; P = .01) and ischemia-driven target-lesion revascularization (9 [1.6%] vs 32 [5.7%]; HR, 0.28; 95% CI, 0.13-0.59; P < .001) in patients receiving biolimus-eluting stents compared with those receiving bare-metal stents.

Rates of cardiac death were not significantly different (16 [2.9%] vs 20 [3.5%], P = .53).

Definite stent thrombosis occurred in 5 patients (0.9%) treated with biolimus-eluting stents and 12 patients (2.1%; HR, 0.42; 95% CI, 0.15-1.19; P = .10) treated with bare-metal stents.

Conclusion:

Compared with a bare-metal stent, the use of biolimus-eluting stents with a biodegradable polymer resulted in a lower rate of the composite of major adverse cardiac events at 1 year among patients with STEMI undergoing primary PCI.

Question 20

EXAMINATION

Answer 20

2014, JACC CVi

Objectives

This study sought to assess the 2-year outcomes of the population included in the EXAMINATION (Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-Segment Elevation Myocardial Infarction) trial beyond the 1-year prescription period of dual antiplatelet therapy.

Background
The EXAMINATION trial compared the performance of everolimus-eluting stents (EES) versus bare-metal stents (BMS) in an all-comer ST-segment elevation myocardial infarction (STEMI) population.

Methods
This was a multicenter, multinational, prospective, randomized, single-blind, controlled trial in patients with STEMI.

The primary endpoint, which was the combined endpoint of all-cause death, any recurrent myocardial infarction, and any revascularization, and the endpoints target lesion revascularization and stent thrombosis were assessed at 2 years.

Results
Between December 31, 2008, and May 15, 2010, 1,498 patients were randomized to receive EES (n = 751) or BMS (n = 747). Compliance with dual antiplatelet regimen was reduced at 2 years to a similar degree (17.3% vs. 17.2%, p = 0.91). At 2 years, the primary endpoint occurred in 108 (14.4%) patients of the EES group and in 129 (17.3%) patients of the BMS group (p = 0.11).

Rate of target lesion revascularization was significantly lower in the EES group than in the BMS group (2.9% vs. 5.6%; p = 0.009).

Rates of definite and definite or probable stent thrombosis were also significantly reduced in the EES group (0.8% vs. 2.1%; p = 0.03, and 1.3% vs. 2.8%; p = 0.04, respectively).

Conclusions
The 2-year follow-up of the EXAMINATION trial confirms the safety and efficacy of the EES compared with BMS in the setting of STEMI. Specifically, both rates of target lesion revascularization and stent thrombosis were reduced in recipients of EES without any signs of late attrition for either of these endpoints.

Question 21

REVELATION

Answer 21

Balao com farmaco no NSTEMI
Sobreponivel PCI vs farmaco

Question 22

PEPCAD NSTEMI

Answer 22

DCB vs BMS no STEMI
Não inferior ao stent

Question 23

TASTE

Answer 23

2013, NEJM

BACKGROUND
The clinical effect of routine intracoronary thrombus aspiration before primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) is uncertain. We aimed to evaluate whether thrombus aspiration reduces mortality.

METHODS
We conducted a multicenter, prospective, randomized, controlled, open-label clinical trial, with enrollment of patients from the national comprehensive Swedish Coronary Angiography and Angioplasty Registry (SCAAR) and end points evaluated through national registries. A total of 7244 patients with STEMI undergoing PCI were randomly assigned to manual thrombus aspiration followed by PCI or to PCI only. The primary end point was all-cause mortality at 30 days.

RESULTS
No patients were lost to follow-up. Death from any cause occurred in 2.8% of the patients in the thrombus-aspiration group (103 of 3621), as compared with 3.0% in the PCI-only group (110 of 3623) (hazard ratio, 0.94; 95% confidence interval [CI], 0.72 to 1.22; P=0.63). The rates of hospitalization for recurrent myocardial infarction at 30 days were 0.5% and 0.9% in the two groups, respectively (hazard ratio, 0.61; 95% CI, 0.34 to 1.07; P=0.09), and the rates of stent thrombosis were 0.2% and 0.5%, respectively (hazard ratio, 0.47; 95% CI, 0.20 to 1.02; P=0.06). There were no significant differences between the groups with respect to the rate of stroke or neurologic complications at the time of discharge (P=0.87). The results were consistent across all major prespecified subgroups, including subgroups defined according to thrombus burden and coronary flow before PCI.

CONCLUSIONS
Routine thrombus aspiration before PCI as compared with PCI alone did not reduce 30-day mortality among patients with STEMI.

Question 24

TOTAL

Answer 24

2015, NEJM

BACKGROUND
During primary percutaneous coronary intervention (PCI), manual thrombectomy may reduce distal embolization and thus improve microvascular perfusion. Small trials have suggested that thrombectomy improves surrogate and clinical outcomes, but a larger trial has reported conflicting results.

METHODS
We randomly assigned 10,732 patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI to a strategy of routine upfront manual thrombectomy versus PCI alone. The primary outcome was a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association (NYHA) class IV heart failure within 180 days. The key safety outcome was stroke within 30 days.

RESULTS
The primary outcome occurred in 347 of 5033 patients (6.9%) in the thrombectomy group versus 351 of 5030 patients (7.0%) in the PCI-alone group (hazard ratio in the thrombectomy group, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P=0.86). The rates of cardiovascular death (3.1% with thrombectomy vs. 3.5% with PCI alone; hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P=0.34) and the primary outcome plus stent thrombosis or target-vessel revascularization (9.9% vs. 9.8%; hazard ratio, 1.00; 95% CI, 0.89 to 1.14; P=0.95) were also similar. Stroke within 30 days occurred in 33 patients (0.7%) in the thrombectomy group versus 16 patients (0.3%) in the PCI-alone group (hazard ratio, 2.06; 95% CI, 1.13 to 3.75; P=0.02).

CONCLUSIONS
In patients with STEMI who were undergoing primary PCI, routine manual thrombectomy, as compared with PCI alone, did not reduce the risk of cardiovascular death, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days but was associated with an increased rate of stroke within 30 days.

Question 25

Ensaio que compara revascularização cirurgica vs PCI no sindrome coronário agudo

Answer 25

Não ha

Question 26

SHOCK Trial

Answer 26

1999, NEJM

Revascularização emergente vs estabilização no AMI-CS
64% PCI, 36% CABG
85% MVD
Mortalidade 30 dias igual
Mortalidade 6 meses inferior

BACKGROUND
The leading cause of death in patients hospitalized for acute myocardial infarction is cardiogenic shock. We conducted a randomized trial to evaluate early revascularization in patients with cardiogenic shock.

METHODS
Patients with shock due to left ventricular failure complicating myocardial infarction were randomly assigned to emergency revascularization (152 patients) or initial medical stabilization (150 patients). Revascularization was accomplished by either coronary-artery bypass grafting or angioplasty. Intraaortic balloon counterpulsation was performed in 86 percent of the patients in both groups. The primary end point was mortality from all causes at 30 days. Six-month survival was a secondary end point.

RESULTS
The mean (±SD) age of the patients was 66±10 years, 32 percent were women, and 55 percent had been transferred from other hospitals. The median time to the onset of shock was 5.6 hours after infarction, and most infarcts were anterior in location. Ninety-seven percent of the patients assigned to revascularization underwent early coronary angiography, and 87 percent underwent revascularization; only 2.7 percent of the patients assigned to medical therapy crossed over to early revascularization without clinical indication. Overall mortality at 30 days did not differ significantly between the revascularization and medical-therapy groups (46.7 percent and 56.0 percent, respectively; difference, –9.3 percent; 95 percent confidence interval for the difference, –20.5 to 1.9 percent; P=0.11). Six-month mortality was lower in the revascularization group than in the medical-therapy group (50.3 percent vs. 63.1 percent, P=0.027).

CONCLUSIONS
In patients with cardiogenic shock, emergency revascularization did not significantly reduce overall mortality at 30 days. However, after six months there was a significant survival benefit. Early revascularization should be strongly considered for patients with acute myocardial infarction complicated by cardiogenic shock.

Question 27

CULPRIT-SHOCK

Answer 27

2017, NEJM

BACKGROUND
In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial.

METHODS
In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke.

RESULTS
At 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal-replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups.

CONCLUSIONS
Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI.

Culprit only vs Multivessel PCI no procedimento index
Menor mortalidade por todas as causas ou necessidade de dialise a 30 dias
Mortalidade a 1 ano igual

Question 28

Ensaios de revascularização completa no STEMI (5)

Answer 28

PRAMI
CvLPRIT
COMPARE-ACUTE
DANAMI-3-PRIMULTI
COMPLETE

Question 29

Benefícios da revascularização completa no STEMI

Answer 29

Redução mortalidade CV
Redução morte CV ou novo EAM

Question 30

Enasios do Timing das lesões não culprit

Answer 30

MULTISTAR-AMI
BIOVASC

Question 31

Ensaios na revascularização completa NSTEMI

Answer 31

FIRE-AMI

Question 32

FAMOUS NSTEMI

Answer 32

2015, EHJ

FFR vs angiografia para management no NSTEMI
EP: Proporção de doentes alocados a terapeutica médica
FFR mudou estrategia em 1/5 dos doentes
Maior proporçao de doentes para terapeutica médica
MACE semelahnte
EAM periprocedimento maior na angio (pq fazem mais PCI)
EAM espontaneo maior na FFR

Aim:

We assessed the management and outcomes of non-ST segment elevation myocardial infarction (NSTEMI) patients randomly assigned to fractional flow reserve (FFR)-guided management or angiography-guided standard care.

Methods and results:

We conducted a prospective, multicentre, parallel group, 1 : 1 randomized, controlled trial in 350 NSTEMI patients with ≥1 coronary stenosis ≥30% of the lumen diameter assessed visually (threshold for FFR measurement) (NCT01764334). Enrolment took place in six UK hospitals from October 2011 to May 2013. Fractional flow reserve was disclosed to the operator in the FFR-guided group (n = 176). Fractional flow reserve was measured but not disclosed in the angiography-guided group (n = 174).

Fractional flow reserve ≤0.80 was an indication for revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG).

The median (IQR) time from the index episode of myocardial ischaemia to angiography was 3 (2, 5) days.

For the primary outcome, the proportion of patients treated initially by medical therapy was higher in the FFR-guided group than in the angiography-guided group [40 (22.7%) vs. 23 (13.2%), difference 95% (95% CI: 1.4%, 17.7%), P = 0.022].

Fractional flow reserve disclosure resulted in a change in treatment between medical therapy, PCI or CABG in 38 (21.6%) patients.

At 12 months, revascularization remained lower in the FFR-guided group [79.0 vs. 86.8%, difference 7.8% (-0.2%, 15.8%), P = 0.054].

There were no statistically significant differences in health outcomes and quality of life between the groups.

Conclusion: In NSTEMI patients, angiography-guided management was associated with higher rates of coronary revascularization compared with FFR-guided management. A larger trial is necessary to assess health outcomes and cost-effectiveness.

Question 33

FLOWER MI

Answer 33

2021, NEJM

Angioplastia multivaso guiada por FFR ou angiografia
STEMI e doença multivaso com PCI com sucesso da culprit
1170 doentes
EP: Morte, EAM ou revascularização urgente
EP secundário EAM nao fatal ou revascularização urgente
Estratégia FFR não teve benificio significativo numa estrategia com base de angiografia no que diz respeito a morte, EAM ou revasvularização urgente

BACKGROUND
In patients with ST-elevation myocardial infarction (STEMI) who have multivessel disease, percutaneous coronary intervention (PCI) for nonculprit lesions (complete revascularization) is superior to treatment of the culprit lesion alone. However, whether complete revascularization that is guided by fractional flow reserve (FFR) is superior to an angiography-guided procedure is unclear.

In this multicenter trial, we randomly assigned patients with STEMI and multivessel disease who had undergone successful PCI of the infarct-related artery to receive complete revascularization guided by either FFR or angiography. The primary outcome was a composite of death from any cause, nonfatal myocardial infarction, or unplanned hospitalization leading to urgent revascularization at 1 year.

RESULTS
The mean (±SD) number of stents that were placed per patient for nonculprit lesions was 1.01±0.99 in the FFR-guided group and 1.50±0.86 in the angiography-guided group. During follow-up, a primary outcome event occurred in 32 of 586 patients (5.5%) in the FFR-guided group and in 24 of 577 patients (4.2%) in the angiography-guided group (hazard ratio, 1.32; 95% confidence interval, 0.78 to 2.23; P=0.31). Death occurred in 9 patients (1.5%) in the FFR-guided group and in 10 (1.7%) in the angiography-guided group; nonfatal myocardial infarction in 18 (3.1%) and 10 (1.7%), respectively; and unplanned hospitalization leading to urgent revascularization in 15 (2.6%) and 11 (1.9%), respectively.

CONCLUSIONS
In patients with STEMI undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization at 1 year. However, given the wide confidence intervals for the estimate of effect, the findings do not allow for a conclusive interpretation.

Question 34

FRAME-AMI

Answer 34

EHJ, 2022

Aims
In patients with acute myocardial infarction (MI) and multivessel coronary artery disease, percutaneous coronary intervention (PCI) of non-infarct-related artery reduces death or MI. However, whether selective PCI guided by fractional flow reserve (FFR) is superior to routine PCI guided by angiography alone is unclear. The current trial sought to compare FFR-guided PCI with angiography-guided PCI for non-infarct-related artery lesions among patients with acute MI and multivessel disease.

Methods and results
Patients with acute MI and multivessel coronary artery disease who had undergone successful PCI of the infarct-related artery were randomly assigned to either FFR-guided PCI (FFR ≤0.80) or angiography-guided PCI (diameter stenosis of >50%) for non-infarct-related artery lesions. The primary end point was a composite of time to death, MI, or repeat revascularization. A total of 562 patients underwent randomization. Among them, 60.0% underwent immediate PCI for non-infarct-related artery lesions and 40.0% were treated by a staged procedure during the same hospitalization. PCI was performed for non-infarct-related artery in 64.1% in the FFR-guided PCI group and 97.1% in the angiography-guided PCI group, and resulted in significantly fewer stent used in the FFR-guided PCI group (2.2 ± 1.1 vs. 2.5 ± 0.9, P < 0.001). At a median follow-up of 3.5 years (interquartile range: 2.7–4.1 years), the primary end point occurred in 18 patients of 284 patients in the FFR-guided PCI group and in 40 of 278 patients in the angiography-guided PCI group (7.4% vs. 19.7%; hazard ratio, 0.43; 95% confidence interval, 0.25–0.75; P = 0.003). The death occurred in five patients (2.1%) in the FFR-guided PCI group and in 16 patients (8.5%) in the angiography-guided PCI group; MI in seven (2.5%) and 21 (8.9%), respectively; and unplanned revascularization in 10 (4.3%) and 16 (9.0%), respectively.

Conclusion
In patients with acute MI and multivessel coronary artery disease, a strategy of selective PCI using FFR-guided decision-making was superior to a strategy of routine PCI based on angiographic diameter stenosis for treatment of non-infarct-related artery lesions regarding the risk of death, MI, or repeat revascularization.

Question 35

COACT

Answer 35

2019, NEJM

Angio + PCI rotina vs apos recuperação neurológica no pos paragem extra hospitalar sem supra

552 doentes
Ritmo inicial desfibrilhável, coma após ROSC
Exclusão: STEMI, choque ou causa não cardíaca óbvia
Braço ativo : CAT assim que possível
Controlo: CAT após recuperação neurológica
EP: sobrevida a 90 dias
64.5% vs 67-2% (OR 0.89, 0.62 - 1.27)
Sem diferença nos vários endpoints secundários
66 anos, 80% homens, GSC 3 admissao, presenciada 80%, 15 min até ROSC, 2 min até SBV
97% vs 65% fez coronariografia
35% sem doença, 30% doença 1 vaso, 17% CADx3 (maioria com doença estável)
15% lesao instável
Só 5% com oclus\oes trombóticas (PCI so é exptavel que melhore em doentes com oclus\ao aguda).
Maioria dos sobreviventes morre de causa neurológica (em linha com estudos de ressuscitação).
Pouco poder - sobrevida foi maior do que o esperado.
33% PCI, 7 % CABG

Question 36

TOMAHAWK

Answer 36

NEJM, 2021, Alemanha

Morte por todas as causas aos 30 dias

Ritmo chocavel + não chocável
91% preenciada
55% desfibrilhavel
60% SBV
15 min ate ROSC
Todos em coma
5 lactato
CAT 96% vs 62%
40% vs 30% sem CAD
33% vs 44 % CAD3V
40% com culprit identiifcada, 40% PCI (so neste subgrupo é expectavel que estratégia mais precoce faça sentido. Todos os outros só têm os riscos do procedimento.
Maioria morre de causa neurológica
Dificil avaliar status neurológico primeiras horas
Estudo aberto

Question 37

POPular AGE

Answer 37

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome

Background: Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST- elevation acute coronary syndrome (NSTE-ACS).

Methods: We did the open-label, randomized controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands.

Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation.

Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all- cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013–001403–37).

Findings Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group.

Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel.

Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority).

Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference –4%, 95% CI –10·0 to 1·4; p=0·03 for non-inferiority).

The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35).

Interpretation In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk.

Question 38

RE-DUAL PCI

Answer 38

Dual Antithrombotic Therapy with Dabigatran after PCI
in Atrial Fibrillation

BACKGROUND
Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding.

METHODS
In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg
12
and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age;
≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleed- ing event during follow-up (mean follow-up, 14 months). The trial also tested for the noninfe- riority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. RESULTS
The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence inter- val [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups.

CONCLUSIONS
Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864.)

Question 39

ENTRUST-AF PCI

Answer 39

Edoxaban-based versus vitamin K antagonist-based
antithrombotic regimen after successful coronary stenting
in patients with atrial fibrillation

Summary
Background We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI).
Methods ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web- based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1–12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15–50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed.
Findings From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2–76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65–1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority).
Interpretation In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events.

Question 40

CHAMPION PHOENIX

Answer 40

Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events

Background
The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)–receptor antagonist that acts rap- idly and has quickly reversible effects.
Methods
In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline- recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.
Results
The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confi- dence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred signifi- cantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.
Conclusions
Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.)

Question 41

CURE

Answer 41

Background Despite current treatments, patients who have acute coronary syndromes without ST-seg- ment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspi- rin in such patients.
Methods We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or pla- cebo (6303 patients) in addition to aspirin for 3 to 12 months.
Results The first primary outcome — a composite of death from cardiovascular causes, nonfatal myocar- dial infarction, or stroke — occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 per- cent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome — the first primary outcome or refractory ischemia — occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86, P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revas- cularization procedures were also significantly lower with clopidogrel. There were significantly more pa- tients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not signif- icantly more patients with episodes of life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hem- orrhagic strokes.
Conclusions The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syn- dromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel. (N Engl J Med 2001;345: 494-502.)

Question 42

PCI-CURE

Answer 42

Background Despite the use of aspirin, there is still a risk of ischaemic events after percutaneous coronary intervention (PCI). We aimed to find out whether, in addition to aspirin, pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI.
Methods 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been randomly assigned double-blind treatment with clopidogrel (n=1313) or placebo (n=1345). Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission, and for a median of 10 days overall. After PCI, most patients (>80%) in both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or urgent target-vessel revascularisation within 30 days of PCI. The main analysis was by intention to treat.
Findings There were no drop-outs. 59 (4·5%) patients in the clopidogrel group had the primary endpoint, compared with 86 (6·4%) in the placebo group (relative risk 0·70 [95% CI 0·50–0·97], p=0·03). Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation (p=0·03), and of cardiovascular death or myocardial infarction (p=0·047). Overall (including events before and after PCI) there was a 31% reduction cardiovascular death or myocardial infarction (p=0·002). There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group (p=0·001). At follow-up, there was no significant difference in major bleeding between the groups (p=0·64).

Interpretation In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo.

Question 43

CHAMPION PLATFORM

Answer 43

Intravenous Platelet Blockade with Cangrelor during PCI

Background
Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) recep- tor antagonist, might reduce ischemic events during percutaneous coronary interven- tion (PCI).
Methods
In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.
Results
The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention- to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant differ- ence in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.
Conclusions
The use of periprocedural cangrelor during PCI was not superior to placebo in re- ducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant in- crease in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

Question 44

EARLY ACS

Answer 44

Background
Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syn- dromes who are undergoing an invasive procedure. The optimal timing of the initia- tion of such therapy is unknown.

Methods
We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes with- out ST-segment elevation and who were assigned to an invasive strategy. Patients were randomly assigned to receive either early eptifibatide (two boluses, each containing 180 μg per kilogram of body weight, administered 10 minutes apart, and a standard infusion ≥12 hours before angiography) or a matching placebo infusion with provi- sional use of eptifibatide after angiography (delayed eptifibatide). The primary effi- cacy end point was a composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention that required bolus therapy opposite to the initial study-group assignment (“thrombotic bailout”) at 96 hours. The key sec- ondary end point was a composite of death or myocardial infarction within the first 30 days. Key safety end points were bleeding and the need for transfusion within the first 120 hours after randomization.

Results
The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23). At 30 days, the rate of death or myocardial in- farction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events.

Conclusions
In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non–life-threatening bleeding and need for transfusion. (ClinicalTrials.gov number, NCT00089895.)

Question 45

CHAMPION PCI trial

Answer 45

Platelet Inhibition with Cangrelor in Patients
Undergoing PCI

Background
Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y12. This agent might have a role in the treatment of patients who require rapid, predictable, and profound but re- versible platelet inhibition.
Methods
We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revas- cularization at 48 hours.
Results
We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which oc- curred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopi- dogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (accord- ing to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend to- ward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P = 0.14).
Conclusions
Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopid- ogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours.

Question 46

PIONEER AF-PCI

Answer 46

Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI

BACKGROUND
In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y inhibitor and aspirin reduces the risk of thrombosis and stroke but increases the risk of bleeding. The effectiveness and safety of antico-
agulation with rivaroxaban plus either one or two antiplatelet agents are uncertain.

METHODS
We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had un-
dergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once
twice daily) plus DAPT for 1, 6, or 12 months (group 2), or standard therapy with a dose- adjusted vitamin K antagonist (once daily) plus DAPT for 1, 6, or 12 months (group 3). The primary safety outcome was clinically significant bleeding (a composite of major bleeding or minor bleeding according to Thrombolysis in Myocardial Infarction [TIMI] criteria or bleeding requiring medical attention).
RESULTS
The rates of clinically significant bleeding were lower in the two groups receiving rivar- oxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001; hazard ratio for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80; P<0.001). The rates of death from cardiovascular causes, myocardial infarction, or stroke weresimilarinthethreegroups(Kaplan–Meierestimates,6.5%ingroup1,5.6%ingroup 2, and 6.0% in group 3; P values for all comparisons were nonsignificant).
CONCLUSIONS
In participants with atrial fibrillation undergoing PCI with placement of stents, the admin- istration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low- dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a vitamin K antagonist plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding ef- ficacy. (Funded by Janssen Scientific Affairs and Bayer Pharmaceuticals; PIONEER AF-PCI ClinicalTrials.gov number, NCT01830543.)

Question 47

SYNERGY Randomized Trial

Answer 47

Enoxaparin vs Unfractionated Heparin in High-Risk Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Managed
With an Intended Early Invasive Strategy

Context Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non–ST-segment elevation acute coronary syn- dromes (ACS) treated with a conservative strategy.
Objectives To compare the outcomes of patients treated with enoxaparin vs un- fractionated heparin and to define the role of enoxaparin in patients with non–ST- segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach.
Design,Setting,andParticipants TheSuperiorYieldoftheNewStrategyofEnoxa- parin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a pro- spective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10027 high-risk patients with non–ST- segment elevation ACS to be treated with an intended early invasive strategy were recruited.
Interventions Subcutaneousenoxaparin(n=4993)orintravenousunfractionatedhep- arin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician.
MainOutcomeMeasures Theprimaryefficacyoutcomewasthecompositeclini- cal end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke.
Results Theprimaryendpointoccurredin14.0%(696/4993)ofpatientsassigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed be- tween enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt clo- sure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/ 2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically sig- nificant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P=.008) but nonsignificant excess in GUSTO (Global Utilization of Strepto- kinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P=.08) and transfusions (17.0% vs 16.0%, P=.16).
Conclusions Enoxaparinwasnotsuperiortounfractionatedheparinbutwasnon- inferior for the treatment of high-risk patients with non–ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the ad- vantages of convenience should be balanced with the modest excess of major bleeding.

Question 48

FUTURA/OASIS-8

Answer 48

Low-Dose vs Standard-Dose Unfractionated Heparin for Percutaneous Coronary Intervention in Acute Coronary Syndromes
Treated With Fondaparinux

Context Theoptimalunfractionatedheparinregimenforpercutaneouscoronaryin- tervention (PCI) in patients with non–ST-segment elevation acute coronary syn- dromes treated with fondaparinux is uncertain.
Objective Tocomparethesafetyof2unfractionatedheparinregimensduringPCI in high-risk patients with non–ST-segment elevation acute coronary syndromes ini- tially treated with fondaparinux.
Design,Setting,andParticipants Double-blindrandomizedparallel-grouptrial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non–ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010.
Interventions Patientsreceivedintravenouslyeitherlow-doseunfractionatedhep- arin, 50 U/kg , regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard- dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT).
MainOutcomeMeasures Compositeofmajorbleeding,minorbleeding,orma- jor vascular access-site complications up to 48 hours after PCI. Key secondary out- comes include composite of major bleeding at 48 hours with death, myocardial in- farction, or target vessel revascularization within day 30.
Results Theprimaryoutcomeoccurredin4.7%ofthoseinthelow-dosegroupvs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P=.27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard- dose group (OR, 0.40; 95% CI, 0.16-0.97; P=.04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P=.05) and for death, myocardial infarction, or target ves- sel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard- dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P=.15).
Conclusion Low-dosecomparedwithstandard-doseunfractionatedheparindidnot reduce major peri-PCI bleeding and vascular access-site complications.

Question 49

TWILIGHT

Answer 49

Ticagrelor with or without Aspirin in High-Risk Patients after PCI

BACKGROUND
Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI).
METHODS
In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocar- dial infarction, or nonfatal stroke, using a noninferiority hypothesis with an ab- solute margin of 1.6 percentage points.
RESULTS
We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving tica- grelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, −0.06 percentage points; 95% CI, −0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority).
CONCLUSIONS
Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke.

Question 50

DAPT Study

Answer 50

Twelve or 30 Months of Dual Antiplatelet Therapy
after Drug-Eluting Stents

Background
Dual antiplatelet therapy is recommended after coronary stenting to prevent throm- botic complications, yet the benefits and risks of treatment beyond 1 year are uncertain.
Methods
Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed. After 12 months of treatment with a thienopyridine drug (clopidogrel or prasugrel) and aspirin, patients were randomly assigned to con- tinue receiving thienopyridine treatment or to receive placebo for another 18 months; all patients continued receiving aspirin. The coprimary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events (a compos- ite of death, myocardial infarction, or stroke) during the period from 12 to 30 months. The primary safety end point was moderate or severe bleeding.
Results
A total of 9961 patients were randomly assigned to continue thienopyridine treat- ment or to receive placebo. Continued treatment with thienopyridine, as compared with placebo, reduced the rates of stent thrombosis (0.4% vs. 1.4%; hazard ratio, 0.29 [95% confidence interval {CI}, 0.17 to 0.48]; P<0.001) and major adverse car- diovascular and cerebrovascular events (4.3% vs. 5.9%; hazard ratio, 0.71 [95% CI, 0.59 to 0.85]; P<0.001). The rate of myocardial infarction was lower with thieno- pyridine treatment than with placebo (2.1% vs. 4.1%; hazard ratio, 0.47; P<0.001). The rate of death from any cause was 2.0% in the group that continued thienopyri- dine therapy and 1.5% in the placebo group (hazard ratio, 1.36 [95% CI, 1.00 to 1.85]; P=0.05). The rate of moderate or severe bleeding was increased with continued thi- enopyridine treatment (2.5% vs. 1.6%, P=0.001). An elevated risk of stent thrombo- sis and myocardial infarction was observed in both groups during the 3 months after discontinuation of thienopyridine treatment.
Conclusions
Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent, as compared with aspirin therapy alone, significantly reduced the risks of stent throm- bosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding. (Funded by a consortium of eight device and drug manufacturers and others; DAPT ClinicalTrials.gov number, NCT00977938.)

Question 51

PEGASUS-TIMI 54

Answer 51

Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction

The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial
infarction has not been established. We investigated the efficacy and safety of ticagrelor in this context

METHODS
We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocar- dial Infarction (TIMI) major bleeding.
RESULTS
The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P = 0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.
CONCLUSIONS
In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial in- farction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.)

Question 52

TOPIC Trial

Answer 52

Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study

Aims Newer P2Y12 blockers (prasugrel and ticagrelor) demonstrated significant ischaemic benefit over clopidogrel after acute coronary syndrome (ACS). However, both drugs are associated with an increase in bleeding complications. The objective of the present study was to evaluate the benefit of switching dual antiplatelet therapy (DAPT) from
aspirin plus a newer P2Y12 blocker to aspirin plus clopidogrel 1 month after ACS.
……………………………………………………………………………………………………………………………………………………………………………
Methods and results
We performed an open-label, monocentric, and randomized trial. From March 2014 to April 2016, patients admit-
ted with ACS requiring coronary intervention, on aspirin and a newer P2Y12 blocker and without adverse event at
1 month, were assigned to switch to aspirin and clopidogrel (switched DAPT) or continuation of their drug regi-
men (unchanged DAPT). The primary outcome was a composite of cardiovascular death, urgent revascularization,
stroke and bleeding as defined by the Bleeding Academic Research Consortium (BARC) classification >_2 at 1 year
post ACS. Six hundred and forty six patients were randomized and 645 analysed, corresponding to 322 patients in
the switched DAPT and 323 in the unchanged DAPT group. The primary endpoint occurred in 43 (13.4%) patients
in the switched DAPT group and in 85 (26.3%) patients in the unchanged DAPT (HR 95%CI 0.48 (0.34–0.68),
P<0.01). No significant differences were reported on ischaemic endpoints, while BARC>_2 bleeding occurred in
13 (4.0%) patients in the switched DAPT and in 48 (14.9%) in the unchanged DAPT group (HR 95%CI 0.30 (0.18–
0.50), P < 0.01). ……………………………………………………………………………………………………………………………………………………………………………
Conclusion A switched DAPT is superior to an unchanged DAPT strategy to prevent bleeding complications without increase in ischaemic events following ACS.

Question 53

TROPICAL-ACS

Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention

Answer 53

Background Current guidelines recommend potent platelet inhibition with prasugrel or ticagrelor for 12 months after an acute coronary syndrome managed with percutaneous coronary intervention (PCI). However, the greatest anti- ischaemic benefit of potent antiplatelet drugs over the less potent clopidogrel occurs early, while most excess bleeding events arise during chronic treatment. Hence, a stage-adapted treatment with potent platelet inhibition in the acute phase and de-escalation to clopidogrel in the maintenance phase could be an alternative approach. We aimed to investigate the safety and efficacy of early de-escalation of antiplatelet treatment from prasugrel to clopidogrel guided by platelet function testing (PFT).

Methods In this investigator-initiated, randomised, open-label, assessor-blinded, multicentre trial (TROPICAL-ACS) done at 33 sites in Europe, patients were enrolled if they had biomarker-positive acute coronary syndrome with successful PCI and a planned duration of dual antiplatelet treatment of 12 months. Enrolled patients were randomly assigned (1:1) using an internet-based randomisation procedure with a computer-generated block randomisation with stratification across study sites to either standard treatment with prasugrel for 12 months (control group) or a step- down regimen (1 week prasugrel followed by 1 week clopidogrel and PFT-guided maintenance therapy with clopidogrel or prasugrel from day 14 after hospital discharge; guided de-escalation group). The assessors were masked to the treatment allocation. The primary endpoint was net clinical benefit (cardiovascular death, myocardial infarction, stroke or bleeding grade 2 or higher according to Bleeding Academic Research Consortium [BARC]) criteria) 1 year after randomisation (non-inferiority hypothesis; margin of 30%). Analysis was intention to treat. This study is registered with ClinicalTrials.gov, number NCT01959451, and EudraCT, 2013-001636-22.

Findings Between Dec 2, 2013, and May 20, 2016, 2610 patients were assigned to study groups; 1304 to the guided de-
escalation group and 1306 to the control group. The primary endpoint occurred in 95 patients (7%) in the guided de-
escalation group and in 118 patients (9%) in the control group (pnon-inferiority=0·0004; hazard ratio [HR] 0·81 [95% CI
0·62–1·06], psuperiority=0·12). Despite early de-escalation, there was no increase in the combined risk of cardiovascular
death, myocardial infarction, or stroke in the de-escalation group (32 patients [3%]) versus in the control group
(42 patients [3%]; p =0·0115). There were 64 BARC 2 or higher bleeding events (5%) in the de-escalation group non-inferiority
versus 79 events (6%) in the control group (HR 0·82 [95% CI 0·59–1·13]; p=0·23).

Interpretation Guided de-escalation of antiplatelet treatment was non-inferior to standard treatment with prasugrel at 1 year after PCI in terms of net clinical benefit. Our trial shows that early de-escalation of antiplatelet treatment can be considered as an alternative approach in patients with acute coronary syndrome managed with PCI.

Question 54

GLOBAL LEADERS

Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent

Answer 54

Background We hypothesised that ticagrelor, in combination with aspirin for 1 month, followed by ticagrelor alone, improves outcomes after percutaneous coronary intervention compared with standard antiplatelet regimens.

Methods GLOBAL LEADERS was a randomised, open-label superiority trial at 130 sites in 18 countries. Patients undergoing percutaneous coronary intervention with a biolimus A9-eluting stent for stable coronary artery disease or acute coronary syndromes were randomly assigned (1:1) to 75–100 mg aspirin daily plus 90 mg ticagrelor twice daily for 1 month, followed by 23 months of ticagrelor monotherapy, or standard dual antiplatelet therapy with 75–100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable coronary artery disease) or 90 mg ticagrelor twice daily (for patients with acute coronary syndromes) for 12 months, followed by aspirin monotherapy for 12 months. Randomisation was concealed, stratified by centre and clinical presentation (stable coronary artery disease vs acute coronary syndrome), and blocked, with randomly varied block sizes of two and four. The primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction as assessed by a core lab in a blinded manner. The key secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01813435, and is closed to new participants, with follow- up completed.

Findings Between July 1, 2013, and Nov 9, 2015, 15 968 participants were randomly assigned, 7980 to the experimental group and 7988 to the control group. At 2 years, 304 (3·81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4·37%) participants in the control group (rate ratio 0·87 [95% CI 0·75–1·01]; p=0·073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0·93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2·04% vs 2·12%; rate ratio 0·97 [95% CI 0·78–1·20]; p=0·77).

Interpretation Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention.

Question 55

SMART-CHOICE

Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients
Undergoing Percutaneous Coronary Intervention

Answer 55

MPORTANCE Data on P2Y12 inhibitor monotherapy after short-duration dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention are limited.

OBJECTIVE TodeterminewhetherP2Y12inhibitormonotherapyafter3monthsofDAPT is noninferior to 12 months of DAPT in patients undergoing PCI.

DESIGN,SETTING,ANDPARTICIPANTS TheSMART-CHOICEtrialwasanopen-label, noninferiority, randomized study that was conducted in 33 hospitals in Korea and included 2993 patients undergoing PCI with drug-eluting stents. Enrollment began March 18, 2014, and follow-up was completed July 19, 2018.

INTERVENTIONS PatientswererandomlyassignedtoreceiveaspirinplusaP2Y12inhibitorfor 3 months and thereafter P2Y12 inhibitor alone (n = 1495) or DAPT for 12 months (n = 1498).
MAINOUTCOMESANDMEASURES Theprimaryendpointwasmajoradversecardiacand cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke) at 12 months after the index procedure. Secondary end points included the components of the primary end point and bleeding defined as Bleeding Academic Research Consortium type 2 to 5. The noninferiority margin was 1.8%.
RESULTS Among2993patientswhowererandomized(meanage,64years;795women [26.6%]), 2912 (97.3%) completed the trial. Adherence to the study protocol was 79.3% of the P2Y12 inhibitor monotherapy group and 95.2% of the DAPT group. At 12 months, major adverse cardiac and cerebrovascular events occurred in 42 patients in the P2Y12 inhibitor monotherapy group and in 36 patients in the DAPT group (2.9% vs 2.5%; difference, 0.4% [1-sided 95% CI, –􏰖% to 1.3%]; P = .007 for noninferiority). There were no significant differences in all-cause death (21 [1.4%] vs 18 [1.2%]; hazard ratio [HR], 1.18; 95% CI, 0.63-2.21; P = .61), myocardial infarction (11 [0.8%] vs 17 [1.2%]; HR, 0.66; 95% CI, 0.31-1.40; P = .28), or stroke (11 [0.8%] vs 5 [0.3%]; HR, 2.23; 95% CI, 0.78-6.43; P = .14) between
the 2 groups. The rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group than in the DAPT group (2.0% vs 3.4%; HR, 0.58; 95% CI, 0.36-0.92; P = .02).
CONCLUSIONSANDRELEVANCE Amongpatientsundergoingpercutaneouscoronary intervention, P2Y12 inhibitor monotherapy after 3 months of DAPT compared with prolonged DAPT resulted in noninferior rates of major adverse cardiac and cerebrovascular events. Because of limitations in the study population and adherence, further research is needed in other populations.

Question 56

STOPDAPT-2

Effect of 1-Month Dual Antiplatelet Therapy Followed
by Clopidogrel vs 12-Month Dual Antiplatelet Therapy
on Cardiovascular and Bleeding Events in Patients Receiving PCI

Answer 56

IMPORTANCE Very short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option

OBJECTIVE To test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events.

DESIGN, SETTING,AND PARTICIPANTS Multicenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019.

INTERVENTIONS Patients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522).

MAIN OUTCOMES AND MEASURES The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%.
The major secondary cardiovascular end point was a composite of cardiovascular death,
MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding.

RESULTS Among 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, −1.34% [95% CI, −2.57% to −0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, −0.55% [95% CI, −1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, −1.13% [95% CI, −1.84% to −0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority).
CONCLUSIONSANDRELEVANCE AmongpatientsundergoingPCI,1monthofDAPTfollowed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations.

Question 57

POPular Genetics

A Genotype-Guided Strategy for Oral P2Y12
Inhibitors in Primary PCI

Answer 57

BACKGROUND
It is unknown whether patients undergoing primary percutaneous coronary interven- tion (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors.

METHODS
We conducted a randomized, open-label, assessor-blinded trial in which patients un- dergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C192 or CYP2C193 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events — defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria — at 12 months (primary combined outcome; tested for noninferior- ity, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome).

RESULTS
For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.0 to 0.7; P<0.001 for noninferiority). The primary bleed- ing outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P=0.04).

CONCLUSIONS
In patients undergoing primary PCI, a CYP2C19 genotype–guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding.

Question 58

TWILIGHT

Ticagrelor with or without Aspirin in High-Risk Patients after PCI

Answer 58

BACKGROUND
Monotherapy with a P2Y12 inhibitor after a minimum period of dual antiplatelet therapy is an emerging approach to reduce the risk of bleeding after percutaneous coronary intervention (PCI).

METHODS
In a double-blind trial, we examined the effect of ticagrelor alone as compared with ticagrelor plus aspirin with regard to clinically relevant bleeding among patients who were at high risk for bleeding or an ischemic event and had undergone PCI. After 3 months of treatment with ticagrelor plus aspirin, patients who had not had a major bleeding event or ischemic event continued to take ticagrelor and were randomly assigned to receive aspirin or placebo for 1 year. The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding. We also evaluated the composite end point of death from any cause, nonfatal myocar- dial infarction, or nonfatal stroke, using a noninferiority hypothesis with an ab- solute margin of 1.6 percentage points.

RESULTS
We enrolled 9006 patients, and 7119 underwent randomization after 3 months. Between randomization and 1 year, the incidence of the primary end point was 4.0% among patients randomly assigned to receive ticagrelor plus placebo and 7.1% among patients assigned to receive ticagrelor plus aspirin (hazard ratio, 0.56; 95% confidence interval [CI], 0.45 to 0.68; P<0.001). The difference in risk between the groups was similar for BARC type 3 or 5 bleeding (incidence, 1.0% among patients receiving ticagrelor plus placebo and 2.0% among patients receiving tica- grelor plus aspirin; hazard ratio, 0.49; 95% CI, 0.33 to 0.74). The incidence of death from any cause, nonfatal myocardial infarction, or nonfatal stroke was 3.9% in both groups (difference, −0.06 percentage points; 95% CI, −0.97 to 0.84; hazard ratio, 0.99; 95% CI, 0.78 to 1.25; P<0.001 for noninferiority).

CONCLUSIONS
Among high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy, ticagrelor monotherapy was associated with a lower incidence of clinically relevant bleeding than ticagrelor plus aspirin, with no higher risk of death, myocardial infarction, or stroke.

Question 59

TICO

Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin
on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome

Answer 59

IMPORTANCE Discontinuing aspirin after short-term dual antiplatelet therapy (DAPT) was evaluated as a bleeding reduction strategy. However, the strategy of ticagrelor monotherapy has not been exclusively evaluated in patients with acute coronary syndromes (ACS).

OBJECTIVE To determine whether switching to ticagrelor monotherapy after 3 months of DAPT reduces net adverse clinical events compared with ticagrelor-based 12-month DAPT in patients with ACS treated with drug-eluting stents.

DESIGN, SETTING, AND PARTICIPANTS A randomized multicenter trial was conducted in 3056 patients with ACS treated with drug-eluting stents between August 2015 and October 2018 at 38 centers in South Korea. Follow-up was completed in October 2019.
INTERVENTIONS Patients were randomized to receive ticagrelor monotherapy (90 mg twice daily) after 3-month DAPT (n = 1527) or ticagrelor-based 12-month DAPT (n = 1529).

MAIN OUTCOMES AND MEASURES The primary outcome was a 1-year net adverse clinical event, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events (death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization). Prespecified secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events.
RESULTS Among 3056 patients who were randomized (mean age, 61 years; 628 women [20%]; 36% ST-elevation myocardial infarction), 2978 patients (97.4%) completed the trial. The primary outcome occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (absolute difference, −1.98% [95% CI, −3.50% to −0.45%]; hazard ratio [HR], 0.66 [95% CI, 0.48 to 0.92]; P = .01). Of 10 prespecified secondary outcomes, 8 showed no significant difference. Major bleeding occurred in 1.7% of patients with ticagrelor monotherapy after 3-month DAPT and in 3.0% of patients with ticagrelor-based 12-month DAPT (HR, 0.56 [95% CI, 0.34 to 0.91]; P = .02). The incidence of major adverse cardiac and cerebrovascular events was not significantly different between the ticagrelor monotherapy after 3-month DAPT group (2.3%) vs the ticagrelor-based 12-month DAPT group (3.4%) (HR, 0.69 [95% CI, 0.45 to 1.06]; P = .09).

CONCLUSIONS AND RELEVANCE Among patients with acute coronary syndromes treated with drug-eluting stents, ticagrelor monotherapy after 3 months of dual antiplatelet therapy, compared with ticagrelor-based 12-month dual antiplatelet therapy, resulted in a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. The study population and lower than expected event rates should be considered in interpreting the trial.

Question 60

HOST-EXAM

Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention

Answer 60

Background Optimal antiplatelet monotherapy during the chronic maintenance period in patients who undergo coronary stenting is unknown. We aimed to compare head to head the efficacy and safety of aspirin and clopidogrel monotherapy in this population.

Methods We did an investigator-initiated, prospective, randomised, open-label, multicentre trial at 37 study sites in South Korea. We enrolled patients aged at least 20 years who maintained dual antiplatelet therapy without clinical events for 6–18 months after percutaneous coronary intervention with drug-eluting stents (DES). We excluded patients with any ischaemic and major bleeding complications. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02044250.

Findings Between March 26, 2014, and May 29, 2018, we enrolled 5530 patients. 5438 (98·3%) patients were randomly assigned to either the clopidogrel group (2710 [49·8%]) or to the aspirin group (2728 [50·2%]). Ascertainment of the primary endpoint was completed in 5338 (98·2%) patients. During 24-month follow-up, the primary outcome occurred in 152 (5·7%) patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 [95% CI 0·59–0·90]; p=0·0035).

Interpretation Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention, clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events.

Question 61

HOST-REDUCE-POLYTECH-ACS

Prasugrel-based de-escalation of dual antiplatelet therapy
after percutaneous coronary intervention in patients with
acute coronary syndrome

Answer 61

Background A potent P2Y12 inhibitor-based dual antiplatelet therapy is recommended for up to 1 year in patients with acute coronary syndrome receiving percutaneous coronary intervention (PCI). The greatest benefit of the potent agent is during the early phase, whereas the risk of excess bleeding continues in the chronic maintenance phase. Therefore, de-escalation of antiplatelet therapy might achieve an optimal balance between ischaemia and bleeding. We aimed to investigate the safety and efficacy of a prasugrel-based dose de-escalation therapy.

Methods HOST-REDUCE-POLYTECH-ACS is a randomised, open-label, multicentre, non-inferiority trial done at 35 hospitals in South Korea. We enrolled patients with acute coronary syndrome receiving PCI. Patients meeting the core indication for prasugrel were randomly assigned (1:1) to the de-escalation group or conventional group using a web-based randomisation system. The assessors were masked to the treatment allocation. After 1 month of treatment with 10 mg prasugrel plus 100 mg aspirin daily, the de-escalation group received 5 mg prasugrel, while the conventional group continued to receive 10 mg. The primary endpoint was net adverse clinical events (all-cause death, non-fatal myocardial infarction, stent thrombosis, repeat revascularisation, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium [BARC] criteria) at 1 year. The absolute non-inferiority margin for the primary endpoint was 2·5%. The key secondary endpoints were efficacy outcomes (cardiovascular death, myocardial infarction, stent thrombosis, and ischaemic stroke) and safety outcomes (bleeding events of BARC grade ≥2). The primary analysis was in the intention-to-treat population. This trial is registered with ClinicalTrials. gov, NCT02193971.

Results From Sept 30, 2014, to Dec 18, 2018, 3429 patients were screened, of whom 1075 patients did not meet the core indication for prasugrel and 16 were excluded due to randomisation error. 2338 patients were randomly assigned to the de-escalation group (n=1170) or the conventional group (n=1168). The primary endpoint occurred in 82 patients (Kaplan-Meier estimate 7·2%) in the de-escalation group and 116 patients (10·1%) in the conventional group (absolute risk difference –2·9%, pnon-inferiority<0·0001; hazard ratio 0·70 [95% CI 0·52–0·92], pequivalence=0·012). There was no increase in ischaemic risk in the de-escalation group compared with the conventional group (0·76 [0·40–1·45]; p=0·40), and the risk of bleeding events was significantly decreased (0·48 [0·32–0·73]; p=0·0007).

Interpretation In east Asian patients with acute coronary syndrome patients receiving PCI, a prasugrel-based dose de-escalation strategy from 1 month after PCI reduced the risk of net clinical outcomes up to 1 year, mainly driven by a reduction in bleeding without an increase in ischaemia.

Question 62

MASTER DAPT

Dual Antiplatelet Therapy after PCI in Patients
at High Bleeding Risk

Answer 62

BACKGROUND
The appropriate duration of dual antiplatelet therapy in patients at high risk for bleeding after the implantation of a drug-eluting coronary stent remains unclear.

METHODS
One month after they had undergone implantation of a biodegradable-polymer sirolimus-eluting coronary stent, we randomly assigned patients at high bleeding risk to discontinue dual antiplatelet therapy immediately (abbreviated therapy) or to continue it for at least 2 additional months (standard therapy). The three ranked primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding; cumulative incidences were assessed at 335 days. The first two outcomes were assessed for noninferior- ity in the per-protocol population, and the third outcome for superiority in the intention-to-treat population.

RESULTS
Among the 4434 patients in the per-protocol population, net adverse clinical events occurred in 165 patients (7.5%) in the abbreviated-therapy group and in 172 (7.7%) in the standard-therapy group (difference, −0.23 percentage points; 95% confidence interval [CI], −1.80 to 1.33; P<0.001 for noninferiority). A total of 133 patients (6.1%) in the abbreviated-therapy group and 132 patients (5.9%) in the standard-therapy group had a major adverse cardiac or cerebral event (difference, 0.11 percentage points; 95% CI, −1.29 to 1.51; P=0.001 for noninferiority). Among the 4579 patients in the intention-to-treat population, major or clinically relevant nonmajor bleeding occurred in 148 patients (6.5%) in the abbreviated-therapy group and in 211 (9.4%) in the standard-therapy group (difference, −2.82 percent- age points; 95% CI, −4.40 to −1.24; P<0.001 for superiority).

CONCLUSIONS
One month of dual antiplatelet therapy was noninferior to the continuation of therapy for at least 2 additional months with regard to the occurrence of net adverse clinical events and major adverse cardiac or cerebral events; abbreviated therapy also resulted in a lower incidence of major or clinically relevant nonmajor bleeding.

Question 63

COMPASS

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

Answer 63

BACKGROUND
We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention.

METHODS
In this double-blind trial, we randomly assigned 27,395 participants with stable athero- scleroticvasculardiseasetoreceiverivaroxaban(2.5mgtwicedaily)plusaspirin(100mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The pri- mary outcome was a composite of cardiovascular death, stroke, or myocardial infarc- tion. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.

RESULTS
The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivar- oxaban-alone group.

CONCLUSIONS
Among patients with stable atherosclerotic vascular disease, those assigned to rivar- oxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.

Question 64

AFIRE

Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease

Answer 64

BACKGROUND
There are limited data from randomized trials evaluating the use of antithrom- botic therapy in patients with atrial fibrillation and stable coronary artery disease.

METHODS
In a multicenter, open-label trial conducted in Japan, we randomly assigned 2236 patients with atrial fibrillation who had undergone percutaneous coronary inter- vention (PCI) or coronary-artery bypass grafting (CABG) more than 1 year earlier or who had angiographically confirmed coronary artery disease not requiring re- vascularization to receive monotherapy with rivaroxaban (a non–vitamin K antago- nist oral anticoagulant) or combination therapy with rivaroxaban plus a single antiplatelet agent. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascular- ization, or death from any cause; this end point was analyzed for noninferiority with a noninferiority margin of 1.46. The primary safety end point was major bleeding, according to the criteria of the International Society on Thrombosis and Hemostasis; this end point was analyzed for superiority.

RESULTS
The trial was stopped early because of increased mortality in the combination- therapy group. Rivaroxaban monotherapy was noninferior to combination therapy for the primary efficacy end point, with event rates of 4.14% and 5.75% per patient- year, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.55 to 0.95; P<0.001 for noninferiority). Rivaroxaban monotherapy was superior to combina- tion therapy for the primary safety end point, with event rates of 1.62% and 2.76% per patient-year, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01 for superiority).

CONCLUSIONS
As antithrombotic therapy, rivaroxaban monotherapy was noninferior to combina- tion therapy for efficacy and superior for safety in patients with atrial fibrillation and stable coronary artery disease.

Question 65

PEGASUS-TIMI 54

Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction

Answer 65

The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial
infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y receptor antagonist with established efficacy after an acute coro
nary syndrome, in this context.

METHODS
We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocar- dial Infarction (TIMI) major bleeding.

RESULTS
The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan–Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P = 0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.

CONCLUSIONS
In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial in- farction, or stroke and increased the risk of major bleeding.

Question 66

OAC-ALONE

Open-Label Randomized Trial Comparing Oral Anticoagulation With and Without Single Antiplatelet Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease Beyond 1 Year After Coronary Stent Implantation

Answer 66

BACKGROUND: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting.

METHODS: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was
a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months.

RESULTS: Mean age was 75.0±7.6 years, and 85.2% of patients were men.
OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79–1.72; P=0.20 for noninferiority, P=0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71–1.39; P=0.016 for noninferiority, P=0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively.

CONCLUSIONS: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population.