Duplice o triplice terapia antitrombotica · Roberta Rossini, MD, PhD Dipartimento emergenza e aree...

Duplice o triplice terapia antitrombotica

Roberta Rossini, MD, PhDDipartimento emergenza e aree critiche

Ospedale S. Croce e CarleCuneo

Conflicts of interest

Payment as an individual for consulting fee or honorarium

from:

• Astra Zeneca

• Bayer

• Boehringer

• Chiesi

• Daiichi Sankyo

• Novartis

• Pfizer

Institutional payments for unrestricted grants from:

• Chiesi

• There is no (strong) evidence

• ST is still the worst complication

(with the exception of ICH)

• It is not a matter of sum, it’s a matter of addends

Triple antithrombotic therapy is the right choice

ROCKET AF PIONEER AF

N of enrolled patients 14,264 2,124

Prior stroke/TIA 55% 0

Inclusion criterion AF within 30 days beforerandomization

AF that occurred within 1 yearbefore screening

Primary end-point Stroke or systemic embolism Clinically significant bleeding

Non-major clinically relevantbleeding

Bleeding requiring medicalintervention, unscheduledcontact temporaryinterruption of study drug,pain, or impairment of dailyactivities.

A bleeding event requiringmedical attention is defined asany bleeding event thatrequires medical treatment, surgical treatment, or laboratory evaluation

Mean CHADS-VASC 0-1 0 10%

Comparison between ROCKET AF and PIONEER-AF

The PIONEER:

• Open-label design

• “Underpowered” to assess ischemic events

• Selection bias? The trial enrolled 5 pts per Center in 3 yrs

• Up to 30% of pts permanently discontinued the treatment before the scheduled termination date

• 1 out of 2 pts in the triple Tx groups were assigned to DAPT for 12 mo

• Would you ever treat an AF pt with rivaroxaban 2,5 bid?

• Would you ever prolong triple TX up to 12 months?

• We do not have rivaroxaban 10 mg (for pts with clearance creatinine <50 treated with double TX according to the PIONEER trial)


• The primary endpoint was time to first ISTH major or clinically relevant non-major

bleeding

• Formally tested and powered endpoints included:

– Non-inferiority of 110 mg and 150 mg dual therapy groups on time to first ISTH

major or clinically relevant non-major bleeding event.

– Non-inferiority of both dual therapy groups combined on time to first event of death,

thromboembolic event (MI, stroke, systemic embolism) or unplanned

revascularization

– Superiority testing of the bleeding endpoints

• 100% of outcome events were independently adjudicated by blinded external committee

Study objective and design

RE-DUAL PCI tests the safety and efficacy of two regimens of dual therapy with

dabigatran without aspirin vs triple therapy with warfarin

N=2725

Cannon CP et al. N Engl J Med. 2017 Oct 19;377(16):1513-1524

https://www.ncbi.nlm.nih.gov/pubmed/28844193


• It was “Underpowered” to assess ischemic events in eachdabigatran arm

• No data on procedural features

• Selection bias? The trial enrolled 2725 pts in 414 Centers in 2 yrs, <6 pts per Center

• The protocol was amended and the comparison of thromboembolic-event rates in the two dual-therapy groupscombined versus the triple therapy group was changed to a secondary end point.

REDUAL-PCI Main limitations

Additional individual thromboembolic endpoints

Dabigatran 110

dual therapy

(n=981) n (%)

Warfarin triple

therapy

(n=981)

n (%)

D110 DT vs warfarin TT

HR (95% CI)

P value

Dabigatran 150

mg dual

therapy

(n=763)

n (%)

Warfarin triple

therapy

(n=764)

n (%)

D150 DT vs warfarin TT

HR (95% CI) P value

All-cause death 55 (5.6) 48 (4.9) 1.12 (0.76–1.65) 0.56 30 (3.9) 35 (4.6) 0.83 (0.51–1.34) 0.44

Stroke 17 (1.7) 13 (1.3) 1.30 (0.63–2.67) 0.48 9 (1.2) 8 (1.0) 1.09 (0.42–2.83) 0.85

Unplanned

revascularization76 (7.7) 69 (7.0) 1.09 (0.79–1.51) 0.61 51 (6.7) 52 (6.8) 0.96 (0.65–1.41) 0.83

MI 44 (4.5) 29 (3.0) 1.51 (0.94–2.41) 0.09 26 (3.4) 22 (2.9) 1.16 (0.66–2.04) 0.61

Stent thrombosis 15 (1.5) 8 (0.8) 1.86 (0.79–4.40) 0.15 7 (0.9) 7 (0.9) 0.99 (0.35–2.81) 0.98

Cannon CP et al. N Engl J Med. 2017 Oct 19;377(16):1513-1524

https://www.ncbi.nlm.nih.gov/pubmed/28844193

• Which dose of dabigatran would you use in dual Tx in an 81 yr-old pt?

• Would safety data be different if triple Tx were maintained for only 1 month in the REDUAL PCI?


Outcome primario di sanguinamento (ITT analysis)

ITT population (N = 1506); overall study period.

Vranckx, P, et al. Lancet. 2019.

ITT population (N = 1506); overall study period.

Vranckx, P, et al. Lancet. 2019.

Edoxaban regimen

VKAregimen

Intent-to-treat analysisNumber of patients 751 755Number of patients with event (%) 128 (17) 152 (20)Annualized event rate (% per year)

20.7 25.6

N Engl J Med 1998;339:1665-71







Thrombosis is a Rare but Life-Threatening Complication

Stent Thrombosis

N= 126

Cardiac Death

Myocardial Infarction

16

3539

P. Urban, G. Guagliumi Circulation 2006, February 21

13.437 patients with FU up and/or MACE to 360 days

Mortality: 40.4%






Warfarin (INR 2 to 3)Apixaban (5 mg BID*)

N = 4600Approximately 500 sites in 34 countries

Key Inclusion Criteria

➢ Aged ≥ 18 years.

➢ AF (prior, persistent/permanent, paroxysmal) or flutter

with planned or existing use of OAC.

➢ ACS and/or PCI within the prior 14 days.

➢ Planned use of P2Y12 inhibitor for at least 6 months.

Key Exclusion Criteria

➢ Other conditions that require anticoagulation eg, mechanical

heart valve, moderate/severe mitral stenosis, DVT, or PE.

➢ Serum creatinine > 2.5 [221 µmol/L] or CrCl < 30 mL/min.

➢ History of intracranial hemorrhage.

➢ Contraindications to VKA, apixaban, intended P2Y12 or ASA.

➢ Recent/planned CABG surgery for index ACS event.

➢ Patients with known ongoing bleeding.

➢ Patients with known coagulopathies.

ASA Placebo

P2Y12 inhibitor for all patients x 6 monthsAspirin for all on the day of ACS and/or PCI until randomization

Aspirin versus placebo after randomization

ACS, acute coronary syndrome; AF, atrial fibrillation; ASA, aspirin; BID, twice daily; CABG, coronary artery bypass graft; CrCl, creatinine clearance; CRNM, clinically relevant non-major; DAPT, dual antiplatelet therapy; DVT, deep vein thrombosis; INR, international normalized ratio; MI, myocardial infarction; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; PE, pulmonary embolism; R, randomized; VKA, vitamin K antagonist.

Study Design

R

R

A Phase IV, Open-label, 2 x 2 Factorial, Randomized Controlled Study

Adapted from Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]

ASA Placebo

R

*Dose reduced to 2.5 mg BID if patients meet 2 or more of the following criteria: age ≥ 80 years, weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 µmol/L)

Randomization stratified by indication (ACS vs PCI)

AUGUSTUS trial

Apixaban 5mg BID VKA (INR 2.0-3.0)

P2Y12 + Aspirin 81 mg/d P2Y12 + Aspirin 81 mg/d With ASA

P2Y12 + Aspirin placebo P2Y12 + Aspirin placebo Without ASA

R

2x2 Factorial design. 1:1:1:1 Randomization stratified by ACS vs PCI

Primary analysis: Apixaban vs VKA

Prim

ary

analy

sis:

Asp

irinvs p

lace

bo

NVAF Patients with ACS and/or

undergoing PCI stratified either

to medically treated (ACS

alone) or undergoing PCI

Study Design

AUGUSTUS trial

Primary Outcome: Apixaban versus VKA ISTH major or CRNM bleeding

All patients were concomitantly receiving P2Y12 therapy

Lopes RD, Heizer G, Aronson R, et al. N Engl J Med. 2019;doi: 10.1056/NEJMoa1817083

VKA: 14.7%

Apixaban: 10.5%

HR 0.69, 95% CI 0.58–0.81P<0.001 for non-inferiorityP<0.001 for superiorityARR=4.2%NNT=24

AUGUSTUS trial

Apixaban vs VKAPrimary Safety and Bleeding Outcomes

By anticoagulant regimen ApixabanN=2290

VKAN=2259

HR (95%CI)

ISTH major bleedingEvent rate per 100 patient-years

69 (3.0%)6.7

104 (4.6%)10.5

0.64 (0.4-0.86)

CRNM major bleedingEvent rate per 100 patient-years

180 (7.9%)18.2

246 (10.9%)26.1

0.69 (0.5-0.84)

GUSTO severe bleedEvent rate per 100 patient-years

5 (0.2%)0.5

8 (0.4%)0.8

0.59 (0.19-1.81)

GUSTO moderate bleedEvent rate per 100 patient-years

37 (1.6%)3.6

64 (2.8%)6.4

0.56 (0.37-0.84)

TIMI major or minor bleedEvent rate per 100 patient-years

96 (4.2%)9.5

132 (5.8%)13.5

0.70 (0.54-0.91)

GUSTO severe or moderate bleedEvent rate per 100 patient-years

41 (1.8%)4.0

68 (3.0%)6.8

0.58 (0.39-0.86)

TIMI major bleedEvent rate per 100 patient-years

TIMI minor bleedEvent rate per 100 patient-years

38 (1.7%)3.7

48 (2.1%)4.8

0.78 (0.5-1.20)

80 (3.5%)7.9

118 (5.2%)12.0

0.65 (0.49-0.86)

Intracranial hemorrhageEvent rate per 100 patient-years

5 (0.2%)0.5

13 (0.6%)1.3

0.39 (0.14-1.12)


AUGUSTUS trial

Primary Outcome: Aspirin versus Aspirin PlaceboISTH major or CRNM bleeding


Placebo: 9.0%

Aspirin: 16.1%HR 1.89, 95% CI 1.59–2.24P<0.001ARI=7.1%NNH=14


AUGUSTUS trial

Aspirin vs PlaceboPrimary Safety and Bleeding Outcomes

By antiplatelet regimen AspirinN=2277

PlaceboN=2279

HR (95%CI)

ISTH major bleedingEvent rate per 100 patient-years

108 (4.7%)11.1

65 (2.9%)6.5

1.70 (1.25-2.31)

CRNM major bleedingEvent rate per 100 patient-years

275 (12.1%)30.0

148 (6.5%)15.2

1.93 (1.58-2.36)

GUSTO severe bleedEvent rate per 100 patient-years

68 (3.0%)6.9

6 (0.3%)0.6

1.19 (0.40-3.53)

GUSTO moderate bleedEvent rate per 100 patient-years

7 (0.3%)0.7

37 (1.6%)3.7

1.73 (1.15-2.59)

TIMI major or minor bleedEvent rate per 100 patient-years

63 (2.8%)6.4

80 (3.5%)8.0

1.88 (.143-2.47)

GUSTO severe or moderate bleedEvent rate per 100 patient-years

40 (1.8%)4.0

1.72 (1.17-2.55)

TIMI major bleedEvent rate per 100 patient-years

TIMI minor bleedEvent rate per 100 patient-years

146 (6.4%)15.2

29 (1.3%)2.9

1.93 (1.23-3.03)

126 (5.5%)13.1

71 (3.1%)7.1

1.82 (1.36-2.44)

55 (2.4%)7.9

Intracranial hemorrhageEvent rate per 100 patient-years

8 (0.4%)0.8

10 (0.4%)1.0

0.82 (0.32-2.07)


AUGUSTUS trial

ISTH or CRNM Bleeding, According to Intervention Combination



VKA + Aspirin (18.7%)

Apixaban + Aspirin (13.8%)

Apixaban + Placebo (7.3%)

VKA + Placebo (10.9%)

AUGUSTUS trial

Secondary Endpoint: Apixaban vs VKADeath or Hospitalization



Apixaban: 23.5%

VKA: 27.4%

HR 0.83, 95% CI 0.74–0.93P=0.002ARR=3.9%NNT=26

AUGUSTUS trial

Secondary Endpoint: Aspirin vs Aspirin PlaceboDeath or Hospitalization



Aspirin: 26.2%

Placebo: 24.7%

HR 1.08, 95% CI 0.96–1.21P=0.20

AUGUSTUS trial

Ischemic Outcomes: Apixaban vs VKA

Endpoint Apixaban(N=2306)

VKA(N=2308)

Hazard Ratio(95%CI)

Death / Ischemic Events (%) 6.7 7.1 0.93 (0.75-1.16)

Death (%) 3.3 3.2 1.03 (0.75-1.42)

CV Death (%) 2.5 2.3 1.05 (0.72-1.52)

Stroke (%) 0.6 1.1 0.50 (0.26-0.97)

Myocardial Infarction (%) 3.1 3.5 0.89 (0.65-1.23)

Definite or Probable Stent Thrombosis (%)

0.6 0.8 0.77 (0.38-1.56)

Urgent Revascularization (%) 1.7 1.9 0.90 (0.59-1.38)

Hospitalization (%) 22.5 26.3 0.83 (0.74-0.93)



AUGUSTUS trial

Ischemic Outcomes: Aspirin vs Placebo

Endpoint Aspirin(N=2307)

placebo(N=2307)

Hazard Ratio(95%CI)

Death / Ischemic Events (%) 6.5 7.3 0.89 (0.71-1.11)

Death (%) 3.1 3.4 0.91 (0.66-1.26)

CV Death (%) 2.3 2.5 0.92 (0.63-1.33)

Stroke (%) 0.9 0.8 1.06 (0.56-1.98)

Myocardial Infarction (%) 2.9 3.6 0.81 (0.59-1.12)

Definite or Probable Stent Thrombosis (%)

0.5 0.9 0.52 (0.25-1.08)

Urgent Revascularization (%) 1.6 2.0 0.79 (0.51-1.21)

Hospitalization (%) 25.4 23.4 1.10 (0.98-1.24)



AUGUSTUS trial

Death or Hospitalization, According to Intervention Combination



VKA + Placebo (27.3%)

Apixaban + Placebo (22.0%)

Apixaban + Aspirin (24.9%)

VKA + Aspirin (27.5%)

AUGUSTUS trial

Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention A North American

Perspective–2018 Update; Angiolillo D.J. Circulation

?

Bridging from oral to IV P2Y12 inhibitors

Angiolillo DJ et al. Circulation. 2017 Nov 14;136(20):1955-1975






VKA always loses

Aspirin may still play an imprtant role

Irreversible harm counts


becuase 2 < 3

and

less is more less

Background

1. Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]2. Adapted from Lopes RD et al. Oral presentation at ACC Apr 2016; Chicago, IL, USA. Abstract number 695-153. Dewilde WJ et al. Lancet 2013;381:1107-1115

ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.

▪ Atrial fibrillation (AF) is the most common cardiac arrhythmia, with increasing prevalence among the elderly.

▪ Approximately 20 to 30% of patients with AF also have concomitant coronary artery disease (CAD) and 5 to 10% of patients who undergo percutaneous coronary intervention (PCI) have AF.

▪ The WOEST trial3 in patients undergoing PCI on a VKA showed that the use of clopidogrel without aspirin was associated with significantly fewer bleeding events than the use of DAPT without an apparent increase in ischemic events.

▪ The WOEST trial3 challenged the accepted paradigm that aspirin must be a cornerstone of therapy in patients with concomitant AF and CAD.

▪ Current guidelines (based mainly on expert consensus) recommend the choice and duration of triple therapy depends on patient bleeding risk, stroke risk, and clinical presentation (ACS or elective PCI).

➢ A clinical conundrum arises when patients with AF on oral anticoagulation (OAC) develop an acute coronary syndrome (ACS) and/or require PCI.

➢ VKAs have not been shown to prevent stent thrombosis and are not indicated for secondary prevention following an ACS, whereas DAPT does not provide a large treatment effect in preventing AF-related strokes.

➢ Triple therapy significantly increases the risk of bleeding and there is a significant unmet need for an oral antithrombotic strategy with an acceptable benefit/risk profile for treating patients with both AF and CAD. Major Bleeding

DAPT OAC+

Stent Thrombosis Stroke

How can you simultaneously prevent all three?2

Background

▪ These trials were not powered or designed to assess whether the bleeding reduction was due to the use of a NOAC or the removal of aspirin from the post-PCI oral antithrombotic strategy.1

▪ Triple therapy with NOAC has never been investigated

1. Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]2. Adapted from Gibson CM et al. N Engl J. Med. 2016;375:2423-24343. Adapted from Cannon CP et al. N Engl J. Med. 2017;377:1513-1524

≠ The licensed dose of Rivaroxaban for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors is 20 mg OD† Dabigatran 110 mg BID is not a licensed dose in the US

AF, atrial fibrillation; ASA, aspirin; CRNM, clinically relevant non major; DAPT, dual antiplatelet therapy; NOAC, non-vitamin K antagonist oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.

PIONEER AF-PCI2 RE-DUAL PCI3

NVAF who

had

undergone

PCI with

stenting

N = 21241:1:1

Rivaroxaban 15 mg OD≠ + P2Y12inhibitor for 12 months

Rivaroxaban 2.5 mg BID≠ + DAPT* for 1, 6, 12 months

VKA + DAPT* for 1, 6, 12 months

N = 2725Warfarin + P2Y12 inhibitor + ASA

for 1 to 3 months

Dabigatran 110 mg BID†

+ P2Y12

Dabigatran 150 mg BID + P2Y12

R

AF who had

undergone

PCI

R

In patients where DAPT (ASA + P2Y12) was received for < 12 months SAPT (ASA) was given instead

In PIONEER AF-PCI2 P2Y12 = clopidogrel, prasugrel, or ticagrelor

▪ PIONEER AF-PCI trial provided a clear signal of fewer bleeding events in regimens including rivaroxaban, whilst the efficacy

outcome (death from cardiovascular causes, MI, and stroke) occurred at similar rates among treatment arms. This bleeding

reduction was observed using doses of rivaroxaban that have not demonstrated proven efficacy in stroke reduction among

patients with AF. This study was not powered for efficacy and effects on ischemic events.

▪ RE-DUAL PCI trial demonstrated a reduction in bleeding in the NOAC arms compared with the traditional VKA based triple

therapy arm. However, RE-DUAL PCI was unable to provide insight into whether the reduction in bleeding in the dabigatran

based arms was due to dabigatran or the removal of aspirin.

▪ Two other trials of antithrombotic therapy strategy among patients with AF requiring DAPT are ongoing:

➢ ENTRUST-AF PCI trial will randomize 1500 patients with a history of AF to an edoxaban-based strategy or VKA on top of

aspirin and a P2Y12 inhibitor. The study will enroll patients outside the US and results are expected in 2019.

➢ SAFE A will randomize 600 patients with AF undergoing PCI with a drug-eluting stent to 1-month or 6-months of P2Y12

inhibitor therapy on background apixaban and aspirin, providing guidance on the optimal duration of an apixaban-based

triple therapy regimen. The primary outcome for both trials will be ISTH major or CRNM bleeding at 1 year.

▪ PIONEER AF-PCI and RE-DUAL PCI provided important randomized data where prior experience was limited. AUGUSTUS

will extend the findings of those trials and will be the first large randomized study to test the WOEST strategy to distinguish

the bleeding contributions of apixaban and the removal of aspirin. The trial will provide unique information that will inform

physicians and guidelines on the optimal antithrombotic strategy in these high-risk patients across the spectrum of CAD.

AF, atrial fibrillation; CAD, coronary artery disease; CRNM, clinically relevant non-major; DAPT, dual antiplatelet therapy; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.

Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]

Background

▪ Pivotal NOAC trials in AF excluded patients needing DAPT, while DAPT trials following acute MI and/or PCI excluded

patients on oral anticoagulation.

▪ AUGUSTUS will help answer important questions about patients with AF and CAD and has some unique features:

➢ It is the largest study in the field, including the whole spectrum of patients with CAD (ACS with/without PCI, elective PCI).

➢ The apixaban dose (5 mg twice daily) used in AUGUSTUS has proven efficacy in stroke prevention in AF.

➢ The unique 2 x 2 factorial design will provide insight into whether aspirin may (or may not) be dropped in patients with AF

and CAD receiving OAC plus a P2Y12 inhibitor.

➢ Unlike PIONEER AF-PCI and RE-DUAL PCI, AUGUSTUS does not exclude patients with a history of prior stroke,

transient ischemic attack, prior gastrointestinal bleeding, or anemia.

➢ The 6 month follow-up will delineate bleeding and ischemic events in the highest-risk time period following the index

event. Guidelines recommend DAPT in stable ischemic patients treated with DES for 6 months only, so patients will not

be subjected to prolonged DAPT used with prior generation DESs. The 14 days window between index event (ACS

and/or PCI) and randomization allows more time for patients to be treated with any antithrombotic strategy until they are

stable.

▪ AUGUSTUS will include both patients with new onset AF as well as those already on a stable anticoagulant regimen.

▪ Apixaban 5 mg twice daily was chosen due to proven efficacy for stroke reduction compared with warfarin in patients with

AF. This dose was associated with increased bleeding in APPRAISE-2 however the comparator was placebo not warfarin.

Lopes RD et al. Am Heart J. March 2018 doi:10.1016/j.ahj.2018.03.001 [Epub ahead of print]

ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DES, drug eluting stent; INR, international normalized ratio; MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.

Background

AUGUSTUS – Research Hypothesis

Two Independent Hypotheses:

Apixaban is at least non-inferior or superior to VKA on the composite outcome of ISTH major bleeding or clinically

relevant non-major (CRNM) bleeding in patients with NVAF who develop ACS and/or require PCI with concomitant

antiplatelet therapy P2Y12 with or without aspirin.

Single antiplatelet therapy with a P2Y12 inhibitor is superior to dual antiplatelet therapy with a P2Y12 inhibitor and

aspirin on the combined outcome of ISTH major bleeding or clinically relevant non-major bleeding in patients with

NVAF with a recent ACS and/or require PCI with concomitant anticoagulant therapy.


AUGUSTUS – Outcomes

Primary Outcome:

• First occurrence of ISTH major or CRNM bleeding

Secondary Outcomes:

• First occurrence of the composite of all-cause death and all-cause hospitalization

• First occurrence of the composite endpoint of death and ischemic events (stroke, MI, stent thrombosis, urgent

revascularization)


Statistical Analysis—Hierarchical Testing

NI = non-inferiority; Sup = superiority Lopes RD, et al. Am Heart J. 2018;200:17-23.

Placebo vs. Aspirin:

Major / CRNM BleedingSup

Death / HospitalizationSup

Death / Ischemic EventsSup

Apixaban vs. VKA:

Major / CRNM BleedingNI then Sup

Death / HospitalizationSup

Death / Ischemic EventsSup

Participating Countries and corresponding Number of Patients

Total (N=4614)

Age, median (25th, 75th), years 70.7 (64.2, 77.2)

Female, % 29.0

CHA2DS2-VASc score, mean (SD) 3.9 (1.6)

HAS-BLED score, mean (SD) 2.9 (0.9)

Prior OAC, % 49.0

P2Y12 inhibitor, %

Clopidogrel 92.6

Prasugrel 1.1

Ticagrelor 6.2

Number of days from ACS/PCI to

randomization, mean (SD)6.6 (4.2)

Qualifying index event, %

ACS and PCI 37.3

ACS and no PCI 23.9

Elective PCI 38.8

Baseline Characteristics

Total Randomized

N=4614

Randomized to ApixabanN=2306

Randomized to VKA

N=2308

Randomized to AspirinN=2307

Randomized to PlaceboN=2307

Study Drug Discontinuation

291 (12.6%) 311 (13.5%) 385 (16.7%) 337 (14.6%)

Lost to Follow-up

6 (0.3%) 7 (0.3%) 5 (0.2%) 8 (0.3%)

Withdrawal of Consent

29 (1.3%) 46 (2.0%) 43 (1.9%) 30 (1.3%)

OAC Aspirin/Placebo

AUGUSTUS – Summary

• ISTH Major / Clinically Relevant Non-major Bleeding

31% lower with apixaban than VKA

89% higher with aspirin than placebo (47% lower with placebo than aspirin)

• Death / Hospitalization

17% lower with apixaban than VKA

Similar between aspirin and placebo

• Death / Ischemic Events

Similar rate between apixaban and VKA

Similar rate between aspirin and placebo


• Compared to VKA regimens (VKA plus a P2Y12 inhibitor with or without aspirin),

apixaban regimens (apixaban plus a P2Y12 inhibitor with or without aspirin) showed

significantly less bleeding and fewer deaths or hospitalizations with a similar rate of death

or ischemic events in patients with NVAF and recent ACS and/or undergoing PCI.

• Compared to no aspirin regimens (P2Y12 inhibitor plus an anticoagulant), regimens with

aspirin plus a P2Y12 inhibitor and anticoagulant showed significantly more bleeding and

similar rates of death or hospitalizations and death or ischemic events in patients with

NVAF and recent ACS and/or undergoing PCI.

AUGUSTUS – Conclusion

Conclusioni (personali)• La triplice terapia aumenta i sanguinamenti

• Il beneficio maggiore (in termini di morte e ospedalizzazioni) viene conferito dalla scelta di apixaban vs warfarin e non dalla sospensione di aspirina

• Può essere ragionevole mantenere una triplice terapia con apixaban a dosaggio pieno per 1-3 mesi dopo PCI dopo attenta valutazione del rischio ischemico ed emorragico



CE mark indication for RESOLUTE

1-month DAPT

RESOLUTE:

Risk of ST in Patients Interrupting DAPT Beyond One Month

Patients who completed follow-up beyond one year had no additional ST events one-year post-interruption. (R-China, R-Japan SVS, R-Asia and R-US 38 mm have not completed follow-up beyond one year and will be included in future analyses.)

4240 182 949

35 6 14

NA 3 250

Patients at risk

No. of events

Median days to

interruption

1 p < 0.05 for comparison to Never Interrupted group. Post-hoc RESOLUTE Pooled DAPT analysis was not powered for the analysis shown.2 Including patients with no DAPT interruption except for ST while on DAPT through 12 months314-day cutoff selected because studies have shown that it takes up to 14 days for the platelet function to recover after DAPT withdrawal.4 Patient with a history of thrombosis was on DAPT at the time of ST event but had interrupted DAPT for two consecutive days prior to the event.

ESC guidelines recommend DAPT duration of 6–12 months after DES implantation in all patients and one year after ACS, irrespective of the type of implanted stent.

949 783 627

1 0 0

250 271 288

Interruption duration > 1 day

Su

bse

qu

ent

ST

(AR

C D

ef/P

rob

) (%

)

0.83

3.301

0.111 0.00.00.11

Interrupted 1−12 moInterruption duration breakout

Timing of First DAPT Interruption and ST Through 1 Year

32

XIENCE - 0% Stent Thrombosis with DAPT

Interruption after 3 Months

XIENCE - 0% Stent Thrombosis with DAPT

Interruption after 3 Months

Source: Derived from Palmerini, T. PCR 2012.

• Pooled data of 10,615

patients from four real-

world trials:

– XIENCE V USA (n=6,516)

– SPIRIT V (n=1,662)

– SPIRIT Women SAS

(n=1,506)

– XIENCE V India (n=931)

• 919 patients interrupted

DAPT between 3 to 12

months with 0% ST

• Definition of

DAPT Interruption: either

aspirin and/or

thienopyridine not taken

for at least 1 day for any

reason

XIENCE - 0% Stent Thrombosis Rate After DAPT

Interruption from 3 to 12 Months

*Including patients with no DAPT interruption except possibly after ST through 365 days

XIENCE shows good safety outcomes

even when DAPT is interrupted after 3 months

|

Primary Endpoint: Total number of TIMI bleeding events WOEST

Days

Cum

ula

tive

incid

en

ce

of b

lee

din

g

0 30 60 90 120 180 270 365

0 %

10 %

20 %

30 %

40 %

50 %

284 210 194 186 181 173 159 140n at risk: 279 253 244 241 241 236 226 208

Triple therapy group

Double therapy group

44.9%

19.5%

p<0.001

HR=0.36 95%CI[0.26-0.50]

Lancet 2013;381:1107-15.

Secondary Endpoint (Death, MI,TVR, Stroke, ST)WOEST

Days

Cum

ula

tive

incid

en

ce

0 30 60 90 120 180 270 365

0 %

5 %

10 %

15 %

20 %

284 272 270 266 261 252 242 223n at risk: 279 276 273 270 266 263 258 234

17.7%

11.3%

p=0.025

HR=0.60 95%CI[0.38-0.94]

Triple therapy groupDouble therapy group

Lancet 2013;381:1107-15.


• Definition of bleeding: it was sufficient to repeat blood tests

• “Underpowered” to assess ischemic events

• Patients with history of prior stroke or TIA were excluded

• No data on procedural features

• Selection bias? The trial enrolled 5 pts per Center in 3 yrs

• The main inclusion criterion was documented AF that occurred within 1 year before screening (1 pt out of 2 had paroxismal AF)

• Up to 30% of pts permanently discontinued the treatment before the scheduled termination date

• 1 out of 2 pts in the triple Tx groups were assigned to DAPT for 12 mo

PIONEER Main limitations

REDUAL PCI: safety end points

Eur Heart J. 2018;39(31):2847-2850


NAO and antiplatelets

NAO and antiplatelets : apixaban

Alexander JH et al. Eur Heart J 2014;35:224-32

Circulation. 2013;127:634-640

Tasso di sanguinamento di edoxaban e warfarinin base alla terapia antipiastrinica

Xu H et al. J Am Heart Assoc. 2016;5: e002587 doi: 10.1161/JAHA.115.002587.*Pazienti trattati con edoxaban 30 mg con peso ≤60 kg, compromissione moderatadella funzionalità renale o uso concomitante di inibitori della P-gp.

1,18

Usereste mai 2,5 x 2 per FA???? (slide su basse dosi)

Pioneer riduce eventi se aggiustamento dose, ma cosa fare per quelli che

avrebbero diritto a 10 mg???

66


Perspective–2018 Update; Angiolillo D.J. CIrculation

Figure 2. Management of antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention

(PCI) treated with an oral anticoagulant (OAC): 2018 North American expert consensus update.

Danish Registry: ischemic and bleeding events

Danish Registry: Early and late hazards of bleeding events

0

2

4

6

8

10

12

ISAR MATTIS

Coumadin

ASA+Ticlo

ASA

n:517 n:350 n:1653n:485

MA

CE

(%

)

Ticlopidine during PCI with use of Coronary Stents

- Schomig et al, N Engl J Med 1996 - Bertrand et al, Circulation 1998

- Urban et al, Circulation 1998 - Leon et al, N Engl J Med 1998

FANTASTIC STARS

Safety of aspirin, clopidogrel, and warfarin after

coronary stenting

0

5

10

15

20

25

30

35

40

45

FA Valve

prosthesis

LV

aneurysm

LV

thrombus

CV

accident

other bleeding

event

9,2%

Orford J Am Heart J 2004;147:463–7

Dipartimento Cardiovascolare

Clinico e di RicercaOspedali Riuniti

Bergamo



Bergamo

64 66 65

83

36 34 35

17

0

20

40

60

80

100

Australia/New

Zeland/Canada

Europe Argentina/Brazil USA

warfarin/dual antiplatelet warfarin/single antiplatelet

Geografical variations in combination

regimen at discharge

P<0.001%



Bergamo



Bergamo

The GRACE Investigators. Eur Heart J 2007;28:1717-1722

OAC + single antiplatelet vs triple therapy

77



Figure 2. Management of antiplatelet therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention

(PCI) treated with an oral anticoagulant (OAC): 2018 North American expert consensus update.

2018 ESC/EACTS Guidelines on myocardial revascularization The Task Force on myocardial revascularization of the European Society of Cardiology (ESC) and European Association for

Cardio-Thoracic Surgery (EACTS); Neumann FJ et al. European Heart Journal (2018) 00, 1–96

79



Bleeding Cumulative Distribution

“Double” vs “Triple” TX

100

90

80

70

60

50

0 200 300 450 600

%

Days

Ble

edin

g e

vent fr

ee s

urv

ival 95.1 %

89.2 %

P=0.13

Double therapy (ASA + Clopidogrel)

Triple therapy (ASA + Clopidogrel + Warfarin)

Rossini, et al. Am J Cardiol 2008

Bleeding Cumulative Distribution by INR

“Double” vs “Triple” TX

Rossini, et al. Am J Cardiol 2008

100

90

80

70

60

50

0 200 300 450 600

%

Double therapy

Triple therapy with INR < 2.6

95.1 %

95.1 %

Days

Ble

edin

g e

vent fr

ee s

urv

ival

Triple therapy with INR ≥ 2.6

66.7 %

†

‡

† P<0.0001 vs Double therapy

‡ P<0.0001 vs Triple with INR <2.6

0

20

40

60

80

100

OR=89.8

(29.9-270)

HR=19.2

(5.6-65.5)

OR=4.8

(2.0-11.1)

HR=13.7

(4.0-46.7)

Odds/

Haza

rd R

ati

o

Iakovou et al

JAMA 2005

Park et al

Am J CARD 2006

Kuchulakanti et al

Circulation 2006

Airoldi et al

Circulation 2006

Premature Discontinuation of Antiplatelet Therapy as Predictor of ST

Mort

alit

y

%

Discontinued

Continued

1 2 3 4 5 6 7 8 9 10 11 120

5

10

15

p<0.001

Months

Discontinuation of Thienopyridine after DES

PREMIER Registry: 500 DES treated MI pts

Spertus et al, Circulation 2006;113:2803-2809

Stone G. TCT 2011

Mega-Meta Analysis XIENCE shows no signal for increased risk of ST from 3 months to 2 years

Interrupted

on or before

1 month

Interrupted

between

1 and 3 months

Interrupted

between

3 and 6 months

Interrupted

between

6 and 12 months

Never Interrupted

through 2-year

study period

Interrupted

between

1 and 2 years

0

1

2

3

ST

thro

ugh

2 Y

ears

(%

)P= 0.04 P= 0.13 P= 0.33P= 0.34P<0.0001

0.63

2.55

2.11

1.38

0.88

0.44

P values vs. never

interrupted

#ST=44 #ST=13 #ST=3 #ST=4 #ST=11 #ST=8

With XIENCE, “DAPT interruption did not result in stent thrombosis in 99.4% of the patients.”

Median # days

off DAPT (IQR)

482.5

(19, 668)

287

(103.5, 351)

374

(8, 731)

379

(365, 481)

518

(59, 566)

0

(0, 0)

Key points

• Clinical events: ST vs ST-unrelated ischemic events

• Power of the studies and length of discontinuation

• Median time from PCI to DAPT

• Type of discontinuation: single vs dual

J Am Coll Cardiol Intv 2011;4:1298-309

XIENCE V USA:

Stent thrombosis and interruption of DAPT

Mehran RM et al. Eur Heart J 2009 June ; 30: 1457-1466

Cox model adjusted for 36 baseline predictors, with MI and major

bleeding (non-CABG) as time-updated covariates

Of 13,819 enrolled pts, 524 (3.8%) died within 1 year

Myocardial infarction 3.1 (2.4-3.9) <0.001

Major bleeding 3.5 (2.7-4.4) <0.001

Blood transfusion 4.5 (3.4-5.9) <0.001

HR ± 95% CI P-valueHR (95% CI)

Influence of Major Bleeding and MI within 30 Days

on Risk of Death Over 1 Year

Major bleeding

No major bleeding

%

Antiplatelet Discontinuation

Major Bleeding and Antiplatelet Discontinuation

G. Musumeci, R. Rossini, C. Lettieri et al Cath Card Interv 2011 Nov 22.[Epub ahead of print]

%

Minor bleeding

No bleeding

P<0.001P=0.001

Minor Bleeding and Long-Term Outcome

G. Musumeci, R. Rossini, C. Lettieri et al Cath Card Interv 2011 Nov 22.[Epub ahead of print]

Date post:	20-Aug-2020
Category:	Documents
Upload:	others
View:	0 times
Download:	0 times

Duplice o triplice terapia antitrombotica · Roberta Rossini, MD, PhD Dipartimento emergenza e aree...

Documents