Nuove evidenze sulla terapia antitrombotica cronica nella ... · Nuove evidenze sulla terapia...

Nuove evidenze sulla terapia antitrombotica

cronica nella CAD e PAD

Dott. Marco Marini

SOD Cardiologia-Emodinamica-UTIC

AOU Ospedali Riuniti di Ancona

Nuove evidenze sulla terapia antitrombotica

cronica nella CAD e PAD

Qual’è la percentuale di rischio residuo di

eventi aterotrombotici in pazienti con

CAD e PAD?

< 5%

5-10%

>10%

High Residual Risk of Atherothrombotic Events Exists in Patients

with CAD and PAD Despite Optimized Antiplatelet Therapy

Trial/regimen Residual risk of

atherothrombotic events (composite

endpoint of CV death/MI/stroke)

CAPRIE: clopidogrel 75 mg od1 5.32%/year

CHARISMA: ASA + clopidogrel 75 mg

od2

6.8% (incidence proportion over a median follow-

up of 28 months)

PEGASUS: ASA + ticagrelor (90 mg

bid or 60 mg bid)3

7.9% with ticagrelor 90 mg bid (3-year rate)

7.8% with ticagrelor 60 mg bid (3-year rate)

EUCLID4 10.6%/year with clopidogrel 75 mg od

10.8%/year with ticagrelor 90 mg bid

TRA2°P-TIMI 50: vorapaxar +

standard antiplatelet therapy (prior

MI)5

8.1% (3-year rate)

TRA2°P-TIMI 50: vorapaxar +

standard antiplatelet therapy (PAD)6

11.3% (3-year rate)

1. CAPRIE Steering Committee, Lancet 1996;348:1329–1339; 2. Bhatt DP et al, N Engl J Med 2006:354:1706–1717; 3 . Bonaca MP et al, N Engl J

Med 2015;372:1791–1800; 4. Hiatt WR et al, N Engl J Med 2017;376:32–40; 5. Scirica BM et al, Lancet 2012;380:1317–13246. Bonaca MP et al,

Circulation 2013;127:1522–1529

Atherosclerosis Is a Generalized Disease with

Multiple Manifestations

Ischaemic stroke

Myocardial infarction (MI)

Transient ischaemic attack (TIA)

Angina:

Stable

Unstable

Peripheral arterial disease (PAD):

Intermittent claudication Rest pain

Gangrene

Necrosis

Atherothrombosis Is a Polyvascular Disease with

Substantial Patient Overlap Between CAD and PAD

REACH registry: enrolled 40,258 patients with established CAD, 8273 patients

with established PAD, and 18,843 patients with established cerebrovascular

disease from 44 countries

PAD CAD

CeVD, cerebrovascular disease

Bhatt DL et al, J Am Med Assoc 2006;295:180–189

CAD

PAD

CeVD

61.5% of patients

with PAD had

concomitant

disease in other

vascular beds

24.7% of patients

with CAD had

concomitant

disease in other

vascular beds

Scientific Evidence Supports Thrombin Involvement

in Cardiovascular Pathophysiological Processes

Thrombin promotes myocardial necrosis, inflammation and endothelial dysfunction

Thrombin promotes thrombosis,

which leads to myocardial

ischaemia and necrosis1

Thrombin promotes vascular

inflammation and can thereby

contribute to the progression

of coronary lesions2

Thrombin stimulates endothelial

dysfunction and can contribute to the

pathophysiology of CAD3,4

- Thrombin

1. Hansen CH et al, Thromb J 2015;13:31; 2. Popović M et al, Mol Cell Biochem 2012;359:301–313;

3. Ming XF et al, Circulation 2004;110:3708–3714; 4. Choi BJ et al, Eur Heart J 2013;34:2047–2054

◄ Index

Both Fibrin and Platelets Are Present in Thrombi

from Patients with Myocardial Infarction

Immunofluorescent micrographs of aspirated thrombi from patients

with acute MI show of GPIIb/IIIa (marker for platelets) and fibrin

Platelets Fibrin Platelets and fibrin

GP, glycoprotein

Yamashita A et al, Am J Cardiol 2006;97:26–28

GPIIb/IIIa

CAD

ASA and P2Y12 ADP Receptor Antagonists Leave

Thrombin-Mediated Pathways in Platelets Uninhibited

Tello-Montoliu A et al, Br J Clin Pharmacol 2011;72:658–671; Franchi F, Angiolillo DJ, Nat Rev Cardiol 2015;12:30–47

◄ Index

Reduction in Thrombin Generation Could Potentially

Stabilize Multiple Pathophysiological Processes

Blood coagulation factors are denoted in Roman numerals, and the active forms are indicated by a small ‘a’.

II indicates prothrombin and IIa thrombin

Spronk H et al, Cardiovasc Res 2014;101:344–351

◄ Index

Tromboembolia arteriosa

Pazienti con CAD/PAD

Acuta

Pazienti con CAD acuta o

instabile

Pazienti con CAD e scompenso

cardiaco

Pazienti con CAD/PAD Cronica

Patologie vascolari

Pazienti con PAD acuta o

instabile

Pazienti con CAD/PAD

cronica o stabile

Rivaroxaban + Aspirin, as an Antithrombotic Therapy Should

be Seen as Part of the Overall Vascular Protective Strategy

*When specifically indicated

Cortés-Beringola A et al. Eur J Prevent Cardiol 2017;24:22–28

Vascular Protection

◄ Index

Cosa ha ridotto nei pazienti con PAD la

terapia antiaggregante?

Evidence Supporting the Use of Aspirin or Clopidogrel to

Prevent CV Events in Patients with PAD is Limited

Aspirin1

Meta-analysis: aspirin vs control

Only non-significant reduction in

MACE with aspirin

However, aspirin significantly reduced

non-fatal stroke rate

Clopidogrel2

CAPRIE trial: clopidogrel vs aspirin

Only this subgroup analysis supports

the use of clopidogrel over aspirin

Outcome HR (95% CI) p-value

CV death 0.94 (0.74–1.19) 0.59

Non-fatal MI 1.04 (0.78–1.39) 0.81

Non-fatal

stroke

0.66 (0.47–0.94) 0.02

Composite 0.88 (0.76–1.04) 0.13

Subgroup RRR (95% CI) p-value

Prior MI -3.7% (-22.1–12.0) 0.66

Prior stroke 7.3 (-5.7–18.7) 0.26

PAD 23.8% (8.9–36.2) 0.0028

All patients 8.7% (0.3–16.5) 0.043

Another meta-analysis by the ATTC showed a reduction in MACE with

antiplatelet treatment3

REACH: no reduction in 4-year CV events with antiplatelet agents

(60% aspirin)4

PAD

1. Berger JS et al, JAMA 2009;301:1909–1919; 2. CAPRIE Steering Committee, Lancet 1996;348:1329–1339; 3. Antithrombotic Trialists'

Collaboration. Br Med J 2002;324:71-86; 4. Abtan J et al, Clin Card 2017; doi: 10.1002/clc.22721

Trials Investigating Intensified Antiplatelet Therapy in

Patients with PAD Show Mixed Results

*Hospitalization for ALI or lower limb revascularization (individual endpoints); #Composite of ALI or peripheral revascularization; ‡No mortality

benefit in the overall trial population5

1. Bhatt DL et al, J Am Coll Cardiol 2007;49:1982–1988; 2. Bonaca MP et al, Circulation 2013;127:1522–1529; 3. Hiatt WR et al, N Engl J Med

2017;376:32–40; 4. Bonaca MP et al, J Am Coll Cardiol 2016;67:2719–2728; 5. Bonaca MP et al, N Engl J Med 2015;372:1791–1800

Clopidogrel + aspirin

vs aspirin in patients

with prior MI, stroke or

symptomatic PAD

CHARISMA

(subgroup

analysis)1

No increase in

severe bleeding

No decrease in

mortality

Ticagrelor vs

clopidogrel

in patients with PAD

EUCLID3

No reduction

in risk of MACE

No increase in major

bleeding

PAD

MACE

↓17%

Vorapaxar + aspirin

vs aspirin

in patients with stable

symptomatic PAD

TRA2°P-TIMI 50

(subgroup

analysis)2

Major

bleeding

1.5 ×

No reduction

in risk of MACE

Hospitalization

for ALI ↓42%

No decrease in

MALE*

No decrease in

mortality

Ticagrelor + aspirin

vs aspirin in patients

with prior MI + PAD

PEGASUS

(subgroup

analysis)4,5

No increase in

major bleeding

No decrease in

MALE#

MACE

↓31%

Mortality

↓48%‡

Current recommendations and unmet needs

Current Management of PAD

The Current ESC Guidelines for PAD Management

Recommend Treatment of Symptomatic PAD

PAD

Patients with… Recommendation Class

Symptomatic PAD Antiplatelet therapy is recommended Ic

Lower extremity PAD In patients requiring antiplatelet therapy, clopidogrel may be preferred

over aspirin

IIb

Anticoagulation with VKAs may be considered after autogenous vein

infrainguinal bypass

IIb

DAPT (aspirin plus clopidogrel) for ≥1 month should be considered

after infra-inguinal stent implantation

IIa

DAPT (aspirin plus clopidogrel) may be considered in the case of

below-knee bypass with a prosthetic graft

IIb

Long-term SAPT is recommended in all patients who have undergone

revascularization

Ic

SAPT is recommended after infrainguinal bypass surgery Ia

1. Aboyans V et al, Eur Heart J 2017; doi: 10.1093/eurheartj/ehx095; 2. Aboyans V et al, Eur J Vasc Endovasc Surg 2017;

doi:10.1016/j.ejvs.2017.07.018

SAPT is recommended for all patients with symptomatic PAD

DAPT is recommended only for a limited period of time after certain revascularization

procedures

2017 ESC guideline recommendations for antithrombotic therapies in

patients with PAD

ATLAS ACS 2 TIMI 51: Rivaroxaban Vascular Dose

Reduced CV Events and Death in Patients with ACS

Patients with elevated cardiac biomarkers and no prior stroke/transient

ischaemic attack

CAD

CV death, MI or stroke

12

Days

2-y

ea

r K

ap

lan–M

eie

r e

sti

ma

te (

%) HR=0.80

(95% CI

0.68–0.94);

p=0.007

Rivaroxaban

2.5 mg bid

Placebo

0

720 0 540 360 180

10

8

6

4

2

CV death

0

5

Days

HR=0.55

(95% CI

0.41–0.74);

p<0.001

NNT=50

Rivaroxaban

2.5 mg bid

Placebo

720 0 540 360 180

4

3

2

1

All-cause death

5

Days

HR=0.58

(95% CI

0.44–0.77);

p<0.001

NNT=49

Rivaroxaban

2.5 mg bid

Placebo

0

720 0 540 360 180

4

3

2

1

CI, confidence interval; HR, hazard ratio; NNT, number needed to treat

Patients also received antiplatelet standard of care: ASA + thienopyridine (~93%) or ASA alone (~7%)

Mega JL et al, Eur Heart J 2014;35(Suppl.):992. Abstract P5518 (poster presentation)

ISTH major and minor bleeding increased in the short- and long-term

in patients with ACS1

No reduction in cardiovascular death, myocardial infarction or ischaemic stroke

was associated with apixaban 5 mg bid compared with placebo (HR=0.95;

95% CI 0.80–1.11)2

NOACs in Acute Coronary Syndrome:

Apixaban in the APPRAISE 2 Study

1. Khan R et al, Heart 2015;101:1475–1484; 2. Alexander JH et al, N Engl J Med 2011;365:699–708

Number at risk

Placebo 3642 3565 3452 3371 3293 3249 3183

Apixaban 3673 3591 3485 3401 3325 3257 3185

0 5 10 15 20 25 30

IST

H m

ajo

r a

nd

min

or

ble

ed

ing

cu

mu

lative

eve

nt ra

te

0.000

0.005

0.010

0.015

Days since randomization

Apixaban 5 mg bid

Placebo

0 100 200 300 400

Number at risk

Placebo 3642 2528 1668 907 333

Apixaban 3673 2442 1587 883 301

Days since randomization

IST

H m

ajo

r a

nd

min

or

ble

ed

ing

cu

mu

lative

eve

nt ra

te

0.00

0.01

0.02

0.03

0.04

0.05

0.06 Apixaban 5 mg bid

Placebo

CAD

The Rivaroxaban Development Program

Cardiologists Treat a Broad Range of Patients

Ischaemic cardiac outcomes in patients with atrial fibrillation treated with

vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial

K.W. Mahaffey et al.European Heart Journal (2014) 35, 233–241

…l’intuizione ed il coraggio di guardare oltre..

A Dual Pathway Approach Targeting Chronic Patients with

CAD or PAD was Investigated in COMPASS

Objective: To determine the efficacy and safety of rivaroxaban, vascular dose of rivaroxaban plus aspirin or aspirin alone for reducing the risk of MI, stroke and cardiovascular death in CAD or PAD

Antithrombotic investigations* were stopped 1 year ahead of expectations in Feb 2017 due to

overwhelming efficacy in the rivaroxaban 2.5 mg bid + aspirin arm

Rivaroxaban 5.0 mg bid

Aspirin 100 mg od

Rivaroxaban 2.5 mg bid + Aspirin 100 mg od

30-day

washout

period

30-day run-in,

aspirin 100 mg

Final

follow-up

visit

R

Final

washout

period visit

1:1:1

N=27,395

Population:

Chronic

CAD (91%)

PAD (27%)

*Patients who were not receiving a proton pump inhibitor (PPI) were randomized to pantoprazole or placebo (partial factorial design); the PPI

pantoprazole component of the study is continuing; data will be communicated once complete

1. Eikelboom JW et al. N Engl J Med 2017; DOI: 10.1056/NEJMoa1709118;

2. Bosch J et al. Can J Cardiol 2017;33(8):1027–1035

Average follow-up: 23 months at early termination of study

Factorial design

± pantoprazole*

Inclusion and Exclusion Criteria Ensured That Patients

Had Chronic CAD and Moderate Cardiovascular Risk

Key inclusion criteria*

CAD (prior MI, multivessel coronary disease or multivessel revascularization)

Plus ≥1 of:

Age ≥65 years

Age <65 years plus atherosclerosis in ≥2 vascular beds or ≥2 additional risk factors

– Current smoker

– Diabetes mellitus

– Renal dysfunction (eGFR<60 ml/min)

– Heart failure

– Non-lacunar ischaemic stroke ≥1 month ago

Key exclusion criteria#

Stroke within the past month or any haemorrhagic or lacunar stroke

Severe HF with known ejection fraction <30% or NYHA class III or IV symptoms

Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy or oral anticoagulant therapy

eGFR <15 ml/min

#Including but not limited to; #Any other exclusion criteria in conjunction with the local Product Information and

any other contraindication listed in the local labelling for rivaroxaban or the comparator have to be considered

Bosch J et al, Can J Cardiol 2017;33:1027–1035

Patients had multiple risk factors

Patients with acute CAD or deemed to be at very high cardiovascular risk

were excluded because of need for DAPT

CAD

Primary Outcomes Investigated in Patients with CAD

Were in Line with the Main Study

Primary efficacy outcome

Composite of cardiovascular death, stroke or MI

Primary safety outcome

Modified ISTH major bleeding

Fatal bleeding

Symptomatic bleeding in a critical area or organ, such as intracranial

Bleeding into a surgical site requiring re-operation

Bleeding leading to hospitalization

Secondary efficacy outcomes

Composite of major thrombotic events

Coronary heart disease death, MI, ischaemic stroke, acute limb ischaemia

Cardiovascular death, MI, ischaemic stroke, acute limb ischaemia

Mortality (all cause)

Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32816-7;

Eikelboom JW et al, N Engl J Med 2017;377:1319-1330;

Dual Pathway Inhibition with Rivaroxaban Vascular Dose 2.5 mg bid

+ Aspirin Significantly Reduced MACE by 26% Versus Aspirin

Outcome Rivaroxaban

2.5 mg bid

+ aspirin

N=8313

Rivaroxaban

5 mg bid

N=8250

Aspirin

N=8261

Rivaroxaban

2.5 mg bid + aspirin

vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%) HR

(95% CI)

p-value HR

(95% CI)

p-value

MACE 347 (4) 411 (5) 460 (6) 0.74

(0.65–0.86) <0.0001

0.89

(0.78–1.02) 0.094

CV death 139 (2) 175 (2) 184 (2) 0.75

(0.60–0.93) 0.010

0.95

(0.77–1.17) 0.63

Stroke 74 (1) 105 (1) 130 (2) 0.56

(0.42–0.75) <0.0001

0.81

(0.62–1.05) 0.10

Ischaemic/

unspecified 60 (1) 79 (1) 120 (2)

0.50

(0.36–0.67) <0.0001

0.66

(0.50–0.87) 0.0037

Haemorrhagic 14 (<1) 27 (<1) 10 (<1) 1.39

(0.62–3.32) 0.43

2.70

(1.31–5.59) 0.0051

MI 169 (2) 176 (2) 195 (2) 0.86

(0.71–1.05) 0.15

0.90

(0.74–1.11) 0.33

CAD

Connolly SJ et al, Lancet 2017; doi:10.1016/S0140-6736(17)32816-7

Dual Pathway Inhibition with Rivaroxaban 2.5 mg bid + Aspirin

Significantly Reduced MACE by 26% Versus Aspirin


Stroke/MI/Cardiovascular death

Cu

mu

lati

ve

in

cid

en

ce

ris

k (

%)

0

2

4

6

8

10

0 1 2 3

Rivaroxaban + Aspirin

Rivaroxaban

Aspirin

Year

Rivaroxaban 2.5 mg bid + aspirin vs aspirin

Rivaroxaban 5 mg bid vs aspirin

HR=0.74 (95% CI 0.65–0.86) p<0.0001

HR=0.90 (95% CI 0.79–1.02) p=0.11

CAD

Bleeding Rates Increased but Low with Rivaroxaban

Vascular Dose 2.5 mg bid + Aspirin Versus Aspirin Alone

Outcome

Rivaroxaban

2.5 mg bid

+ aspirin

N=8313

Rivaroxaban

5 mg bid

N=8250

Aspirin

N=8261

Rivaroxaban


vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%) HR

(95% CI) p-value

HR

(95% CI) p-value

Major bleeding 263 (3) 236 (3) 158 (2) 1.66

(1.37–2.03) <0.0001

1.51

(1.23–1.84) <0.0001

Fatal 14 (<1) 12 (<1) 9 (<1) 1.55

(0.67–3.58) 0.30

1.33

(0.56–3.16) 0.51

ICH 19 (<1) 32 (<1) 19 (<1) 0.99

(0.52–1.87) 0.98

1.69

(0.96–2.99) 0.065

Critical organ 36 (<1) 42 (1) 25 (<1) 1.42

(0.85–2.36) 0.18

1.70

(1.04–2.79) 0.033

Other 194 (2) 150 (2) 105 (1) 1.85

(1.46–2.34) <0.0001

1.44

(1.12–1.84) 0.0041


CAD

No significant increase in critical organ bleeding

including intracranial or fatal bleeding

Bleeding Rates Increased but Low with Rivaroxaban

2.5 mg bid + Aspirin Versus Aspirin Alone

Major bleeding


CAD

Aspirin

Rivaroxaban

Rivaroxaban + Aspirin

Year

Rivaroxaban 2.5 mg bid + aspirin vs aspirin

Rivaroxaban 5 mg bid vs aspirin

HR=1.69 (95% CI 1.39–2.06) p<0.0001

HR=1.51 (95% CI 1.23–1.85) p<0.0001

Cu

mu

lati

ve

in

cid

en

ce

ris

k (

%)

0

2

4

6

8

10

0 1 2 3

22% Reduction in Risk of the Composite Net Clinical Benefit Outcome

with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin vs Aspirin

For every 1000 patients with CAD treated with rivaroxaban plus aspirin,

13 MACE events would be prevented and 2 fatal or critical organ bleeds

would be caused over a mean 23-month period

Rates at mean

follow-up of

23 months

Rivaroxaban

2.5 mg bid

+ aspirin

N=8313

Rivaroxaban

5 mg bid

N=8250

Aspirin

N=8261

Rivaroxaban


vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%) HR

(95% CI)

p-value HR

(95% CI)

p-value

Net clinical benefit

(CV death, stroke,

MI, fatal or critical

organ bleeding)

392 (5) 462 (6) 494 (6) 0.78

(0.69–0.90) 0.0003

0.94

(0.82–1.06) 0.31

All-cause mortality 262 (3) 316 (4) 339 (4) 0.77

(0.65–0.90) 0.0012

0.93

(0.80–1.09) 0.37

CV death 139 (2) 175 (2) 184 (2) 0.75

(0.60–0.93) 0.010

0.95

(0.77–1.17) 0.63

Non-CV death 123 (2) 141 (2) 155 (2) 0.79

(0.62–1.00) 0.048

0.91

(0.73–1.15) 0.43


CAD

Efficacy of Rivaroxaban Vascular Dose 2.5 mg bid +

Aspirin Was Consistent Across Subgroups

Subgroup

Rivaroxaban

2.5 mg bid +

aspirin

n/N (%)

Aspirin alone

n/N (%) HR (95% CI) HR (95% CI) p-value

All participants 347/8313 (4) 460/8261 (6) 0.74 (0.65–0.86)

Age 0.20

<65 years 69/1864 (4) 115/1890 (6) 0.61 (0.45–0.82)

65–75 years 168/4707 (9) 223/4661 (5) 0.74 (0.61–0.91)

≥75 years 110/1742 (6) 122/1710 (7) 0.87 (0.67–1.13)

Baseline diabetes 0.62

Yes 155/3043 (5) 212/3040 (7) 0.72 (0.58–0.88)

No 192/5270 (4) 248/5221 (5) 0.77 (0.64–0.93)

Concomitant PAD 0.37

Yes 94/1656 (6) 138/1641 (8) 0.67 (0.52–0.87)

No 253/6657 (4) 322/6620 (5) 0.77 (0.66–0.91)

TIMI risk score* 0.92

0–1 57/2611 (2) 77/2582 (3) 0.73 (0.52–1.03)

2 88/2399 (4) 108/2316 (5) 0.79 (0.59–1.04)

3–8 202/3303 (6) 275/3363 (8) 0.74 (0.61–0.88)

Guideline-recommended therapy# 0.89

Yes 150/3431 (4) 194/3406 (6) 0.75 (0.61–0.93)

No 197/4882 (4) 266/4855 (5) 0.74 (0.61–0.89)

0,1 1 10

Favours rivaroxaban


Favours

aspirin alone

*TIMI risk score gives one point each to the following criteria: current

smoker, heart failure, diabetes, CABG surgery, stroke, hypertension,

age >75 years, estimated glomerular filtration rate <60 mL/min; #Non-

smokers receiving lipid-lowing drugs, β-blockers and an ACEI/ARB


CAD

Efficacy of Rivaroxaban Vascular Dose 2.5 mg bid +

Aspirin Was Consistent Across Subgroups

Subgroup

Rivaroxaban

2.5 mg bid +

aspirin

n/N (%)

Aspirin alone

n/N (%) HR (95% CI) HR (95% CI) p-value

All participants 347/8313 (4) 460/8261 (6) 0.74 (0.65–0.86)

History of MI 0.93

<2 years prior 49/1218 (4) 67/1205 (6) 0.70 (0.48–1.01)

2–5 years prior 71/1612 (4) 91/1665 (5) 0.81 (0.59–1.10)

≥5 years prior 127/2824 (4) 174/2849 (6) 0.72 (0.57–0.91)

No MI prior 100/2661 (3.8) 128/2540 (5) 0.76 (0.58–0.98)

History of PCI/PTCA 0.85

Yes 201/4971 (4) 270/4905 (6) 0.74 (0.61–0.88)

No 146/3342 (4) 190/3356 (6) 0.76 (0.61–0.94)

History of CABG 0.01

Yes 121/2232 (5) 117/2143 (5) 0.99 (0.77–1.28)

No 226/6081 (4) 343/6119 (6) 0.66 (0.56–0.78)

MI or PCI or CABG >2 years 0.71

Yes 78/2269 (3) 102/2141 (5) 0.71 (0.53–0.95)

No 269/6044 (4) 358/6120 (6) 0.76 (0.65–0.89)


0,1 1 10

Favours rivaroxaban


Favours

aspirin alone

CAD

Persistent Reduction in MACE with Dual Pathway

Inhibition; Increased Bleeding only in the First Year

Rivaroxaban


n/N (%)

Aspirin alone

n/N (%) HR (95% CI) HR (95% CI)

MACE

<1 year 176/8313 (2) 221/8261 (3) 0.79 (0.65–0.96)

1–<2 years 113/7228 (2) 169/7125 (2) 0.66 (0.52–0.83)

>2 years 58/3655 (2) 70/3621 (2) 0.82 (0.58–1.16)

Major bleeding

<1 year 163/8313 (2) 70/8261 (1) 2.32 (1.75–3.07)

1–<2 years 70/7189 (1) 59/7183 (1) 1.19 (0.84–1.68)

>2 years 30/3626 (1) 30/3628 (1) 1.05 (0.63–1.75)

Net clinical benefit

<1 year 207/8313 (2) 237/8261 (3) 0.87 (0.72–1.04)

1–<2 years 124/7201 (2) 182/7112 (3) 0.67 (0.53–0.84)

>2 years 61/3637 (2) 75/3604 (2) 0.80 (0.57–1.12)

All death

<1 year 117/8313 (1) 145/8261 (2) 0.80 (0.63–1.02)

1–<2 years 93/7323 (1) 120/7242 (2) 0.77 (0.59–1.01)

>2 years 52/3743 (1) 74/3762 (2) 0.70 (0.49–1.00)

Landmark analysis for key efficacy and safety outcomes


0,1 1 10

Favours rivaroxaban


Favours

aspirin alone

CAD

COMPASS PAD Analysis

Inclusion and Exclusion Criteria Ensure That

Patients with Chronic PAD are Enrolled

Key inclusion criteria

Previous peripheral artery

revascularization

Previous limb or foot amputation for

arterial vascular disease

Intermittent claudication plus:

Low ABI (<0.90), or

Significant peripheral artery

stenosis (≥50%)

Previous carotid revascularization,

or asymptomatic carotid artery

stenosis ≥50%

CAD + low ABI (<0.90)

Key exclusion criteria

High risk of bleeding

Stroke within 1 month

History of haemorrhagic/lacunar

stroke

Severe heart failure (ejection

fraction <30%)

eGFR <15 ml/min

A need for dual antiplatelet therapy

A need for non-aspirin antiplatelet

therapy

An indication for anticoagulation

therapy

Anand SS et al, Lancet 2017;doi:10.1016/S0140-6736(17)32757-5

PAD CAD

PAD-Specific Limb Outcomes Were Added to

Main Study Outcomes for COMPASS

Primary cardiovascular outcome was MACE, defined as:

Composite of cardiovascular death, stroke or MI

Key composite outcomes for PAD:

Primary limb outcome was major adverse limb events (MALE),

defined as development of ALI or CLI and major amputations not included in

ALI or CLI

The composite of MACE and MALE

The composite of MACE, MALE and major amputations not included in

ALI or CLI

PAD


ALI, acute limb ischaemia; CAD, coronary artery disease; CLI, chronic limb ischaemia; MACE, major

adverse cardiovascular events; MI, myocardial infarction; PAD, peripheral artery disease

Major Adverse Limb Events and Major Amputation

Were Included in PAD-Specific Net Clinical Benefit

Primary safety outcome: modified ISTH

Major bleeding defined as:

– Fatal bleeding, or

– Bleeding into a critical organ, or

– Surgical site bleeding requiring reoperation, or

– Bleeding requiring hospitalization

Net clinical benefit outcome defined as:

MACE

MALE including major amputation

Fatal bleeding

Bleeding into a critical organ

PAD


Dual Pathway Inhibition with Rivaroxaban Vascular Dose 2.5 mg

bid + Aspirin Reduced MACE by 28% Versus Aspirin Alone

Outcome

Rivaroxaban

2.5 mg bid

+ aspirin

N=2492

Rivaroxaban

5 mg bid

N=2474

Aspirin

N=2504

Rivaroxaban


vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%) HR

(95% CI) p-value

HR

(95% CI) p-value

MACE 126 (5) 149 (6) 174 (7) 0.72 (0.57–

0.90) 0.0047

0.86

(0.69–1.08) 0.19

CV

death 64 (3) 66 (3) 78 (3)

0.82

(0.59–1.14) –

0.86

(0.62–1.19) –

Stroke 25 (1) 43 (2) 47 (2) 0.54

(0.33–0.87) –

0.93

(0.61–1.40) –

MI 51 (2) 56 (2) 67 (3) 0.76

(0.53–1.09) –

0.84

(0.59–1.20) –

PAD


Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin Significantly

Reduced Major Amputation by 70% Versus Aspirin Alone

Outcome

Rivaroxaban

2.5 mg bid

+ aspirin

N=2492

Rivaroxaban

5 mg bid

N=2474

Aspirin

N=2504

Rivaroxaban


vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%) HR

(95% CI) p-value

HR

(95% CI) p-value

MALE 30 (1) 35 (1) 56 (2) 0.54

(0.35–0.84) 0.0054

0.63

(0.41–0.96) 0.032

Major

amputation 5 (<1) 8 (<1) 17 (<1)

0.30

(0.11–0.80) 0.011

0.46

(0.20–1.08) 0.068

PAD


Bleeding Increased but Low with Rivaroxaban Vascular Dose 2.5 mg bid + Aspirin

Versus Aspirin Alone, with No Differences Seen in Fatal and Intracranial Bleeding

Outcome

Rivaroxaban

2.5 mg bid

+ aspirin

N=2492

Rivaroxaban

5 mg bid

N=2474

Aspirin

N=2504

Rivaroxaban


vs aspirin

Rivaroxaban

5 mg bid

vs aspirin

N (%) N (%) N (%) HR

(95% CI) p-value

HR

(95% CI) p-value

Major bleeding 77 (3) 79 (3) 48 (2) 1.61

(1.12–2.31) 0.0089

1.68

(1.17–2.40) 0.0043

Fatal 4 (<1) 5 (<1) 3 (<1) – – – –

Intracranial 5 (<1) 6 (<1) 9 (<1) – – – –

Fatal or

symptomatic

bleeding into

a critical

organ

21 (1) 26 (1) 19 (1) 1.10

(0.59–2.05) -

1.39

(0.89–3.09) -

PAD


Vascular Dose Rivaroxaban Showed Improved Outcomes for

PAD Patients with a Need for Increased Vascular Protection

Rivaroxaban vascular dose 2.5 mg BID plus aspirin reduced the

composite endpoint of stroke, MI or CV death by 28%.

MALE by 46%

Major amputations by 70%

Despite an expected increase in major bleeding events with

Rivaroxaban 2.5 mg BID plus aspirin, no significant increase was

observed in fatal or critical organ bleeding

This dual pathway inhibition of Rivaroxaban vascular dose and aspirin

represents a major advance in the management of PAD and is the only

available therapeutic option to significantly reduce both MACE and

MALE

PAD

*Defined as CV death, MI, stroke, MALE, major amputation, fatal bleeding or critical organ bleeding


CONCLUSIONI…. uno sguardo al futuro… che prospettive?

CONCLUSIONI

La forza dell’equilibrio…

Rischio ischemico

Rischio emorragico

Antiaggregazione

+

Rivaroxaban 2,5 x 2

Nuove evidenze sulla terapia antitrombotica cronica nella ... · Nuove evidenze sulla terapia...

Documents

Transcript of Nuove evidenze sulla terapia antitrombotica cronica nella ... · Nuove evidenze sulla terapia...