Δ. ΣΥΡΣΕΛΟΥΔΗΣ

ΚΑΡΔΙΟΛΟΓΙΚΟ ΤΜΗΜΑ

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Καμία

NSAIDs REACTIONS

PSEUDOALLERGIC

• Non-immunologic, related to COX-1 inhibition

ALLERGIC

• Abnormal immunologic- IgE mediated-reactions

IDIOSYNCRATIC

• Immune mechanisms

PSEUDOALLERGIC

Type 1

Asthma and rhinosinusitis (+ nasal polyposis = AERD)

Rhinorrhea, nasal congestion, periorbital edema, conjunctival

injection, bronchospasm, laryngospasm, flushing,

abdominal pain, diarrhea, hypotension

Type 2

Urticaria/Angioedema in pts with chronic

urticaria

Type 3Urticaria/Angioedema in asymptomatic pts

Type 4

Mixed respiratory/ cutaneous reactions in

asymptomatic pts

Bronchospasm,

rhinitis,

urticaria/ angioedema.

ALLERGIC

Type 5 Urticaria/Angioedema

Type 6

Anaphylaxis

(NOT ASA)

Anaphylactoid reaction to ASA:

Hypotension

Swelling

Laryngeal oedema

Pruritus

IDIO

SY

NC

RA

TIC

Aseptic meningitis

Hypersensitivity pneumonitis

Thrombocytopenia

Interstitial nephritis

Erythema muliform

Fixed drug eruptions

Stevens- Johnson syndrome

Erythema nodosum

Maculopapular eruptions

Bullous leukocytoclastic

vasculitis

PREVALENCE OF ASA REACTIONS

LARGELY UNKNOWN

0.3-0.9

GENERAL POPULATION

Reaction

1,5

CAD

Reaction

7-14

ASTHMA PATIENTS

AERD

0.07-0.2

GENERAL POPULATION

URTICARIA

J.Rajan. J Allergy Clin Immunol 2015 R.Gollapudi. JAMA 2004

K. Cook. Curr Allergy Asthma Rep 2016 C.Feng. Ann Allergy Asthma Immunol. 2013

MANAGEMENT

Administer ASA to ASA sensitive pts

Stabilize first – Deal with ASA

sensitivity later

• GPI

• Cangrelor

OPTIONS

ASA DESENSITIZATION

SAPT

P2Y12 + VKA/ NOAC (RIVAROXABAN)

CLOPIDOGREL/TICAGRELOR/PRASUGREL + other

antiplatelet ?

ASA DESENSITIZATION

ASPIRIN DESENSITIZATION

Type of reaction

AERD CUTANEOUS REACTION BLENDED REACTIONANAPHYLACTOID

IDIOSYNCRATIC REACTION

Hx of adverse reactions to ASA/NSAIDs

Signs and symptoms Single or multiple agentsUnderlying disorders

(asthma, polyps, sinusitis, urticaria)

CV ptnt w ASA sensitivity

S. Ramanuja. Circulation 2004

• AERD

• CUTANEOUS

• BLENDED REACTION

• ASA DESENSITIZATION

TYPE OF REACTION

• ANAPHYLACTOID

• IDIOSYNCRATIC (SJ/TEN, DRESS)

• ALTERNATE AGENT

S. Ramanuja. Circulation 2004

ASA DESENSITIZATION

Multiple ASA doses

starting with a low dose

dose escalation up to the maintenance dose

prespecified time intervals

PROTOCOLS differ in

Starting ASA dose

Time intervals between doses

Choice of protocol depends on type of reaction

ASA DESENSITIZATION

ICU +/- Allergist

Expertise

Medications, equipment

Support stuff

Allergy symptom control

FEV1>70% + >1.5L

Oral, inhaled, nasal corticosteroids

Long acting brongchodilators

Urticaria: antihistamines tapered to lowest effective dose

AERD:24h d/c of antihistamines

d/c medications that increase likelihood or interfere w treatment of anaphylaxis (ACEi – BBs)

S. Ramanuja. Circulation 2004

Positive reactionBronchoconstriction (CAUTION may represent type 6 anaphylactic reaction)

FEV1: 25% reduction

Naso-ocular symptoms

Cutaneous symptoms

NO

Maintain daily ASA therapy

YES

Treat symptoms and continue desensitization protocol

Maintain daily ASA therapy

(d/c of therapy for ≥ 72h : sensitivity returns)

S. Ramanuja. Circulation 2004

DESENSITIZATION PROTOCOLS

ROSSINI PROTOCOL

WONG PROTOCOL

Procedings of UCLA healthcare 2012

SAPT

DOES ASA REALLY MAKE A DIFFERENCE IN DES

PATIENTS?

ADAPT DES

G. Stone. Lancet 2013

8449 post PCI pts, VerifyNow, f/u 365 d,

Definite ST 53 (0.63%)

Probable ST 17 (0.20%)0

0

1

2

3

4

5

6

7

8

9

Death MI TVR Stroke ST

Doubletherapy group

Triple therapygroup

MI=any myocardial infarction; TVR= target vessel revascularisation (PCI + CABG); ST= stent thrombosis

2.6

6.4

3.3

4.7

7.3

6.8

1.1

2.9

1.5

3.2

p=0.027p=0.382

p=0.128p=0.165

p=0.876

WOEST- Secondary endpoint

W.Dewilde. Lancet 2013

284 post- PCI pts: VKA + ASA + Clopidogrel

279 post- PCI pts: VKA + Clopidogrel

The study was powered to show superiority on the primary bleeding endpoint, but not to show non-inferiority on the secondary endpoint

Circulation 2012

SAPT w STANDARD vs DOUBLE CLOPIDOGREL

DOSE CURRENT-OASIS 7Definite/probable ST Definite ST

S. Mehta. Lancet 2010

25086 ACS pts, 16323 stent

Clopi HD: 600 mg loading, 150 mg 2-7, 75 mg/ SD: 300 mg loading, 75 mg

ASA HD: 300 - 325 mg / SD:75-100 mm

Definite ST HD vs SD:

Day 1-2: 16 vs 34 Day 3-10: 30 vs 54 - 46% reduction with HD Clopi

HD ASA no difference

BMS: 58%

TWILIGHT:

TICAGRELOR + ASA for 3 months

followed by

TICAGRELOR + PLACEBO vs TICAGRELOR + ASA

GLOBAL LEADERS:

TICAGRELOR + ASA for 1 month

followed by

TICAGRELOR + PLACEBO vs TICAGRELOR + ASA

P2Y12 + other antiplatelet agent

17779 prior MI pts

2.5 mg vorapaxar vs

placebo

on top of

ASA (98%) +/-

thienopyridine (78%)

Modest decrease in CV

death, MI, stroke w

increase in bleeding

events including ICH

Thrombin Receptor Antagonist in Secondary Prevention

of Atherothrombotic Ischemic Events (TRA 2P-TIMI 50)

D. Morrow. NEJM 2012

C. Laham. SCAI LBCT May 2015

Cilostazol – OUTSIDE START

cilostazol 100mg po bid

95 pts 167 procedures

2.2% MACE in PES

P2Y12 + OAC

ATLAS ACS 2 TIMI 51 - Rivaroxaban

15526 pts w recent ACS

2.5 or 5 mg rivaroxaban on top of

ASA and thienopyridine

CV death, MI or Stroke

2.5 mg decreased CV and all cause

death

J. Mega. NEJM 2013

SAPT + VKA

Oral anticoagulants inferior to ASA +

thienopyridine in several studies in the first stent era FANTASTIC M.Bertrand.Circulation 1998

MATTIS P.Urban. Circulation 1998

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

WOEST: reduction in CV

death, MI, TVR, Stroke, ST

Is it clopidogrel+ VKA

or clopidogrel that made a

difference?

W.Dewilde. Lancet 2013

CONCLUSIONS

We lack solid evidence of efficacy and safety for any alternative to DAPT (ASA + P2Y12 inhibitor)regimen

Ptnt stabilization/ PCI should be prioritized and can be done under GPI or cangrelor coverage

ASA desensitization can be fast and simple and represents a viable option in certain patients with ASA sensitivity

ASA true anaphylaxis has not been reported

Severe reactions SJ/TEN, interstitial nephritis, anaphylactoidreactions warrant an alternative regimen etc

Alternative regimens could include:

P2Y12 inhibitor monotherapy

Combination of P2Y12 inhibitors with other antiplatelet agents (Cilostazol, Vorapaxar)

Combination of P2Y12 inhibitors with OAC