NOACs offer equivalent or improved therapeutic profiles compared

Transcript

NOACs offer equivalent or improved therapeutic profiles compared to warfarin, ideally
with less bleeding risk, no interactions with food, and no FDA requirements for routine
laboratory monitoring
It is estimated that the cost of NOACs may exceed 60 times the cost of warfarin
Arch Pathol Lab Med. 2015;139:687–692
Novel oral anticoagulants (NOACs)
Direct factor Xa inhibitors (apixaban and rivaroxaban) and direct
thrombin inhibitors (dabigatran) are approved for stroke prevention
in atrial fibrillation and prophylaxis and treatment of venous
thromboembolism (VTE) in the US and Europe, though dabigatran is
not yet approved for VTE prophylaxis in the US
More recently, another direct factor Xa inhibitor, edoxaban, was
approved for stroke prevention in atrial fibrillation and VTE treatment
and prevention of VTE recurrence in the US and Europe
Compared to warfarin, NOACs have decreased bleeding risk with
non-inferior efficacy in patients with atrial fibrillation
A meta-analysis of 12 randomized controlled trials involving 102,607
patients demonstrated the superior safety of NOACs compared to
warfarin for the treatment of VTE or atrial fibrillation
Vascular Health and Risk Management 2016:12 35–44
Unlike warfarin, which may be
reversed with fresh frozen plasma
(FFP) and vitamin K, there are no
approved reversal agents for (all)
NOACs.
Despite the relative safety of
NOACs
with
respect
to
hemorrhagic complications, these
complications do occur, and up
until idarucizumab’s recent US
Food and Drug Administration
(FDA) approval, there existed an
unmet need for dedicated reversal
agents.
There are 3 areas of uncertainty with respect to management of NOACs:
perioperative
management
• challenging (lack of data from large randomized studies)
• The timing of cessation of NOAC prior to surgery depends
on the half-life of the agent, procedure-specific bleeding
risks, and renal function of the patient.
In general, Factor Xa inhibitors must be stopped at least
24–48 hrs prior to surgery with moderate bleeding risk and
48–72 hrs prior to surgery with high bleeding risk.
Dabigatran may be stopped >72 hrs prior to surgeries with
moderate bleeding risk. Patients with impaired renal
function should have NOACs stopped earlier.
For moderate risk surgeries, NOACs may be restarted 24
hrs after the procedure if hemostasis is achieved. For higher
risk surgeries, a 48-hrs period may be more appropriate.
Unlike warfarin, the time to effective anticoagulation is
within hours of first administration for all NOACs
laboratory
monitoring of
anticoagulation
• Routine coagulation studies (including INR and aPTT)
may not accurately reflect the level of anticoagulation
among patients receiving NOACs and are not
recommended
For dabigatran
Specialized assays [including thrombin time (TT), dilute
thrombin time (dTT), and ecarin-clotting time (ECT)] are
currently used in research studies – dTT and ECT assays
are not commercially available at most institutions.
For apixaban and rivaroxaban
The anti-factor Xa chromogenic assay yields results
consistent with dose–response, but results may not be
available in a timely fashion
While the lack of routine monitoring is convenient and may help to mitigate some of the costs
associated with NOACs, it may be informative to measure NOAC levels in
• patients presenting with relatively high or low body weight,
• renal insufficiency (dabigatran),
• patients taking other medications that alter P-glycoprotein and cytochrome P3A4 metabolism
• patient populations that were not included in NOAC clinical trials
In addition, the lack of a well-characterized NOAC laboratory assay may complicate the management of
cases of NOAC overdose, NOAC-associated life-threatening bleeding, or the scheduling of urgent
surgery in patients taking NOACs
management of
bleeding
The Chinese character for blood is 血 (xuè). It is also
informally pronounced as 血 (xiě) or 血 (xuě). At the base
is the character 皿 (mǐn), which means a utensil, a dish or
a container. And, as you can see, there is a drop of blood
that is dripping into this container.
management of
bleeding
• guidelines for NOACs are currently unavailable
• Supportive care (mechanical compression, i.v. hydration,
packed red blood cells, platelet transf.), withdrawal of the
offending agent, use of specific and non-specific
hemostatic therapies
Hemostatic therapies can be categorized as follows:
•Reduce absorption (charcoal within 1-2 h) or remove from
circulation (hemodialysis for dabigatran-associated bleed.)
•Antifibrinolytic agents – a. tranexamic and a. aminocaproic
•Therapy with plasma factors: prothrombin complex
concentrates (PCCs), fresh frozen plasma (FFP), and
cryoprecipitate
•Specific antidotes: idarucizumab, andexanet alfa and
ciraparantag
management of
bleeding
• guidelines for NOACs are currently unavailable
• Supportive care (mechanical compression, i.v. hydration,
packed red blood cells, platelet transf.), withdrawal of the
In certain clinical situations,
hemodialysis
is
offending
agent, may
usebeofconsidered,
specific as
anddabigatran
non-specific
only 35% bound to plasma
proteins
and, according to the manufacturer,
hemostatic
therapies
hemodialysis may remove 49% to 57% of dabigatran within 4 hours
Hemostatic therapies can be categorized as follows:
•Reduce absorption (charcoal within 1-2 h) or remove from
circulation (hemodialysis for dabigatran-associated bleed.)
•Antifibrinolytic
a. plasma
tranexamic
and a.
aminocaproic
Rivaroxaban and apixaban
are highlyagents
bound–to
proteins
and
therefore,
unlike dabigatran, there
is no role
hemodialysis
management
of
•Therapy
with forplasma
factors:in the
prothrombin
complex
bleeding associated with their use
concentrates (PCCs), fresh frozen plasma (FFP), and
cryoprecipitate Arch Pathol Lab Med. 2015;139:687–692
•Specific antidotes: idarucizumab, andexanet alfa and
ciraparantag
Antidotes currently in development for NOAC reversal
Idarucizumab (BI655075-Dabi-Fab)
Idarucizumab is 100 times larger than
dabigatran and the Vd of the former or
idarucizumab-dabigatran complex is
significantly lower than dabigatran
alone.
Humanized monoclonal antibody fragment
(FAB, molecular weight is 47.8 kDa) that
tightly binds and irreversibly inhibits
dabigatran in a 1:1 ratio
The affinity of idarucizumab to dabigatran
is 350 times the affinity of dabigatran to
thrombin - immediate and complete
reversal of dabigatran’s anticoagulant
activity ments. The drug did not interact
with other thrombin substrates.
The half-life is 45 min in healthy volunteers and
elimination occurs primarily by a renal route.
Current Opinion in Pharmacology 2016, 27:86–91
Idarucizumab
(Praxbind,
Boehringer
Ingelheim Pharmaceuticals, Ridgefield,
Connecticut, United States) was approved
for human use by FDA on October 16,
2015 for emergency reversal of dabigatran
anticoagulant.
Praxbind is supplied in vials, each
containing 2.5g/50mL of idarucizumab
Note:
Idarucizumab vials contain sorbitol, and there is a potential risk
of adverse events, including hypoglycemia, vomiting and
metabolic acidosis, in patients with hereditary fructose
intolerance
Andexanet alfa (r-antidote-PRT064445)
Recombinant modified factor X molecule (factor X decoy) that possesses
a specific binding site for factor X/Xa inhibitors.
It lacks the membrane binding γ-carboxylglutamate (Gla) domains and
catalytic site, and therefore does not exert a procoagulant effect.
Note:
The Gla domain enables factor X/Xa to bind phospholipid (i.e. cell surfaces) in a
calcium dependent manner; a requirement for assembly of the prothrombinase
complex.
Factor Xa from which the Gla domain has been removed (as by limited chymotryptic
digestion) does not bind to phospholipid-factor Va and is virtually inactive
Unlike in the coagulation
cascade with factor X (to
obtain factor Xa), andexanet
alfa did not require any
activation steps by factors VIIa
(from the extrinsic pathway) or
IXa (from the intrinsic pathway)
AMSRJ 2014; 1(1):16—28
It lacks the membrane binding γ-carboxylglutamate domains and catalytic
site, and therefore does not exert a procoagulant effect.
The drug can reverse the anticoagulant activity of direct factor Xa inhibitors
in a dose-dependent manner. Andexanet alfa also retains its ability to bind
antithrombin III and can reverse antithrombin III-mediated indirect factor Xa
inhibitors, including low molecular weight heparins and fondaparinux
AMSRJ 2014; 1(1):16—28
It lacks the membrane binding γ-carboxylglutamate domains and catalytic
site, and therefore does not exert a procoagulant effect.
The drug can reverse the anticoagulant activity of direct factor Xa inhibitors
in a dose-dependent manner. Andexanet alfa also retains its ability to bind
antithrombin III and can reverse antithrombin III-mediated indirect factor Xa
inhibitors, including low molecular weight heparins and fondaparinux
Andexanet alfa (Portola Pharmaceuticals, San Francisco, CA, USA) was
submitted for break through designation in November 2013 and also as an
orphan drug therapy in February 2015. It is not currently approved for
human use (Trials of factor Xa inhibitor reversal with andexanet alfa
among patients with severe bleeding are currently enrolling patients
(NCT02329327)).
Ciraparantag (PER977, Perosphere, Aripazine)
Small synthetic and cationic molecule that binds direct Xa inhibitors,
direct thrombin inhibitors, and heparin (UFH and LMWH) through noncovalent hydrogen bonds and charge–charge interactions
In a preliminary study involving 80 healthy patients,
PER977 (100–300 mg IV) was administered to subjects 3
hours after receiving edoxaban (60 mg oral). PER977
restored baseline hemostasis within 10–30 minutes and
effects were sustained for 24 hours.
Phase II trials investigating reversal of edoxaban with
escalating doses of PER977 are underway. Plans for
Phase III trials with edoxaban have also been
announced.
Ciraparantag (PER977, Perosphere, Aripazine)
Semin Hematol. 2014 Apr;51(2):89-97.
Dabigatran is predominantly eliminated by
the renal route - 80% of active substance
(dabigatran), and fecal elimination of the
remaining substance as acylglucoronide (it
also displays anticoagulant action).
Renal function is the only parameter with
relevant influence on the pharmacokinetic
and
pharmacodynamic
parameters
of
dabigatran.
Impaired liver function increased bleeding risk not by impaired elimination of dabigatran, but by the
lower level of procoagulant proenzymes synthesized by the liver, resulting in a different balance
between the endogenous procoagulant activity, and the anticoagulant activity of dabigatran, resulting
in a “relative overdose” of dabigatran
P-glycoprotein (P-GP) inhibitors (including amiodaron, verapamil, quinidine) result in increased
plasma concentrations of dabigatran, whereas and P-GP inducers (such as rifampicine, St. John’s
wort, phenytoin, carbamazepine) reduce the plasma concentration of dabigatran
Protein binding
~92-95%
Simultaneous treatment with CYP3A4 or P-glycoprotein inhibitors leads to elevated plasma
concentrations of rivaroxaban. Simultaneous treatment with ketoconazole and ritornavir is
contraindicated.
Inducers of CYP3A4 and P-glycoprotein, such as rifampicin, as well as St. John’s wort, lead to a
reduction of rivaroxaban plasma levels
Impaired renal and/or liver function result in an enhanced effect of rivaroxaban, with prolonged halflife and increased AUC
Liver disease is often associated with decreased hepatic synthesis of coagulation factors, which may
lead to increased bleeding risk, as the total capacity for generation of factor Xa and thrombin is
reduced.
Protein binding
~92-95%
The rather low dependency upon renal
elimination may be advantageous in patients
with impaired renal function
Protein binding
~87%
Similar to rivaroxaban, treatment with CYP3A4
and P-glycoprotein inhibitors results in elevated
plasma levels of apixaban and increased
anticoagulant activity. Inducers of CYP 3A4 or Pglycoprotein tend to reduce plasma levels of
apixaban
Approved by EMA (June 2015):
• to prevent stroke and systemic embolism in patients with non-valvular
atrial
fibrillation
Protein
binding
~92-95%
• to treat deep-vein thrombosis (DVT) and pulmonary embolism, and to prevent DVT and pulmonary
embolism from re-occurring
A 50% dose reduction is suggested in patients receiving concomitant strong P-glycoprotein inhibitors
Protein binding
~87%
Protein binding
~20-59%
Protein binding
~92-95%
Protein binding
~87%
Protein binding
~20-59%
Curr Opin Pharmacol. 2016 Apr;27:86-91.
NOTE
As NOACs do not share the relevant properties with heparins, problems with
anti-heparin–platelet factor 4 (PF4) antibodies are not to be expected.
In vitro experiments showed no interaction of dabigatran or rivaroxaban with
anti-heparin–PF4 antibodies. Consequently, dabigatran, rivaroxaban, apixaban,
or other similar drugs can also be used in patients with earlier heparin-induced
thrombocytopenia (HIT), although treatment of patients with acute newly
diagnosed HIT-2 is currently discouraged due to the lack of support from
clinical trials or other high-quality data, or dose recommendations for this
indication.
As acute HIT-2 is a condition with strongly activated coagulation system,
associated with generation of high concentrations of factor Xa and thrombin,
the standard dose of DOACs might be insufficient. Similar to acute deep vein
thrombosis or pulmonary embolism, a higher dose might be necessary
Anticoagulanti orali
Impieghi terapeutici
Il dabigatran, il rivaroxaban e l’apixaban sono già in commercio dal 2008 per la
prevenzione delle complicazioni tromboemboliche in pazienti sottoposti a chirurgia
ortopedica maggiore. Hanno dimostrato pari efficacia e sicurezza nei confronti delle
eparine a basso peso molecolare in studi di non-inferiorità con il vantaggio della
somministrazione orale al posto di quella parenterale.
A partire dal 2011, queste nuove molecole hanno ricevuto l’indicazione anche nella
prevenzione dell’ictus in pazienti con fibrillazione atriale non valvolare. Hanno
dimostrato non inferiorità/equivalenza in termini di efficacia, minor rischio di
emorragie intracraniche ma maggiore tendenza a sanguinamenti GI e con il dabigatran
si è osservato un maggior rischio di infarto. L’apixaban ha evidenziato di avere minori
rischi complessivi di sanguinamenti
Nota:
L’arrivo degli antidoti dei nuovi anticoagulanti probabilmente determinerà un
incremento delle prescrizioni di questi nuovi farmaci (nel 2014 il warfarin è stato il più
prescritto a livello mondiale con vendite globali pari a 600 milioni di dollari, contro i 6,1
miliardi di dollari complessivi delle nuove molecole).
Antiaggreganti piastrinici
1. INIBITORI DELLE CICLOSSIGENASI
(aspirina)
2. INIBITORI DELLE FOSFODIESTERASI
(dipiridamolo)
3. INIBITORI DEL RECETTORE DELLÀDP
(clopidogrel, prasugrel, ticagrelor, cangrelor)
4. ANTAGONISTI DEL RECETTORE GPIIb-IIIa
(eptifibatide, abciximab, tirofiban)
5. PROSTANOIDI
(Epoprostenolo – PGI2)
Dosaggi < di quelli richiesti per
atttivita’ antinfiammatoria
Non efficace cpntro attivazione
piastrinica da ADP o trombina
Dopo aspirina, neosintesi di TXA2 non riparte fino a che il
pool di piastrine che sono state influenzate dal farmaco
non vengono rimpiazzate (circa 7-10 giorni)
Antagonisti recettori P2Y12
ADP
+
Prasugrel
Ticagrelor*
Cangrelor*
Profarmaci, inibitori irreversibili (eccetto ticagrelor e cangrelor)
Clopidogrel
• Attivita’
antiaggregante
richiede
bioattivazione
epatica che determina ritardo nell’insorgenza effetto
• Polimorfismi possono determinare resistenza
• Insieme all’aspirina utilizzati spesso in ACS
Prasugrel
• Attivita’
antiaggregante
richiede
bioattivazione
• Comparabile efficacia del clopidogrel, ma effetto
antiaggregante maggiore e piu’ rapido
• Efficace in pazienti con resistenza al clopidogrel
Ticagrelor
• Inibitore non competitivo di P2Y12, non richiede
bioattivazione epatica
Clin Pharmacokinet (2015) 54:1125–1138
Ticagrelor is predominantly metabolized by
CYP3A4 and to some extent by CYP3A5;
Elimination is through hepatic metabolism.
No dose adjustment is required in patients
with renal impairment
Nature Reviews Cardiology 10, 121-122 (March 2013)
Ticagrelor is a moderate inhibitor of CYP3A4, CYP2C9, CYP3A5 and CYP2D6
Ticagrelor should be avoided in patients on CYP3A4 inhibitors (ketoconazole,
clarithromycin, nefazodone, ritonavir and atazanavir) and CYP3A4 inducers
(rifampicin, dexamethasone, phenytoin, carbamazepine and phenobarbital)
• Attivita’
antiaggregante
richiede
bioattivazione
ThereClopidogrel
are two other non-thienopyridine
P2Y12 receptor
antagonists
that have
been tested in patients. epatica che determina ritardo nell’insorgenza effetto
Polimorfismi
• ATP •analogue;
it’spossono
a directdeterminare
acting andresistenza
reversibly binding
P2Y12 receptor antagonist
• Insieme all’aspirina utilizzati spesso in ACS
• It’s intended for acute treatment only, as the compound is
short• acting
(t1/2 3–6
min) and not orally
administered
Attivita’
antiaggregante
richiede
bioattivazione
Prasugrel
che
determinaitritardo
nell’insorgenza
effetto
• Given epatica
as bolus
+ infusion,
provides
immediate, consistent,
and profound platelet inhibition that is rapidly reversible
• Approved by FDA as anantiaggregante
adjunct to PCImaggiore
to reduceethe
of periprocedural MI,
piu’risk
rapido
repeat coronary revascularization, and stent thrombosis in patients who have
not been pretreated with
a P2Y12
platelet
inhibitor
andalare
not receiving a
• Efficace
in pazienti
con
resistenza
clopidogrel
glycoprotein IIb/IIIa inhibitor.
Cangrelor
Inibitore the
non
di cardiovascular
P2Y12, non richiede
Ticagrelor
• Approved
by EMA for•reducing
riskcompetitivo
of thrombotic
events in
patients with CAD undergoing PCI who did not receive an oral P2Y12 inhibitor
before PCI procedu., and in whom oral P2Y12 inhib. is not feasible or desirable
Br J Pharmacol. 2016 Apr;173(7):1163-78.; Pharmacol Ther. 2016 Mar;159:102-9.
Cangrelor
Pros of cangrelor vs oral P2Y12 receptor inhibitors:
• In the setting of ACS, particularly STEMI, oral P2Y12 antagonists may take
several hours to achieve maximal platelet inhibition
• In ACS patients, the bioavailability of oral P2Y12 antagonists might be severely
decreased in the presence of nausea, emesis, use of opiates, intubation,
impaired gut perfusion in cardiogenic shock, or therapeutic hypothermia.
• With oral P2Y12 antagonists, it takes 3–10 days for platelet inhibition to fully
reverse. This is particularly problematic when the antiplatelet effect is no longer
desirable, as in settings where emergent cardiac surgery is needed
Pharmacol Ther. 2016 Mar;159:102-9.
• Attivita’
antiaggregante
richiede
bioattivazione
ThereClopidogrel
are two other non-thienopyridine
P2Y12 receptor
antagonists
that have
been tested in patients. epatica che determina ritardo nell’insorgenza effetto
Elinogrel
• direct• acting
reversibly
binding
P2Y12 receptor
antagonist
Polimorfismi
possono
determinare
resistenza
• intended
both for
p.o. and utilizzati
i.v. administration,
but development
• Insieme
all’aspirina
spesso in ACS
was stopped in Phase II clinical trials
Prasugrel
• Attivita’
antiaggregante
richiede
bioattivazione
antiaggregante maggiore e piu’ rapido
Ticagrelor
• Inibitore non competitivo di P2Y12, non richiede
Br J Pharmacol. 2016 Apr;173(7):1163-78.; Pharmacol Ther. 2016 Mar;159:102-9.
Pharmacology & Therapeutics 159 (2016) 102–109
British Journal of Pharmacology (2016) 173 1163–1178
Illustration of plasma exposure of active drug over 24 h
following ticagrelor 90 mg twice daily (A) and clopidogrel 75
mg once daily or prasugrel 10 mg once daily (B).
The presence of an active drug in the systemic circulation
throughout 24 h provides what can be referred to as a
systemic potential. This systemic potential means that
ticagrelor apart from platelet P2Y receptors should be able to
reach additional targets
One can therefore argue that the
Clopidogrel and Prasugrel have limited or
no systemic exposure, and one may
hypothesize that the platelet inhibition by
these drugs mainly takes place in the
hepatic circulation where the active
metabolites are formed and therefore likely
present at higher concentrations. Because
of their irreversible mode of action,
however, they can overcome the shorter
duration of action of their active metabolite
so that they still can provide platelet
inhibition over 24 h
In A, ticagrelor (dotted red line), ARC124910XX (dashed red line) and the sum of ticagrelor and AR-C124910XX (solid red line). In B,
clopidogrel active metabolite (AM) (purple line) and prasugrel-AM (green line). Illustration is based on published patient exposure
data (Wallentin et al., 2008; Storey et al., 2007). Dotted black lines represent IC50 values, using ADP-induced light transmission
aggregometry in human PRP in vitro. In A, IC50 is the mean of ticagrelor and AR-C124910XX data presented in Table 1. In B,
clopidogrel-AM and prasugrel-AM IC50 data is from Sugidachi et al., 2007.
Additional benefits seen with ticagrelor may be due to the unique inhibition of
nonplatelet P2Y12 receptors such as those in vascular smooth muscle (stimulate
vasoconstriction).
Systemically active drugs, such as ticagrelor, are able to penetrate the vascular wall,
prevent vasospasm and aid in myocardial perfusion. Prodrugs, such as clopidogrel,
have not been shown to inhibit these receptors potentially due to the physical and
chemical properties of the metabolite
Nature Reviews Cardiology 6, 737-738 (December 2009)
Juvenile platelets
Clopidogrel
Prasugrel
Patients with increased platelet turnover have higher
levels of immature platelets, and an increase in the
immature platelet count has been found to be
associated with worse outcome, supporting the
hypothesis that these juvenile platelets are more prothrombotic.
A continuous systemic exposure of an active compound,
as true for ticagrelor, should theoretically inhibit newly
formed, juvenile platelets equally well as the old platelets.
This should not be the case for the thienopyridines as the
platelets formed after elimination of the active
metabolites from the circulation will not be inhibited until
the next dose of prodrug on the next day.
Ticagrelor
Clopidogrel: bioattivazione
Clopidogrel
2-oxo-Clopidogrel
Metabolita attivo
Xie HG et al, Pharmacology and Therapeutics 2010, doi:10.1016/j.pharmthera.2010.10.001;
Mackenzie IS et al., Journal of Internal Medicine 2010, 268:516-529
Clopidogrel: bioattivazione
Clopidogrel
2-oxo-Clopidogrel
Metabolita attivo
Varianti geniche possono predisporre a un riscio maggiore di sanguinamento
o di trombosi (15-30% non responsivi a clopidogrel)
Xie HG et al, Pharmacology and Therapeutics 2010, doi:10.1016/j.pharmthera.2010.10.001;
Biotrasformazione delle tienopiridine e possibili
interazioni con gli inibitori di pompa protonica
+ aspirin
+ aspirin
Primary results of the PLATO (Study of Platelet Inhibition and Patient Outcomes)
trial (ticagrelor vs. clopidogrel in acute coronary syndromes). Cumulative KaplanMeier estimates of the rate of the primary efficacy end point (death from vascular
causes, myocardial infarction, or stroke) for ticagrelor and clopidogrel at 12 months
No significant difference in the rates of major
bleeding was found between the groups
receiving ticagrelor or clopidogrel, although
ticagrelor was associated with a higher rate
of major bleeding not related to CABG
(coronary artery bypass graft). In addition,
rates of fatal intracranial bleeds, although
low, were more common with ticagrelor
Predefined hierarchical testing of secondary
end points showed significant differences in
the rates (lower in ticagrelor treated group) of
MI alone and death from vascular causes but
not stroke alone. The rate of death from any
cause was also reduced with ticagrelor
The most common adverse effect with
ticagrelor in this study was dyspnea.
Although there were also more frequent
episodes of ventricular pauses ≥ 3 seconds
Primary results of the PLATO (Study with
of Platelet
Inhibition
and the
Patient
ticagrelor
during
firstOutcomes)
week of
trial (ticagrelor vs. clopidogrel in acutetreatment
coronarycompared
syndromes).
withCumulative
clopidogrel,Kaplanby 30
Meier estimates of the rate of the primary
end point were
(deathnot
from
vascular
days efficacy
the differences
statistically
causes, myocardial infarction, or stroke)
for ticagrelor and clopidogrel at 12 months
significant
JACC Vol. 63, No. 23, 2014 June 17, 2014:2503–9
JACC Vol. 63, No. 23, 2014 June 17, 2014:2503–9
Intented to reduce bleeding risk
NOTE:
“Matching the identical PLATO ticagrelor dose (180 mg/daily) with
PEGASUS revealed identica mortality with placebo. […] Failure of
ticagrelor in PEGASUS to confirm the death benefit observed in
PLATO shifted the entire paradigm.”
Serebruany, International Journal of Cardiology, 2015
Chronic antithrombotic therapy impairs the essential abilities of clot formation (higher
bleeding rates) and stabilising tumour cell arrest in the vasculature (higher cancer risks).
Maintaining the tumour-platelet barrier, at least in part, is of compensatory nature,
limiting tumour dissemination and keeping cancer cells in situ.
Thromb Haemost 2015; 114: 1104–1112
“We may effectively prevent cardiovascular events, but if cancer risks are higher, and
it seems they are, then balancing the risk/benefit ratio of modern antithrombotic
strategies is way more complex than just matching vascular occlusions with
bleeding. To make it perfectly clear, the existing cancer signal will not eliminate dual
antiplatelet therapy after acute vascular events, but may impact duration and potency
of optimal therapy.”
“Based on the current knowledge, we should not omit aspirin at all because the
other drugs might otherwise increase solid tumor risks even further if used as
monotherapy”
Thromb Haemost 2015; 114: 1104–1112
“Even worse is that solid cancer risks may not be exclusively attributed to
antiplatelet agents, but anticoagulants as well.”
Thromb Haemost 2015; 114: 1104–1112
Blood. 2015;125(22):3484-3490
In human PRP treated with ticagrelor or TAM,
MEDI2452 reversed the antiplatelet effect of both
in a concentration-dependent manner (A). Its
potency (IC50) to reverse 1 µM ticagrelor or 1 µM
TAM was 0.64 and 0.78 µM, respectively.
Maximal reversals of 78% and 62% for ticagrelor
and TAM, respectively, were achieved with
concentrations of MEDI2452 up to 1 µM as
expected, given that MEDI2452 binds 1:1 with
ticagrelor and TAM
MEDI2452
reduced
the
free-ticagrelor
concentration in human PRP, with an IC50 value
of 0.49 µM (B), which inversely correlated with
restoration of ADP-induced platelet aggregation.
Total ticagrelor = 1 µM
Blood. 2015;125(22):3484-3490
MEDI2452 has a half-life similar to that of ticagrelor and TAM in
humans, which is 9.8 and 12.4 hours, respectively.
Blood. 2015;125(22):3484-3490
Nat. Rev. Cardiol. 12, 30–47 (2015)
Offset of action
Clin Med (Lond). 2016 Apr;16(2):152-60
Clin Med (Lond). 2016 Apr;16(2):152-60
Antagonisti recettori GPIIb/IIa
Farmaci che inibiscono un punto chiave sul
quale convergono tutte le vie dell’attivazione
piastrinica
Abiciximab
• (Fab) Si lega irreversibilmente a GPIIb/IIIa (durata
d’azione piu’ lunga della sua breve t½ di 30 min)
• S.e.v. (bolo iniziale, poi infusione continua)
• Riduce aggregazione piastrinica >90% (effetti
rapidi, ma attivita’ piastrinica ripristinata 48 h
dopo cessazione infusione)
Tirofiban
• (non peptide) Si lega reversibil. a GPIIb/IIIa (t½ di 2 h)
• Infusione continua; elimin. renale; aggregazione
riprende piu’ rapidamente che con abiciximab
piastrinica
Abiciximab
• (Fab) Si lega irreversibilmente a GPIIb/IIIa (durata
d’azione piu’ lunga della sua breve t½ di 30 min)
• Riduce aggregazione piastrinica >90% (effetti
rapidi, ma attivita’ piastrinica ripristinata 48 h
dopo cessazione infusione)
Poiche’ la durata d’azione e’
lunga (anche giorni), se si
verifica
un’emorragia
importante o un’emergenza
chirurgica, la trasfusione
piastrinica puo’ annullare
difetto di aggregazione
Tirofiban
• (non peptide) Si lega reversibil. a GPIIb/IIIa (t½ di 2 h)
• Infusione continua; elimin. renale; aggregazione
riprende piu’ rapidamente che con abiciximab
piastrinica
Eptifibatide
• Peptide ciclico inibitore di GPIIb/IIIa (t½ di 2.5 h)
• Eliminazione renale
• Ripristino aggregazione piastrinica entro 6-12 h
da sospensione infusione
Inibitori GP IIb/IIIa (no formulazioni per os perche’ associate a mortalita’):
Mostrano rapidita’ d’azione ed effetti antiaggreganti marcati
Migliorano gli outcomes ischemici in pazienti con ACS sottoposti a PCI
Possibile scelta per pazienti ACS ad alto rischio che si sottop. a PCI (attenenz. a sangu.)
Dipiridamolo
Interferisce con la funzione piastrinica aumentando le concentrazioni di
nucleotidi ciclici (es. cAMP, cGMP) – effetto mediato da inibizione PDE e/o
blocco ricaptazione adenosina che a sua volta attiva recettori A2)
Dipiridamolo
Interferisce con la funzione piastrinica aumentando le concentrazioni di
nucleotidi ciclici (es. cAMP, cGMP) – effetto mediato da inibizione PDE e/o
blocco ricaptazione adenosina che a sua volta attiva recettori A2)
L’assorbimento dopo somministrazione per os richiede un pH acido (attenzione se
concomitanti terapie antiacide)
Per la sua azione vasodilatante puo’ causare ipotensione
Dipiridamolo utilizzato anche come stress farmacologico per la circolazione
coronarica, al fine di individuare un’ischemia miocardica in pazienti che non sono
in grado di effettuare attivita’ fisica (basato su fenomeno del furto coronarico)
Vorapaxar
Selective, potent PAR-1 inhibitor that blocks thrombinmediated platelet activation without interfering with
thrombin-mediated cleavage of fibrinogen
P T. 2011 Sep; 36(9): 564–568.; Nat. Rev. Cardiol. 12, 30–47 (2015)
Vorapaxar
2.5 mg/die indicated for the reduction of thrombotic
cardiovascular events in patients with a history of MI or
with peripheral arterial disease
Must be used in addition to standard-of-care antiplatelet
therapy (aspirin, clopidogrel, or both), because no studies
have investigated vorapaxar monotherapy
Vorapaxar
Marketing authorization EMA (19-01-2015)
Zontivity (vorapaxar), co-administered with acetylsalicylic acid
and, where appropriate, clopidogrel (no data with other P2Y12
antagonists), is indicated for the reduction of atherothrombotic
events in adult patients with a history of myocardial infarction.
Zontivity (2.08 mg/die) should be initiated at least 2 weeks after a MI and preferably
within the first 12 months from the acute event. A delayed onset of action (at least 7
days) should be expected when starting therapy with Zontivity. There are limited data
on the efficacy and safety of Zontivity beyond 24 months.
Vorapaxar
Contraindications
Patients with a history of stroke or TIA
Patients with a history of intracranial haemorrhage
Patients with any active pathological bleeding
Hypersensitivity to the active substance/excipients
Severe hepatic impairment
Vorapaxar
NOTE
Withholding Zontivity for a brief period will not be useful
in preventing or managing an acute bleeding event
because of its long half-life. There is no known
treatment to reverse the antiplatelet effect of Zontivity.
Based on results of pre-clinical studies that investigated bleeding while on
vorapaxar on the background of acetylsalicylic acid and clopidogrel, it may be
possible to restore hemostasis by administering exogenous platelets.
Usi clinici:
• Prevenzione dell’ictus embolico e di TIA
• Prevenzione secondaria dopo infarto miocardico
• Prevenzione dell’infarto miocardico in presenza di
angina o di una malattia vascolare periferica
• Prevenzione primaria della cardiopatia ischemica nei
pazienti con ipertensione che hanno un rischio di
malattia cardiovascolare > 20 % nell’arco di 10 anni
• Inibizione coagulazione nella circolazione extracorporea
• Riduzione complicanze ischemiche da chirurgia vasale
(es. inserimento di stent coronarico)
Clin Ther. 2016, in press
Nat. Rev. Cardiol. 12, 30–47 (2015)
Many TP-receptor antagonists also
exert
an
inhibitory
effect
on
thromboxane A synthase
Despite favourable results in early
phase investigations, the results from
clinical
studies
of
TP-receptor
antagonists so far have been
disappointing
Nat. Rev. Cardiol. 12, 30–47 (2015)
Agenti fibrinolitici
L’efficacia di qualsiasi farmaco fibrinolitico dipende dall’eta’ del trombo (maggiore efficacia contro trombi
recenti) e dalla superficie del trombo esposta al farmaco
L’efficacia di qualsiasi farmaco fibrinolitico dipende dall’eta’ del trombo (maggiore efficacia contro trombi
recenti) e dalla superficie del trombo esposta al farmaco
Ha emivita (≈1 h) piu’ lunga di alteplasi e
reteplase (≈0.5 h), ma simile a tenecteplase
Forme modificate del t-PA, rispetto al quale
mostrano una maggiore durata d’azione
(reteplase, tenecteplase) e una minore
suscettibilita’ ai PAI (tenecteplase)
Farmacocinetica
• Somministrazione i.v. o i.a.
• Plasminogeno-streptokinasi
degradato
sanguigno; streptokinasi libera eliminata
prodotto da precedenti esposizione o
streptococco (Ab possono persistere con
per diversi anni)
nel
circolo
anche da Ab
infezione da
titolo elevato
• Alteplasi e analoghi metabolizzati nel fegato
• Streptokinasi ha un’inizio d’azione + lento (bassa velocita’
di associazione con plasminogeno) rispetto ad alteplasi e
analoghi
Effetti indesiderati
• Emorragia (generalmente lieve ma puo’ essere grave) –
contrastata da antifibrinolitici o trasfusione di plasma
fresco congelato
• Ipotensione (dose dipendente per rilascio di BK); +
frequente con streptokinasi
• Reazioni allergiche; + frequente con streptokinasi
Usi clinici
• Infarto miocardio acuto
• Ictus ischemico
• Tromboembolia arteriosa periferica
• Embolia polmonare o trombosi venosa profonda
Usi clinici
• Streptokinasi di solito utilizzata per infusione breve (1 ora) per
trattamento dell’occlusione coronarica (per occlusioni arteriose
periferiche o per embolismo polmonare possono essere effettuate
infusioni + lunghe)
• Alteplasi (emivita breve) utilizzata per infusione lunga (3-24h); se
obiettivo e’ lisi di un trombo coronarico, e’ necessaria terapia
anticoagulante con eparina per le successuve 48 h (per ridurre
rischio di riocclusione)
• Reteplase somministrato in bolo di due iniezioni a distanza di 90 min,
il tenecteplase come singolo bolo; eparina somministrata anche dopo
reteplase e tenecteplase

NOACs offer equivalent or improved therapeutic profiles compared

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