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RESEARCH ARTICLE

Prasugrel in percutaneous coronary intervention (PIPCI): a single

centre study
2 Matthew Van Wees, Alice Lam, Iouri Banakh
Frankston Hospital, Peninsula Health, Frankston, Australia

No. of pages: 7

CE: Saravanan S
Dispatch: 10.5.16

Background: Prasugrel is a potent antiplatelet agent for use in percutaneous coronary interventions, but it carries a signicant risk
of adverse events.
Aims: The aims of this study were to review the use of prasugrel in a population requiring treatment for acute coronary syndrome
(ACS), review adherence to guidelines, and assess the adverse event (AE) rates associated with its use.
Method: This study was a retrospective single-centre case series conducted at a metropolitan hospital in Victoria, Australia. All
patients who were admitted for treatment intervention for ACS and initiated on prasugrel between July 2011 and April 2013 were
included. The primary outcome was the adherence to international cardiac guidelines and subsidy restrictions. Secondary outcomes
included adherence to guidelines for prasugrel and heparin dosing, rates of concomitant use of glycoprotein IIb/IIIa inhibitors, rates
of AEs and the severity of these according to TRITON-TIMI criteria. Chi-squared testing was conducted using SPSS 19.
Results: Prasugrel was initiated in 79 patients during the study period. Of these patients, 87% were deemed high risk for further
cardiovascular events and the use of prasugrel adhered to international guidelines. Over 10% of patients were started on prasugrel
despite being assessed as high risk for bleeding, with haemorrhages occurring in 29.1% of patients. A signicant proportion of
patients had prasugrel dosing outside the guideline recommendations in relations to age and weight.
Conclusions: The majority of patients initiated on prasugrel conformed to international and national guidelines; however, a high
bleeding rate was observed, which may warrant reviews with larger studies.

PE: Nagappan

Abstract

Address for correspondence: Iouri Banakh, Pharmacy Department, Frankston Hospital, 2 Hastings Road, Victoria 3199, Australia
E-mail: ibanakh@phcn.vic.gov.au

2016 Society of Hospital Pharmacists of Australia

METHODS
Prasugrel in percutaneous coronary intervention (PIPCI)
was a retrospective, single-centre case series study.
Journal of Pharmacy Practice and Research (2016)
doi: 10.1002/jppr.1225

1225

Prasugrel is a potent and irreversible inhibitor of platelet

aggregation via binding to P2Y12 receptors and is indicated for management of coronary artery disease with
percutaneous intervention.1 Compared to other drugs of
the same class, based on clinical trials, prasugrel is associated with higher rates of bleeding, especially when given
to patients with histories of a previous cerebrovascular
accidents (CVA), transient ischaemic attacks (TIA) or cerebral haemorrhages.13 Prasugrel is therefore reserved for
patients at high risk of cardiovascular events with low
haemorrhagic predisposition as recommended by the current guidelines.4 Clinical trials identied that high-risk
patients such as those with histories of diabetes mellitus
beneted most from prasugrel treatment when compared
with the previous standard P2Y12 inhibitor clopidogrel.57

Notwithstanding the bleeding risks, prasugrel has been

approved by the Australian federal government, via the
Pharmaceutical Benets Scheme (PBS) for patients who
have received a percutaneous coronary artery angioplasty
without restriction criteria for other comorbidities.8
Prasugrels haemorrhagic complications that concern
clinicians usually involve, but are not limited to, gastrointestinal bleeding (haematemesis or malena), haematoma formation, complications arising from sheath
removal after the procedure and intracranial haemorrhage.1 Given its potency and high risk for adverse
events (AE)s, a review was carried out on prasugrel use
for acute coronary syndrome (ACS) management at a
single percutaneous coronary intervention (PCI) centre
in Victoria, Australia.

Manuscript No.

INTRODUCTION

J P P R

Keywords: prasugrel, percutaneous coronary intervention, acute coronary syndrome, haemorrhage, safety, treatment.

Journal Code

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Patients included into the study were admitted for management of ACS with PCI and prasugrel initiation by
the primary interventional cardiologists at our hospital
between July 2011 and April 2013. The only exclusion
criterion for this study was preadmission prasugrel use.
Patients were identied and data was collected using
pharmacy dispensing and angiography records if they
had prasugrel initiated while undergoing a coronary
intervention. Discharge prescriptions were also reviewed
by a pharmacist, providing further opportunities to conrm initiation of prasugrel post-angiography rather than
continuing supply from preadmission.

Data Collection
Patients histories were audited via review of digitised
and/or paper copies of medical records stored at the
institutions Health Information Services. Data collected
included:
demographics,
patients
comorbidities,
patients weights, all inpatient haemorrhagic events and
complications, prasugrel dosing for loading and maintenance, use of anticoagulants and other antiplatelet
agents peri-procedurally and at discharge.

Ethics
Prasugrel in percutaneous coronary intervention study
received Human Research Ethics Committee exemption
as the study had no direct patient contact and due to
the audit nature of the study.

End-Points
The primary endpoints for this study were adherence to
current international and national guidelines for prasugrel prescribing for high-risk patients as well as adherence to the PBS subsidisation restrictions.8 The 2013
American College of Chest Physicians/American Heart
Association (ACCP/AHA) guideline for the management
of ST-elevation myocardial infarction4 and the 2012
European Society of Cardiology guidelines for the management of myocardial infarction presenting with STsegment elevation7 clearly dene prasugrels place in
therapy as an alternative to clopidogrel for high-risk
patients, including: clopidogrel-naive patients without
haemorrhagic risk factors, specically those without a
history of previous CVA/TIA, weighing more than 60 kg
and aged below 75 years, with larger myocardial
infarcts or with diabetes mellitus. In order for prescribing to be considered as adhering to the guidelines, highrisk patients were dened as those with pre-existing
major adverse cardiovascular events (MACE), such as

Journal of Pharmacy Practice and Research (2016)

M. Van Wees et al.

acute myocardial infarction (AMI) or stenosis or occlusion of a stent, history of diabetes mellitus or at
increased risk of in-stent thrombosis. Additional risk factors for stent thrombosis such as current smoker status,
diabetes mellitus and previous stent thrombosis were
also recorded.9
To conrm applicability for prasugrel therapy,
patients were conrmed not to have any contraindications to prasugrel treatment as specied in the product
information and treatment guidelines.
To successfully have met PBS approval criteria for
prasugrel subsidisation of both the 10 mg and the 5 mg
strengths, patients were required to have undergone a
PCI for the treatment of ACS, with concurrent aspirin
therapy.8

Safety End-Points
Due to prasugrels haemorrhagic AE prole, a maintenance dose reduction from 10 to 5 mg in patients aged
over 75 years of age or with weight less than 60 kg is
recommended in both the product information and
treatment guidelines.1,4,7 The criteria to determine if a
bleeding AE occurred was adopted from the prasugrel
registration trial, TRITON-TIMI 38.10 There were three
different classications of bleeding: major, minor and
minimal. Major bleeding was dened as an intracranial
haemorrhage, clinically overt bleeding with or without
imaging evidence or a haemoglobin drop of more than
5 g/dL. Additionally, a major bleed had to also meet
any one of the following criteria: hypotension requiring
inotropic support, requiring surgical intervention for
ongoing bleeding, necessitating a transfusion of four or
more units of blood (whole blood or packed red blood
cells) over a 48-h period, or a symptomatic intracranial
haemorrhage. A minor bleed was dened as clinically
overt bleeding with or without imaging evidence and
haemoglobin drop of between 3 and 5 g/dL, while a
minimal bleed was dened as clinically overt bleeding
with or without imaging evidence with a haemoglobin
drop less than 3 g/dL.
Heparin dosing was reviewed to check for adherence
to the guidelines, due to contribution to haemorrhagic
adverse events, with recommended doses of 50
70 units/kg (up to a maximum of 7000 units) when used
with a glycoprotein IIb/IIIa inhibitor or 60100 units/kg
(up to a maximum of 10 000 units) when used without
a glycoprotein IIb/IIIa inhibitor.4
Additional analysis was conducted to compare the
single-centre population and AE rates to that of TRITON-TIMI 38 for safety and population selection purposes.

2016 Society of Hospital Pharmacists of Australia

Prasugrel in percutaneous coronary intervention

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Statistics

Table 1 Patient characteristics

An odds ratio was calculated and v2 test was used to

evaluate the signicance of haemorrhagic outcomes
between populations. SPSS 19 (SPSS Inc., Chicago, IL,
USA) was used for statistical analyses.

Demographics

RESULTS
Over the study period there were 79 patients who met the
inclusion criteria. The median age was 60 years and 75%
of patients were male. Common comorbidities among the
study population included hypertension (53%), hyperlipidaemia (58%) as well as other high risk factors, such as
smoking (35.5%), MACE (21.5%) and diabetes mellitus
(22.8%). See Table 1 for patient characteristics. At least
one risk factor for stent thrombosis was identied in more
than 40% of all patients, with over 20% of patients carrying more than two risk factors (refer to Table 2).
As part of ACS treatment, the majority of the patients
received bare-metal stents during their PCI, 37.9% of
patients received drug-eluting stents, and 11% had more
than one stent inserted. ACS management included glycoprotein IIb/IIIa inhibitor (primarily abciximab) administration in addition to heparin-based anticoagulation in
nearly 25% of the study population. Approximately 95%
of patients received heparin during PCI, but only 20%
had dosage adjustment for their weight as recommended by treatment guidelines. Appropriateness of
heparin dosing could not be determined for 10% of
patients as there were no weights recorded in their medical notes or angiography records.
The majority of patients met the primary end-point of
adherence to the treatment guidelines for prasugrel use,
as well as PBS subsidy restriction. All but one patient
received concurrent prasugrel and aspirin therapies
post-PCI. The patient who did not undergo a PCI when
prasugrel treatment was initiated had the procedure
1 week prior.
While prescribing for the majority of patients adhered
to the treatment guidelines, haemorrhagic AEs were
reached by 29.1% of all patients. Most of these AEs were
mild, with 21% of the bleeding events not requiring
alteration to therapy. Patients who did require treatment
changes had: prasugrel treatment stopped as the bleeding risk was deemed too high (n = 3); addition of other
medications to manage bleeding, including proton pump
inhibitors to control gastrointestinal bleeding (n = 2); or
blood transfusions (n = 1). Three patients were readmitted to hospital to manage haematomas as a bleeding
complication. Only 8.7% of bleeding events were considered minor bleeds, with the remaining 91.3% being
2016 Society of Hospital Pharmacists of Australia

Median age (IQR)

Weight (average, kg)
Gender
Male (%)
Female (%)
Smoking status
Never smoked (%)
Ex-smoker (%)
Currently smoking (%)
Diabetes
No (%)
Yes (%)
Hypertension (%)
Hyperlipidaemia (%)
Previous MI/PCI/CABG (%)
Patients with prior CVA (%)
Type of stent
BMS (%)
DES (%)
Not documented (%)
Use of glycoprotein IIb/IIIa
inhibitor
Received abciximab (%)
Received tiroban (%)
Taking warfarin (%)
Using aspirin concurrently (%)
Underwent PCI (%)
Number of stents inserted
1 (%)
2 or more (%)
Heparin use
Received heparin (%)
Correct dose (%)
Not assessable (%)

PIPCI

TRITON-TIMI 38

60 (53, 67)
82.8

61 (53,69)
NA

74.7
25.3

75
25

32.9
31.6
35.5

NA
NA
38

77.2
22.8
53
58
21.5
1.26

77
23
64
56
18
0

56.9
37.9
5.2
24

48
52
0
54

23
1
7.6
98.7
98.7

NA
NA
0
NA
99

89
11

NA
NA

94.9
20.2
10.1

66
NA
NA

BMS = bare metal stent; CABG = coronary artery bypass graft;

CVA = cerebrovascular accident (including haemorrhagic or
ischaemic stroke, transient ischaemic attack); DES = drug eluting
stent; IQR = interquartile range; MI = myocardial infarction;
PCI = percutaneous coronary intervention.

Table 2 Number of risk factorsa

Number of risk factors

Number of patients (%)

0
1
2
3 or more

14
33
19
13

(17.7)
(41.8)
(24)
(16.5)

Risk factors considered included presence of diabetes, age over

65 years, prior myocardial infarction/coronary artery bypass
graft/percutaneous coronary intervention, previous stent thrombosis and combinations of at least two of the following factors:
active smoking, hyperlipidaemia and/or hypertension.23

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M. Van Wees et al.

classied as minimal bleeding events. No major bleeding

events were identied during the study period.
3 Anticoagulation in addition to DAPT following PCI is
a haemorrhagic risk and 6.3% of our population
received triple therapy with warfarin, aspirin and prasugrel. The bleeding AE rate among patients on dual
antiplatelet therapy of prasugrel with aspirin was 22.7%
(18/73), while in patients on triple therapy including
warfarin, the bleeding rate was 83% (5/6) with an odds
ratio of 15.3, 95% CI 1.67139.5 (p = 0.0157). In the subgroup analysis of bleeding rates, 50% of patients over
75 years of age or under 60 kg suffered a haemorrhagic
event compared to 23% of those patients less than
75 years of age and over 60 kg.
As part of a safety audit it was identied that 88.6% of
patients received prasugrel loading prior to PCI, with the
remainder being loaded with clopidogrel. Over 75% of
patients received a standard daily maintenance dose of
10 mg, with the remainder either receiving the appropriately adjusted dose of 5 mg or maintenance dose that is
not aligned with the current recommendations. Prasugrel
dosing is described in Table 3. A signicant proportion
of patients (8.8%) did not receive the recommended dose
reductions to 5 mg, and one patient was treated with
prasugrel despite a recorded contraindication of prior
CVA. It was also identied that two patients had their
dose adjusted to 5 mg after PCI with no documentation
for the reason behind the adjustment.

DISCUSSION
This study demonstrates that the majority of prasugrel
prescribed at our institution is in-line with the current

Table 3 Prasugrel dosing

Prasugrel dose outcomes

Received prasugrel 60 mg load
Incorrect loading dosea
Received prasugrel 10 mg maintenance
Dose reductions
Over 75 years old, not reduced to 5 mg daily
Under 60 kg, not reduced to 5 mg daily
Wrong dose adjustment under 75 years old
Prasugrel used after CVA

Number of
patients (%)
70 (88.6)
9 (11.4)
62 (78.5)
3
4
2
1

(3.8)
(5)
(2.5)
(1.3)

CVA = cerebrovascular accident (incl. haemorrhagic or ischaemic

stroke, transient ischaemic attack).
a
Incorrect loading dose included loading twice with prasugrel,
loading with both prasugrel and clopidogrel, omitting a loading
dose of prasugrel.

Journal of Pharmacy Practice and Research (2016)

national and international guidelines, and there was also

a high level of adherence to the PBS restrictions. During
the study period only one patient did not qualify for
subsidy as the patient required warfarin therapy on initiation of prasugrel, with aspirin cessation. However,
this patient on dual therapy with warfarin developed a
haematoma approximately 1 month later, necessitating
the cessation of prasugrel and the use of aspirin as the
alternative antiplatelet treatment. The recorded AEs
from this study showed that 29% of patients had haemorrhages with 9% of these being minor bleeds and the
remaining 91% as minimal bleeds. Three patients
required readmission for haematoma formation following initiation of prasugrel. No major or fatal bleeds
occurred during the study period. In other aspects, the
PIPCI study population was representative and comparable to that of the TRITON-TIMI 38 trial population for
median age 60 versus 61, female gender 25.3% versus
25%, diabetes 22.8% versus 23% and smoking history
35.5% versus 38%, respectively. The one difference of
importance between the study populations is that fewer
patients were treated at our institution with glycoprotein IIb/IIIa inhibitors, which may be reective of local
guidelines, greater use of other anticoagulants in TRITON-TIMI 38 such as bivalirudin and low molecular
weight heparins or perhaps lower-risk patients (Table 4). 4
As in TRITON-TIMI 38, safety has emerged as a signicant issue, with a dose reduction from 10 mg maintenance to 5 mg in patients aged over 75 years of age or
weight less than 60 kg recommended in the product
information based on pharmacokinetic data only at the
time of this study. Recently, evidence from the TRILOGY
ACS trial conrmed that a dose reduction is appropriate
in these patient groups.11 PIPCI subgroup analysis of 5
bleeding rates indicated that patients at higher risk of
haemorrhagic AEs from prasugrel had a 50% AE rate,
while the lower-risk group of patients, younger than
75 years of age and over 60 kg, had a 23% AE rate.
These results for haemorrhagic AEs are higher than that

Table 4 Adverse events

Adverse event

Number of patients (%)

Haematemesis
Haematoma
Ooze/bleed from wound site
Patients who had alterations to
therapy due to above bleedinga

3
13
7
5

(3.8)
(16.5)
(8.9)
(6.3)

a
Alterations to therapy include cessation of the drug, addition
of another medication (e.g. proton pump inhibitor) to control
bleeding.

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reported from the registration trial, where the high-risk

subgroup had a 9.7% rate of minimal bleeds, and the
lower-risk group had an 8.3% rate of bleeding.11 Given
the evidence specifying the need for dose adjustment in
such populations and the contraindications for patients
with histories of CVA/TIA, it was identied that 12.6%
of patients either received a dose of prasugrel that did
not meet the recommendations or received prasugrel
when deemed inappropriate according to the prescribing information and harmful by ACCP/AHA guidelines.4 In this case series only one patient was prescribed
prasugrel with a history of CVA, which is lower than
the results of a larger audit of prasugrel usage, where
13.9% of patients received prasugrel despite a history of
CVA.12 In a separate audit of prasugrel use, between 6
and 10% of patients were inappropriately initiated and
discharged on the P2Y12 inhibitor.13
Beyond the maintenance dose adjustments, the decision on whether or not to load a patient with a second
antiplatelet agent when switching between agents is an
area of uncertainty. The PIPCI population had 10% of
patients either loaded with both clopidogrel and prasugrel, with no clear documentation for the duplication, or
received no loading dose of the second agent but a
switch of P2Y12 inhibitor for maintenance therapy. One
patient was loaded twice with prasugrel despite a
recorded AE of haematemesis. Recent pharmacokinetic
studies indicate that when swapping from clopidogrel
to prasugrel after a 600 mg clopidogrel loading dose,
30 mg of prasugrel is sufcient to suppress platelet reactivity to a similar level of a 60 mg prasugrel loading
dose.14 This antiplatelet loading strategy was not followed during our study period and may have contributed to AE development. However, there is currently
a lack of prospective data regarding the clinical efcacy
of this approach.
In addition to uncertainty in antiplatelet loading
strategies, triple therapy with inclusion of anticoagulant
has emerged as an important safety issue. Despite the
small numbers included in our study, which is lower
compared to 15.4% in other reviews,12 the results indicate that there is a signicant increase in bleeding rates
among patients using warfarin with prasugrel; hence
there is a need to determine if the combination of warfarin and prasugrel has a place in therapy. Patients who
required warfarin were excluded from the TRITONTIMI 38 trial.10 As age is a major risk factor for atrial
brillation and ACS, the need for combination therapy
and the challenge of balancing risk of thrombosis versus
the risk of bleeding will rise with the aging population.
The WOEST trial compared triple therapy (aspirin,
clopidogrel and warfarin) to dual therapy (clopidogrel
and warfarin) in patients post-stent insertion.15 This
2016 Society of Hospital Pharmacists of Australia

study found lower bleeding rates in the dual therapy

group compared to triple therapy and it identied that
patients treated with dual therapy alone had lower allcause mortality; however, this study was not powered
to detect these differences. In another prospective study
of triple therapy with prasugrel or clopidogrel, the prasugrel arm had signicantly higher rates of minor or
major bleeding (adjusted hazards ratio: 3.2, 95% CI: 1.1
9.1) with no therapeutic benet.16 There have also been
case reports of fatal bleeding associated with prasugrel
triple therapy.17 More recent studies have identied that
triple therapy, especially among the elderly, as a major
clinical issue18 due to haemorrhagic AE and our study
adds to the data.
Additionally, data regarding the co-administration of
prasugrel with the new oral anticoagulants such as dabigatran and the factor Xa inhibitors are required, given
the increasing utilisation of these medications with
improved safety prole relative to warfarin in atrial a
brillation population. The addition of rivaroxaban to
aspirin following non-ST-segment elevation myocardial
infarction has survival benets and evidence shows lowdose rivaroxaban has survival benets in ACS patients
as demonstrated in the ATLAS ACS-2 TIMI-51 study.19
Prasugrel on the other hand is more likely to be harmful
as indicated by the more recent TRANSLATE-ACS
study with prasugrel triple therapy compared to clopidogrel triple therapy in ACS and atrial brillation
patients.20
Another safety signal identied during the PIPCI
study is that only 20% of patients had their heparin
dosage adjusted for body weight and glycoprotein IIb/
IIIa inhibitor use. This potentially could have contributed to the increase in bleeding rates for minimal
bleeds when compared to TRITON-TIMI 38. Activated
clotting time (ACT) was not recorded, due to the poor
correlation between ACT and bleeding.21 Previous studies have shown that the dosing of heparin is often above
that recommended in guidelines prior to PCI and is a
potential target for further quality improvement initiatives.22 However, due to the study design, no analysis
on heparin dosing and bleeding rates was done.
This study indicates that the Australian experience
with prasugrel may mirror that seen internationally,
warranting further investigation at other institutions that
have prasugrel available on their formulary for ACS
management. However, this study was limited by the
small number of patients included in the study despite
the period covered. Furthermore, there is a lack of
power for statistical analysis to be applied to the results.
This study was also limited by the incomplete recording
in patients histories as evident by missing data. Therefore, the study ndings need to be conrmed with
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larger studies and until then can only be considered as

hypothesis raising of safety issues identied.

CONCLUSION
Prasugrel was prescribed in accordance with national
and international guidelines, as well as PBS restrictions
for the majority of patients during the study period. Prasugrel loading dose approaches when switching
between antiplatelet agents was identied as a practice
issue in the study. The safety prole of prasugrel was
also identied to be signicantly different to that quoted
in the trial data used to gain approval for the medication in terms of minimal bleeding. However, as the
study was limited by size and period, further audits of
prasugrel use at PCI-capable centres is warranted before
considering changes to clinical practice.

Competing Interests
None declared.

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Received: 28 October 2015
Revised version received: 12 April 2016
Accepted: 13 April 2016

Journal of Pharmacy Practice and Research (2016)

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