European Heart Journal Supplements (2018) 20 (Supplement B), B1–B9

The Heart of the Matter

doi:10.1093/eurheartj/sux041

Bleeding on dual antiplatelet therapy: real-life

challenges

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Niteen V. Deshpande, Parag Admane, and Harshawardhan M. Mardikar*
Spandan Heart Institute and Research Center, 31, Off Chitale Marg, Dhantoli, Nagpur 440012, India

Dual antiplatelet therapy (DAPT) is recommended for pa- variable such as age, creatinine clearance, haemoglobin,
tients presenting with acute coronary syndromes and white-blood cell count, and previous spontaneous bleed-
patients undergoing coronary angioplasty with drug eluting ing.6 Although there are no established norms for personal-
stent implantation to prevent ischaemic recurrences.1 The izing DAPT, use of this score in conjunction with the
advocated duration of DAPT for both these conditions is knowledge of coronary anatomy and the clinical condition
1 year after the initial event. Standard DAPT includes a may help in choosing appropriate therapy and its duration.7
P2Y12 inhibitor either Clopidogrel, Prasugrel, or Ticagrelor We describe four case scenarios to highlight the bleeding is-
in addition to aspirin. Due to inconsistent platelet inhibi- sues related to DAPTand therapeutic decisions about inter-
tion observed with clopidogrel, most of the centres today ruption/continuation of antiplatelet agents in patients
use either Prasugrel or Ticagrelor as preferred P2Y12 an- who suffer bleeding episode while receiving DAPT.
tagonist. Platelet inhibition observed with these two
agents is more consistent and stronger as compared with
clopidogrel. However, DAPT carries a risk of bleeding while Case 1
offering protection against ischaemic events like stent
A 62-year-old gentleman presented with acute anterior
thrombosis.2 Since bleeding on DAPT is as an independent
wall myocardial infarction at a peripheral centre with chest
predictor of long-term outcome, it is important to identify
pain of 4 h duration. He was known case of Type 2 DM and
patients who are at risk of bleeding. The recognized factors
hypertension taking regular therapy for past 6 years. On ad-
contributing to increased bleeding risk include advanced
mission, his pulse rate was 116/min and blood pressure was
age >75 years, prior history of bleeding, heart failure, pe-
100/70 mmHg. He had bi-basal crepitations and resting
ripheral artery disease, hypertension, abnormal renal, or
oxygen saturation was 94%. He was immediately thrombo-
liver function and prior stroke. Other contributory factors
lysed with injection TNK-tPA (40 mg) following 60 mg of
include chronic steroid use, smoking, alcohol abuse, anae-
enoxaparin (30 mg subcutaneous and 30 mg IV). He also re-
mia, and malignancy.3 The incidence of bleeding reported
ceived loading dose of Aspirin 325 mg and Ticagrelor
in ADAPT-DES registry was 6.2% at median time of 300 days
180 mg. He was shifted after 6 h to our centre for further
following discharge.4 It is also known that almost two-
management due to ongoing angina and borderline haemo-
thirds of the bleeding episodes occur from the gastrointes-
dynamics. On admission to our centre (12 h following
tinal (GI) tract. Overall GI bleeding is estimated to occur in
thrombolysis), he was maintaining blood pressure of 90/
1.2–2.4% patients undergoing coronary interventions.
70 mmHg, and his heart rate was 130/min. He had exten-
Identifying patients at higher bleeding risk prior to coro-
sive crepitations and oxygen saturation was 88%. His elec-
nary intervention can help in reducing the occurrence of
trocardiogram (ECG) showed persistent ST elevations in
bleeding complications. The DAPT study developed a risk
anterior leads (Figure 1) and bedside echo showed akinetic
score to identify patients at higher risk of bleeding if DAPT
anterior wall, hypokinetic lateral wall with left ventricular
is continued beyond 1 year.5 This score can be applied to
ejection fraction of 25%. In view of failed thrombolysis, he
patients who have tolerated DAPT up to 1 year following
was considered for rescue angioplasty. Patient was intu-
the initial event. Identifying patients at risk of bleeding at
bated and put on mechanical ventilation, inotropes were
the initiation of DAPTcan now be done using PRECISE-DAPT
started, and he was shifted to cath lab for insertion of in-
score, which is a simple score calculated from five simple
tra-aortic balloon pump (IABP) and PTCA. Prior to shifting
ICCU resident attempted to introduce Ryles’ tube after
*Corresponding author. Tel: þ91 712 2443333, Fax: þ91 712 2542436, endo-tracheal intubation unsuccessfully. His coronary angio
Email: drmardikar@cadindia.co.in done following IABP insertion revealed critical distal left

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C The Author(s) 2018.

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B2
Figure 1 Electrocardiogram on admission showing persistent ST elevation in anterior leads.
Figure 2 Coronary angiogram showing critical distal left main stenosis involving ostia of left anterior descending and left circumflex artery both (A) re-
sult after coronary angioplasty (B).
main stenosis involving origins of left anterior descending
(LAD) and left circumflex artery (Figure 2A), which was
treated with bifurcation stenting (Figure 2B). Patient re-
ceived a bolus dose of unfractionated heparin 5000 IU be-
fore PTCA. ACT at the end of the procedure was 286.
Profuse nasal bleeding was noted at towards end of the pro-
cedure. Local compression for prolonged period did not
stop the bleed and an ENT surgeon was called in the cath
lab for management who managed the nasal bleed with na-
sal packs and prolonged compression. Since there was no
recurrence of the nasal bleed during ICU stay patient was
continued of Aspirin and Ticagrelor. He had stable post-
procedure course and was extubated after 24 h and IABP
was weaned off 12 h later. Patient had uneventful subse-
quent course in hospital and was discharged on fifth day
following PTCA. The medications at discharge included
Aspirin, Ticagrelor, Atorvastatin, Ramipril, Metoprolol,
Frusemide, and Spironolactone. His PRECISE-DAPT score
calculated from the pre-discharge parameters was 17 indi-
cating a low-risk of bleeding and more benefit from DAPT
for 12 months than shorter DAPT of 3–6 months on the
ischaemic endpoints (Figure 3).
He consulted physician after 3 weeks with history of
melena for 4 days, easy fatigability. His haemoglobin (Hb)
N.V. Deshpande et al.
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was 7.2 g% (pre-discharge Hb was 11.4 g%) while other in-
vestigations were normal. He was diagnosed as severe
anaemia secondary to GI bleeding, was transfused 2 units
of packed red blood cells and was referred back for further
evaluation. His haemoglobin on admission was 9.8 g% and
stool examination for occult blood was negative. Liver
function test showed normal liver parameters and INR was
normal. His serum creatinine had increased to 1.7 mg%
form a pre-discharge value of 1.1 mg% and urine examina-
tion was non-contributory. He was subjected to upper GI
endoscopy, which was suggestive of a small gastric ulcer.
The ulcer was treated using injection therapy. Patient was
observed for 48 h for fresh bleeding and was discharged on
DAPT in view of recent left main stenting.
Case Discussion
This patient experience bleeding episodes twice within
1 month of myocardial infarction. First episode of nasal
bleeding was most probably related to local trauma due to
attempts of pushing Ryles’ tube in a patients who had re-
ceived thrombolytic, low-molecular weight heparin, and
Ticagrelor loading dose 12 h prior. The ESC 2017 STEMI
Bleeding on dual antiplatelet therapy: real-life challenges
Figure 3 Calculated PRECISE-DAPT score.
guidelines suggest use of potent P2Y12 inhibitors
(Prasugrel, Ticagrelor) only after 48 h in patients receiving
thrombolytic therapy and undergoing PCI. This recommen-
dation is made due to lack of data on use of these potent
P2Y12 inhibitors along with fibrinolytic therapy in first
48 h.8 A combination of thrombolytic, heparin, and potent
P2Y12 inhibitors is considered to have higher risk of bleed-
ing in early phase of myocardial infarction by the experts
constituting the guidelines committee and hence the DAPT
with thrombolysis should be combination of aspirin and clo-
pidogrel. Patient may be switched to either of the potent
agents after 48 h.
GI bleeding of DAPT is an important issue especially in
the first 3 months as interruption of DAPT during this period
may increase chances of stent thrombosis. The best course
of action should include aggressive search for the source of
bleeding and definitive treatment of the cause as was done
in this case. Once the bleeding ulcer is treated, continua-
tion of DAPT becomes easier preventing chances of sub-
acute stent thrombosis. However these patients need
careful monitoring and frequent follow-up to ensure that
there is no fresh bleeding.9 Long-term use of proton pump
inhibitors is safe and offers protection from further GI
bleeding in such patients.
Case 2
A 48-year-old diabetic, hypothyroid male with recent acute
coronary syndrome with single-vessel disease with fair left
ventricular (LV) systolic function underwent coronary an-
gioplasty to LAD with one DES implantation (Figure 4). He
was discharged with DAPT comprising of Aspirin 75 mg OD,
Ticagrelor 90 mg BID, and ACE inhibitor, Beta blockers, and
high intensity statins in addition to his oral hypoglycaemic
agents. He was not prescribed with any antacid or proton
pump inhibitor on long-term. The PRECISE-DAPT score
B3
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calculated for this patient was very low, which suggested
benefit of continued DAPT for 12 months (Figure 5).
He was doing well till 9 months of procedure when he
came back with history of malena. On examination patient
was afebrile, Pulse 86/min, regular, blood pressure 120/
80 mmHg, RR 16/min, SPO2 99% in room air, CVS S1, S2 nor-
mal, no murmur, RS Clear, P/A Soft, liver spleen not palpa-
ble, CNS conscious oriented, no focal neurodeficit. His
haemoglobin was 7.6 g% (PCV was 28), which had decreased
from earlier level of 12.4 g% done at the 6 month follow-up.
His ECG showed deep symmetrical Twave inversion in leads
V1–V6 without any fresh changes (Figure 6). His KFT, LFT,
and coagulation profile is normal. His stool examination for
occult blood was positive. Patient underwent upper GI en-
doscopy, which showed duodenal ulcer (Figure 7). He
underwent injection therapy and hemoclip application.
Since the patient had single-vessel disease treated with sec-
ond generation DES, and he had no ischaemic recurrence in
9 months following angioplasty, his DAPT was stopped. He
was discharged on clopidogrel monotherapy (75 mg OD)
along with proton pump inhibitors, while other background
medications were continued.
Case Discussion
This patient of single-vessel disease was treated with sec-
ond generation DES and tolerated DAPT for 9 months when
he presented with bleeding due to duodenal ulcer. He had
no ischaemic recurrence in 9 months. Although the initial
intended duration of DAPT was 1 year, he was switched to
clopidogrel monotherapy10 after the duodenal ulcer was
treated. Studies in healthy human volunteers have shown
that unlike aspirin, clopidogrel does not induce macro-
scopic changes in gastric mucosa.11 However, clopidogrel
monotherapy has been shown to result in more bleeding re-
currences than aspirin therapy combined with PPI in clini-
cal studies.12 This is believed to be the result of impaired
B4 N.V. Deshpande et al.

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Figure 4 Coronary angiogram showing critical proximal left anterior descending lesion (A) and left circumflex artery after stent implantation (B).

Figure 5 Calculated PRECISE-DAPT score.

Figure 6 Electrocardiogram showing deep symmetric T wave inversion in anterior chest leads.
Bleeding on dual antiplatelet therapy: real-life challenges B5

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Figure 7 Endoscopy showing duodenal ulcer (A) and hemoclip application (B).

Figure 8 Coronary angiogram showing long segment left anterior descending lesion (A), left anterior descending after coronary stenting (B), critical
proximal right coronary artery lesion (C), and right coronary artery following stenting (D).

ulcer healing with clopidogrel.13 We switched this patient
to clopidogrel monotherapy at 9 months along with PPI as
he was still within 12 months of coronary angioplasty need-
ing stronger antiplatelet effect.
Case 3
A 72-year-old male presented with Troponin positive acute
coronary syndrome. He was a known case of hypertension
for past 16 years and was on regular medications. After
medical stabilization he underwent coronary angiography,
which revealed double vessel disease. Left anterior de-
scending artery had a long lesion, and he had a critical right
coronary artery stenosis. He was treated with coronary an-
gioplasty (two overlapping DES in LAD and one DES in right
coronary artery (RCA), Figure 8). His hospital course was
uneventful and was discharged on DAPT consisting of
Aspirin 75 mg OD and Ticagrelor 90 mg BD in addition to
Telmisartan 80 mg OD, Cilnidipine 20 mg BD, Metoprolol
50 mg OD, Atorvastatin 40 mg OD, and isosorbide
Mononitrate 20 mg BD. His blood pressure was maintained
at 140/84 mm of Hg with the above combination of
B6
Figure 9 Electrocardiogram showing T wave inversion in lead V2 to V4 (same as earlier electrocardiogram).
Figure 10 Coronary angiogram showing critical mid right coronary artery lesion (A) and right coronary artery after coronary stenting (B).
antihypertensives and was in regular follow-up of his physi-
cian for subsequent 4 months.
He presented with sudden onset bleeding through his
nose and mouth after 4 month and was brought to emer-
gency department. His blood pressure had increased to
200/110 mmHg and pulse rate was 106/min. His chest was
clear and there were no fresh ECG changes (Figure 9). A
provisional diagnosis of accelerated hypertension with epi-
staxis was made and he was hospitalized for control of hy-
pertension and observation for bleeding. Hypertension was
controlled with intravenous nitroglycerine and additional
dose of sublingual nifedipine. He also received cold com-
pression for epistaxis which controlled the nasal bleed. A
subsequent endoscopy did not reveal any local lesion in the
nose or nasopharynx, and he was advised to continue DAPT.
Case Discussion
Epistaxis in hypertensive patients is related to accelerated
hypertension and the treatment focuses on better control
of blood pressure. DAPT need not be interrupted for epi-
staxis as it can expose the patient to risk of stent thrombo-
sis. This patient has overlapping stents in LAD and another
DES in RCA. Interruption of DAPT in such patients could be
N.V. Deshpande et al.
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dangerous and thus DAPT consisting of aspirin and
Ticagrelor was continued. His antihypertensive therapy
was adjusted through frequent follow-up visits. Despite of
continuation of DAPT he did not have repeat episodes of
epistaxis over follow-up of 1 year.
Case 4
A 68 years lady, known case of Type 2 DM with hypertension
with exertional angina with double vessel disease with nor-
mal LV function underwent coronary angioplasty to RCA
with DES implantation (Figure 10). She was discharged with
Aspirin 75 mg OD, Prasugrel 10 mg OD and statin, ARB, and
beta-blocker. She was already put on clopidogrel 1 month
prior to PTCA for worsening angina by her physician.
Platelet function assay was done on the day of angioplasty
showed inadequate platelet inhibition (Figure 11), and
hence she was given loading dose of prasugrel and contin-
ued with it following PTCA. Her PRECISE-DAPT score was
high (Figure 12) which suggested increased risk of bleeding
with longer DAPT (>6 month) as compared to shorter DAPT
(3–6 months) Hence DAPTwas planned for 6 months for her.
She presented after 3 months of PTCA, with complaints
of generalized weakness, easy fatigability. No history of
Bleeding on dual antiplatelet therapy: real-life challenges
chest pain, breathlessness, palpitation. She denied any his-
tory of haematemesis or malena. On examination patient
was afebrile, pulse 70/min, regular, blood pressure
140/80 mmHg, SPO2 96% in room air, CVS S1, S2 normal, no
Figure 11 Platelet function assay showing inadequate platelet inhibi-
tion with clopidogrel.
Figure 12 Calculated PRECISE-DAPT score.
B7
murmur, RS clear, P/A soft, liver spleen not palpable, CNS
conscious oriented, no focal neuro deficit. ECG did not
show any new changes (Figure 13). Her haemoglobin was
8.6 g%, peripheral smear showed microcytic, hypochromic
RBC. Her stool for occult blood was positive while other in-
vestigations like renal function test, liver function test,
and coagulation profile was normal. In view of anaemia and
presence of occult blood in stools, she was advised upper
GI endoscopy which revealed diffuse erosive gastritis
(Figure 14). She also tested positive for Helicobacter py-
lori. She was treated with intravenous proton pump inhibi-
tors for 48 h along with treatment for pylori infection and
DAPT was withheld for 48 h. She was advised to continue
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oral PPI’s for long-term. Since she had undergone PTCA
3 months earlier, although with a second generation DES,
we decided to continue her DAPT for at least 6 months. Her
P2Y12 inhibitor was changed from prasugrel to clopidogrel
and low dose aspirin (75 mg) was continued along with clo-
pidogrel. The patients did well and had no recurrence of
bleeding over following 3 months.
Case Discussion
Gastric erosions are known with aspirin therapy and can
lead to significant GI blood loss. Use of PPI in patients con-
sidered to be a higher risk of bleeding has been shown to re-
duce chances of bleeding and should be considered along
with DAPT in suitable patients.14 This patient was receiving
DAPT and was not on PPI at the time of presentation.
Interruption of Aspirin therapy following GI bleed helps in
reducing bleeding recurrence but causes more deaths due
to cardiovascular causes. Further, discontinuation of DAPT
in the early post-intervention phase may increase ischae-
mic recurrences significantly leading to increased mortal-
ity. Recurrent bleeding due to aspirin therapy is rarely a
life threatening issue and consideration must be prevention
of ischaemic recurrences which can jeopardize life.
B8 N.V. Deshpande et al.

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Figure 13 Unremarkable electrocardiogram changes.

While converting from the DAPT to aspirin monotherapy at

the end of intended DAPT duration, long-term use of PPI is
important in reducing recurrent bleeding. Clopidogrel
monotherapy instead of aspirin has not been shown to re-
duce bleeding recurrences in small studies, but can be con-
sidered for patients who are intolerant to aspirin.

Conflict of interest: none declared.

References
Figure 14 Endoscopy showing diffuse erosive gastritis.
Continuation of DAPT for at least 6 months was considered
necessary with possible extension to 1 year and hence
DAPTwas continued. Clopidogrel was added instead of pra-
sugrel, which is shown to result in more bleeding
complications as compared with clopidogrel. Patient was
followed up closely for next 3 months with frequent moni-
toring of haemoglobin, which did not indicate a significant
fresh GI blood loss and in-fact she was advised to continue
DAPT consisting of aspirin and clopidogrel for next
6 months.
DAPT significantly reduces ischaemic complications at
the cost of increased risk of bleeding. Careful assessment
of patients prior to instituting DAPT can help decreasing
bleeding and scores like PRECISE-DAPT can be used to as-
sess the bleeding risk. Bleeding through the GI tract is most
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tality in these patients. Most of the GI bleeding episodes
are not life threatening and hence withholding DAPT is not
advocated. Duration of DAPT in patients with history of
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