Keywords
acute coronary syndrome - treatment modifications - ticagrelor
Introduction
Patients presenting with acute coronary syndrome (ACS) are frequently treated with
potent P2Y12-inhibitors, such as ticagrelor.[1] Ticagrelor reversibly binds to the P2Y12-receptor and as a result prevents platelet activation and aggregation.[2] The antiplatelet activity of ticagrelor is not reliant on metabolic activation and
ticagrelor therefore has a more rapid and predictable effect compared with clopidogrel.[3] In the double-blind, randomized Platelet Inhibition and Patient Outcomes (PLATO)
trial, ticagrelor significantly reduced the composite of cardiovascular death, myocardial
infarction (MI), or stroke compared with clopidogrel in patients presenting with ACS.[4] Ever since, ACS patients are frequently treated with ticagrelor on top of aspirin
(i.e., dual antiplatelet therapy [DAPT]) for at least 12 months.[1] However, not all patients tolerate ticagrelor. Common side effects include bleeding
and dyspnea, and although these side effects are usually mild and transient, some
patients require treatment modification within 12 months.[5] Clinical reasons and underlying context for treatment modification are heterogeneous,
and it is unclear what, if any, excess cardiovascular risk can be attributed to these
modifications. Previous studies have mostly classified patients using a binary, on-versus-off
treatment approach, whereas differentiation in type and reason for modification might
be important.[6]
[7] Therefore, using real-world data from the FORCE-ACS registry, our study aimed to
examine (1) the incidence of, (2) reasons for, and (3) clinical implications of treatment
modifications in patients discharged on ticagrelor.
Methods
Study Design and Patient Population
The rationale and design of the FORCE-ACS registry have been described previously.[8] In short, the FORCE-ACS registry is an ongoing prospective registry of nine Dutch
hospitals. The primary aim of the registry is to provide insight into different aspects
of the diagnosis, management, and follow-up of patients with ACS. From 2015 onward,
all consecutive adult patients admitted for (suspected) ACS were eligible for participation.
For the present study, all patients who were discharged with an active ticagrelor
prescription after their initial hospital admission were included. Patients were treated
with ticagrelor 90 mg twice daily following a loading dose of 180 mg in line with
current guidelines.[1] The institutional review boards of the participating centers approved the protocol
of the FORCE-ACS registry, and written informed consent was obtained from each patient.
The present study complies with the principles of the Declaration of Helsinki and
reports according to the STrengthening the Reporting of OBservational studies in Epidemiology
statement.[9]
Definitions
Treatment modifications were classified as discontinuation, alteration, interruption,
or disruption. For discontinuation, interruption and disruption definitions previously
set out by Mehran et al in the patterns of nonadherence to antiplatelet regimens in
stented patients (PARIS) registry were used.[6] Hence, discontinuation was defined as physician-recommended withdrawal of ticagrelor
for patients thought to no longer need ticagrelor. Alteration was defined as a switch
from ticagrelor to clopidogrel or prasugrel. Interruption was defined as temporary
cessation of ticagrelor, for example, due to surgical necessity, with planned reinstitution
within 14 days and disruption was defined as cessation of ticagrelor treatment due
to bleeding or noncompliance. The primary ischemic endpoint was time till the first
occurrence of all-cause death, MI, or stroke. MI and stroke were included in the primary
ischemic endpoint regardless of etiology. MI was classified according to the 4th universal definition of MI, which includes stent thrombosis (MI type 4b).[10]
Follow-up
Treatment modifications and clinical events were reported via questionnaires at 1
and 12 months after hospital admission. If patients did not complete the questionnaires,
they were contacted by phone. Additionally, the electronic health records of all patients
were checked. In case of treatment modification and/or a clinical event, relevant
source document was collected and patients were asked to provide information about
the date of and reason for treatment modification. Information regarding treatment
modification was corroborated by prescription data reported by the pharmacy. Treatment
modifications and clinical events were reviewed and adjudicated by the first two authors
who had full access to the patient's electronic health record.
Statistical Analysis
Continuous variables were reported as mean ± standard deviation or median with interquartile
range (IQR) as appropriate and categorical variables were reported as frequencies
and percentages. Patient characteristics were compared by modification status using
an independent t-test for continuous variables and a chi-square test or a Fisher's exact test for
categorical variables using patients without treatment modification as a reference.
Since patients could have more than one type of treatment modification, patients were
grouped according to the most severe type of modification (disruption was considered
the most severe type of modification followed by interruption, alteration, and discontinuation).
Clinical implications of treatment modifications were assessed using the Cox regression
models using time-updated modification variables as independent variable. The patient's
follow-up time was broken into time periods spent in each modification type based
on the previously described hierarchy (i.e., patients were only reclassified if a
more severe treatment modification occurred). All models were adjusted for the following
potential confounders: age, sex, initial diagnosis (i.e., unstable angina, non-ST-segment
elevation myocardial infarction [NSTEMI] or ST-segment elevation myocardial infarction
[STEMI]), revascularization during initial hospital admission (i.e., percutaneous
coronary intervention [PCI] or coronary artery bypass grafting [CABG]) and presence
of at least one concomitant chronic disease (i.e., diabetes, atrial fibrillation,
chronic kidney disease, chronic obstructive pulmonary disease, or peripheral artery
disease). Potential confounders were selected based on literature, clinical judgement,
and availability during hospital admission. In case of treatment modification on the
same day as an ischemic event, the model took into account the exact moment of treatment
modification (i.e., before or after the ischemic event). Results are presented as
hazard ratio (HR) with corresponding 95% confidence interval (CI) per modification
type. Significance was set at a p-value of <0.05. Statistical analyses were performed using SPSS version 28 (SPSS Inc.,
Chicago, Illinois, United States) and illustrative graphics were composed using GraphPad
Prism version 8.3 (GraphPad Software, San Diego, California, United States).
Results
Patient Characteristics
From January 2015 until December 2020, 8,029 patients were included in the FORCE-ACS
registry. Patients who were ultimately not diagnosed with ACS (n = 886) or who did not survive the index hospital admission (n = 148) were excluded. In total, 4,387 out of 6,995 patients (62.7%) were discharged
on ticagrelor, whereas 2,076 patients (29.7%) were treated with clopidogrel, 42 patients
(0.6%) with prasugrel, and 490 patients (7.0%) without a P2Y12-inhibitor. Patients (n = 109) who did not complete 12 months of follow-up were excluded. Hence, 4,278 patients
were included in the present analysis. A detailed flowchart is provided in [Fig. 1].
Fig. 1 Flowchart. ACS, acute coronary syndrome.
The mean age at time of enrollment was 63.6 ± 11.5 years and 26.1% of patients were
female ([Table 1]). Overall, 5.2, 46.4, and 48.5% of patients were diagnosed with unstable angina,
NSTEMI and STEMI, respectively. Almost all patients (98.3%) underwent coronary angiography
during initial hospital admission and 80.1 and 7.3% of patients subsequently underwent
PCI or CABG ([Table 2]). Per design, all patients included in the present analysis were treated with ticagrelor
at time of discharge, whereas 98.0% of these patients were also treated with aspirin.
Moreover, 76.0, 78.1, and 95.6% of patients were treated with a β-blocker, an angiotensin-converting
enzyme inhibitor or angiotensin receptor blocker and at least one cholesterol-lowering
drug (e.g., statin, ezetimibe, or a PSCK9-inhibitor). Based on the PRECISE-DAPT and
DAPT scores, 19.7 and 41.4% of patients were considered at high bleeding risk (defined
as a PRECISE-DAPT score ≥ 25) and high ischemic risk (defined as a DAPT score ≥ 2),
respectively.
Table 1
Baseline characteristics of patients with and without treatment modification
|
No modification
|
Discontinuation
|
Alteration
|
Interruption
|
Disruption
|
|
n = 2,312
|
n = 910
|
p-Value
|
n = 814
|
p-Value
|
n = 111
|
p-Value
|
n = 131
|
p-Value
|
|
Age (y)
|
62.6 ± 11.5
|
64.0 ± 11.6
|
<0.01
|
64.9 ± 11.2
|
<0.01
|
67.0 ± 11.0
|
<0.01
|
66.8 ± 11.8
|
<0.01
|
|
Body mass index (kg/m2)[a]
|
27.6 ± 4.4
|
27.2 ± 4.3
|
0.02
|
27.8 ± 4.8
|
0.28
|
27.6 ± 4.0
|
0.89
|
27.9 ± 4.4
|
0.53
|
|
Female sex (%)
|
559 (24.2%)
|
230 (25.3%)
|
0.52
|
250 (30.7%)
|
<0.01
|
27 (24.3%)
|
0.97
|
49 (37.4%)
|
<0.01
|
|
Current or former smokers (%)
|
1,403 (60.7%)
|
539 (59.3%)
|
0.46
|
519 (63.8%)
|
0.03
|
72 (64.8%)
|
0.16
|
85 (64.8%)
|
0.05
|
|
Hypertension (%)
|
1,127 (48.7%)
|
420 (46.2%)
|
<0.01
|
420 (51.6%)
|
0.37
|
67 (60.4%)
|
0.04
|
74 (56.5%)
|
0.23
|
|
Hyperlipidemia (%)
|
1,191 (51.5%)
|
450 (49.6%)
|
0.02
|
436 (53.6%)
|
0.46
|
57 (51.4%)
|
0.99
|
74 (56.5%)
|
0.13
|
|
Diabetes mellitus (%)
|
387 (16.7%)
|
123 (13.5%)
|
0.02
|
159 (19.6%)
|
0.12
|
33 (29.7%)
|
<0.01
|
25 (19.1%)
|
0.57
|
|
Chronic kidney disease (%)[b]
|
274 (11.9%)
|
117 (12.9%)
|
0.43
|
116 (14.3%)
|
0.08
|
21 (18.9%)
|
0.03
|
16 (12.2%)
|
0.90
|
|
COPD
|
136 (5.9%)
|
52 (5.7%)
|
0.86
|
61 (7.5%)
|
0.10
|
14 (12.6%)
|
<0.01
|
13 (9.9%)
|
0.06
|
|
Peripheral artery disease
|
102 (4.4%)
|
33 (3.6%)
|
0.32
|
58 (7.1%)
|
<0.01
|
12 (10.8%)
|
<0.01
|
9 (6.9%)
|
0.19
|
|
Atrial fibrillation (%)
|
30 (1.3%)
|
11 (1.2%)
|
0.84
|
21 (2.6%)
|
0.01
|
1 (0.9%)
|
0.72
|
3 (2.3%)
|
0.34
|
|
Prior stroke or TIA (%)
|
112 (4.8%)
|
43 (4.7%)
|
0.89
|
61 (7.5%)
|
<0.01
|
7 (6.3%)
|
0.47
|
7 (5.3%)
|
0.80
|
|
Prior MI (%)
|
386 (16.8%)
|
125 (13.7%)
|
0.04
|
163 (20.0%)
|
0.03
|
25 (22.9%)
|
0.10
|
28 (21.5%)
|
0.16
|
|
Prior PCI (%)
|
386 (16.8%)
|
132 (14.6%)
|
0.12
|
175 (21.6)
|
<0.01
|
29 (26.4%)
|
<0.01
|
26 (20.0%)
|
0.34
|
|
Prior CABG (%)
|
106 (4.6%)
|
29 (3.2%)
|
0.08
|
62 (7.6%)
|
<0.01
|
10 (9.0%)
|
0.03
|
8 (6.1%)
|
0.42
|
|
Cardiac arrest at admission (%)
|
98 (4.2%)
|
31 (3.4%)
|
0.55
|
17 (2.1%)
|
0.02
|
3 (2.7%)
|
0.68
|
3 (2.3%)
|
0.51
|
|
Killip class (%)
I
II
III
IV
|
2,094 (90.7%)
163 (7.1%)
5 (0.2%)
22 (1.0%)
|
831 (91.8%)
57 (6.3%)
0 (0.0%)
9 (1.0%)
|
0.60
|
731 (89.9%)
63 (7.7%)
2 (0.2%)
5 (0.6%)
|
0.69
|
93 (83.8%)
15 (13.5%)
0 (0.0%)
2 (1.8%)
|
0.39
|
118 (90.1%)
9 (6.9%)
0 (0.0%)
1 (0.8%)
|
0.28
|
|
Clinical diagnosis (%)
Unstable angina
NSTEMI
STEMI
|
103 (4.5%)
1,027 (44.4%)
1,182 (51.1%)
|
35 (3.8%)
414 (45.5%)
461 (50.7%)
|
0.68
|
59 (7.2%)
408 (50.1%)
347 (42.6%)
|
<0.01
|
12 (10.8%)
61 (55.0%)
38 (34.2%)
|
<0.01
|
12 (9.2%)
73 (55.7%)
46 (35.1%)
|
<0.01
|
|
PRECISE-DAPT score ≥ 25 (%)
|
402 (17.4%)
|
208 (22.9%)
|
<0.01
|
167 (20.5%)
|
0.05
|
29 (26.1%)
|
0.02
|
38 (29.0%)
|
<0.01
|
|
DAPT score ≥ 2 (%)
|
1,013 (43.8%)
|
335 (36.8%)
|
<0.01
|
334 (41.0%)
|
0.15
|
47 (42.3%)
|
0.67
|
42 (32.1%)
|
0.01
|
Abbreviations: CABG, coronary artery bypass grafting; COPD, chronic obstructive pulmonary
disease; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction;
PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction;
TIA, transient ischemic attack.
Note: Values are presented as mean ± standard deviation or number of patients (%).
a Body mass index was missing in 237 cases (5.5%).
b Chronic kidney disease was defined as a glomerular filtration rate < 60 mL/min/1.73 m2.
Table 2
In-hospital management of patients with and without treatment modification
|
No modification
|
Discontinuation
|
Alteration
|
Interruption
|
Disruption
|
|
n = 2,312
|
n = 910
|
p-Value
|
n = 814
|
p-Value
|
n = 111
|
p-Value
|
n = 131
|
p-Value
|
|
Coronary angiography (%)
|
2,281 (98.7%)
|
888 (97.6%)
|
0.03
|
805 (98.9%)
|
0.61
|
109 (98.2%)
|
0.66
|
122 (93.1%)
|
<0.01
|
|
PCI (%)
|
1,945 (84.6%)
|
683 (75.1%)
|
<0.01
|
645 (79.2%)
|
<0.01
|
82 (74.5%)
|
<0.01
|
71 (55.9%)
|
<0.01
|
|
CABG (%)
|
148 (6.4%)
|
77 (8.5%)
|
0.04
|
57 (7.0%)
|
0.55
|
11 (10.0%)
|
0.14
|
18 (13.7%)
|
<0.01
|
|
Aspirin (%)
|
2,270 (98.2%)
|
892 (98.0%)
|
0.76
|
794 (97.5%)
|
0.26
|
109 (98.2%)
|
0.99
|
127 (96.9%)
|
0.31
|
|
Oral anticoagulants (%)
|
57 (2.5%)
|
29 (3.2%)
|
0.25
|
25 (3.1%)
|
0.35
|
3 (2.7%)
|
0.88
|
5 (3.8%)
|
0.34
|
|
Beta-blocker (%)
|
1,784 (77.2%)
|
681 (74.8%)
|
0.16
|
606 (74.4%)
|
0.12
|
87 (78.4%)
|
0.77
|
95 (72.5%)
|
0.22
|
|
ACE-inhibitor or ARB (%)
|
1,835 (79.4%)
|
712 (78.2%)
|
0.48
|
621 (76.3%)
|
0.07
|
82 (73.9%)
|
0.16
|
93 (71.0%)
|
0.02
|
|
Cholesterol lowering-drugs (%)
|
2,214 (95.8%)
|
867 (95.3%)
|
0.54
|
779 (95.7%)
|
0.94
|
109 (98.2%)
|
0.21
|
120 (91.6%)
|
0.03
|
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker;
CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.
Note: Values are presented as number of patients (%).
Treatment Modifications
The cumulative incidence of treatment modifications during the first 12 months of
follow-up is shown in [Fig. 2]. Reasons for treatment modification are shown in [Fig. 3]. Most treatment modifications were physician-recommended discontinuation of ticagrelor
after the intended treatment duration was completed (26.7%). Median time until discontinuation
was 357 days (IQR: 298–365). Rates for alteration, interruption, and disruption were
20.1, 2.8, and 3.1%, respectively. Alteration most often occurred before 6 months
(median time until alteration 73 days [IQR 38–149]) and common reasons were dyspnea
(47.2%), other side effects (15.8%), and a new indication for oral anticoagulation
(8.3%). Alteration due to bleeding (7.6%) or new ischemic events (0.8%) was less common.
Most patients with an alteration due to bleeding switched from ticagrelor to clopidogrel
(98.6%) and only 1.4% to prasugrel. Patients with an alteration for other reasons
switched to clopidogrel and prasugrel in 80.6% and 19.4% of cases, respectively. Interruption
was primarily due to surgical necessity (71.1%). The most common reasons for disruption
were bleeding (52.2%) and dyspnea (17.9%). Interruption and disruption most frequently
occurred between 6 and 12 months after initial hospital admission. Most patients (38.4%)
had only one treatment modification during follow-up, and 324 patients (7.6%) had
two or more modifications.
Fig. 2 Cumulative incidence of treatment modification. Note that individual patients could
have more than one type of treatment modification.
Fig. 3 Underlying reasons for treatment modification. Note that individual patients could
have more than one type of treatment modification. Sample size (n) refers to number of individual patients for each type of modification.
Clinical Implications of Modification
The overall incidence of ischemic events was 6.6% (n = 284) at 12 months of follow-up. Incidences of the individual components of the
primary ischemic endpoint were 1.9% (n = 81) for all-cause death, 4.2% (n = 181) for MI, and 0.9% (n = 38) for stroke. The incidence of cardiovascular death was 1.0% (n = 43). In total, 57 out of 284 events (20.1% of all events) occurred after one or
more treatment modification, so most events (79.9% of all events) occurred while patients
were still on uninterrupted ticagrelor therapy. Estimated risk associations for the
different types of treatment modification are shown in [Fig. 4]. Physician-recommended discontinuation (adjusted HR: 0.62, 95% CI: 0.25–1.54, p = 0.31) and alteration (adjusted HR: 1.23, 95% CI: 0.85–1.78, p = 0.26) were not associated with a difference in ischemic events. Conversely, interruption
was associated with an increased risk of ischemic events (adjusted HR: 2.93, 95% CI:
1.48–5.79, p < 0.01). Similarly, disruption was also associated with an increased risk of ischemic
events (adjusted HR: 2.33, 95% CI: 1.07–5.07, p = 0.03).
Fig. 4 Clinical implications of treatment modification. Values are presented as adjusted
hazard ratios (HRs) and corresponding 95% confidence interval (CI) for (A) ischemic events defined as all-cause death, myocardial infarction, and stroke, (B) all-cause death, (C) myocardial infarction, and (D) stroke. *There were no patients who had a stroke after disruption, and therefore,
no HR could be calculated.
Discussion
The most important findings of the study are as follows: (1) treatment modifications
are common within 12 months of follow-up, especially physician-recommended discontinuation
and alteration, (2) reasons for treatment modification depend on the type of modification,
and (3) treatment interruption and disruption are associated with excess cardiovascular
risk. These findings reaffirm the clinical relevance of treatment modifications in
patients discharged on ticagrelor and provide novel insights into the interaction
between type of modification and cardiovascular risk.
In line with previous studies, our study demonstrated that treatment modifications
are common within the first 12 months following hospital admission for ACS. Pooled
data from randomized controlled trials evaluating the efficacy and safety of ticagrelor
showed premature discontinuation or nonadherence in up to 25% of the 66,870 included
patients.[11] Commonly cited reasons for discontinuation or nonadherence were bleeding and dyspnea,
but the exact type and implications of treatment modification were not specified.
In the PARIS registry, which enrolled 5,031 patients undergoing PCI between 2009 and
2010, the rates of physician-recommended discontinuation, interruption, and disruption
were 11.5, 4.6, and 9.8% at 12 months of follow-up. Notably, the rate of discontinuation
was much lower compared with the rate in our cohort (26.7% at 12 months), even though
more than half of all patients in the PARIS registry presented with chronic coronary
syndrome instead of ACS. Possibly, physicians continued DAPT due to concerns of late
and very late stent thrombosis, which occurred more often in the era of first-generation
drug-eluting stents.[12]
[13] However, in the PARIS registry discontinuation was associated with a significantly
lower rate of major adverse cardiovascular events defined as the composite of cardiac
death, definite or probable stent thrombosis, MI, or target lesion revascularization.[6] Importantly, the PARIS investigators argued that this does not imply causal inference
between physician-recommended discontinuation and subsequent cardiac risk. This phenomenon
is more likely due to appropriate discontinuation of antiplatelet therapy in patients
at relatively low risk of ischemic events, which is supported by our finding that
the percentage of patients with predicted low ischemic risk was lower in patients
who discontinued ticagrelor within 12 months compared with patients without treatment
modification. In our study, most patients discontinued ticagrelor (almost) 12 months
after initial hospital admission and discontinuation was not associated with an increase
(or reduction) in ischemic risk.
In the Treatment With ADP Receptor Inhibitors: Longitudinal Assessment of Treatment
Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) registry, 28.3%
of patients discharged on ticagrelor after PCI for MI switched to clopidogrel (87.5%)
or prasugrel (12.5%) after a median of 50 days.[14] In contrast to our findings, the most cited reason for treatment alteration was
socioeconomic (i.e., out-of-pocket costs). The incidence of ischemic events in the
30 days after treatment alteration was low, but only 226 out of 8,672 patients included
in the TRANSLATE-ACS registry were discharged on ticagrelor, limiting statistical
power to examine the association between alteration and ischemic events. Interestingly,
most patients in our cohort were switched to clopidogrel and not to prasugrel, even
though bleeding was a relatively infrequent reason for alteration. Prasugrel has a
potent inhibitory effect on platelet aggregation and therefore is an alternative to
ticagrelor without concerns of a trade-off in efficacy.[15] Pharmacodynamic studies have suggested that switching from ticagrelor to clopidogrel
is associated with an increase in platelet reactivity, but this has not translated
into an increased ischemic risk in studies examining treatment alteration or de-escalation
usually after a short period of ticagrelor therapy.[16] In fact, some studies have even suggested that planned guided (i.e., based on CYP2C19
genotyping) or unguided de-escalation from ticagrelor to clopidogrel is noninferior
to standard treatment with ticagrelor with respect to ischemic events and results
in a lower incidence of bleeding.[17]
[18] However, whether this should be the preferred strategy for patients requiring unplanned
(e.g., due to side-effects) alteration remains unclear. In general, it is important
to counsel patients regarding common side-effects of ticagrelor both at time of discharge
and during follow-up.[11] More specifically, patients should be reassured that ticagrelor-induced dyspnea
is not associated with compromised cardiac or pulmonary function.[5]
Temporary treatment interruption was almost always due to surgical necessity in our
study. Previous studies have reported that 4 to 9% of patients undergo noncardiac
surgery within 12 months of PCI and/or ACS hospitalization.[19]
[20] These patients have an increased risk of ischemic events following surgery compared
with patients without underlying cardiovascular disease.[21] A comprehensive meta-analysis of observational studies including over 50,000 patients
indicated that interruption of antiplatelet therapy before noncardiac surgery reduced
the risk of reoperation for major bleeding by more than 50%, but interruption of antiplatelet
therapy is also an important predictor of ischemic events following surgery.[22] A retrospective single-center study previously reported that 2.7% of patients interrupt
or discontinue ticagrelor due to planned major surgery, which is in line with the
incidence (2.8% at 12 months) observed in our cohort.[23] However, observational studies have yielded conflicting results in terms of the
excess cardiovascular risk associated with treatment interruption. For example, in
the PARIS registry, there was no association between interruption and subsequent ischemic
events. Importantly, in the PARIS registry more than half of all interruptions happened
between 12 and 24 months when the risk of ischemic events, especially stent-related
events, is relatively low. In our study, interruption was associated with an almost
3-fold increase in ischemic risk at 12 months of follow-up. Our findings therefore
support current guideline recommendations to delay elective surgery until 12 months
after ACS if possible.[24]
Disruption due to bleeding or noncompliance has previously been associated to a substantial
increase in ischemic risk. Previous studies have demonstrated that this increased
risk is highest directly following treatment disruption and attenuates over time.[6] It was not possible to assess the temporal effects of disruption in our cohort due
to the limited number of events. Given that bleeding was the most important reason
for disruption, strategies to mitigate bleeding are of the utmost importance. This
includes early identification of patients at high bleeding risk, routine consideration
of proton pump inhibitor therapy and minimal use of bleeding prone drugs, such as
nonsteroidal anti-inflammatory drugs.[25]
In recent years, P2Y12-inhibitor monotherapy after a short course of DAPT has emerged as an promising treatment
strategy following ACS.[26] Ticagrelor seems to be the agent of choice in most cases, due to its reliable effect
on platelet reactivity and its predominant use in clinical trials evaluating P2Y12-inhibitor monotherapy.[27] Future studies will need to address what the clinical impact of treatment modifications
are in patients treated with P2Y12-inhibitor monotherapy instead of DAPT.
Limitations
This study has several important limitations. First, 2.5% of patients were lost to
follow-up. In theory, this could have resulted in selection bias. However, this group
only forms a small proportion of the total study population. Second, treatment modifications
were primarily self-reported and therefore subjected to recall bias, although electronic
health records and pharmacy prescription logs were also used to corroborate information
regarding treatment modification. Third, a statistically significant association between
several types of treatment modifications and clinical outcomes as seen in this study
does not imply causality. For example, it is unclear if the excess risk associated
with interruption or disruption can be attributed to these treatment modifications
or (at least in part) should be attributed to other factors, such as comorbidities
or procedural factors (e.g., for patients undergoing surgery). Finally, patients included
in the present study were exclusively treated with ticagrelor; therefore, results
should not be generalized to patients treated with other P2Y12-inhibitors.
Conclusion
In clinical practice, treatment modifications in ACS patients discharged on ticagrelor
are common, although type and reasons for modification are heterogeneous. Treatment
interruption and disruption are associated with excess cardiovascular risk and, although
causality cannot be implied from our study, these types of modification should preferably
only occur under strict supervision or be avoided altogether.
What is known about this Topic?
-
Patients presenting with acute coronary syndrome are frequently treated with potent
P2Y12-inhibitors, such as ticagrelor.
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Some patients require treatment modification within 12 months, but clinical reasons
and underlying context for treatment modification are heterogeneous and it is unclear
what, if any, excess cardiovascular risk can be attributed to these modifications.
What does this Paper Add?
-
Treatment modifications in acute coronary syndrome patients discharged on ticagrelor
are common within 12 months of follow-up, especially physician recommended discontinuation
and alteration.
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Treatment interruption and disruption are associated with excess cardiovascular risk
and should therefore only occur under strict supervision or be avoided altogether.
