Kardiologia Polska 2016; 74, 1: 61–67; DOI: 10.5603/KP.a2015.0117
ISSN 0022–9032
ARTYKUŁ ORYGINALNY / ORIGINAL ARTICLE
Prediction of high risk of non-adherence
to antiplatelet treatment
Aldona Kubica1, Karolina Obońska2, 3, Michał Kasprzak2, 3, Beata Sztuba4, Eliano Pio Navarese3,
Marek Koziński5, Iwona Świątkiewicz3, Magdalena Kieszkowska3, Małgorzata Ostrowska5,
Grzegorz Grześk2, Jacek Kubica3
1
Department of Health Promotion, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
2
Department of Pharmacology and Therapy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
3
Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
4
National Health Found, Bydgoszcz, Poland
5
Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
Abstract
Background: Dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel is the standard of care for secondary
prevention. Premature discontinuation of clopidogrel is associated with an increased risk of myocardial infarction (MI) or
death, and greater health care expenditure.
Aim: To develop an objective method for identification of patients with high risk of non-adherence to clopidogrel after MI.
Methods: A total of 189 patients were enrolled into a prospective, observational, single-centre study with a nine-month
follow-up. Patients received a 600-mg loading dose and 75-mg maintenance dose of clopidogrel in combination with ASA
doses of 300 mg and 75 mg, respectively. Adenosine diposphate-induced platelet aggregation (ADP-PA) was assessed during
baseline hospitalisation and at three, six, and nine months after discharge. Adherence to medication with clopidogrel was
defined as the proportion of drug availability based on data from the National Health Fund regarding prescribed drug purchases. Adherence was arbitrarily judged adequate when the proportion exceeded 80%.
Results: According to our hypothesis, ADP-PA in non-adherent patients should be higher at follow-up visits (at least once) as
compared with measurement at hospitalisation. Based on the ROC curve analysis, the optimal cut-off point equal to 4 U was
defined (p < 0.0001, 95% CI 0.562–0.654; sensitivity: 60.6%, specificity: 57.1%, positive predictive value: 63.3%, negative
predictive value: 54.2%). The prevalence of true adherence to medication in groups of high and low probability of adherence
defined according to developed criteria amounted 60 (50.8%) and 23 (32.4%) cases, respectively (p = 0.01).
Conclusions: The newly developed method of objective identification of patients with high risk of non-adherence to clopidogrel after MI is easily applicable and cheap, and, despite relatively low sensitivity and specificity, it efficiently differentiates
patients with regard to clinical end-points during follow-up.
Key words: clopidogrel, ADP-induced platelet aggregation, adherence to medication
Kardiol Pol 2016; 74, 1: 61–67
INTRODUCTION
Dual antiplatelet therapy (DAT) with acetylsalicylic acid (ASA)
and clopidogrel reduces the risk of thrombotic events and is
recommended in the management of patients with acute coronary syndromes (ACS) and in patients after stent implantation
[1, 2]. Premature discontinuation of clopidogrel, shown to be
associated with an increased risk of myocardial infarction (MI)
or death, and greater health care expenditure [3–5], remains
one of the concerns regarding this therapy. Patients identified to have a high risk of non-adherence to clopidogrel may
benefit from additional educational interventions aimed at
improvement of adherence to clopidogrel instead of instan-
Address for correspondence:
Małgorzata Ostrowska, MD, PhD, Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, ul. Marii Skłodowskiej-Curie 9,
85–094 Bydgoszcz, Poland, e-mail: ostrowska.go@gmail.com
Received: 08.01.2015
Accepted: 07.05.2015
Available as AoP: 18.06.2015
Kardiologia Polska Copyright © Polskie Towarzystwo Kardiologiczne 2016
www.kardiologiapolska.pl
Aldona Kubica et al.
taneous switching to newer P2Y12 inhibitors. Unfortunately,
non-adherence to treatment with clopidogrel remains common and difficult to detect due to often misleading patient
declarations [6–9].
Despite DAT, platelet activation usually achieves its
highest level early after ACS due to inflammation and plaque
rupture [10]. Several other biological factors, including
diabetes and genetic polymorphism of CYP2C19 enzyme,
have a more stable impact on response to clopidogrel during
hospitalisation and follow-up [11–13]. Thus, we hypothesised
that after exclusion of drug–drug interactions, it is mainly patients’ non-adherence to medication that leads to clopidogrel
therapy failure resulting in insufficient inhibition of platelet
aggregation [13, 14].
The aim of the study was to develop an objective method
for identification of patients with high risk of non-adherence
to clopidogrel after MI.
METHODS
Study design and patient characteristics
Two hundred consecutive patients treated with primary percutaneous coronary intervention (pPCI) for acute MI, who
gave their informed, written consent, were initially enrolled
into this prospective, observational, single-centre study
with a 12-month clinical follow-up. The study population
comprised 189 patients for whom data from at least one
follow-up visit were available. Clinical follow-up was carried
out on the basis of data derived from the National Health
Fund. Patients received a 600-mg loading dose and 75-mg
maintenance dose of clopidogrel in combination with ASA
doses of 300 mg and 75 mg, respectively. To avoid additional
confounding factors, concomitant therapy was standardised
and included bisoprolol, perindopril, and simvastatin if no
contraindications were present. When therapy with a proton
pump inhibitor was indicated, only pantoprazole was allowed
because no interaction between this drug and clopidogrel has
been revealed [13]. Patients requiring any additional treatment
were excluded due to potential drug–drug interactions. All
patients were informed regarding the need for systematic
intake of prescribed drugs and the dangers of their premature
termination. Study population characteristics are displayed
in Table 1. Follow-up visits were scheduled at three, six, and
nine months after discharge.
Patients’ adherence to the medication regimen was assessed based on data from the National Health Fund regarding
the purchase of prescribed drugs. Adherence was defined as
the proportion of drug availability (the number of purchased
clopidogrel tablets) to drug requirement (the number of clopidogrel tablets needed to complete the treatment = number
of follow-up days). Following previously published studies
[15–18], adherence was arbitrarily judged adequate when
the proportion exceeded 80%.
62
Table 1. Study population characteristics (n = 189)
Feature
Median (upper quartile–
–lower quartile) or no. (%)
Male
141 (74.6%)
Age [years]
60.0 (53.0–67.0)
Height [cm]
169.9 (164.0–176.0)
Body mass [kg]
80.0 (70.0–90.0)
Waist [cm]
96.0 (89.0–103.5)
BMI > 25 kg/m2
140 (74.1%)
Hypertension
104 (55.0%)
Diabetes
61 (32.3%)
Smokers
98 (51.9%)
LDL ≥ 115 mg/dL
141 (74.6%)
Extent of CAD:
1-vessel disease
80 (42.3%)
2-vessel disease
48 (25.4%)
3-vessel disease
61 (32.3%)
Baseline coronary flow:
TIMI 0
82 (43.4%)
TIMI 1
18 (9.5%)
TIMI 2
20 (10.6%)
TIMI 3
69 (36.5%)
Post-PCI coronary flow:
TIMI 0
0 (0%)
TIMI 1
1 (0.5%)
TIMI 2
4 (2.1%)
TIMI 3
184 (97.4%)
Number of stents:
1
133 (70.4%)
2
38 (20.1%)
≥3
18 (9.5%)
Total length of stents [mm]
24.0 (15.0–32.0)
CAD — coronary artery disease; BMI — body mass index; LDL — low
density lipoprotein; PCI — percutaneous coronary intervention
The study protocol was approved by the Ethical Committee of Nicolaus Copernicus University.
Platelet function assessment
Adenosine diphosphate induced platelet aggregation (ADP-PA)
was assessed during baseline hospitalisation and at every
follow-up visit. Blood samples were collected at 10:00 a.m.
for impedance aggregometry. Whole blood was tested with
impedance aggregometry using a Multiplate Analyser (Medical
Cyclotron, Munich, Germany). The analyser detects the impedance change related to platelet adherence onto the sensor
wires, and transforms it into arbitrary aggregation units (AU)
that are plotted against time. The area under the aggregation
curve (AUC) is an estimator of platelet aggregation displayed in
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Adherence to antiplatelet treatment
Table 2. Adherence to medication with clopidogrel with regard to results of adenosine diphosphate induced platelet aggregation
(ADP-PA) measurements at follow-up visits
Quartiles
Adherence [%]*
P
I (n = 120)
II (n = 128)
III (n = 120)
IV (n = 134)
ADP-PA < 11
11 ≤ ADP-PA < 19
19 ≤ ADP-PA ≥ 29
ADP-PA ≥ 29
84.4 (47.5–92.1)
88.2 (53.7–99.7)
84.4 (35.7–99.7)
76.7 (32.4–99.7)
0.15
*Range of patients’ adherence to the medication regimen defined as the proportion of drug availability (the number of purchased clopidogrel
tablets) to drug requirement (the number of clopidogrel tablets needed to complete the treatment = number of follow-up days)
arbitrary units (10 AU × min = 1 U). Examination of ADP-PA
was used to reflect the effect of P2Y12 receptor inhibition by
clopidogrel active metabolite.
According to our hypothesis, patients non-adherent to
clopidogrel have higher ADP-PA at follow-up visit (at least
once) as compared with ADP-PA assessed during hospitalisation [18]. Receiver operating characteristics (ROC) curve
analysis was used to determine cut-off points defining patients
with high risk of non-adherence. The DeLong method was
applied for evaluation of the significance of the area under
the ROC curves. We compared the prevalence of adverse
clinical events in patients divided into groups according to
the risk of non-adherence to clopidogrel during follow-up
visits. ADP-PA ≤ 45 U at follow-up visit was arbitrarily defined
as a borderline value of adequate response to clopidogrel
according to previously performed research [19].
Statistical analysis
According to the Shapiro-Wilk test, the investigated continuous variables were non-normally distributed; therefore, they
were reported as medians and interquartile ranges (IQR). For
comparisons between two and three groups, the Mann-Whitney unpaired rank sum test and the Kruskal-Wallis one-way
analysis of variance were used, respectively. Categorical variables were expressed as the number of patients presenting the
given feature and the percentage of patients in the analysed
group. Categorical variables were compared using the c2 test
with the Yates’ correction if required. The Cochran-Armitage
test was used to assess the presence of linear trends among
categorical variables. Differences were considered significant
at p < 0.05. The statistical analysis was carried out using the
Statistica 10.0 package (StatSoft, Tulsa, USA).
RESULTS
Of 189 patients, 177 (93.7%) declared regular intake of
clopidogrel during all follow-up visits. According to self-declarations, only 12 (6.3%) patients were non-adherent to antiplatelet treatment at least once, while according to the data
from the National Health Fund the number of such patients
was 84 (46.7%).
According to ADP-PA assessment, an overall number
of 45 cases of insufficient response to clopidogrel (> 45 U)
were revealed during follow-up visits in 36 patients, while
in the remaining 153 patients (457 measurements) ADP-PA
was ≤ 45 U. Adherence to clopidogrel in both groups
amounted to 52.8% (30.7–100.0%) and 84.4% (47.5–99.7%),
respectively (p = 0.13). The prevalence of patients defined
as non-adherent to medication with clopidogrel (drug availability ≤ 80%) was not significantly different in both groups
(55.6% vs. 41.2%; p = 0.09). No significant difference regarding clinical end-points between the groups was found (STEMI
0% vs. 4.6%, p = 0.41; ACS 11.1% vs. 7.2%, p = 0.66;
unscheduled cardiac hospitalisation 27.8% vs. 14.4%,
p = 0.054). The results of ADP-PA measurements obtained
during follow-up visits did not reflect adherence to medication
(Table 2). However, the curves reflecting changes of ADP-PA
during the study period in patients adherent to clopidogrel
(drug availability > 80%) and those who were non-adherent
(drug availability ≤ 80%) suggest an increasing rate of non-adherence to clopidogrel at the end of follow-up (Figs. 1, 2).
According to our hypothesis, ADP-PA in non-adherent
patients should be higher at follow-up visits (at least once)
as compared to measurements taken at hospitalisation [20].
Using the drug availability proportion as the reference, a ROC
curve analysis was performed to determine ADP-PA cut-off
points defining patients at high risk of non-adherence. The
area under the curve was 0.609 (p < 0.0001); 95% confidence interval (CI) 0.562–0.654; positive predictive value:
63.3%; negative predictive value: 54.2%; and the optimal
cut-off point was identified at 4 U. According to this definition, a difference in ADP-PA between hospitalisation and
any of the follow-up visits of more than 4 U is associated
with high risk of non-adherence to clopidogrel (≤ 80% drug
availability) with a sensitivity of 60.6% and a specificity of
57.1%, identifying the non-adherence (N-A) group (n = 118).
The remaining 71 patients, who were supposed to be adherent to antiplatelet medication, constituted the adherence
(A) group (Table 3). Drug availability in group A was higher
(p = 0.04) as compared with group N-A, 92.1% (53.7–99.7%)
vs. 76.7% (32.4–96.1%), respectively. As a consequence, the
prevalence of patients defined as adherent to medication
with clopidogrel was 60 (50.8%) in group A and 23 (32.4%)
in group N-A (p = 0.01). The developed definition was tested
as a clinical differentiation tool, with the following clinical
end-points being evaluated: cardiovascular death, acute MI,
any ACS, and unscheduled cardiac hospitalisation (Table 3).
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Aldona Kubica et al.
Figure 1. Results of adenosine diphosphate-induced platelet
aggregation (ADP-PA) evaluation in adherence group
Figure 2. Results of adenosine diphosphate-induced platelet
aggregation (ADP-PA) evaluation in not-adherence group
Table 3. Prevalence of clinical end-points in patients with high risk of non-adherence to medication with clopidogrel (N-A group)
as compared with low risk of non-adherence patients (A group)
Clinical end-points
N-A group (n = 118)
A-group (n = 71)
P
0 (0%
0 (0%)
–
5 (4.2%)
2 (2.8%)
0.91
Acute coronary syndrome
13 (11.0%)
2 (2.8%)
0.044
Unscheduled cardiac hospitalisation
25 (21.2%)
7 (9.9%)
0.04
Cardiovascular death
Acute myocardial infarction
DISCUSSION
Antiplatelet therapy is the cornerstone of treatment for patients
with ACS and/or those undergoing PCI. The pharmacodynamic response to clopidogrel shows substantial inter-patient variability, and patients with coronary disease and lesser platelet
inhibition in response to clopidogrel appear to be at increased
risk of cardiovascular events [3, 11]. Genetic factors, accelerated platelet turnover, up-regulation of the P2Y12 pathways,
high baseline platelet reactivity, poor adherence to medication, under-dosing, and drug–drug interactions play important
roles in the antiplatelet effect of clopidogrel [12, 21, 22].
All mechanisms of ineffective platelet inhibition, except for
non-adherence to medication, can be overcome by replacing
clopidogrel with newer P2Y12 inhibitors [23]. Thus, identification of patients who do not follow doctors’ recommendations
is pivotal [24]. Poor adherence to medication is probably
the major cause of clopidogrel “resistance” [25]. Despite the
importance of secondary prevention, non-adherence rates
for patients with MI range from 13% to 60% for prescribed,
evidence-based medicines [4, 7, 8, 26, 27]. However, it is
difficult to prove without additional confirmatory measures
that the drug has not been administered. Kronish et al. [28]
used an electronic chip stored in the pill bottle cap for this
purpose. Detection of plasma levels of unchanged clopidogrel,
64
an active thiol metabolite, and inactive carboxyl metabolite
was tested by Serebruany et al. [6] as an objective method
of patient-adherence assessment. They revealed that plasma
inactive carboxyl metabolite, but not unchanged clopidogrel,
or active thiol metabolite are useful markers to monitor
compliance to clopidogrel. However, these methods cannot
be used in everyday practice [6, 28]. Other simple methods
based on patients’ declarations or monitoring of drug prescription purchases are ineffective due to low credibility or the
need for long observation periods. Single measurements of
P2Y12 receptor inhibition may also not reflect adherence due
to the multifactorial mechanism of the patient’s responsiveness
to clopidogrel [29]. However, we hypothesised that patient
non-adherence to DAT is the strongest factor that may increase
platelet activity during the follow-up period above the level
observed during the acute phase. Based on this hypothesis,
we tried to develop an objective identification method for
patients with high risk of non-adherence to clopidogrel after
MI. According to the ROC curve analysis, ADP-PA during any
follow-up visit > 4 U, as compared with the initial in-hospital
assessment, is associated with high risk of non-adherence
to clopidogrel. The relatively low sensitivity and specificity
indicates that this is not the best tool to differentiate patients
with regard to adherence to medication. Nevertheless, we
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Adherence to antiplatelet treatment
have proven the clinical usefulness of the developed definition with regard to study population differentiation according
to clinical end-points. The prevalence of ACSs was almost
four-fold higher, and unscheduled cardiac hospitalisation was
more than two-fold more frequent in patients at high risk of
non-adherence to clopidogrel.
Limitations of the study
The current analysis has several potential limitations. First,
our study was a single-centre and relatively small research
project. Therefore, the generalisability of our findings is uncertain. Second, drug availability does not necessarily reflect
its actual intake. This methodological limitation, however,
should be initially taken into account at choice-making regarding approaches to be used for evaluation of adherence
to medication. Third, despite relatively high reproducibility
and precision of the multiplate analyser [30], the difference of
4 U between assessment during hospitalisation and follow-up
visit is low. Thus, any result of ADP-PA evaluation during any
follow-up visit higher than at baseline suggests a possibility of
non-adherence to medication with clopidogrel. Our study also
has several strengths, including the high follow-up attendance
with clinical and platelet aggregation assessment.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
CONCLUSIONS
In conclusion, this study demonstrated a newly developed
method of objective identification of patients at high risk of
non-adherence to clopidogrel after MI. The method is easily
applicable and cheap, and, despite its relatively low sensitivity
and specificity, it efficiently differentiates patients with regard
to clinical end-points during follow-up.
16.
17.
Acknowledgements
The study was supported by scientific grant No. 202 from
Nicolaus Copernicus University.
18.
Conflict of interest: none declared
References
1.
2.
3.
4.
5.
Wijns W, Kolh P, Danchin N et al. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and
the European Association for Cardio-Thoracic Surgery (EACTS);
European Association for Percutaneous Cardiovascular Interventions (EAPCI), Guidelines on myocardial revascularization. Eur
Heart J, 2010; 31: 2501–2555. doi: 10.1093/eurheartj/ehq277.
Kubica J. The optimal antiplatelet treatment in emergency setting.
Folia Med Copernicana, 2014; 2: 73–76.
Campo G, Fileti L, Valgimigli M et al. Poor response to clopidogrel:
current and future options for its management. J Thromb Thrombolysis, 2010; 30: 319–331. doi: 10.1007/s11239-010-0457-5.
Moussa ID, Colombo A. Antiplatelet therapy discontinuation
following drug-eluting stent placement: dangers, reasons, and
management recommendations. Catheter Cardiovasc Interv,
2009; 74: 1047–1054. doi: 10.1002/ccd.22167.
Roy P, Bonello L, Torguson R et al. Temporal relation between
Clopidogrel cessation and stent thrombosis after drug-eluting
stent implantation. Am J Cardiol, 2009; 103: 801–805. doi:
10.1016/j.amjcard.2008.11.038.
19.
20.
21.
22.
23.
Serebruany V, Cherala G, Williams C et al. Association of platelet
responsiveness with clopidogrel metabolism: role of compliance in the assessment of “resistance”. Am Heart J, 2009; 158:
925–932. doi: 10.1016/j.ahj.2009.10.012.
Garavalia L, Garavalia B, Spertus JA, Decker C. Exploring patients’
reasons for discontinuance of heart medications. J Cardiovasc
Nurs, 2009; 24: 371–379. doi: 10.1097/JCN.0b013e3181ae7b2a.
Melloni C, Alexander KP, Ou FS et al. Predictors of early discontinuation of evidence-based medicine after acute coronary
syndrome. Am J Cardiol, 2009; 104: 175–181. doi: 10.1016/j.
amjcard.2009.03.013.
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med,
2005; 353: 487–497.
Kubica A, Kasprzak M, Siller-Matula J et al. Time-related changes
in determinants of antiplatelet effect of clopidogrel in patients after myocardial infarction. Eur J Pharmacol. 2014; 742: 47–54. doi:
10.1016/j.ejphar.2014.08.009.
Kozinski M, Bielis L, Wisniewska-Szmyt J et al. Diurnal variation in platelet inhibition by clopidogrel. Platelets, 2011; 22:
579–587. doi: 10.3109/09537104.2011.582900.
Kubica A, Kozinski M, Grzesk G et al. Genetic determinants of
platelet response to clopidogrel. J Thromb Thrombolysis, 2011;
32: 459–466. doi: 10.1007/s11239-011-0611-8.
Kubica A, Koziński M, Grześk G, Goch A. Clinical significance
of interactions between clopidogrel and proton pump inhibitors. Kardiol Pol, 2011; 69: 610–616.
Kubica A, Kasprzak M, Obońska K et al. Impact of CYP2C19 polymorphisms on antiplatelet efficacy of clopidogrel in patients after
myocardial infarction. Folia Med Copernicana, 2013; 1: 12–17.
Ho PM, Lambert-Kerzner A, Carey EP et al. Multifaceted intervention to improve medication adherence and secondary
prevention measures after acute coronary syndrome hospital
discharge: a randomized clinical trial. JAMA Intern Med, 2014;
174: 186–193. doi: 10.1001/jamainternmed.2013.12944.
Zhu B, Zhao Z, McCollam P et al. Factors associated with
clopidogrel use, adherence, and persistence in patients with
acute coronary syndromes undergoing percutaneous coronary
intervention. Curr Med Res Opin, 2011; 27: 633–641. doi:
10.1185/03007995.2010.551657.
Tuppin P1, Neumann A, Danchin N et al. Evidence-based pharmacotherapy after myocardial infarction in France: adherence-associated factors and relationship with 30-month mortality and
rehospitalization. Arch Cardiovasc Dis, 2010; 103: 363–375. doi:
10.1016/j.acvd.2010.05.003.
Pallares MJ1, Powers ER, Zwerner PL et al. Barriers to clopidogrel adherence following placement of drug-eluting stents. Ann
Pharmacother, 2009; 43: 259–267. doi: 10.1345/aph.1L286.
Kubica A, Kasprzak M, Obońska K et al. Discrepancies in assessment of adherence to antiplatelet treatment after myocardial
infarction. Pharmacol, 2015; 95: 50–58. doi: 10.1159/000371392.
Laskowska E, Ostrowska M, Kasprzak M et al. Influence of genetic polymorphisms on pharmacodynamics of clopidogrel in
patients with myocardial infarction during short- and long-term
follow-up. Folia Med Copernicana, 2015; 3: 62–71.
Tantry US, Jeong YH, Navarese EP et al. Influence of genetic polymorphisms on platelet function, response to antiplatelet drugs and
clinical outcomes in patients with coronary artery disease. Expert
Rev Cardiovasc Ther, 2013; 11: 447–462. doi: 10.1586/erc.13.20.
Koziński M, Obońska K, Stankowska K et al. Prasugrel overcomes high on-clopidogrel platelet reactivity in the acute phase
of acute coronary syndrome and maintains its antiplatelet
potency at 30-day follow-up. Cardiol J, 2014; 21: 547–556. doi:
10.5603/CJ.a2014.0026.
Navarese EP, Verdoia M, Schaffer A et al. Ischaemic and
bleeding complications with new, compared to standard,
ADP-antagonist regimens in acute coronary syndromes: a me-
www.kardiologiapolska.pl
65
Aldona Kubica et al.
24.
25.
26.
27.
ta-analysis of randomized trials. QJM, 2011; 104: 561–569. doi:
10.1093/qjmed/hcr069.
Navarese EP, Buffon A, Kozinski M et al. A critical overview
on ticagrelor in acute coronary syndromes. QJM, 2013; 106:
105–115. doi: 10.1093/qjmed/hcs187.
Muntner P, Mann DM, Woodward M et al. Predictors of Low
Clopidogrel Adherence Following Percutaneous Coronary Intervention. Am J Cardiol, 2011; 108: 822–827. doi: 10.1016/j.
amjcard.2011.04.034.
Ferreira-González I, Marsal JR, Ribera A et al. Double antiplatelet
therapy after drug-eluting stent implantation: risk associated with
discontinuation within the first year. J Am Coll Cardiol, 2012;
60: 1333–1339. doi: 10.1016/j.jacc.2012.04.057.
Ferreira-Gonzalez I, Marsal JR, Ribera A et al. Background,
incidence, and predictors of antiplatelet therapy discontinuation during the first year after drug-eluting stent implantation.
Circulation, 2010; 122: 1017–1025. doi: 10.1161/CIRCULATIONAHA.110.938290.
28. Kronish IM, Rieckmann N, Shimbo D, et al. Aspirin adherence,
aspirin dosage, and C-reactive protein in the first 3 months
after acute coronary syndrome. Am J Cardiol, 2010; 106: 1090–
–1094. doi: 10.1016/j.amjcard.2010.06.018.
29. Siller-Matula J, Lang IM, Neunteufl T et al. Interplay between
genetic and clinical variables affecting platelet reactivity and
cardiac adverse events in patients undergoing percutaneous
coronary intervention. PLoS One, 2014; 9: e102701. eCollection
2014. doi: 10.1371/journal.pone.0102701.
30. Paniccia R, Antonucci E, Maggini et al. Assessment of platelet
function on whole blood by multiple electrode aggregometry
in high-risk patients with coronary artery disease receiving
antiplatelet therapy. Am J Clin Pathol, 2009; 131: 834–842. doi:
10.1309/AJCPTE3K1SGAPOIZ.
Cite this article as: Kubica A, Obońska K, Kasprzak M et al. Prediction of high risk of non-adherence to antiplatelet treatment. Kardiol
Pol, 2016; 74: 61–67. doi: 10.5603/KP.a2015.0117.
66
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Identyfikacja zwiększonego ryzyka
nieprzestrzegania zaleceń lekarskich dotyczących
stosowania leków antyagregacyjnych
Aldona Kubica1, Karolina Obońska2, 3, Michał Kasprzak2, 3, Beata Sztuba4, Eliano Pio Navarese3,
Marek Koziński5, Iwona Świątkiewicz3, Magdalena Kieszkowska3, Małgorzata Ostrowska5,
Grzegorz Grześk2, Jacek Kubica3
Katedra i Zakład Promocji Zdrowia, Collegium Medicum, Uniwersytet Mikołaja Kopernika, Bydgoszcz
1
Katedra i Zakład Farmakologii i Terapii, Collegium Medicum, Uniwersytet Mikołaja Kopernika, Bydgoszcz
2
Katedra i Klinika Kardiologii i Chorób Wewnętrznych, Collegium Medicum, Uniwersytet Mikołaja Kopernika, Bydgoszcz
3
Narodowy Fundusz Zdrowia, Bydgoszcz
4
Zakład Podstaw Medycyny Klinicznej, Collegium Medicum, Uniwersytet Mikołaja Kopernika, Bydgoszcz
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Streszczenie
Wstęp: Podwójna terapia przeciwpłytkowa złożona z kwasu acetylosalicylowego (ASA) i klopidogrelu stanowi standard leczenia
w prewencji wtórnej. Przedwczesne zaprzestanie stosowania klopidogrelu wiąże się z większym ryzykiem zawału serca (MI)
lub zgonu, a także większymi wydatkami na służbę zdrowia.
Cel: Celem pracy było stworzenie obiektywnej metody identyfikacji pacjentów cechujących się zwiększonym ryzykiem nieprzestrzegania zaleceń lekarskich dotyczących stosowania klopidogrelu po MI.
Metody: Do prospektywnego, obserwacyjnego, jednoośrodkowego badania włączono 189 pacjentów, których obserwowano
przez 9 miesięcy. Pacjenci otrzymali klopidogrel w dawce nasycającej (600 mg), a następnie w dawce podtrzymującej (75 mg)
w połączeniu z ASA w dawkach, odpowiednio, 300 mg i 75 mg. Agregację płytek krwi indukowaną ADP (ADP-PA) oznaczano
w trakcie hospitalizacji oraz 3, 6 i 9 miesięcy po wypisaniu ze szpitala. Stosowanie się do zaleceń lekarskich dotyczących
przyjmowania klopidogrelu oparto na danych uzyskanych z Narodowego Funduszu Zdrowia, a zdefiniowane było ono przez
stosunek ilości leku wykupionego do ilości leku niezbędnej do kontynuacji terapii. Arbitralnie przyjęto, że stosowanie się do
zaleceń lekarskich jest zadowalające, jeśli stosunek ten przekracza 80%.
Wyniki: Nawiązując do naszej hipotezy, ADP-PA u pacjentów nieprzestrzegających zaleceń lekarskich powinno być wyższe
w czasie wizyt kontrolnych (przynajmniej podczas jednej wizyty) w porównaniu z danymi reaktywności płytek krwi uzyskanymi
w trakcie hospitalizacji. Na podstawie analizy krzywych ROC za optymalny punkt odcięcia uznano wartość 4 U (p < 0,0001;
95% CI 0,562–0,654; czułość: 60,6%, swoistość: 57,1%, pozytywna wartość predykcyjna: 63,3%, negatywna wartość predykcyjna: 54,2%). W zdefiniowanych na podstawie tych kryteriów grupach — o wysokim i niskim prawdopodobieństwie
stosowania się do zaleceń lekarskich — rzeczywista liczba stosujących się do zaleceń wynosiła odpowiednio 60 (50,8%) oraz
23 pacjentów (32,4%); p = 0,01.
Wnioski: Nasza nowo opracowana metoda pozwala obiektywnie zidentyfikować pacjentów cechujących się podwyższonym
ryzykiem nieprzestrzegania zaleceń lekarskich w zakresie stosowania klopidogrelu po MI. Łatwa w zastosowaniu, tania, pomimo
stosunkowo niskiej czułości i swoistości, skutecznie różnicuje pacjentów w odniesieniu do klinicznych punktów końcowych.
Słowa kluczowe: klopidogrel, agregacja płytek krwi indukowana ADP, stosowanie się do zaleceń lekarskich
Kardiol Pol 2016; 74, 1: 61–67
Adres do korespondencji:
dr n. med. Małgorzata Ostrowska, Zakład Podstaw Medycyny Klinicznej, Collegium Medicum, Uniwersytet Mikołaja Kopernika, ul. Marii Skłodowskiej-Curie 9,
85–094 Bydgoszcz, e-mail: ostrowska.go@gmail.com
Praca wpłynęła: 08.01.2015 r.
Zaakceptowana do druku: 07.05.2015 r.
Data publikacji AoP: 18.06.2015 r.
www.kardiologiapolska.pl
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