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Abstract

Introduction/Objectives:

In patients who have undergone recent percutaneous coronary intervention (PCI), poor adhesion to antiplatelet agents may increase the risk of stent thrombosis and death. We aimed to investigate the adherence to different P2Y12 receptor inhibitors after PCI with drug-eluting stent in stable and unstable patients and to evaluate the factors associated with low adherence.

Method:

In a prospective study conducted between 2014 and 2018, the 8-item Morisky scale was applied at 30 days and 6 months post-PCI to measure P2Y12 receptor inhibitors adherence. Also, we describe the characteristics of patients using different platelet receptor P2Y12 inhibitors. Regression models were used to identify predictors of poor adherence.

Results:

A total of 214 patients were included (65 ± 12 years, 81% man, 61% acute coronary syndromes). Patients in the clopidogrel group were older than those in the prasugrel (68 ± 12 vs 59 ± 11 years, P < .01, respectively) or ticagrelor group (68 ± 12 vs 62 ± 12 years, P < .01). Patients with low/moderate adherence at 30 days and 6 months represented, respectively, 19.8% and 27.5% of our sample. Current smokers and preexisting cardiovascular disease at presentation were associated with lower adherence at 30 days.

Conclusions:

We found substantial rates of moderate and low adherence to P2Y12 receptor inhibitors early after PCI. Current smokers and preexisting cardiovascular disease at presentation were associated with a lower likelihood of adherence. These results highlight the need of monitoring adherence to medical treatment after PCI.

Keywords

medication adherence coronary artery disease percutaneous coronary intervention platelet aggregation inhibitors drug-eluting stents

Introduction

Dual antiplatelet therapy is currently the standard of care for patients with acute coronary syndromes (ACSs) treated with percutaneous coronary intervention (PCI). Prasugrel and ticagrelor have been compared to clopidogrel, both newer agents showing decreased ischemic events, with an increased tendency in hemorrhagic events.^1,2 Due to the beneficial net clinical gain, prasugrel and ticagrelor have been increasingly adopted as the medication of choice in practice guidelines. Accordingly, the proportion of patients discharged after angioplasty with a prasugrel or ticagrelor prescription has ranged from 25% to 35% in the United States^3
-5 and between 45% and 70% in Europe,^6
-8 with progressive increase over the last decade.

Previous studies demonstrated substantial rates of poor adherence to antiplatelet agents after acute myocardial infarction or PCI, which was associated with increased risk for subsequent thrombotic events.^9,10 Specifically, both ticagrelor¹¹ and prasugrel⁹ seem to be associated with a significantly higher rate of medication withdrawal. An understanding of the factors that modulate drug discontinuation is cardinal to formulate active measures to mitigate it.

The availability of standardized methods to measure medication adherence is of major value for researchers and clinicians. Unstructured or inaccurate assessment of adherence may lead to misinterpretation about treatment effectiveness and side effects, may influence the usage of diagnostic testing, and may induce erroneous modification of the therapeutic strategy.

The present study, therefore, aimed to investigate the level of adherence to P2Y12 receptor inhibitors after PCI using validated semiquantification methods, as well as evaluate the factors associated with impaired adherence.

Methods

Population and Study Design

This is a single-center (Hospital Israelita Albert Einstein), single-arm, observational, prospective study. Patients aging >18 years were enrolled if treated with PCI using drug-eluting stents for chronic or acute coronary disease. Exclusion criteria included treatment with any bare metal stents or balloon dilatation only, non-self-administration of postprocedure medications, or refusal to answer the adherence questionnaire. All patients were prospectively followed up after hospital discharge. The study was approved by the local ethics committee, and written informed consent was obtained for every patient.

Data Collection

Adherence was measured using an adapted version of the 8-item Morisky Medication Adherence Scale (MMAS-8),¹² which was applied by telephone interview by a team of trained nurses at 30 ± 4 days and at 6 months (±20 days) after the index procedure. The MMAS-8 is a comprehensive method that showed higher sensitivity than the previous 4-item scale and has been widely used in medical treatment adherence studies. It encompasses 8 questions formulated to avoid positive response bias by reversing adherence-related response choices, assessing factors such as health beliefs, forgetfulness, and side effects. Adherence is ultimately determined by the resulting score, being classified as high (8 points), moderate (6 and 7 points), or low (<6 points). The scale was adapted to evaluate adherence to clopidogrel after PCI in accordance with a previous version proposed by Muntner et al.¹³ Following the identification of the P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor), a drug-specific questionnaire was administered.

Statistical Analysis

Continuous variables were described as the mean ± standard deviation or median and interquartile range. Categorical variables were presented as relative and absolute frequencies. Comparison between continuous variables was performed using the Student t test or analysis of variance (variables with normal distribution) or the Mann-Whitney and Kruskal-Wallis or Friedman test (variables with asymmetric distribution), and the χ² test was used for categorical variables. Pearson or Spearman correlation test was used to analyze the correlation between 2 continuous variables. Logistic regression was used to identify independent predictors of low medication adherence. Variables that had a descriptive level lower than 0.10 (P < .10) in the unadjusted analyses were included in the regression. Variables were selected using stepwise backward approach, and only significant variables (P < .05) were retained in the multiple logistic regression model. A P < .05 was considered statistically significant. All analyses were performed with the aid of specific programs, with statistical support, using SPSS version 22.0 (IBM Corp).

Results

Between 2014 and 2017, a total of 258 patients were screened. From those, 13 patients were excluded due to angioplasty without stent placement (n = 3) or non-self-administrated medications (n = 10). Also, one patient who stopped the P2Y12 inhibitor upon medical advice before 30 days was excluded from analysis. In addition, one patient died before discharge and 29 other patients refused to answer the questionnaire at 30 days and were excluded from the study. The remaining 214 patients comprised the present study population. Therefore, we analyzed 214 patients (65 ± 12 years, 81% men, 61% ACSs). Table 1 presents the characteristics of these patients.

Table 1.

Characteristics of Patients Undergoing PCI With a P2Y12 Inhibitor.

P2Y12 receptor inhibitor	Clopidogrel (n = 108)	Ticagrelor (n = 60)	Prasugrel (n = 46)	P value
Age (years)	68 ± 12	62 ± 12	59 ± 11	<.001
Male sex	82 (76%)	49 (82%)	42 (91%)	.08
Weight (kg)	82 ± 14	83 ± 17	88 ± 12	.19
BMI (kg/m²)	28 ± 4	28 ± 5	29 ± 5	.63
Hypertension	74 (68%)	33 (55%)	28 (61%)	.21
Diabetes	38 (35%)	17 (28%)	16 (35%)	.64
High cholesterol	70 (65%)	33 (55%)	33 (72%)	.19
Current smoker	18 (17%)	16 (27%)	6 (13%)	.15
Previous CAD	41 (38%)	23 (38%)	19 (41%)	.92
Previous TIA/stroke	4 (4%)	0 (0%)	0 (0%)	.06
Previous angioplasty	32 (30%)	15 (25%)	14 (30%)	.77
Previous MR	11 (10%)	3 (5%)	4 (9%)	.48
ACS at PCI index	67 (62%)	44 (73%)	18 (39%)	.002

Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; MR, myocardial revascularization; PCI, percutaneous coronary intervention; TIA, transient ischemic stroke.

From 214 patients who answered the MMAS-8 30 days after the angioplasty, 108 (50.5%) were using clopidogrel, 60 (28%) were using ticagrelor, and 46 (21.5%) were using prasugrel. Patients in the clopidogrel group were older than those in the prasugrel group (68 ± 12 vs 59 ± 11 years, P < .01, respectively) and the ticagrelor group (68 ± 12 vs 62 ± 12 years, P < .01). The percentage of patients who underwent angioplasty due to unstable coronary artery disease (CAD; unstable angina and myocardial infarction) was significantly lower in the prasugrel group (39%) than in the clopidogrel (62%) and ticagrelor (73%) groups (P = .002). There were no significant differences among the groups in the other characteristics. Figure 1 shows the proportional reduction in clopidogrel use and the increased use of prasugrel between 2014 and 2017 (χ² for trend P = .043).

Figure 1.

Use of P2Y12 platelet receptor inhibitor per year.

Comparing high adherent patients to patients with moderate/low adherence at the 30-day assessment, we found rates of high adherence to clopidogrel, ticagrelor, and prasugrel of 83.7%, 77.2%, and 76.1%, respectively (P = .450), with no significant difference as described in Table 2. The overall percentage of patients with moderate/low adherence to P2Y12 receptor inhibitors was 19.8% at 30 days after the PCI.

Table 2.

Adherence at 30 Days and at 6 Months.^a

Adherence at 30 days	Medication at 30 days						Total		P value
	Clopidogrel		Ticagrelor		Prasugrel		Total
	n	%	n	%	n	%	n	%
Moderate/low adherence	17	16.3	13	22.8	11	23.9	41	19.8	.450
High adherence	87	83.7	44	77.2	35	76.1	166	80.2
Total	104	100	57	100	46	100	207	100
	Medication at 6 months
	Clopidogrel		Ticagrelor		Prasugrel		Total
Adherence at 6 months	n	%	n	%	n	%	n	%	P value
Moderate/low adherence	24	24.7	11	31.4	11	31.4	46	27.5	.634
High adherence	73	75.3	24	68.6	24	68.6	121	72.5
Total	97	100	35	100	35	100	167	100

^a χ² test.

In the reassessment of adherence at 6 months after PCI, we found an overall high adherence to P2Y12 receptor inhibitors of 72.5%, with no significant difference among the 3 groups (respectively, 75.3% for clopidogrel, 68.6% for ticagrelor, and 68.6% for prasugrel, P = .63).

A multiple logistic regression analysis was performed to evaluate the factors associated with lower adherence. Patients with a history of smoking and previously known CAD had lower adherence 30 days after PCI (respectively, odds ratio [OR] of 0.43, 95% CI: 0.18-0.99, P = .049; and 0.34, 95% CI: 0.16-0.74, P = .007). Hypertensive and diabetic patients exhibited a higher likelihood of adherence after 30 days (respectively, OR: 2.20, 95% CI: 1.03-4.71, P = .043; and 2.51, 95% CI: 1.02-6.14, P = .045; Table 3).

Table 3.

Significant Predictors of High Adherence at 30 Days.^a

Odds of high adherence
Variable	OR	95% CI		P value
Variable	OR	Lower	Upper	P value
Current smoker	0.43	0.18	0.99	.049
Hypertension	2.20	1.03	4.71	.043
Diabetes	2.51	1.02	6.14	.045
Preexisting CAD	0.34	0.16	0.74	.007

Abbreviations: CAD, coronary artery disease; OR, odds ratio.

^a Multiple logistic regression.

Discussion

In our study, conducted in a large private general hospital in Brazil, including patients with stable and unstable CAD who underwent PCI with drug-eluting stents, we found a higher proportion of patients using clopidogrel (50.5%) than ticagrelor (28%) and prasugrel (21.5%). Prescriptions for more potent P2Y12 receptor inhibitors (ticagrelor and prasugrel) have increased since their approval by the Food and Drug Administration, the European Medicines Agency and the Brazilian agency (ANVISA). In the United States study,¹¹ the use of prasugrel and ticagrelor increased from 0% to 36.9% between 2008 and 2015. We found that patients using prasugrel in our sample were younger than those in the clopidogrel group (59 vs 68 years, P < .001), possibly due to the increased risk of bleeding, especially in individuals older than 75 years, as observed in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 study.¹ Similarly, there was a difference in age between clopidogrel and ticagrelor users (68 vs 62 years, respectively, P = .006), which may also reflect concerns about the increased chance of bleeding with ticagrelor in a subset of patients (ie, non-CABG major bleeding) from the Study of Platelet Inhibition and Patient Outcomes (PLATO) .²

Interestingly, we found a large proportion of patients with stable CAD in the ticagrelor group (27%) and an even greater proportion in the prasugrel group (61%); when prasugrel was compared to clopidogrel, the difference was significant (P = .002). Considering that previous large clinical trials with ticagrelor and prasugrel were performed in patients with ACSs^1,2 and that these drugs are recommended as first-line therapy in patients with ACS by current international guidelines, we found unexpected high rates of these P2Y12 receptor inhibitors use in stable coronary patients treated with PCI. Nevertheless, despite the US dual antiplatelet therapy guidelines, as well as the European guidelines, recommend the routine use of clopidogrel in stable patients undergoing PCI,¹⁴ the European guidelines consider ticagrelor and prasugrel as second-line options when there is an unsatisfactory clinical response to clopidogrel or when there is high ischemic potential and an acceptable risk of bleeding.¹⁵

Considering a high-risk clinical setting for thrombotic events, such as the short-term period post-PCI, we found less adherence to P2Y12 receptor inhibitors inhibitors than expected.

During clinical follow-up, the suboptimal adherence was sustained in the 6-month analysis. These findings are particularly relevant, considering the increased risk of stent thrombosis associated with early antiplatelet interruption after PCI. We demonstrated that adherence to the P2Y12 receptor inhibitors was not significantly different among the 3 drugs in the entire follow-up, although it was numerically higher in the clopidogrel group. The high adherence levels in our study were similar from another that compared adherence rates among these 3 drugs using prescription filling data from patients with ACS.¹¹ In the mentioned study, high adherence was slightly higher for clopidogrel compared with prasugrel and ticagrelor (medication possession rates of 0.85 vs 0.79 vs 0.76, respectively, P < .001). The main factor implicated in this difference was cost, and this difference was even higher in the lower income subgroup. Although we did not assess individual income data in our study, all PCI procedures were performed in a private hospital that cares for high-income patients, a factor that may have attenuated the lower adherence to the more expensive drugs in our sample. Another possible factor is the twice daily dosing of ticagrelor compared to once daily dosing of clopidogrel and prasugrel. The prescribed number of doses per day is inversely related to adherence, especially in treatment of chronic conditions such as hypertension.¹⁶

In addition, we demonstrated that current smokers and preexisting cardiovascular disease at presentation were both associated with lower adherence to P2Y12 receptor inhibitors. Previous studies found a large heterogeneity in the factors associated with lower adherence to P2Y12 receptor inhibitors. In the PARIS registry, smoking was also a factor associated with lower adherence, as well as older age and ACS.¹⁷ Additionally, self-underestimation of cardiovascular risk among smokers has been identified¹⁸ and that finding could help explain the lack of treatment adherence in this subset of patients. A previous meta-analysis on this subject identified the following factors associated with poor adherence after PCI: bleeding, lower educational level, immigrant patients, and lower orientation to dual antiplatelet therapy.¹⁹ Similarly to our results, a previous study demonstrated that preexisting CAD was associated with lower odds of medical treatment adherence.¹⁰ These findings may suggest that failure in secondary prevention in patients with previous known CAD, with consequent need for new PCI procedures, could be related to the lack of adherence in this clinical setting.

Although a large amount of resources are directed to the development of new medical treatments, the lack of adherence to established therapies is a known and undervalued problem.²⁰ In some developed countries, patient adherence to the treatment of various chronic diseases reaches only 50% of the proposed treatment.²¹ Adherence levels seem to be even worse in developing countries. In the PURE study,²² low adherence to antiplatelet drugs, β-blockers, angiotensin-converting enzyme inhibitors, and statins was observed in individuals with history of CAD or stroke, especially in low-income countries and rural areas.

Therefore, our findings demonstrate an early and sustained suboptimal adherence to P2Y12 inhibitors after PCI. These data suggest that current practice is not sufficient to ensure high medication adherence and therapeutic success in a high-risk clinical setting, such as in patients treated with PCI. Importantly, several strategies may improve medical treatment after PCI. Facilitating pharmacological dosing after PCI, a clinical setting in which patients require several classes of drugs for the treatment of CAD and comorbidities. For instance, reducing the number of drug doses, using combinations of medications and polypills, has been proven effective in patients with cardiovascular diseases.^23,24 Additionally, the reduction in medication costs with generic formulations, strategic subsidies, and less expensive drugs increased adherence and reduced cardiac events after myocardial infarction.²⁵ On the other hand, interventions to improve health knowledge, such as the use of images, video presentations explaining the effects of medications in layman terms, and communication training for health care providers, seems to be ineffective, showing inconclusive or neutral results in most studies.²⁶ Finally, behavioral strategies that facilitate the integration of the use of medications into patients’ daily routines seem to be more effective than educational strategies. Packaging that includes calendars, pill holders, the use of diaries, simplification of the therapeutic regimen, alert devices, the encouragement of self-monitoring (eg, blood pressure and blood sugar), positive reinforcement, and motivational counseling are examples of behavioral interventions that have shown good results in clinical studies.^27,28

Our study has limitations that deserve attention. The failure to show a statistically significant difference in adherence between the 3 P2Y12 receptor inhibitors may be due to a small sample size. We evaluated adherence using a questionnaire, which tends to overestimate adherence and is subject to recall bias. Nevertheless, this method was previously validated, and it has been widely used in several clinical studies. The absence of important variables related to adherence, such as socioeconomic factors, sedentarism, psychiatric disorders, and cardiac rehabilitation, represents a further limitation. In addition, at 6 months follow-up analysis, we did not have assess for data from a part of the original sample fact that would affect adjusted models of predictive factors for nonadherence. Another limitation is the follow-up of only 6 months in patients with ACS who should use the P2Y12 receptor inhibitors for at least one year.

In conclusion, in patients treated with PCI, the use of ticagrelor and prasugrel has increased in the last years, in both stable and unstable clinical settings. We found substantial rates of moderate and low adherence to P2Y12 receptor inhibitors early after PCI (ie, at 30 days) which remained high at 6-month follow-up. Current smokers and preexisting cardiovascular disease at presentation were associated with a lower likelihood of adherence. Our findings highlight that adherence to medical treatment should be monitored in patients treated with PCI, early after hospital discharge and during midterm follow-up. Future studies should evaluate strategies to improve adherence in this setting.

Footnotes

Author Contribution

Fernando Morita, Mauricio Wajngarten, Marcelo Katz and Antonio E. Pesaro designed the study, analyzed the data and wrote the manuscript. Miguel Morita Fernandes-Silva, Adriano Caixeta, Marcelo Franken and Pedro A. Lemos analyzed the data and wrote the manuscript.

Authors’ Note

Use of the ©MMAS is protected by US copyright laws. Permission for use is required. A license agreement is available from: Donald E. Morisky, ScD, ScM, MSPH, Professor, Department of Community Health Sciences, UCLA School of Public Health, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.

Declaration of Conflicting Interests

Marcelo Katz reports receiving consulting fees from Abbvie and EMS Pharma.

No other potential conflict of interest relevant to this article was reported.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Fernando Morita

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