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Long-term medication persistence in stroke patients treated with intravenous thrombolysis
Clinical Neurology and Neurosurgery 141 (2016) 19–22
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Long-term medication persistence in stroke patients treated with intravenous thrombolysis Maja Stefanovic Budimkic a , Tatjana Pekmezovic b,c , Ljiljana Beslac-Bumbasirevic b , Marko Ercegovac a,b , Ivana Berisavac a,b , Predrag Stanarcevic a , Visnja Padjen a , Dejana R. Jovanovic b,∗ a
Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia Medical Faculty University of Belgrade, Belgrade, Serbia c Institute of Epidemiology, Belgrade, Serbia b
a r t i c l e
i n f o
Article history: Received 18 June 2015 Received in revised form 20 November 2015 Accepted 9 December 2015 Available online 14 December 2015 Keywords: Intravenous thrombolysis Stroke outcome Medication persistence
a b s t r a c t Objective: There are no data regarding long-term medication persistence in stroke survivors treated with intravenous thrombolysis (IVT), which is one of the most important determinants of treatment success. Our objective was to determine long-term medication persistence in stroke patients treated with IVT. Methods: This retrospective observational study included 203 IVT-treated and 197 non-IVT treated patients with acute ischemic strokes (IS) admitted to the Stroke Unit between January 2007 and January 2013. Results: During a median follow-up period of 3 years (range 1–7 years), 56 (21.6%) patients in the IVTgroup and 62 (23.9%) patients in the non-IVT-group died. There was a higher medication persistence for all secondary stroke prevention medications (anti-thrombotic agents, anti-hypertensive drugs, statins and hypoglycemic drugs) in the IVT-group compared to the non-IVT group (88.7% vs. 69.0%; OR = 3.68, 95% CI = 2.17–6.23). After adjusting for baseline characteristics and possible confounders IVT was the independent predictor of medication persistence (OR = 2.93, 95% CI = 1.48–5.81, p = 0.002). Higher medication persistence was observed in patients with favorable long-term functional outcome, both in the IVT-group (OR = 4.37, 95% CI = 1.83–10.40, p < 0.001) and the non-IVT-group (OR = 3.46, 95% CI = 1.84–6.52, p < 0.001). Conclusion: Medication persistence was higher among IVT-treated patients compared to non-IVT-treated patients. The higher rate of non- medication persistence was recorded among patients with more pronounced disabilities after stroke. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Recurrent strokes constitute a notable proportion of all preventable strokes (up to 30%) and are more disabling, fatal and costly than the first stroke [1]. Strategies to reduce the increasing global burden of stroke include not only mass population high-risk approaches to prevent first-ever stroke but also the treatment of acute stroke patients and the secondary prevention of recurrent stroke. Preventive treatments such as medications and a healthy lifestyle have shown efficacy on stroke recurrence [2]. Despite the evident success in reducing stroke recurrence, the long-term
∗ Corresponding author. Clinical Centre of Serbia, Neurology Clinic, Dr Subotica 6, PO Box 12, 11129 Belgrade 102, Serbia. Fax: +381 11 2644667. E-mail address: [email protected] (D.R. Jovanovic). http://dx.doi.org/10.1016/j.clineuro.2015.12.003 0303-8467/© 2015 Elsevier B.V. All rights reserved.
persistence of preventive medications in stroke survivors is frequently quite low and varies from 45 to 90% [3–7]. Data regarding long-term medication persistence in stroke survivors treated with intravenous thrombolysis (IVT) are lacking. Our objective in the current study to determine long-term medication persistence in stroke patients treated with IVT compared to patients not treated with IVT. 2. Methodology This retrospective observational study included patients with acute ischemic stroke (IS) admitted to the Stroke Unit of the Department of Emergency Neurology of Clinical center of Serbia in Belgrade, between January 2007 and January 2013. The inclusion criteria for the study were as follows: (1) the absence of comorbidities that would significantly affect patient outcome, such as
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proven malignant disease or terminal renal insufficiency, (2) presence of pre-stroke functional independence (modified Rankin score (mRS) 0–1) and (3) the accessibility of long-term outcome information. Two hundred fifty-nine patients with acute IS treated with IVT and 259 controls with acute IS not treated with IVT who were admitted to the Stroke Unit within 24 h from stroke onset were included in the study. All subjects treated with IVT are the part of an ongoing, prospective, multicenter, open, observational Serbian Experience with Thrombolysis in Ischemic Stroke registry (SETIS), as published previously [8]. Patients’ clinical characteristics and outcome measures were obtained from the SETIS registry for the IVT group and from the hospital registry of the Stroke Unit for the non-IVT group. Clinical outcome was assessed by examining the subsequent outpatient reports and telephone interviews with the patients or their caregivers one year after stroke or later. During follow- up all of the patients had regularly scheduled check-up examinations. For the purpose of this study, all of the patients were also examined and interviewed between June 2013 and January2014. The following data were collected: (1) the use of medication in stroke survivors prescribed by their stroke physicians at the time of discharge from the Stroke Unit (anti- thrombotic agents, antihypertensive drugs, statins and hypoglycemic drugs), (2) follow-up persistence, (3) discontinuation rates (physician recommendation or self-discontinued), and (4) the degree of functional recovery expressed by modified Rankin score at the moment of contact with the patient (excellent functional outcome is defined as a mRS = 0 or 1). The primary outcome measure was persistence with secondary stroke prevention medications, defined as continuation with recommended therapy or class of therapy from discharge through the follow-up period [9]. Medication continuation was determined by comparing the recommended hospital discharge medications (or prescribed list of medications by the stroke physician during check-ups) with the current medications reported by the patients. These information was collected during check-up examinations and interviews conducted by Lj.B.B, D.R.J. and M.S.B. In addition, we asked patients whether or not they took prescribed medications as recommended from a stroke care physician or some other physician. The study was approved by the Ethics Committee of the Medical Faculty University of Belgrade (Serbia). Written informed consent for the participation in the study was obtained from all participants or their proxies. 2.1. Statistics Comparisons between groups were assessed using parametric and nonparametric tests (Analysis of variance; t-test, 2 test, Mann–Whitney U-test and Kruskall–Wallis test), as appropriate. Statistical significance was set at a P < 0.05 (2-sided). Multiple logistic regression with stepwise backward variable removal (P > 0.05 as the removal criterion) was performed to test for an association between medication persistence and previous IVT treatment with baseline demographic and clinical characteristics as possible confounders. SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. 3. Results During a median follow-up period of 3 years (range 1–7 years), 56 (21.6%) patients in the IVT-group and 62 (23.9%) patients in the non-IVT-group died. Therefore, a total of 203 subjects in the IVT-group and 197 subjects in the non-IVT-group were included in
Fig. 1. Long-term medication persistence and functional recovery in IVT and nonIVT treated patients.
the analysis. Patient baseline clinical characteristics and functional outcome at 3-months are shown in Table 1. The characteristics among stroke survivors in both groups of patients did not differ significantly, except for a better 3-month functional recovery in the IVT-treated group. Table 2 shows the persistence of medications prescribed at discharge according to IVT treatment. Medication persistence was greater the in IVT-group for all classes of medications, with the greatest differences between groups for anti-platelet and antihypertensive drugs. Primary care physician recommended discontinuing antiplatelet therapy in 3 patients in the IVT-group and 17 patients in the non-IVT group, without a reasonable medical justification, while six patients in IVT-group and 13 patients in the non-IVT group have self-discontinued anti-platelet therapy. With respect to the use of oral anti-coagulants, three thrombolysed patients versus eight non-thrombolysed patients discontinued the recommended anti-coagulant therapy prescribed for atrial fibrillation. Statins were discontinued by primary care physician for 17 subjects in the IVT-group and 10 subjects in the control group because of normalization of serum cholesterol levels after initiation of statin therapy. Self-discontinuation of statin therapy occurred in 21 cases and 37 controls; of note these patients lost control of serum cholesterol levels. All of the patients who were persistent in taking the prescribed medication for secondary stroke prevention reported that they took medications as recommended by of a health care provider. Persistence with all prescribed medications was higher in the IVT-group (88.7% of patients in the IVT-group vs. 69% in the nonIVT group). After adjusting for baseline characteristics and possible confounders IVT was an independent predictor of medication persistence (OR = 3.36, 95% CI = 1.90-5.11, p = 0.001, Table 3). Higher medication persistence was observed in patients with excellent long-term functional outcome, both in IVT-group (OR = 4.37, 95% CI = 1.83- 10.40, p < 0.001) and non-IVT-group (OR = 3.46, 95% CI = 1.84–6.52, p < 0.001), as presented in Fig. 1.
4. Discussion No studies have investigated long-term medication persistence in stroke patients treated with IVT. We noted that there was higher persistence to secondary stroke prevention medications among stroke patients treated with IVT compared to non-IVT treated patients, and patients with better recovery were more persistent in taking all of the medications prescribed. It is possible that stroke patients with better recovery are ready to take the necessary steps to prevent future strokes. Also, it is possible that patients with more pronounced disabilities and dependence have a low percep-
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21
Table 1 Baseline characteristics of stroke survivors according to IVT treatment. IVT group (N = 203)
Control group (N = 197)
p
55 (48–62) 140 (69.0) 178 (87.7) 46 (22.7)
56(48–63) 138 (70.0) 153 (77.6) 56 (28.4)
0.432 0.829 0.008 0.207
Stroke severity NIHSS score, median (IQR) NIHSS score ≥15, n (%)
9 (6–15) 53 (26.1)
8 (6–14) 41 (20.8)
0.329 0.239
Vascular risk factors, n (%) Hypertension Hyperlipoproteinemia Smoking, current Diabetes mellitus Atrial fibrillation
158 (77.8) 132 (65.0) 103 (50.7) 30 (14.8) 38 (18.7)
148 (75.1) 142 (72.1) 99 (50.2) 42 (21.3) 28 (14.2)
0.636 0.194 1.000 0.092 0.229
Clinical stroke syndromea , n (%) TACS PACS LACS POCS
57 (28.1) 75 (36.90) 40 (19.7) 31 (15.3)
47 (23.9) 77 (39.1) 33 (16.70) 40 (20.3)
Stroke etiologyb , n (%) LAA Small artery occlusion Cardioembolism Other Undetermined
42 (20.7) 34 (16.7) 45 (22.2) 30 (14.8) 52 (25.6)
47 (23.9) 32 (16.2) 36 (18.3) 37 (18.8) 45 (22.8)
0.640
Prior use of antithrombotics, n (%) Warfarin Antiplatelets
6 (2.9) 40 (19.7)
12 (6.1) 32 (16.2)
0.152 0.435
Prior use of statins, n (%)
14 (6.9)
16 (8.1)
0.706
Charlson comorbidity index [10], mean (SD)
0.50 ± 0.75
0.58 ± 0.81
0.312
Symptomatic ICH (ECASS-2)c , n (%)
6 (3.0)
1 (0.5)
0.486
mRS 0–1 after 3 months, n (%)
131 (64.5)
109 (55.3)
0.05
Persistence to medications for secondary prevention of stroke at 3 months after index stroke, n (%)
195 (96.1)
180 (91.3)
0.063
Length of follow-up (y) Median (IQR), range Median ≥3 y, n (%)
3 (1–4), range 1–7 102 (50.2)
3 (1–5), range 1–7 99 (50.2)
1.000 1.000
Age (y), median (IQR) Male sex, n (%) Married/partnered pre-stroke, n (%) Education level (≥14 years of school)
0.438
IVT:indicates intravenous thrombolysis; NIHSS:national Institute of Health Stroke Scale; PACS:partial anterior circulation stroke; POCS:posterior circulation stroke; TACS:total anterior circulation stroke, LACS:lacunar stroke; ICH:intracranial hemorrhage. a According to Oxfordshire Community Stroke Project classification [11]. b According to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification [12]. c sICH, Symptomatic intracranial hemorrhage according to the ECASS-2 trial definitions [13]. Table 2 Follow-up persistence by drug class according to IVT treatment.
Anti-platelets Oral anti-coagulants Anti-hypertensive drugs Statins Hypoglycemic drugs
Prescription at Hospital Discharge, n
Persistence, n (%)
IVT(N = 203)
IVT
Non-IVT
OR, 95% CI
148 (91.9) 40 (93.0) 163 (94.8) 142 (91.0) 33 (91.7)
131 (81.4) 29 (78.4) 144 (85.7) 125 (77.2) 33 (71.7)
2.61 (1.30–5.21) 3.68 (0.90–15.07) 3.02 (1.36–6.71) 3.00 (1.55–5.81) 3.15 (0.93–10.69)
161 43 172 156 36
Non-IVT(N = 197) 161 37 168 162 46
Table 3 Predictors of follow-up persistence.
IVT Hypertension Marital status mRS 0–1 after 3 months mRS 4–5 after 3 months
Univariate analysisOR, 95% CI
Multivariate analysisOR, 95% CI
3.51 (2.07–5.96) 0.48 (0.29–0.92) 0.45 (0.26–0.80) 1.25 (1.01–2.03) 0.49 (0.26–0.98)
3.36 (1.90–5.61)
tion of benefits from medications and more difficulties in returning to follow-up visits with the stroke physician.
In our study population there was high persistence with all medications prescribed by physicians at the 3-months follow-
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up (up to 96%), in comparison to previously reported studies (75.5% of subjects in the Adherence Evaluation After Ischemic Stroke—Longitudinal (AVAIL) Registry) [5]. As expected, in comparison to the 3-month persistence, the proportion of patients taking all prescribed medications declined during the follow-up period, which is in agreement with the results of a previously study [3]. We observed a higher rate of long-term persistence with secondary stroke prevention medications in both groups, than was previously reported [3,4]. In the nationwide follow-up study from the Swedish Stroke Register, only 45–74% of the patients discharged with a specific preventive drug were still regularly using that drug 2 years after stroke [3]. This finding might be due to the fact that our study was a single center study with all patients recruited from a Stroke Unit where the medical staff are generally more committed to providing patients with detailed explanations about stroke and the necessity of secondary stroke prevention [7]. We are aware of the possible risk of overestimation of persistence because of the self-reported drug use in our study. In conclusion, we have shown that medication persistence was higher among IVT-treated stroke patients compared to non-IVTtreated stroke patients and that the higher rate of non-persistence occurred in patients with more pronounced disabilities after stroke. Disclosures D.R.J. has received honoraria from Boehringer Ingelheim; L.B.-B. has received honoraria from Boehringer Ingelheim. The remaining authors declare no conflicts of interest. Funding Funding was received from the Ministry of Science, Republic of Serbia (Projects no. 175022 and no. 175087).
References [1] R. Luengo-Fernandez, A.M. Gray, P.M. Rothwell, Oxford Vascular Study, A population-based study of hospital care costs during 5 years after transient ischemic attack and stroke, Stroke 43 (2012) 3343–3351. [2] S.M. Davis, G.A. Donnan, Clinical practice. Secondary prevention after ischemic stroke or transient ischemic attack, N. Engl. J. Med. 366 (2012) 1914–1922. [3] E.L. Glader, M. Sjölander, M. Eriksson, M. Lundberg, Persistent use of secondary preventive drugs declines rapidly during the first 2 years after stroke, Stroke 41 (2) (2010) 397–401. [4] T. Sappok, A. Faulstich, E. Stuckert, H. Kruck, P. Marx, H.C. Koennecke, Compliance with secondary prevention of ischemic stroke: a prospective evaluation, Stroke 32 (8) (2001) 1884–1889. [5] C.D. Bushnell, L.O. Zimmer, W. Pan, et al., Persistence with stroke prevention medications 3 months after hospitalization, Arch. Neurol. 67 (2010) 1456–1463, http://dx.doi.org/10.1001/archneurol.2010.190. [6] R.E. O’Carroll, J.A. Chambers, M. Dennis, C. Sudlow, M. Johnston, Improving adherence to medication in stroke survivors: a pilot randomized controlled trial, Ann. Behav. Med. 46 (2013) 358–368. [7] H. Lummis, I. Sketris, G. Gubitz, M. Joffres, G. Flowerdew, Medication persistence rates and factors associated with persistence in patients following stroke: a cohort study, BMC Neurol. 8 (2008) 25, http://dx.doi.org/10.1186/ 1471-2377-8-25. [8] D.R. Jovanovic, Lj. Beslac-Bumbasirevic, M. Budimkic, SETIS Investigation Group, et al., Do women benefit more fromsystemic thrombolysis in acute ischemic stroke? A Serbian experience with thrombolysis in ischemic stroke (SETIS) study, Clin. Neurol. Neurosurg. 111 (2009) 729–732. [9] J.A. Cramer, A. Roy, A. Burrell, et al., Medication compliance and persistence: terminology and definitions, Value Health 11 (1) (2008) 44–47, http://dx.doi. org/10.1111/j.1524-4733.2007.00213.x. [10] L.B. Goldstein, G.P. Samsa, D.B. Matchar, R.D. Horner, Charlson Index comorbidity adjustment for ischemic stroke outcome studies, Stroke 35 (2004) 1941–1945. [11] J. Bamford, P. Sandercock, M. Dennis, et al., Classification and natural history of clinically identifiable subtypes of cerebral infarction, Lancet 337 (1991) 1521–1526. [12] H.P. Adams Jr, B.H. Bendixen, L.J. Kappelle, et al., Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment, Stroke 24 (1993) 35–41. [13] W. Hacke, M. Kaste, C. Fieschi, et al., Randomized doubleblind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II), Lancet 352 (1998) 1245–1251.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Long-term medication persistence in stroke patients treated with intravenous thrombolysis Maja Stefanovic Budimkic a , Tatjana Pekmezovic b,c , Ljiljana Beslac-Bumbasirevic b , Marko Ercegovac a,b , Ivana Berisavac a,b , Predrag Stanarcevic a , Visnja Padjen a , Dejana R. Jovanovic b,∗ a
Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia Medical Faculty University of Belgrade, Belgrade, Serbia c Institute of Epidemiology, Belgrade, Serbia b
a r t i c l e
i n f o
Article history: Received 18 June 2015 Received in revised form 20 November 2015 Accepted 9 December 2015 Available online 14 December 2015 Keywords: Intravenous thrombolysis Stroke outcome Medication persistence
a b s t r a c t Objective: There are no data regarding long-term medication persistence in stroke survivors treated with intravenous thrombolysis (IVT), which is one of the most important determinants of treatment success. Our objective was to determine long-term medication persistence in stroke patients treated with IVT. Methods: This retrospective observational study included 203 IVT-treated and 197 non-IVT treated patients with acute ischemic strokes (IS) admitted to the Stroke Unit between January 2007 and January 2013. Results: During a median follow-up period of 3 years (range 1–7 years), 56 (21.6%) patients in the IVTgroup and 62 (23.9%) patients in the non-IVT-group died. There was a higher medication persistence for all secondary stroke prevention medications (anti-thrombotic agents, anti-hypertensive drugs, statins and hypoglycemic drugs) in the IVT-group compared to the non-IVT group (88.7% vs. 69.0%; OR = 3.68, 95% CI = 2.17–6.23). After adjusting for baseline characteristics and possible confounders IVT was the independent predictor of medication persistence (OR = 2.93, 95% CI = 1.48–5.81, p = 0.002). Higher medication persistence was observed in patients with favorable long-term functional outcome, both in the IVT-group (OR = 4.37, 95% CI = 1.83–10.40, p < 0.001) and the non-IVT-group (OR = 3.46, 95% CI = 1.84–6.52, p < 0.001). Conclusion: Medication persistence was higher among IVT-treated patients compared to non-IVT-treated patients. The higher rate of non- medication persistence was recorded among patients with more pronounced disabilities after stroke. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Recurrent strokes constitute a notable proportion of all preventable strokes (up to 30%) and are more disabling, fatal and costly than the first stroke [1]. Strategies to reduce the increasing global burden of stroke include not only mass population high-risk approaches to prevent first-ever stroke but also the treatment of acute stroke patients and the secondary prevention of recurrent stroke. Preventive treatments such as medications and a healthy lifestyle have shown efficacy on stroke recurrence [2]. Despite the evident success in reducing stroke recurrence, the long-term
∗ Corresponding author. Clinical Centre of Serbia, Neurology Clinic, Dr Subotica 6, PO Box 12, 11129 Belgrade 102, Serbia. Fax: +381 11 2644667. E-mail address: [email protected] (D.R. Jovanovic). http://dx.doi.org/10.1016/j.clineuro.2015.12.003 0303-8467/© 2015 Elsevier B.V. All rights reserved.
persistence of preventive medications in stroke survivors is frequently quite low and varies from 45 to 90% [3–7]. Data regarding long-term medication persistence in stroke survivors treated with intravenous thrombolysis (IVT) are lacking. Our objective in the current study to determine long-term medication persistence in stroke patients treated with IVT compared to patients not treated with IVT. 2. Methodology This retrospective observational study included patients with acute ischemic stroke (IS) admitted to the Stroke Unit of the Department of Emergency Neurology of Clinical center of Serbia in Belgrade, between January 2007 and January 2013. The inclusion criteria for the study were as follows: (1) the absence of comorbidities that would significantly affect patient outcome, such as
20
M.S. Budimkic et al. / Clinical Neurology and Neurosurgery 141 (2016) 19–22
proven malignant disease or terminal renal insufficiency, (2) presence of pre-stroke functional independence (modified Rankin score (mRS) 0–1) and (3) the accessibility of long-term outcome information. Two hundred fifty-nine patients with acute IS treated with IVT and 259 controls with acute IS not treated with IVT who were admitted to the Stroke Unit within 24 h from stroke onset were included in the study. All subjects treated with IVT are the part of an ongoing, prospective, multicenter, open, observational Serbian Experience with Thrombolysis in Ischemic Stroke registry (SETIS), as published previously [8]. Patients’ clinical characteristics and outcome measures were obtained from the SETIS registry for the IVT group and from the hospital registry of the Stroke Unit for the non-IVT group. Clinical outcome was assessed by examining the subsequent outpatient reports and telephone interviews with the patients or their caregivers one year after stroke or later. During follow- up all of the patients had regularly scheduled check-up examinations. For the purpose of this study, all of the patients were also examined and interviewed between June 2013 and January2014. The following data were collected: (1) the use of medication in stroke survivors prescribed by their stroke physicians at the time of discharge from the Stroke Unit (anti- thrombotic agents, antihypertensive drugs, statins and hypoglycemic drugs), (2) follow-up persistence, (3) discontinuation rates (physician recommendation or self-discontinued), and (4) the degree of functional recovery expressed by modified Rankin score at the moment of contact with the patient (excellent functional outcome is defined as a mRS = 0 or 1). The primary outcome measure was persistence with secondary stroke prevention medications, defined as continuation with recommended therapy or class of therapy from discharge through the follow-up period [9]. Medication continuation was determined by comparing the recommended hospital discharge medications (or prescribed list of medications by the stroke physician during check-ups) with the current medications reported by the patients. These information was collected during check-up examinations and interviews conducted by Lj.B.B, D.R.J. and M.S.B. In addition, we asked patients whether or not they took prescribed medications as recommended from a stroke care physician or some other physician. The study was approved by the Ethics Committee of the Medical Faculty University of Belgrade (Serbia). Written informed consent for the participation in the study was obtained from all participants or their proxies. 2.1. Statistics Comparisons between groups were assessed using parametric and nonparametric tests (Analysis of variance; t-test, 2 test, Mann–Whitney U-test and Kruskall–Wallis test), as appropriate. Statistical significance was set at a P < 0.05 (2-sided). Multiple logistic regression with stepwise backward variable removal (P > 0.05 as the removal criterion) was performed to test for an association between medication persistence and previous IVT treatment with baseline demographic and clinical characteristics as possible confounders. SPSS 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. 3. Results During a median follow-up period of 3 years (range 1–7 years), 56 (21.6%) patients in the IVT-group and 62 (23.9%) patients in the non-IVT-group died. Therefore, a total of 203 subjects in the IVT-group and 197 subjects in the non-IVT-group were included in
Fig. 1. Long-term medication persistence and functional recovery in IVT and nonIVT treated patients.
the analysis. Patient baseline clinical characteristics and functional outcome at 3-months are shown in Table 1. The characteristics among stroke survivors in both groups of patients did not differ significantly, except for a better 3-month functional recovery in the IVT-treated group. Table 2 shows the persistence of medications prescribed at discharge according to IVT treatment. Medication persistence was greater the in IVT-group for all classes of medications, with the greatest differences between groups for anti-platelet and antihypertensive drugs. Primary care physician recommended discontinuing antiplatelet therapy in 3 patients in the IVT-group and 17 patients in the non-IVT group, without a reasonable medical justification, while six patients in IVT-group and 13 patients in the non-IVT group have self-discontinued anti-platelet therapy. With respect to the use of oral anti-coagulants, three thrombolysed patients versus eight non-thrombolysed patients discontinued the recommended anti-coagulant therapy prescribed for atrial fibrillation. Statins were discontinued by primary care physician for 17 subjects in the IVT-group and 10 subjects in the control group because of normalization of serum cholesterol levels after initiation of statin therapy. Self-discontinuation of statin therapy occurred in 21 cases and 37 controls; of note these patients lost control of serum cholesterol levels. All of the patients who were persistent in taking the prescribed medication for secondary stroke prevention reported that they took medications as recommended by of a health care provider. Persistence with all prescribed medications was higher in the IVT-group (88.7% of patients in the IVT-group vs. 69% in the nonIVT group). After adjusting for baseline characteristics and possible confounders IVT was an independent predictor of medication persistence (OR = 3.36, 95% CI = 1.90-5.11, p = 0.001, Table 3). Higher medication persistence was observed in patients with excellent long-term functional outcome, both in IVT-group (OR = 4.37, 95% CI = 1.83- 10.40, p < 0.001) and non-IVT-group (OR = 3.46, 95% CI = 1.84–6.52, p < 0.001), as presented in Fig. 1.
4. Discussion No studies have investigated long-term medication persistence in stroke patients treated with IVT. We noted that there was higher persistence to secondary stroke prevention medications among stroke patients treated with IVT compared to non-IVT treated patients, and patients with better recovery were more persistent in taking all of the medications prescribed. It is possible that stroke patients with better recovery are ready to take the necessary steps to prevent future strokes. Also, it is possible that patients with more pronounced disabilities and dependence have a low percep-
M.S. Budimkic et al. / Clinical Neurology and Neurosurgery 141 (2016) 19–22
21
Table 1 Baseline characteristics of stroke survivors according to IVT treatment. IVT group (N = 203)
Control group (N = 197)
p
55 (48–62) 140 (69.0) 178 (87.7) 46 (22.7)
56(48–63) 138 (70.0) 153 (77.6) 56 (28.4)
0.432 0.829 0.008 0.207
Stroke severity NIHSS score, median (IQR) NIHSS score ≥15, n (%)
9 (6–15) 53 (26.1)
8 (6–14) 41 (20.8)
0.329 0.239
Vascular risk factors, n (%) Hypertension Hyperlipoproteinemia Smoking, current Diabetes mellitus Atrial fibrillation
158 (77.8) 132 (65.0) 103 (50.7) 30 (14.8) 38 (18.7)
148 (75.1) 142 (72.1) 99 (50.2) 42 (21.3) 28 (14.2)
0.636 0.194 1.000 0.092 0.229
Clinical stroke syndromea , n (%) TACS PACS LACS POCS
57 (28.1) 75 (36.90) 40 (19.7) 31 (15.3)
47 (23.9) 77 (39.1) 33 (16.70) 40 (20.3)
Stroke etiologyb , n (%) LAA Small artery occlusion Cardioembolism Other Undetermined
42 (20.7) 34 (16.7) 45 (22.2) 30 (14.8) 52 (25.6)
47 (23.9) 32 (16.2) 36 (18.3) 37 (18.8) 45 (22.8)
0.640
Prior use of antithrombotics, n (%) Warfarin Antiplatelets
6 (2.9) 40 (19.7)
12 (6.1) 32 (16.2)
0.152 0.435
Prior use of statins, n (%)
14 (6.9)
16 (8.1)
0.706
Charlson comorbidity index [10], mean (SD)
0.50 ± 0.75
0.58 ± 0.81
0.312
Symptomatic ICH (ECASS-2)c , n (%)
6 (3.0)
1 (0.5)
0.486
mRS 0–1 after 3 months, n (%)
131 (64.5)
109 (55.3)
0.05
Persistence to medications for secondary prevention of stroke at 3 months after index stroke, n (%)
195 (96.1)
180 (91.3)
0.063
Length of follow-up (y) Median (IQR), range Median ≥3 y, n (%)
3 (1–4), range 1–7 102 (50.2)
3 (1–5), range 1–7 99 (50.2)
1.000 1.000
Age (y), median (IQR) Male sex, n (%) Married/partnered pre-stroke, n (%) Education level (≥14 years of school)
0.438
IVT:indicates intravenous thrombolysis; NIHSS:national Institute of Health Stroke Scale; PACS:partial anterior circulation stroke; POCS:posterior circulation stroke; TACS:total anterior circulation stroke, LACS:lacunar stroke; ICH:intracranial hemorrhage. a According to Oxfordshire Community Stroke Project classification [11]. b According to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification [12]. c sICH, Symptomatic intracranial hemorrhage according to the ECASS-2 trial definitions [13]. Table 2 Follow-up persistence by drug class according to IVT treatment.
Anti-platelets Oral anti-coagulants Anti-hypertensive drugs Statins Hypoglycemic drugs
Prescription at Hospital Discharge, n
Persistence, n (%)
IVT(N = 203)
IVT
Non-IVT
OR, 95% CI
148 (91.9) 40 (93.0) 163 (94.8) 142 (91.0) 33 (91.7)
131 (81.4) 29 (78.4) 144 (85.7) 125 (77.2) 33 (71.7)
2.61 (1.30–5.21) 3.68 (0.90–15.07) 3.02 (1.36–6.71) 3.00 (1.55–5.81) 3.15 (0.93–10.69)
161 43 172 156 36
Non-IVT(N = 197) 161 37 168 162 46
Table 3 Predictors of follow-up persistence.
IVT Hypertension Marital status mRS 0–1 after 3 months mRS 4–5 after 3 months
Univariate analysisOR, 95% CI
Multivariate analysisOR, 95% CI
3.51 (2.07–5.96) 0.48 (0.29–0.92) 0.45 (0.26–0.80) 1.25 (1.01–2.03) 0.49 (0.26–0.98)
3.36 (1.90–5.61)
tion of benefits from medications and more difficulties in returning to follow-up visits with the stroke physician.
In our study population there was high persistence with all medications prescribed by physicians at the 3-months follow-
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M.S. Budimkic et al. / Clinical Neurology and Neurosurgery 141 (2016) 19–22
up (up to 96%), in comparison to previously reported studies (75.5% of subjects in the Adherence Evaluation After Ischemic Stroke—Longitudinal (AVAIL) Registry) [5]. As expected, in comparison to the 3-month persistence, the proportion of patients taking all prescribed medications declined during the follow-up period, which is in agreement with the results of a previously study [3]. We observed a higher rate of long-term persistence with secondary stroke prevention medications in both groups, than was previously reported [3,4]. In the nationwide follow-up study from the Swedish Stroke Register, only 45–74% of the patients discharged with a specific preventive drug were still regularly using that drug 2 years after stroke [3]. This finding might be due to the fact that our study was a single center study with all patients recruited from a Stroke Unit where the medical staff are generally more committed to providing patients with detailed explanations about stroke and the necessity of secondary stroke prevention [7]. We are aware of the possible risk of overestimation of persistence because of the self-reported drug use in our study. In conclusion, we have shown that medication persistence was higher among IVT-treated stroke patients compared to non-IVTtreated stroke patients and that the higher rate of non-persistence occurred in patients with more pronounced disabilities after stroke. Disclosures D.R.J. has received honoraria from Boehringer Ingelheim; L.B.-B. has received honoraria from Boehringer Ingelheim. The remaining authors declare no conflicts of interest. Funding Funding was received from the Ministry of Science, Republic of Serbia (Projects no. 175022 and no. 175087).
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