Association between insufficient medication of antihypertensives and the severity of acute ischemic stroke
© Lee et al. 2016
Received: 26 September 2015
Accepted: 4 February 2016
Published: 19 February 2016
Although recent studies have suggested that adherence to antihypertensive treatment reduced stroke incidence, the relationship of adherence to antihypertensives with stroke severity has not been studied. This study attempted to know whether nonadherence before stroke is associated with initial severity of acute ischemic stroke.
Consecutive patients with acute ischemic stroke were identified in Soonchunhyang University Hospital from Mar 2005 to Aug 2014, excluding the cases without hypertension or information of antihypertensive adherence. We compared the mean of National Institute of Health Stroke Scale (NIHSS) score between adherence groups and insufficient medication group, and additionally in each stroke subtype. Multiple linear regression model was established for initial NIHSS score adjusting alleged factors linked to stroke severity.
Initial NIHSS score were higher in insufficient medication group than adherence group (6.5 ± 7.2 VS 5.4 ± 5.7, P = .11). In large artery atherosclerosis (LAA) and small vessel occlusion (SVO), initial NIHSS score were significantly higher in insufficient medication group (6.1 ± 6.5 VS 4.4 ± 4.4, P = .004 for LAA; 3.8 ± 3.5 VS 2.7 ± 1.8, P = .014 for SVO). In multiple linear regression model, insufficient medication to antihypertensives had a significant effect on NIHSS score (t = 3.417, P = .001) after adjusting covariates.
Insufficient medication of antihypertensives before stroke was independently associated with the severity of acute ischemic stroke. Further studies with prospective designs are warranted to evaluate clinical implication of adherence to antihypertensives for ischemic stroke.
KeywordsAntihypertensive Stroke severity NIHSS Hypertension Adherence
Benefits of blood pressure lowering for primary stroke risk reduction are broadly consistent across a range of different population [1–4]. Recent studies support that more intensive control of blood pressure reduces risk of stroke more than less intensive control [5–8]. However, high adherence to antihypertensive treatment in terms of reduction of cardiovascular events has been relatively underscored in the field of evidence-based therapies of population .
Adherence to antihypertensive is closely related to the time within therapeutic range, and may influence on the cardiovascular prognosis . The associations between non-adherence and stroke events followed a dose-response pattern, and the poorer the adherence, the greater the risk of death and hospitalization due to stroke . The World Health Organization (WHO) had estimated that between 20–80 % of patients receiving treatment for hypertension are adherent . In Korea, among people aged more than 30 years with hypertension, 61.9 % were on regular treatment, and only 43.6 % had their blood pressure under control . Nonadherence to antihypertensive treatment is a common problem for cardiovascular prevention in Korean population.
The initial stroke severity has been reported as the most important predictor for poststroke outcome [14–16], and is correlated with stroke subtypes . A few study reported a controversial class effect of antihypertensive drugs [18, 19] and the combination with antiplatelet or statin on stroke severity , but the relationship between the pre-stroke non-adherence to antihypertensives and stroke severity has been largely unknown.
This study aimed to investigate whether nonadherence to antihypertensives prior to acute ischemic stroke is associated with initial stroke severity in patients with hypertension.
A total 2335 consecutive patients with first acute (<7 days) ischemic stroke or imaging-positive transient ischemic attack were registered in Soonchunhyang University Hospital from Mar 2005 through Aug 2014. This web-based registry contains clinical characteristics, laboratory/imaging findings, and cardiovascular outcomes after discharge . The study design was approved by the Soonchunhyang institutional review board before investigation. Hypertension was detected in 1660 (71.1 %) patients. The diagnostic criteria of hypertension were 1) history of diagnosis prior to acute ischemic stroke or 2) systolic/diastolic blood pressure (SBP/DBP) of ≥160/95 mmHg in at least two subsequent measurement after stable state of acute stroke or 3) evidence of left ventricular hypertrophy in echocardiography or hypertensive retinopathy during hospitalization. LVH with diabetes or other metabolic causes was excluded in case of no history of hypertension.
Data collection and workup
Data were prospectively collected including history of hypertension, medication history, vascular risk factors, laboratory findings, stroke subtypes, initial National Institute of Health Stroke Scale (NIHSS) Score. Adherence to antihypertensives during the last one month were captured by patient’s or caregiver’s information, and were categorized into two groups: adherence (regular medication) and insufficient medication (diagnosed but no medication, irregular medication, and undetected before index stroke). The patients who took medications more than 80 % of the last one month were categorized as regular medication. The cases with missing data for adherence to antihypertensives prior to acute ischemic stroke were excluded (n = 93, 5.6 %).
Stroke subtypes were determined by extensive workups including magnetic resonance imaging/angiography, echocardiography, and Holter monitoring in all patients: large artery atherosclerosis (LAA), small vessel occlusion (SVO), cardioembolism (CE), and undetermined etiology (SUE). Stroke with other determined etiology were excluded (n = 29). Finally, 1538 cases were analyzed.
Categorical variables were reported as frequency and continuous variables as mean ± standard deviation. Chi-square test was used to determine the relationship with categorical variables, and student T-test to compare the means of continuous variables between adherence and insufficient medication group. The difference of NIHSS score between adherence group and insufficient medication group were determined by T-test in each stroke subtype. Multiple linear regression model was established for initial NIHSS score adjusting covariates which have an influence on initial stroke severity in univariate analysis and previous reports. Statistical significance was defined as P <0.01 in multiple linear regression. All statistical analyses were done with SPSS 18.0 for Windows (Chicago, USA).
Baseline characteristics between adherence and insufficient medication group
Adherence (n = 1232, 80.1 %)
Insufficient medication (n = 306, 19.9 %)
69.6 ± 11.5
66.1 ± 12.2
704 (57.1 %)
156 (51.0 %)
24.0 ± 3.3
24.5 ± 3.6
5.4 ± 5.7
6.5 ± 7.2
Initial SBP, mmHg
146.6 ± 26.4
151.6 ± 28.2
Initial DBP, mmHg
85.8 ± 14.3
91.0 ± 15.6
Previous stroke history
284 (23.1 %)
57 (18.6 %)
103 (8.7 %)
17 (5.6 %)
97 (7.9 %)
15 (4.9 %)
538 (43.7 %)
61 (37.2 %)a
271 (22.0 %)
33 (20.1 %)
406 (33.0 %)
52 (31.7 %)
117 (9.5 %)
23 (14.0 %)
303 (24.6 %)
34 (20.7 %)
546 (44.3 %)
133 (43.5 %)
302 (24.5 %)
152 (49.7 %)
256 (20.8 %)
103 (33.7 %)
323 (26.2 %)
48 (15.7 %)
Total cholesterol, mg/dL
167.0 ± 42.4
216.1 ± 44.2
Initial glucose, mg/dL
133.5 ± 60.5
141.0 ± 60.0
Hemoglobin A1c, %
6.6 ± 1.5
6.9 ± 1.9
Mean NIHSS score among stroke subtypes
Large artery atherosclerosis
4.4 ± 4.4
6.1 ± 6.5
Small vessel occlusion
2.7 ± 1.8
3.8 ± 3.5
9.3 ± 7.4
12.7 ± 11.0
7.0 ± 6.8
8.4 ± 8.3
5.5 ± 5.7
6.5 ± 7.2
Multiple linear regression model for initial NIHSS in acute ischemic stroke
Body Mass Index
Previous stroke history
This study demonstrates that low antihypertensive medication adherence was related to severe acute ischemic stroke. Nonadherence is an important and very amenable factor to change among cardiovascular risk factors for hypertensive patients . Self-reported adherence to cardiovascular medications in patients who have coronary artery disease is less than 40 % . However, the nonadherence to antihypertensive for primary cardiovascular prevention would be as high as 50 % . The efficacy of antihypertensives has been evaluated in randomized clinical trials (RCTs), but in actual practice, many patients who would be excluded from RCTs receive medication for a long time, and may not be as adherent with medication as those included in RCTs . A tertiary medical center in Korea reported that average non-compliance to the single drug antihypertensive regimen was 16 % in the cardiology practice . In general Korean population, however, about one third are not on regular antihypertensive treatment . The overall rate of nonadherence was about 20 % in our 10-year observation study, and the fraction of nonadherence was higher in female.
Assessing adherence to hypertensive therapy for cardiovascular prevention is a complex process influenced by multiple factors . Previous studies differentiates between adherent and nonadherent patients by prescription claim, drug refill, patients’ records, motivation and knowledge [23, 28, 29]. This study collected data about the regularity of medication by patient’s or caregiver’s description during the last one month before acute ischemic stroke. Given an observational nature of our study, this would lead to many epidemiological bias. However, because complicated scales could not be applied in the setting of acute stroke enrolling consecutive patients, we have used simple item to evaluate adherence before stroke in registry system. Although unrecognized hypertension should be considered separately from nonadherence to antihypertensives, this study was to measure stroke severity in whom blood pressure were not adequately controlled. Therefore, hypertension diagnosed at admission were included within insufficient medication group. Most previous study obtained the adherence data at one point of several years before stroke event [9, 11, 30], out study checked shortly before stroke reflecting recent adherence.
The pathophysilogic mechanisms between uncontrolled hypertension and severe stroke needs to be studied. One previous study suggested that prestroke beta-blocker use is related to less severe ischemic stroke by sympatholytic effect . High blood pressure can result in increased glucocorticoid level and inflammatory marker which can aggravate cell death in penumbra area [31–34]. Reduction in arterial pressure by hydralazine with hydrochlorothiazide or an angiotensin converting enzyme inhibitor is protective against focal cerebral ischemia in stroke-prone spontaneously hypertensive rats model . Nonadherence to antihypertensive medication prior to first stroke was associated with a 5.7-fold increased odds of fatal stroke during the year of death and a two-fold increased risk of nonfatal stroke . Higher odds of fatal stroke than that of nonfatal stroke may indicate that nonadherence is closely related to more severe stroke.
It is noteworthy that the achievement of target BP goal is an important factor for preventing stroke. Although there was a significant difference in the stroke severity between adherence and insufficient medication groups, mean SBP/DBP were higher in insufficient medication group. The values of mean SBP/DBP which failed to reach a target goal may influence on the severity of acute ischemic stroke. However, the acute hypertensive response is very common in acute stroke period (occurring in >75 % of cases), and may be induced by increased sympathoadrenal tone, direct brain injury, systemic condition or stress response . The difference of SBP/DBP can be a consequence of more severe stroke in insufficient group. For this reason a strict definition should be needed for the “history of hypertension” in acute stroke registry. The definition of hypertension in this study was 160/95 instead of 140/90. In the Framingham cohort, the “definite hypertension” was defined as 160/95 . Previous studies assessed the history of stage II hypertension as blood pressure ≥160/95 mm Hg or use of antihypertensive medicine at baseline questionnaire .
Our study has several limitations. First, the data of insufficient medication were captured only for antihypertensives, but not for antiplatlets, antidiabetics or lipid lowering agents. Prestroke antiplatelets may be associated with stroke severity [39, 40]. However, the proportion of antiplatelet user before stroke was neither high nor different between the two groups in our study population (8.7 % VS 5.6 %, P = .121). Moreover, individual adherences to medications were not different across vascular risk factors . Second, this study was single center-based, although the number of subjects was enough to be compared with previous studies. Our results need external validation to confirm the association between insufficient medication and stroke severity. Third, it is known that the NIHSS score does not generally show normal distribution to be an outcome variable in linear regression model. However, the case number of our study was sufficiently large with good explanation power and model fitness (R square = 0.653; F = 18.716, P < .001), and there was no multicollinearity between variables in our regression model (VIF <2). Finally, in our study, insufficient medication patients had more smokers and higher serum cholesterol level. Although the association between insufficient medication and stroke severity was significant after adjusting these variables, the social habit and healthy conditions should be considered as influencing factors on nonadherence in Korean.
In conclusion, our study in the patients with acute ischemic stroke, insufficient medication to antihypertensives before stroke was independently associated with stroke severity. Further prospective cohort are warranted to evaluate clinical implication of adherence to medications for prevention of cardiovascular disease.
This study was supported by 1) the Soonchunhyang University Research Fund, and 2) a grant of Kuhnil Pharmaceutical Company.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: Prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–74.View ArticlePubMedGoogle Scholar
- MacMahon S. Antihypertensive drug treatment: The potential, expected and observed effects on vascular disease. J Hypertens Suppl. 1990;8:S239–44.View ArticlePubMedGoogle Scholar
- Neal B, MacMahon S, Chapman N. Effects of ace inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Blood pressure lowering treatment trialists’ collaboration. Lancet. 2000;356:1955–64.View ArticlePubMedGoogle Scholar
- Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. Us population data. Arch Intern Med. 1993;153:598–615.View ArticlePubMedGoogle Scholar
- Lee M, Saver JL, Hong KS, Hao Q, Ovbiagele B. Does achieving an intensive versus usual blood pressure level prevent stroke? Ann Neurol. 2012;71:133–40.View ArticlePubMedGoogle Scholar
- Barzilay JI, Howard AG, Evans GW, Fleg JL, Cohen RM, Booth GL, et al. Intensive blood pressure treatment does not improve cardiovascular outcomes in centrally obese hypertensive individuals with diabetes: The action to control cardiovascular risk in diabetes (accord) blood pressure trial. Diabetes Care. 2012;35:1401–5.PubMed CentralView ArticlePubMedGoogle Scholar
- Cushman WC, Evans GW, Byington RP, Goff Jr DC, Grimm Jr RH, Cutler JA, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575–85.View ArticlePubMedGoogle Scholar
- Wright Jr JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16.View ArticlePubMedGoogle Scholar
- Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordino V, et al. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation. 2009;120:1598–605.View ArticlePubMedGoogle Scholar
- Chobanian AV. Impact of nonadherence to antihypertensive therapy. Circulation. 2009;120:1558–60.View ArticlePubMedGoogle Scholar
- Herttua K, Tabak AG, Martikainen P, Vahtera J, Kivimaki M. Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: Population-based study. Eur Heart J. 2013;34:2933–9.PubMed CentralView ArticlePubMedGoogle Scholar
- World health organization. Adherence to long-term therapies: Evidence for action. Geneva: WHO; 2003.Google Scholar
- Ministry of Health and Welfare of Korea, Korea Centers for Disease Control and Prevention. 2010 Korea Health Statistics. Seoul: Ministry of Health and Welfare of Korea; 2011.
- Vibo R, Korv J, Roose M. One-year outcome after first-ever stroke according to stroke subtype, severity, risk factors and pre-stroke treatment. A population-based study from tartu, estonia. Eur J Neurol. 2007;14:435–9.View ArticlePubMedGoogle Scholar
- Jamrozik K, Broadhurst RJ, Lai N, Hankey GJ, Burvill PW, Anderson CS. Trends in the incidence, severity, and short-term outcome of stroke in perth, western australia. Stroke. 1999;30:2105–11.View ArticlePubMedGoogle Scholar
- Rincon F, Dhamoon M, Moon Y, Paik MC, Boden-Albala B, Homma S, et al. Stroke location and association with fatal cardiac outcomes: Northern manhattan study (nomas). Stroke. 2008;39:2425–31.PubMed CentralView ArticlePubMedGoogle Scholar
- Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to toast criteria: Incidence, recurrence, and long-term survival in ischemic stroke subtypes: A population-based study. Stroke. 2001;32:2735–40.View ArticlePubMedGoogle Scholar
- Laowattana S, Oppenheimer SM. Protective effects of beta-blockers in cerebrovascular disease. Neurology. 2007;68:509–14.View ArticlePubMedGoogle Scholar
- Sacco S, Toni D, Bignamini A, Zaninelli A, Gensini G, Carolei A, et al. Effect of prior medical treatments on ischemic stroke severity and outcome. Funct Neurol. 2011;26:133–9.PubMed CentralPubMedGoogle Scholar
- De Raedt S, Haentjens P, De Smedt A, Brouns R, Uyttenboogaart M, Luijckx GJ, et al. Pre-stroke use of beta-blockers does not affect ischaemic stroke severity and outcome. Eur J Neurol. 2012;19:234–40. doi:10.1111/j.1468-1331.2011.03475.x. Epub 02011 Jul 03421.View ArticlePubMedGoogle Scholar
- Kim BJ, Park JM, Kang K, Lee SJ, Ko Y, Kim JG, et al. Case characteristics, hyperacute treatment, and outcome information from the clinical research center for stroke-fifth division registry in south korea. J Stroke. 2015;17:38–53.PubMed CentralView ArticlePubMedGoogle Scholar
- Bailey JE, Wan JY, Tang J, Ghani MA, Cushman WC. Antihypertensive medication adherence, ambulatory visits, and risk of stroke and death. J Gen Intern Med. 2010;25:495–503.PubMed CentralView ArticlePubMedGoogle Scholar
- Newby LK, LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER, et al. Long-term adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation. 2006;113:203–12.View ArticlePubMedGoogle Scholar
- Garfield FB, Caro JJ. Compliance and hypertension. Curr Hypertens Rep. 1999;1:502–6.View ArticlePubMedGoogle Scholar
- Evans A, Kalra L. Are the results of randomized controlled trials on anticoagulation in patients with atrial fibrillation generalizable to clinical practice? Arch Intern Med. 2001;161:1443–7.View ArticlePubMedGoogle Scholar
- Sung J, Choi JH, On YK, Lee SC, Park SW, Gwon HC, et al. Study of compliance to antihypertensive medication in korean hypertensive patients using medication event monitoring system. Korean Circ J. 2005;35:821–6.View ArticleGoogle Scholar
- Ockene JK, Schneider KL, Lemon SC, Ockene IS. Can we improve adherence to preventive therapies for cardiovascular health? Circulation. 2011;124:1276–82. doi:10.1161/CIRCULATIONAHA.1110.968479.View ArticlePubMedGoogle Scholar
- Morisky DE, Levine DM, Green LW, Shapiro S, Russell RP, Smith CR. Five-year blood pressure control and mortality following health education for hypertensive patients. Am J Public Health. 1983;73:153–62.PubMed CentralView ArticlePubMedGoogle Scholar
- Bushnell C, Zimmer L, Schwamm L, Goldstein LB, Clapp-Channing N, Harding T, et al. The adherence evaluation after ischemic stroke longitudinal (avail) registry: Design, rationale, and baseline patient characteristics. Am Heart J. 2009;157:428–35. e422.View ArticlePubMedGoogle Scholar
- Degli Esposti L, Saragoni S, Benemei S, Batacchi P, Geppetti P, Di Bari M, et al. Adherence to antihypertensive medications and health outcomes among newly treated hypertensive patients. Clinicoecon Outcomes Res. 2011;3:47–54.View ArticlePubMedGoogle Scholar
- Mikdashi J, Handwerger B, Langenberg P, Miller M, Kittner S. Baseline disease activity, hyperlipidemia, and hypertension are predictive factors for ischemic stroke and stroke severity in systemic lupus erythematosus. Stroke. 2007;38:281–5.View ArticlePubMedGoogle Scholar
- Macko RF, Ameriso SF, Barndt R, Clough W, Weiner JM, Fisher M. Precipitants of brain infarction. Roles of preceding infection/inflammation and recent psychological stress. Stroke. 1996;27:1999–2004.View ArticlePubMedGoogle Scholar
- Virdis A, Dell’Agnello U, Taddei S. Impact of inflammation on vascular disease in hypertension. Maturitas. 2014;78:179–83.View ArticlePubMedGoogle Scholar
- Savoia C, Schiffrin EL. Inflammation in hypertension. Curr Opin Nephrol Hypertens. 2006;15:152–8.PubMedGoogle Scholar
- Fujii K, Weno BL, Baumbach GL, Heistad DD. Effect of antihypertensive treatment on focal cerebral infarction. Hypertension. 1992;19:713–6.View ArticlePubMedGoogle Scholar
- Qureshi AI. Acute hypertensive response in patients with stroke: Pathophysiology and management. Circulation. 2008;118:176–87.View ArticlePubMedGoogle Scholar
- Kannel WB, Wolf PA, Verter J, McNamara PM. Epidemiologic assessment of the role of blood pressure in stroke: The framingham study. 1970. JAMA. 1996;276:1269–78.View ArticlePubMedGoogle Scholar
- Hu G, Sarti C, Jousilahti P, Peltonen M, Qiao Q, Antikainen R, et al. The impact of history of hypertension and type 2 diabetes at baseline on the incidence of stroke and stroke mortality. Stroke. 2005;36:2538–43.View ArticlePubMedGoogle Scholar
- Dowlatshahi D, Hakim A, Fang J, Sharma M. Pre admission antithrombotics are associated with improved outcomes following ischaemic stroke: A cohort from the registry of the canadian stroke network. Int J Stroke. 2009;4:328–34.View ArticlePubMedGoogle Scholar
- Kim WJ, Ko Y, Yang MH, Im SH, Park JH, Lee J, et al. Differential effect of previous antiplatelet use on stroke severity according to stroke mechanism. Stroke. 2010;41:1200–4.View ArticlePubMedGoogle Scholar