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Response of Day-to-Day Home Blood Pressure Variability by Antihypertensive Drug Class After Transient Ischemic Attack or Nondisabling Stroke Alastair J.S. Webb, DPhil; Michelle Wilson, MSc; Nicola Lovett, MRCP; Nicola Paul, DPhil; Urs Fischer, MD; Peter M. Rothwell, FMedSci Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 Background and Purpose—Visit-to-visit variability in systolic blood pressure (SBP) is associated with an increased risk of stroke and was reduced in randomized trials by calcium channel blockers and diuretics but not by renin–angiotensin system inhibitors. However, time of day effects could not be determined. Day-to-day variability on home BP readings predicts stroke risk and potentially offers a practical method of monitoring response to variability-directed treatment. Methods—SBP mean, maximum, and variability (coefficient of variation=SD/mean) were determined in 500 consecutive transient ischemic attack or minor stroke patients on 1-month home BP monitoring (3 BPs, 3× daily). Hypertension was treated to a standard protocol. Differences in SBP variability from 3 to 10 days before to 8 to 15 days after starting or increasing calcium channel blockers/diuretics versus renin–angiotensin system inhibitors versus both were compared by general linear models, adjusted for risk factors and baseline BP. Results—Among 288 eligible interventions, variability in SBP was reduced after increased treatment with calcium channel blockers/diuretics versus both versus renin–angiotensin system inhibitors (−4.0 versus 6.9 versus 7.8%; P=0.015), primarily because of effects on maximum SBP (−4.6 versus −1.0 versus −1.0%; P=0.001), with no differences in effect on mean SBP. Class differences were greatest for early-morning SBP variability (3.6 versus 17.0 versus 38.3; P=0.002) and maximum (−4.8 versus −2.0 versus −0.7; P=0.001), with no effect on midmorning (P=0.29), evening (P=0.65), or diurnal variability (P=0.92). Conclusions—After transient ischemic attack or minor stroke, calcium channel blockers and diuretics reduced variability and maximum home SBP, primarily because of effects on morning readings. Home BP readings enable monitoring of response to SBP variability-directed treatment in patients with recent cerebrovascular events. (Stroke. 2014;45:2967-2973.) Key Words: antihypertensive agents ◼ home blood pressure monitoring ◼ stroke E pisodic hypertension, maximum systolic blood pressure (SBP), and visit-to-visit variability in SBP between clinic appointments1,2 were strong predictors of incident and recurrent cardiovascular events in 5 large cohorts. Calcium channel blockers (CCBs) and thiazide diuretics reduced maximum SBP and SBP variability in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOTBPLA) and Medical Research Council 2 (MRC-2) studies compared with renin–angiotensin system inhibitors (RASi) or β-blockers,3 explaining differences in stroke risk between treatment groups, with similar effects in meta-analyses of all published studies.4–6 Drug effects on SBP variability were seen in a wide range of patients4 and persisted when used in combination.7 However, clinical readings are impractical for prospectively assessing the effects of drug changes on SBP variability and maximum SBP, particularly in secondary prevention of acute cerebrovascular events when rapid control of BP variability may be desirable.8 Furthermore, clinical readings in these randomized trials were performed during office hours with no consistent time of measurement. Therefore, clinical readings from randomized controlled trials (RCTs) cannot be used to determine differences in drug class effects on BP variability at different times of day. Day-to-day SBP variability on home BP monitoring (HBPM) is also significantly associated with the risk of stroke and cardiovascular events in both primary prevention9,10 and cerebrovascular disease,11 with particularly strong associations on day-to-day readings in the early morning, before the time of clinical readings used in estimating visit-to-visit BP variability.9,10 This may reflect the association between the Received May 3, 2014; final revision received July 11, 2014; accepted July 28, 2014. From the Stroke Prevention Research Unit, Oxford University, Oxford, United Kingdom. Guest Editor for this article was Stephen M. Davis, MD, FRACP. The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 114.005982/-/DC1. Correspondence to Peter M. Rothwell, FMedSci, Stroke Prevention Research Unit, Department of Clinical Neurology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom. E-mail [email protected] © 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.114.005982 2967 2968 Stroke October 2014 morning surge in BP and risk of cardiovascular events, with episodic morning surges potentially being responsible for the association between high maximum SBP and stroke risk,1,11 as well as a parallel relationship between diurnal variability in BP and stroke risk.12 HBPM potentially offers a practical method of assessing the effects of antihypertensive treatment on SBP variability in clinical practice and could also determine whether drug class effects on BP variability are greater in the early morning, when day-to-day variability has the greatest prognostic significance, but which cannot be assessed in large RCTs. In an observational study of HBPM after transient ischemic attack or minor stroke, we investigated whether drug class effects on visit-to-visit variability in SBP demonstrated in large randomized controlled trials can be identified on day-today home SBP variability and whether drug class effects on day-to-day variability are different at different times of day. Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 Methods Study Population Consecutive patients were recruited between April 2008 and January 2012 from the Oxford Vascular Study’s (OXVASC)13 transient ischemic attack and minor stroke clinic usually <24 hours of referral.14 The OXVASC population consists of 92 728 individuals registered with 100 primary care physicians in 9 practices in Oxfordshire, United Kingdom, with high ascertainment of cardiovascular events through multiple overlapping methods of ascertainment.13 All patients requiring treatment for probable transient ischemic attack or stroke for whom consent was given underwent a standardized medical history and examination, ECG, and routine blood tests, with follow-up at 1,3, 6, 12, 24, and 60 months, usually face-to-face. The majority of patients underwent a stroke protocol MRI brain and contrast-enhanced MR angiography of the extracranial brain supplying arteries, with the remaining patients having a computed tomography brain and either a carotid Doppler ultrasound or computed tomography angiogram. The large majority of patients also routinely underwent transcranial Doppler ultrasound, echocardiography, and 5 days of ambulatory cardiac monitoring. Procedures Clinical BP was measured at ascertainment and 1-month follow-up visit in the nondominant arm, by trained personnel, in the sitting position after 5 minutes of rest, with 2 measurements made 5 minutes apart. From the ascertainment visit, or the earliest opportunity after discharge, all patients performed sets of 3 home BP readings, 3× daily (on waking, midmorning, and before sleep) with a Bluetoothenabled, regularly calibrated, telemetric BP monitor, either an IEM Stabil-o-Graph or an A&D UA-767 BT.15 Patients were instructed to relax in a chair for 5 minutes before performing readings in the nondominant arm, or the arm with the higher reading if the mean BP differed by >20 mm Hg between arms, and were assessed at doing so at ascertainment. Anonymized measures were transmitted by Bluetooth radio to a mobile phone for secure transmission to a server hosting a password-protected website for review and download of readings (t+ Medical, Abingdon, United Kingdom). Patients continued home monitoring until at least the 1-month follow-up appointment, if tolerated, but could continue to achieve adequate BP control. Mean BP was treated to a target of <130/80 on home monitoring, except in the minority of patients with an hemodynamically significant stenosis (bilateral carotid stenosis >70% or severe end-artery stenosis) when targets were determined on an individual basis. Patients could be treated at the treating physician’s discretion, but were most commonly treated according to a standardized protocol: a combination of perindopril 5 mg and indapamide 1.25 mg followed by addition of amlodipine 5 mg, then amlodipine 10 mg or indapamide 2.5 mg, with dose increases or the addition of other agents as required. Treatment was started in clinic if necessary, or after at least 1 week of HBPM. The choice of drug followed this standardized protocol regardless of BP level, BP variability, or demographic factors, but could be altered on the basis of absolute or relative contraindications, such as a previous reaction or heart failure (in the case of CCBs). Analysis Analyses were performed comparing baseline home readings acquired from 3 to 10 days before starting or increasing the dose of a drug to follow-up readings acquired from 8 to 15 days after the intervention. For each time period, the mean, minimum, and maximum SBP and diastolic BP (DBP) were derived from the average of the last 2 readings of each cluster of 3 readings at a specific time of day. Diurnal variability in SBP was measured as the coefficient of variation of the cluster averages for each day (SD of 3 time points/mean). Day-to-day variability in SBP and DBP was measured as the residual coefficient of variation about a moving average >5 days (to remove the influence of both mean BP and any underlying trend in BP) for the mean of all clusters and the mean of clusters at each time of day.16 All follow-up measures were then expressed as a percentage change compared with the baseline period. Eligible medication changes were identified as any initiation or dose increase occurring after day 7 with ≤7 days of BP monitoring data before the drug change, and a minimum of 10 days after, excluding changes in which another drug was altered within these time limits. Changes were classified as increases in treatment (starting or increasing dose) of a drug associated with low variability in SBP in RCTs (CCBs/diuretics) or high variability in SBP (RASi or β-blockers), or treatment with a combination of a drug from each class, usually a RASi and a diuretic. Second, changes were classified as increased treatment with a CCB, diuretic, RASi, or a combination of RASi and diuretic. Statistical Analysis Unadjusted differences in BP indices between patient groups were assessed by t tests or ANOVA. Univariate correlations with continuous demographic indices were measured by linear regression, and differences between groups in frequency of discrete variables were compared by χ2 tests. Multivariate general linear models (SPSS sum of squares type IV) were derived for each SBP or DBP index with independent variables including drug class allocation, age, sex, atrial fibrillation (premorbid or diagnosed <6 weeks of the event), creatinine, current smoking and a history of hypertension, diabetes mellitus, hyperlipidemia, or family history of stroke. A second model included these variables plus baseline mean SBP and baseline coefficient of variation. All analyses were performed with Matlab R2012a, Microsoft Excel 2010, and IBM SPSS 20. The study received ethical approval from the Oxfordshire Research Ethics Committee, and all participants or their relatives provided informed consent to perform home monitoring. Results Five hundred of 536 patients had adequate home readings (1 died, 8 noncerebrovascular diagnoses, 27 inadequate recordings; Figure I in the online-only Data Supplement), with a median of 15 premorbid BP measurements (interquartile range, 6.4–30.5) and 83.6 BP clusters on home monitoring (interquartile range, 56–174) >30.8 days (interquartile range, 21.1–64.5), with 2.9 BPs per cluster (SD, 0.4). Of 462 drug changes made after day 7, 112 were made <10 days of stopping monitoring and 62 were made too close to another drug change. Of the remaining 288 eligible changes, there were 131 with CCBs (69 drug initiation, 62 dose increases), 55 with RASi (35 drug initiation, 20 dose increase), 47 with diuretics (33 drug initiation, 14 dose increases), 5 with Webb et al Drug Effects on Morning Home BP Variability 2969 Table 1. Characteristics of Individuals Starting a Drug or Increasing the Dose for Each Drug Class CCB (n=131) RASi (n=55) Diuretic (n=47) RASi Plus D (n=50) P Value Male sex 55 (42) 27 (49) 21 (45) 21 (42) 0.83 Hypertension 84 (64) 31 (56) 27 (57) 28 (56) 0.64 Family history 31 (24) 18 (33) 9 (19) 14 (28) 0.41 Hyperlipidemia 56 (43) 21 (38) 17 (36) 20 (40) 0.86 Diabetes mellitus 23 (18) 9 (16) 3 (6) 9 (18) 0.30 Heart failure 11 (8) 5 (9) 2 (4) 2 (4) 0.59 AF 18 (14) 2 (4) 8 (17) 6 (12) 0.16 Smoker 19 (15) 6 (11) 10 (21) 7 (14) 0.52 Stroke vs TIA Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 76 (58) 32 (58) 24 (51) 26 (52) 0.75 Myocardial infarction 3 (2) 1 (2) 4 (9) 3 (6) 0.19 Age 69.8 69.7 68.6 69.1 0.96 BMI 27.4 27.8 28.3 27.2 0.70 Creatinine 92.2 93.3 83.3 94.2 0.12 Cholesterol 5.1 5.4 5.3 5.1 0.59 TSH 2.3 2.2 2.1 2.2 0.96 Frequencies (%) are given, compared by χ2 tests, means by ANOVA. AF indicates atrial fibrillation; BMI, body mass index; CCB, calcium channel blocker; D, diuretic; RASi, renin–angiotensin system inhibitor; TIA, transient ischemic attack; and TSH, thyroidstimulating hormone. β-blockers (4 drug initiation, 1 drug increase), and 50 with a combination of a RASi and a diuretic (12 drug initiation, 38 dose increase). Of these eligible interventions, 100 were with amlodipine, 52 with perindopril (39 in combination with indapamide), 25 with ramipril, and 32 with indapamide alone. Baseline demographic characteristics were well-matched between intervention groups (Table 1), and there were no significant differences between groups in baseline SBP or DBP variability in day-to-day BP variability (Table 2; Table I in the online-only Data Supplement), but baseline mean and maximum SBP were slightly higher in patients treated with low-variability drugs. There was a significant reduction in variability in home SBP after treatment with CCBs or diuretics compared with RASi, with an intermediate effect of combinations containing both (Table 2) and no difference between CCBs and diuretics in effects on SBP variability (Table I in the online-only Data Supplement). There was no difference in change in global variability in DBP between drug groups (Table II in the online-only Data Supplement). Differences in change in SBP Table 2. Differences in Baseline SBP and SBP Variability and Percentage Change in Each Measure 8 Days After Starting or Increasing the Dose of Each Class of Antihypertensive Drug 3–10 d Before Intervention High 62 Combined 50 Low 178 % Change >8 d After Intervention P Value High 62 Combined 49 Low 178 P Value All measures Mean 129.5 127.7 132.4 0.038* −1.9 −2.4 −3 0.39 Minimum 110.2 109.4 112.3 0.26 −1.6 −3.6 −1.3 0.26 Maximum 149.4 147.2 154.2 0.017* rCV 7.9 8 −1.0 −1.0 7.9 0.98 7.8 6.9 134.3 0.13 −1.6 −4.6 0.001† −4 0.015* −3.7 0.09 Morning Mean 131.9 129.9 −3 Minimum 120.4 117.5 122.1 0.09 −1.9 −1.7 −2.5 0.76 Maximum 143.7 142.1 147.2 0.13 −0.7 −2.0 −4.8 0.001† rCV 5.3 5.9 5.6 0.62 38.3 7 Diurnal SD 9.8 9.1 10.4 0.23 −0.6 0.6 −1.9 3.6 0.92 0.002† Diurnal CV 7.5 7.4 7.8 0.64 2.0 3.8 1.0 0.92 Treatment groups are defined as low-variability drugs (calcium channel blockers or diuretic), high-variability drugs (renin–angiotensin system inhibitor [RASi] or βblockers), or a combination of a RASi and a diuretic. Mean values are compared by ANOVA. CV indicates coefficient of variation; rCV, residual CV about a 5-d moving average; and SBP, systolic blood pressure. *P<0.05; †P<0.01. 2970 Stroke October 2014 Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 BP variability with RASi, but the differences persisted >day 8 (Figure II in the online-only Data Supplement). Differences in drug class effects on SBP variability reflected greater differences in effects on maximum SBP than mean or minimum SBP (Table 2; Figure 2), with a similar distribution of effects at each level of maximum SBP. The effect of treatment on maximum SBP with a combination of a low- and a high-variability drug was intermediate between the 2 monotherapy interventions. Similar effects were found when treatment groups were defined as CCBs versus other drugs or as CCBs versus diuretics versus any regimen containing a RASi. There was no significant difference between groups in change in mean, minimum, or maximum DBP (Table I in the onlineonly Data Supplement). The reduction in day-to-day variability in SBP and maximum SBP with low-variability drugs was greatest for day-today early-morning SBP readings, with a significant increase in patients treated with RASi, no significant change in patients treated with CCBs or diuretics, and an intermediate effect of treatment with a combination of the 2 classes (Table 2). There was no significant difference between groups in change in day-to-day variability in SBP in the middle of the morning (P=0.79) or in the evening (P=0.72), and no difference between groups in change in diurnal variability (Table 2). The differences between drug groups in day-to-day SBP variability immediately after waking persisted after adjustment for age, sex, cardiovascular risk factors, baseline mean SBP, and baseline variability in SBP (Figure 2; Table IV in the onlineonly Data Supplement). Again drug class differences in earlymorning SBP variability primarily reflected greater reductions in maximum SBP with CCBs or diuretics (Table 2), with no difference in change in mean or minimum SBP between groups. Discussion Figure 1. Distribution of changes in mean, maximum, and variability in systolic blood pressure (SBP) after intervention with calcium channel blockers (CCBs)/diuretics vs renin–angiotensin system inhibitors (RASi). Distributions are presented as frequency of interventions resulting in a percentage change in mean SBP (A), maximum SBP (B), and residual coefficient of variation (C), comparing initiation or dose increases of CCBs or diuretics vs RASi. variability persisted after adjustment for age, sex, and cardiovascular risk factors and baseline mean and variability in SBP (CCB/diuretic versus combination versus RASi; P=0.005, post hoc; CCB/diuretic versus RASi; P=0.008; CCB/diuretic versus combination; P=001) and for models including CCBs versus diuretics versus RASi versus combinations (P=0.004). Differences between drug groups were consistent at different levels of baseline SBP variability (Figure 1). Differences between drug classes in variability in SBP were greatest immediately after the intervention, due partly to an increase in CCBs and diuretics reduced variability in SBP and maximum SBP on HBPM compared with RAS inhibitors. These drug class effects persisted with combinations of diuretics and RASi and were particularly evident with day-to-day SBP variability on early-morning readings. Effects on day-to-day variability were primarily because of a significantly greater reduction in maximum SBP with CCBs or diuretics in the morning with no differences between drugs in reduction of mean SBP at any time of day. This is the first study to demonstrate the effect of antihypertensive medications on day-to-day home SBP variability, with CCBs and diuretics reducing SBP variability compared with RASi, due primarily to effects on maximum SBP, with no significant drug class differences in effects on mean SBP. These differences were similar for maximum and variability in SBP across the population. Although the 4% reduction in BP variability with low-variability agents seems small, this is significantly different to the 7.8% increase with high-variability agents and is likely to reflect greater reductions in some patients. This effect is consistent with the effect of CCBs and diuretics on visit-to-visit SBP variability and maximum SBP in large RCTs1–6 and may explain the reduction in the subsequent risk of stroke, although an appropriate choice of Webb et al Drug Effects on Morning Home BP Variability 2971 Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 Figure 2. Differences between change in variability or maximum systolic blood pressure (SBP) after initiation of drugs associated with lower SBP variability, higher SBP variability, or a combination of both. Results presented are mean percentage change in maximum SBP or residual coefficient of variation (rCV) in SBP for d 8 to 15 after starting or increasing each treatment compared with 3 to 10 d before the intervention, adjusted for age, sex, diabetes mellitus, history of hypertension, current smoking, family history of stroke, dyslipidemia, atrial fibrillation, creatinine baseline mean SBP and baseline maximum SBP, or SBP-rCV. P values and confidence intervals are derived from general linear models, comparing drugs associated with lower SBP variability (low) with drugs associated with higher SBP variability (high). antihypertensives also needs to consider other demographic factors such as ethnicity and comorbidities. Nonetheless, this study suggests that HBPM offers a potential practical method of monitoring the change in BP variability in response to antihypertensive treatment, with the potential to reduce BP variability–associated cardiovascular risk. The effect of CCBs and diuretics on day-to-day SBP variability was greatest immediately after waking compared with other times of day, with a similar effect on maximum SBP but with no difference in effects on mean or minimum SBP after waking. This implies that the most important effect of CCBs or diuretics on SBP variability results from limiting episodic peaks in SBP after waking, which is consistent with the greater prognostic significance of morning day-to-day variability in SBP compared with the evening.10 This may be because of a reduction in day-to-day variability in the morning surge in BP, which is predictive of future cardiovascular events and the timing of which matches the increased risk of stroke in the morning compared with later in the day.12 These effects are not because of consistent changes in the magnitude of the morning surge every day because there was no difference in mean diurnal variability, but are likely to result from limiting episodic surges. Therefore, the shorter half-life of RASi is unlikely to explain the difference with CCBs and diuretics, because this would cause a consistent difference in diurnal coefficient of variation. There were too few drugs used in this study from each class to determine if there were differences between agents within drug classes. In fact, amlodipine, perindopril, and indapamide were the most commonly used drugs, and it is 2972 Stroke October 2014 Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 possible that the differences found in this study are driven by specific differences between these drugs rather than drug classes. However, such differences within drug classes were not found in previous meta-analyses of drug class effects on other forms of BP variability.4 This study also demonstrated that the combination of a RASi and indapamide resulted in an intermediate effect on day-to-day SBP variability compared with RASi or diuretics alone. This is consistent with a previous meta-analysis of RCTs7 that used interindividual SBP variability as an indirect measure of intraindividual SBP variability. Therefore, in patients with increased SBP variability on a RASi, the addition of a diuretic will limit variability in SBP. There were some limitations to this study. First, patients received antihypertensive drugs at the nonrandomized discretion of the treating physician, guided by a standard protocol. However, the primary aim of this study was to investigate the effects of antihypertensive treatment on home day-to-day SBP variability at different times of day, rather than prove the existence of any effect on SBP variability because this has already been demonstrated in analyses of large RCTs.1–4 Second, the study was performed in patients with acute transient ischemic attack or minor stroke, limiting its generalizability, but this is the optimal group of patients to investigate because they are at the highest risk of recurrent stroke, and currently there is only limited evidence of the effect of antihypertensives on SBP variability in secondary prevention.1–4 Third, diurnal variability on HBPM was only measured at 3 time points in each day rather than using ambulatory BP monitoring. However, repeated ABPM would be impractical for the assessment of treatment responses, and multiple HBPM readings on different days produce a more reliable estimate than can be obtained with a single day of ambulatory readings.17,18 Fourth, patients receiving CCBs had higher premorbid BPs, and there were more dose adjustments in this group, which could potentially confound between-group comparisons. However, because we used within-individual change in BP variability, and as the results are highly consistent with previous findings of RCTs, it is unlikely that there is significant confounding. Fifth, there was no direct measure of medication compliance, but as BP was monitored daily, any clinically significant lack of compliance resulted in contact with the patient. Sixth, relatively few patients received eligible drug changes because not all patients required treatment or else required treatment changes within the first 7 days of the study, or close to stopping monitoring, and therefore change in BP variability could not be reliably analyzed. Nonetheless, there were adequate interventions within the major drug classes to enable analysis. Finally, all readings were taken in a relaxed sitting position at home, which may not accurately reflect real-life BP behavior. However, this does not necessarily reduce its prognostic significance and is likely to increase reproducibility and accuracy by limiting artefactual surges in measured BP.19 In summary, CCBs and diuretics reduced self-measured home BP variability in the secondary prevention of cerebrovascular events compared with RASi, because largely of a reduction in day-to-day variability and maximum SBP after waking. These effects persisted when used in combinations. This supports the use of these drugs in the secondary prevention of patients with cerebrovascular disease, particularly in patients with increased BP variability or excessive morning surges in SBP, and raises the potential for the use of HBPM as a method of monitoring the response to SBP variability– directed treatment. Acknowledgments We acknowledge the invaluable support from the facilities provided by the Oxford Acute Vascular Imaging Centre. Sources of Funding The Oxford Vascular Study has been funded by the Wellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute of Health Research (NIHR), Medical Research Council, and the NIHR Oxford Biomedical Research Centre. Dr Webb is in receipt of an MRC Clinical Training Research Fellowship. Disclosures None. References 1. Rothwell PM. Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet. 2010;375:938–948. 2. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895–905. 3. Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlöf B, et al; ASCOT-BPLA and MRC Trial Investigators. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9:469–480. 4. Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensivedrug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010;375:906–915. 5. Webb AJ, Fischer U, Rothwell PM. Effects of β-blocker selectivity on blood pressure variability and stroke: a systematic review. Neurology. 2011;77:731–737. 6. Webb AJ, Rothwell PM. Blood pressure variability and risk of new-onset atrial fibrillation: a systematic review of randomized trials of antihypertensive drugs. Stroke. 2010;41:2091–2093. 7. Webb AJ, Rothwell PM. Effect of dose and combination of antihypertensives on interindividual blood pressure variability: a systematic review. Stroke. 2011;42:2860–2865. 8. Robinson TG, James M, Youde J, Panerai R, Potter J. Cardiac baroreceptor sensitivity is impaired after acute stroke. Stroke. 1997;28:1671–1676. 9. Kikuya M, Ohkubo T, Metoki H, Asayama K, Hara A, Obara T, et al. Day-by-day variability of blood pressure and heart rate at home as a novel predictor of prognosis: the Ohasama study. Hypertension. 2008;52:1045–1050. 10. Johansson JK, Niiranen TJ, Puukka PJ, Jula AM. Prognostic value of the variability in home-measured blood pressure and heart rate: the FinnHome Study. Hypertension. 2012;59:212–218. 11. Webb AJS, Wilson M, Paul NL, Fischer U, Rothwell PM. Clinical and physiological validity of maximum blood pressure on multi-day home measurement versus single-day ambulatory monitoring: frequency versus duration? Cer Dis. 2013;35(suppl 3):124. 12.Kario K, Shimada K, Pickering TG. Clinical implication of morning blood pressure surge in hypertension. J Cardiovasc Pharmacol. 2003;42(suppl 1):S87–S91. 13. Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, et al; Oxford Vascular Study. Change in stroke incidence, mortality, casefatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet. 2004;363:1925–1933. 14. Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty O, Redgrave JN, et al; Early Use of Existing Preventive Strategies for Stroke (EXPRESS) Study. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS Webb et al Drug Effects on Morning Home BP Variability 2973 study): a prospective population-based sequential comparison. Lancet. 2007;370:1432–1442. 15. Webb AJS, Wilson M, Paul NL, Fischer U, Lovett NG, Li L, et al. Identification of missed hypertension and hypertensive arteriopathy with home versus ambulatory blood pressure measurement in patients with TIA or minor stroke. Cer Dis. 2013;35(suppl 3):72. 16. Webb AJ, Rothwell PM. Physiological correlates of beat-to-beat, ambulatory, and day-to-day home blood pressure variability after transient ischemic attack or minor stroke. Stroke. 2014;45:533–538. 17. García-García Á, García-Ortiz L, Recio-Rodríguez JI, Patino-Alonso MC, Agudo-Conde C, Rodriguez-Sanchez E, et al. Relationship of 24-h blood pressure variability with vascular structure and function in hypertensive patients. Blood Press Monit. 2013;18:101–106. 18. Hansen TW, Thijs L, Li Y, Boggia J, Kikuya M, Björklund-Bodegård K, et al; International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes Investigators. Prognostic value of readingto-reading blood pressure variability over 24 hours in 8938 subjects from 11 populations. Hypertension. 2010;55:1049–1057. 19. Calvo C, Hermida RC, Ayala DE, López JE, Fernández JR, Domínguez MJ, et al. The ‘ABPM effect’ gradually decreases but does not disappear in successive sessions of ambulatory monitoring. J Hypertens. 2003;21:2265–2273. Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 Response of Day-to-Day Home Blood Pressure Variability by Antihypertensive Drug Class After Transient Ischemic Attack or Nondisabling Stroke Alastair J.S. Webb, Michelle Wilson, Nicola Lovett, Nicola Paul, Urs Fischer and Peter M. Rothwell Downloaded from http://stroke.ahajournals.org/ by guest on June 16, 2017 Stroke. 2014;45:2967-2973; originally published online August 21, 2014; doi: 10.1161/STROKEAHA.114.005982 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/45/10/2967 Data Supplement (unedited) at: http://stroke.ahajournals.org/content/suppl/2014/08/21/STROKEAHA.114.005982.DC1 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/ SUPPLEMENTAL MATERIAL Response of day-to-day home blood pressure variability by antihypertensive drug class after TIA or non-disabling stroke Alastair JS Webb DPhil, Michelle Wilson MSc, Nicola Lovett MRCP, Nicola Paul DPhil, Urs Fischer MD, Peter M Rothwell FMedSci Figure I. Flow chart of patients and drug interventions included in study Patient referred to TIA / minor stroke clinic Diagnosis of probable TIA / minor stroke 623 Eligible patients offered inclusion in OXVASC study 38 refused participation in OXVASC 585 patients offered inclusion in COMMIT study 22 refused BP monitoring 13 unable do monitoring 8 monitoring inappropriate (eg cancer) 6 assessed too late after event 536 patients consented to the COMMIT study 1 died 8 alternative diagnosis 27 performed inadequate readings 500 patients with adequate home BP monitoring 288 eligible drug interventions 131 CCB changes: 62 Initiation 69 Dose increase 55 RASi changes: 35 Initiation 20 Dose increase 47 Diuretic changes: 33 Initiation 14 Dose increase 50 RASi + Diuretic 12 Initiation 38 Dose increase Table I. Differences in baseline SBP and SBP variability and per centage change in each measure 8 days after starting or increasing the dose of each class of antihypertensive drug. CCB= calcium channel blocker; RASi=renin-angiotensin system inhibitor, with or without diuretic; Diuretic=diuretic alone. SD=standard deviation; CV=coefficient of variation; rCV=residual CV about a 5 day moving average. Mean values are compared by ANO VA. *p<0.05; ** p<0 .01; *** p<0.001. RASi 53 Baseline RASi/Diur CCB 49 131 All Measures Mean Minimum Maximum rCV 129.5 110.3 149.4 7.81 127.7 109.4 147.2 7.98 133.4 112.5 155.7 8.13 129.7 111.9 149.7 7.38 0.03 0.46 0.01 0.45 Early Morning Mean Minimum Maximum rCV 132.1 120.6 143.9 5.3 129.9 117.5 142.1 5.86 135.4 123.1 148.8 5.68 131 119.6 142.5 5.26 0.06 0.07 0.04 0.6 9.8 7.5 9.1 7.4 10.4 7.8 10.2 7.7 0.63 0.81 Diurnal SD Diurnal CV % Change > 8 days after intervention RASi RASi/Diur CCB Diuretic 53 49 131 47 p-val Diuretic 47 p-val * ** * -2.1 -2.3 -1.1 9.01 -2.4 -3.6 -1 6.94 -3 -1.2 -4.5 -3.26 -3 -1.6 -4.7 -6.02 0.72 0.4 0.004 0.026 ** * -1.6 -2 -0.6 40.68 -3 -1.7 -2 16.99 -3.9 -3 -5.1 3.6 -3.1 -1 -3.8 3.68 0.15 0.46 0.002 0.003 ** ** 0.1 2.7 0.6 3.8 -2.9 0.2 0.8 3.4 0.93 0.95 Table II. Differences in baseline diastolic BP and DBP variability and percentage change in e ach me asure 8 days after starting or increasing the dose of e ach class of antihypertensive drug. Tr eatment groups are defined as low variability drugs (CCB or diuretic), high variability drugs( RASi or beta -blockers) or a combination of a RASi and a diuretic. SD=standard deviation; CV=coefficient of variation; rCV=residual CV about a 5 day moving average. Mean values are compared by ANOVA. *p<0.05; ** p<0.01; *** p<0.001. 3-10 days before intervention High Combination Low 62 50 178 p-val % Change > 8 days after intervention High Combination Low 62 49 178 p-val All Measures Mean Minimum Maximum rCV 76.2 63.8 89.1 8.5 75.5 64 88.1 8.2 77.2 65.2 89.8 8 0.46 0.49 0.65 0.41 -1.8 -0.6 -2.6 5 -2.1 -2.2 -2.6 5.4 -3 -2 -4.3 0.1 0.27 0.57 0.21 0.41 Early Morning Mean Minimum Maximum rCV 78.3 70.9 85.8 5.8 77.4 69.4 85.1 6.1 79 71.4 86.7 5.9 0.61 0.45 0.69 0.88 -1.9 -1.5 -1.7 18.6 -2.6 -0.3 -3.3 7.4 -3.4 -2.3 -4.4 3.3 0.24 0.39 0.06 0.28 Diurnal SD Diurnal CV 5.9 7.7 5.8 7.7 5.8 7.6 0.92 0.97 8.9 10.9 -2.5 0.7 2.2 5 0.31 0.39 Table III. Differences in baseline DBP and DBP variability and percentage change in each measure 8 days after starting or increasing the dose of each class of antihypertensive drug. CCB= calcium channel blocker; RASi=renin-angiotensin system inhibitor, with or without diuretic; Diuretic=diuretic alone. SD=standard deviation; CV=coefficient of variation; rCV=residual CV about a 5 day moving average. Mean values are compared by ANO VA. *p<0.05; ** p<0 .01; *** p<0.001. RASi 53 Baseline RASi/Diur CCB 49 131 Diuretic 47 p-val % Change > 8 days after intervention RASi RASi/Diur CCB Diuretic 53 49 131 47 p-val All Measures Mean Minimum Maximum rCV 75.8 63.7 88.7 8.33 75.5 64 88.1 8.23 77.3 64.9 90.2 8.04 77.1 65.9 88.9 7.71 0.61 0.62 0.69 0.64 -1.8 -1.5 -2.6 7.12 -2.1 -2.2 -2.6 5.42 -2.8 -1.9 -4.2 0.96 -3.3 -2.3 -4.7 -2.44 0.45 0.97 0.35 0.39 Early Morning Mean Minimum Maximum rCV 77.9 70.5 85.2 5.77 77.4 69.4 85.1 6.08 79.1 71.5 87.1 5.87 78.5 71.2 85.4 5.81 0.73 0.64 0.61 0.95 -1.8 -1.5 -1.4 23.2 -2.6 -0.3 -3.3 7.38 -3.6 -2.7 -4.8 4.91 -2.8 -1.3 -3.5 -1.16 0.31 0.46 0.05 0.22 Diurnal SD Diurnal CV 5.9 7.7 5.8 7.7 5.9 7.8 5.4 7.2 0.63 0.72 9.8 12.1 -2.5 0.7 0.9 4.1 5.9 7.5 0.36 0.47 Table IV. Clinical determinants of differences in baseline SBP and SBP variability, and determinants of percentage change in baseline follow ing initiation of any drug. 2 Results for categorical variables are given as mean (SD) with p-values by t-tests. Associations with continuous variables are give as r and p-values from linear regression. *p<0.05 ; ** p<0 .01; *** p<0.001. Baseline Characteristics Age Mean 0.04 0.001 Male vs Female 131.2 (11) 130.6 (15) Hypertension 127.8 (10) Minimum ** 0 0.466 0.1 <0.001 112.3 (11) 109.9 (15) 151.4 (15) 152.5 (20) 0.679 0.115 133 (14) 131.3 (13) 108.8 (11) *** <0.001 Family History CVA 129.7 (12) 111.7 (13) 131.8 (13) Diabetes 130.2 (12) 129.7 (12) 130.5 (12) 112.9 (13) 134.7 (16) 130.9 (13) 110.8 (12) * 136.6 (16) 111 (13) Smoker 130.8 (13) 130.8 (13) 110.8 (13) -1 (4) 129.3 (8) 111.5 (13) 0.095 Myocardial 131 (13) Infarction BMI Creat Cholesterol TSH 108.9 (12) 152.3 (17) * 113.6 (17) 151.2 (17) 151.2 (16) 0 0.674 0.004 0 0.367 0.01 0.037 ** * 8 (3) 149.4 (16) 108.6 (8) 151.4 (17) 151.7 (17) 7.9 (3) 8.1 (3) 3.1 (45) ** 104.1 (12) 151.1 (17) 7.7 (3) 0 0.251 0 0.121 0 0.147 -2.2 (9) -1.1 (9) -3.2 (7) -3.1 (9) 1.8 (34) -1.1 (32) -2.1 (6) -2.1 (10) -1.5 (9) -3.9 (7) -2.6 (8) 0.1 (36) 0.726 155.6 (19) -2.4 (6) -3.3 (6) 160.8 (23) 154.8 (20) -2.2 (6) -2.9 (6) 8.7 (3) 152.7 (18) -1.1 (5) -2.7 (6) 9.3 (2) 8 (3) 7.2 (3) -2.6 (6) 0.2 (49) 68.6 (98) -3.8 (10) 7.8 (3) 0.574 ** 10.2 (3) 0.24 0 0.272 0 0.663 0.04 <0.001 0 0.251 0 0 0.729 0 16.9 (40) -5.2 (77) ** -2.6 (7) 0.711 -5 (7) 3.1 (33) 0.243 -2.9 (8) 0 (0) 106.1 (79) -0.7 (13) -3.1 (8) -4.5 (7) -0.1 (31) 18.9 (96) -1.6 (8) -17.9 (22) ** 4.4 (41) * 0.041 *** <0.001 0.761 2.3 (32) 0.002 0.932 0.107 -1.8 (9) 0.5 (33) 0.496 -2.9 (8) -1.3 (8) 7.2 (31) 0.513 -4.6 (9) 0.792 0.002 -0.6 (33) 0.593 0.5 (9) -0.8 (33) 0.415 -0.4 (8) -3 (8) 0.182 -1.8 (9) -2.7 (6) ** 0.005 0 -2 (9) -2.7 (4) 1.5 (33) 0.063 -3.4 (8) 1.3 (25) 0.998 -2.6 (9) -3.6 (8) 0.665 0.977 0.008 154.7 (14) -2.1 (8) 0.82 -1.6 (9) -2.3 (7) 0.3 (35) 0.119 -1.7 (9) 0.459 -2.9 (9) -3.5 (7) 0.8 (31) 0.57 0.521 -1.1 (9) * -3.2 (8) -2.7 (5) ** 0.08 -8.5 (14) -2.2 (9) 0.922 0.001 -3.2 (8) 0.13 0.04 0.205 7.7 (3) -1.9 (10) 0.277 8.4 (3) 7.9 (3) * -1.7 (9) 0.531 0.397 0.646 -2.9 (5) 0.266 0.459 0.937 0.3 8.3 (3) 7.9 (3) 0.41 0.178 0.084 0.152 151.7 (17) 0.651 -2.6 (7) 0.195 0.729 -2.8 (9) 0 -3.5 (5) 7.6 (3) rCV -2.7 (5) 0.909 0.277 113.7 (12) *** ** 0.002 0.015 0.059 0.02 8.5 (3) 0.107 0.005 0.665 <0.001 0.539 0.177 1.3 (2) 0.13 ** Percentage change from Baseline during Follow-up Minimum Maximum Mean 7.5 (3) 0.151 0.195 131.9 (11) -6 (1) 152.7 (17) 114.4 (12) 111.6 (13) 0.599 Stroke vs TIA 109.9 (12) 0.26 0.944 *** 154.3 (19) 0.003 0.187 * 0.039 AF ** 0.01 0.027 Heart Failure 148.2 (14) 0.296 0.156 rCV 0.577 112.9 (14) 0.009 0.34 Hyperlipidaemia Maximum -3.2 (9) -6.5 (1) 0.305 0.2 (33) 0.997 8.6 (35) 0.767 0.01 0.075 0 0.119 0 0.155 0 0.328 0 0.323 0.02 0.013 * 0 0.911 0 0.456 0 0.508 0.01 0.032 0.135 0.02 0.007 ** 0 0.68 0 0.905 0 0.906 0 0.865 0.117 0.01 0.035 * 0 0.235 0 0.507 0 0.458 0 0.612 *** * Percentage change from baseline Figure II. Percentage change in variability in systolic blood pressure after starting or increasing the dose of each class of drug. Variability is measured as the coefficient of variation from three days previous to three days after each timepoint. 10 CCB 8 RASi 6 Diuretics 4 2 0 -2 -4 -6 -8 -10 -10 -5 0 5 10 15 20 Days from change in drug