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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.
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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
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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
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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
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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
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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.
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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
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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