Research

JAMA Internal Medicine | Original Investigation

Benefits and Harms of Antihypertensive Treatment

in Low-Risk Patients With Mild Hypertension
James P. Sheppard, PhD; Sarah Stevens, PhD; Richard Stevens, PhD; Una Martin, FRCP; Jonathan Mant, MD;
F. D. Richard Hobbs, FMedSci; Richard J. McManus, FRCGP

Supplemental content
IMPORTANCE Evidence to support initiation of pharmacologic treatment in low-risk patients
with mild hypertension is inconclusive, with previous trials underpowered to demonstrate
benefit. Clinical guidelines across the world are contradictory.

OBJECTIVE To examine whether antihypertensive treatment is associated with a low risk of

mortality and cardiovascular disease (CVD) in low-risk patients with mild hypertension.

DESIGN, SETTING, AND PARTICIPANTS In this longitudinal cohort study, data were extracted
from the Clinical Practice Research Datalink, from January 1, 1998, through September 30,
2015, for patients aged 18 to 74 years who had mild hypertension (untreated blood pressure
of 140/90-159/99 mm Hg) and no previous treatment. Anyone with a history of CVD or CVD
risk factors was excluded. Patients exited the cohort if follow-up records became unavailable
or they experienced an outcome of interest.

EXPOSURES Prescription of antihypertensive medication. Propensity scores for likelihood of

treatment were constructed using a logistic regression model. Individuals treated within 12
months of diagnosis were matched to untreated patients by propensity score using the
nearest-neighbor method.

MAIN OUTCOMES AND MEASURES The rates of mortality, CVD, and adverse events among
patients prescribed antihypertensive treatment at baseline, compared with those who were
not prescribed such treatment, using Cox proportional hazards regression.

RESULTS A total of 19 143 treated patients (mean [SD] age, 54.7 [11.8] years; 10 705 [55.9%]
women; 10 629 [55.5%] white) were matched to 19 143 similar untreated patients (mean [SD]
age, 54.9 [12.2] years; 10 631 [55.5%] female; 10 654 [55.7%] white). During a median
follow-up period of 5.8 years (interquartile range, 2.6-9.0 years), no evidence of an
association was found between antihypertensive treatment and mortality (hazard ratio [HR],
1.02; 95% CI, 0.88-1.17) or between antihypertensive treatment and CVD (HR, 1.09; 95% CI,
0.95-1.25). Treatment was associated with an increased risk of adverse events, including
hypotension (HR, 1.69; 95% CI, 1.30-2.20; number needed to harm at 10 years [NNH10], 41),
syncope (HR, 1.28; 95% CI, 1.10-1.50; NNH10, 35), electrolyte abnormalities (HR, 1.72; 95% CI,
1.12-2.65; NNH10, 111), and acute kidney injury (HR, 1.37; 95% CI, 1.00-1.88; NNH10, 91).
Author Affiliations: Nuffield
Department of Primary Care Health
CONCLUSIONS AND RELEVANCE This prespecified analysis found no evidence to support
Sciences, University of Oxford,
guideline recommendations that encourage initiation of treatment in patients with low-risk Oxford, United Kingdom (Sheppard,
mild hypertension. There was evidence of an increased risk of adverse events, which suggests S. Stevens, R. Stevens, Hobbs,
that physicians should exercise caution when following guidelines that generalize findings McManus); School of Pharmacy,
University of Birmingham,
from trials conducted in high-risk individuals to those at lower risk.
Birmingham, United Kingdom
(Martin); Department of Public
Health and Primary Care, University
of Cambridge, Cambridge, United
Kingdom (Mant).
Corresponding Author: James P.
Sheppard, PhD, Nuffield Department
of Primary Care Health Sciences,
University of Oxford, Woodstock
Road, Oxford, OX2 6GG, United
JAMA Intern Med. doi:10.1001/jamainternmed.2018.4684 Kingdom (james.sheppard
Published online October 29, 2018. @phc.ox.ac.uk).

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 Research Original Investigation Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension
H
igh blood pressure (hypertension) is a major risk fac-
tor for cardiovascular disease (CVD),1 the leading cause
of mortality worldwide.2 Hypertension is typically de-
fined as a sustained blood pressure at or above 140/90 mm Hg
taken in the clinic, and clinical guidelines recommend treat-
ment with lifestyle or pharmacologic interventions depend-
ing on the underlying risk of CVD.3-11 Most recently, guide-
lines from the American College of Cardiology/American Heart
Association (ACC/AHA)10 recommend that pharmacologic treat-
ment is initiated in high-risk patients with a blood pressure of
130/80 mm Hg or higher and for all individuals with a blood
pressure of 140/90 mm Hg or higher regardless of risk.
These recommendations are considered to be controver-
sial particularly with regard to treatment of people with low CVD
risk and mild hypertension (ie, sustained blood pressure of
140/90-159/99 mm Hg), for whom there is a lack of clinical trial
evidence to support initiation of pharmacologic treatment.12-17
The ACC/AHA guidelines define mild, stage 1 hypertension at
even lower thresholds (130/80-139/89 mm Hg); therefore, all the
patients referred to in this article as having mild hypertension
would now be considered to have stage 2 hypertension in the
United States. These revised definitions are primarily based on
findings of the Systolic Blood Pressure Intervention Trial
(SPRINT),18 but although this trial included a large number of
people with mild hypertension at recruitment, all participants
were considered to be at high risk of CVD and 90% were al-
ready undergoing treatment. The Heart Outcomes Prevention
Evaluation 3 (HOPE-3) trial19 found benefit of treatment in pa-
tients with a baseline systolic blood pressure higher than 143.5
mm Hg, but this group included participants with moderate hy-
pertension (mean systolic blood pressure, 154 mm Hg) and
intermediate risk not low risk of CVD. Meta-analyses of these
and other trials demonstrated that blood pressure lowering is
effective to at least 140 mm Hg systolic, but this was predomi-
nately in groups at higher cardiovascular risk.20-22
An appropriately powered study in low-risk patients is un-
likely to be conducted because of the low prevalence of out-
come events in this population and the unfeasibly large sample
sizes required to detect a treatment effect.10,16 Therefore, the
present study aimed to use routine electronic health records
to examine the association between antihypertensive treat-
ment prescriptions and all-cause mortality, CVD, and adverse
events in low-risk patients with mild hypertension.
Methods
Design
This retrospective longitudinal cohort study was conducted
from January 1, 1998, to September 30, 2015, using linked data
from the Clinical Practice Research Datalink (CPRD), a data-
base of electronic health records from England. The CPRD
population has previously been shown to represent the UK
population.23 Detailed extended methods are available in the
eAppendix in the Supplement. The study protocol was ap-
proved by CPRD’s Independent Scientific Advisory Commit-
tee in March 2016 before obtaining the data relevant to the proj-
ect (protocol given in the eAppendix in the Supplement). All
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Key Points
Question Is antihypertensive treatment associated with lower
risk for mortality and cardiovascular disease in patients with mild
hypertension?
Findings In this study of electronic health records of 38 286
low-risk patients with mild hypertension, no evidence of an
association was found between exposure to antihypertensive
treatment and mortality or cardiovascular disease. There was
evidence that treatment may be associated with an increased risk
of adverse events, such as hypotension, syncope, and acute
kidney injury.
Meaning The findings suggest that physicians should be cautious
when initiating treatment in low-risk patients with mild
hypertension, particularly because such an approach may affect
millions of individuals with little evidence of benefit.
data are fully anonymized so consent was not required. A proj-
ect summary is published on the CPRD website (https://www
.cprd.com/isac).
Study Population
Individual patient data were extracted from the medical rec-
ords of all patients registered at general practices that contrib-
ute to the CPRD in England with linked data to the Basic In-
patient Hospital Episode Statistics and Office for National
Statistics mortality register. Eligible patients were those with
mild hypertension (defined as 3 consecutive blood pressure
readings of 140/90-159/99 mm Hg within 12 months) and low
CVD risk (eTable 1 in the Supplement). Low-risk patients were
identified by excluding anyone with a history of CVD, left ven-
tricular hypertrophy, atrial fibrillation, diabetes, chronic kid-
ney disease, or family history of premature heart disease. When
planning the study, we decided that patients’ cardiovascular
risk status would be defined by comorbidities, not cardiovas-
cular risk score, because of concerns about the amount of rel-
evant data that might be missing in electronic health records.
A total of 7720 patients (20.2%) included in the main analysis
had a previous risk score recorded, and an additional 9096
(23.8%) had available risk factor information to calculate a
QRISK2 score.24 It was possible to estimate a QRISK2 score
for the remaining 21 050 patients older than 25 years by
inserting age- and sex-standardized mean cholesterol values
and Townsend scores from the Health Survey for England25
into the algorithm to replace missing data. The resulting
QRISK2 scores were used to redefine the study population
(further excluding patients deemed to be at high risk of
CVD) and reanalyze the primary and secondary outcomes in
sensitivity analyses not prespecified in the original protocol
(described below).
Patients entered the study on the index date, defined as
12 months after the date of the third consecutive blood
pressure reading within the range (140/90-159/99 mm Hg)
occurring after the study start date (January 1, 1998). Patients
exited the study when follow-up records became unavailable
(ie, the date of the most recent data upload from the practice
to which a given patient was registered, the date at which a
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 Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension Original Investigation Research

given patient transfered out of a registered CPRD practice, or

Table 1. Population Characteristics at the Index Datea
the date of death or specific outcome of interest) (eTable 1 in
the Supplement). The last day of follow-up for those remain- Nonexposed (Control) Exposed (Treatment)
Characteristic (n = 19 143) (n = 19 143)
ing in the study was September 30, 2015 (last day of fol- Age at index, mean 54.9 (12.2) 54.7 (11.8)
low-up in linked data). (SD), y
BMI, mean (SD) 29.1 (5.6) 29.2 (5.6)

Exposures Sex
The exposure was defined as any antihypertensive listed in the Female 10 641 (55.5) 10 705 (55.9)
British National Formulary (code list 1 in the eAppendix in the Male 8512 (44.5) 8438 (44.1)
Supplement) that was prescribed in the 12 months between Race/ethnicity
hypertension diagnosis (third consecutive blood pressure read- White 10 654 (55.7) 10 629 (55.5)
ing within range) and the index date. Black 388 (2.0) 369 (1.9)
South Asian 303 (1.6) 306 (1.6)

Outcomes Mixed race 1634 (8.5) 1673 (8.7)

All-cause mortality was chosen as the primary outcome be- Other 263 (1.4) 241 (13.0)
cause it is accurately captured in routine health data as part Unknown 5901 (30.8) 5925 (31.0)
of the Office for National Statistics mortality register. Second- Current smoking 4685 (24.5) 4618 (24.1)
ary outcomes included the following: (1) death or hospitaliza- Alcohol, mean (SD), 13.0 (14.9)b 12.1 (15.0)b
units per week
tion from major cardiovascular events (myocardial infarction IMD score of 5 (most 2419 (12.6) 2372 (12.4)
[MI], non-MI acute coronary syndrome [ACS], stroke, heart fail- deprived)
ure, or death from CVD)18; (2) death or hospitalization from Systolic BP, mean (SD), 145.6 (5.5) 145.6 (5.9)
mm Hgc
stroke, MI, non-MI ACS, heart failure, or cancer (negative con-
Diastolic BP, mean 88.5 (5.2)b 88.7 (5.6)b
trol); and (3) hospitalization with suspected adverse effects to (SD), mm Hgc
medication (hypotension, syncope, bradycardia, electrolyte ab- Mean CVD risk score, 8.1 (6.6)b 7.9 (6.6)b
mean (SD)
normalities, falls, or acute kidney injury). Outcomes were cap-
Statin prescription 4329 (22.6) 4221 (22.0)
tured from coded hospital admissions in the Basic Inpatient
Antiplatelet 2181 (11.4) 2147 (11.2)
Hospital Episode Statistics, coded diagnoses in the CPRD, prescription
and death certificates from the Office for National Statistics
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided
for deaths that occurred after the index date (code list 2 in the by height in meters squared); BP, blood pressure; CVD, cardiovascular risk;
eAppendix in the Supplement). IMD, Index of Multiple Deprivation
a
Data are presented as number (percentage) of patients unless otherwise
indicated. Data were missing for the following: BMI (15 892 records), alcohol
Covariates
(25 203 records), and CVD risk score (based on previous, estimated, or
Data on age, sex, race/ethnicity, patient-level deprivation imputed score [420 records]).
(Index of Multiple Deprivation), smoking status, alcohol con- b
Significant difference between groups based on 2-sample t test (P<.01).
sumption (units per week), body mass index (BMI), pretreat- c
Mean of 3 readings from 3 visits before treatment initiation. Data were
ment blood pressure readings (in the preceding 12 months), normally distributed (eAppendix and eFigures 2 and 3 in the Supplement).
comorbidities (rheumatoid arthritis, hypercholesterolemia
[code or most recent total cholesterol value ≥290 mg/dL; to con-
vert to millimoles per liter, multiply by 0.0259]), and all pre- dependent variables included risk factors for cardiovascular
scribed statin and antiplatelet medications were extracted from disease, calendar year of the index date, and the general prac-
the medical records of eligible patients. tice to which the patient was registered (Table 1). Interactions
A total of 91 patients (0.001%) were missing Index of Mul- with age, BMI, smoking, and deprivation were included. Pa-
tiple Deprivation data and were excluded from the regression tients were matched 1:1 using the nearest neighbor method, en-
analyses. The BMI was missing for 46 644 patients (42.8%) and suring optimal balancing of groups at the expense of a larger
was therefore imputed using multiple imputation. Separate sample size. The χ2, Wilcoxon rank sum, and t tests were used
imputation models were created for each outcome and in- to compare patient characteristics between groups. A 2-tailed
cluded all covariates examined in each logistic regression model P < .05 was considered to be statistically significant.
and the outcome event of interest, as is recommended when The validity of propensity score matching was examined
creating propensity score models with partially observed using a negative control: the association of antihypertensive
covariates.26 Each model was based on 20 imputations. treatment with an outcome not known to be affected by such
treatment (cancer was used in the present study). It was hy-
Statistical Analysis pothesized that if treatment with antihypertensives had a sig-
Analyses were conducted using Stata, versions 13.1 and 14.2 nificant association with this outcome, there was something
(StataCorp). Propensity scores were used to match individuals missing in the propensity score (ie, an unmeasurable factor
who were prescribed antihypertensive treatment (prior to the of propensity for treatment, such as being generally unwell or
index date) to similar individuals not prescribed treatment. Vari- having an unhealthy lifestyle) causing an imbalance between
ables associated with antihypertensive medication prescrip- the treatment and control groups, rather than a true treat-
tion were explored in a logistic regression model (Table 1). In- ment effect.

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 Research Original Investigation Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension
Main Analyses
The efficacy of antihypertensive treatment was examined with
Cox proportional hazards modeling comparing all-cause
mortality among those prescribed antihypertensive treat-
ment before the index date compared with those not pre-
scribed treatment. Patients were analyzed in these groups re-
gardless of whether they subsequently stopped or started
treatment during follow-up. Cumulative hazard plots were pro-
duced to display the cumulative incidence of all-cause mor-
tality in each group. Hazard ratios (HRs) were adjusted for pre-
vious cancer diagnosis, which was found to be unbalanced at
baseline but was not prespecified as a covariate in the propen-
sity score model. A post hoc decision was made to stratify the
analysis by each matched pair. Numbers needed to harm were
estimated for outcomes significantly associated with treat-
ment from event rates in each group at 5 and 10 years by using
the formula described by Altman and Andersen.27 Separate
models were created to examine secondary end points.
Subgroup and Sensitivity Analyses
Subgroup analyses were conducted to examine the associa-
tion between antihypertensive treatment and mortality or CVD,
stratified by age (±65 years), sex, and antihypertensive drug
class. Post hoc subgroup analyses examined the association be-
tween treatment and outcomes, stratified by baseline sys-
tolic blood pressure (±150 mm Hg). Post hoc sensitivity analy-
ses were conducted using estimated cardiovascular risk scores
by including patients’ cardiovascular risk score in each pro-
pensity score model, matching and rerunning the main analy-
sis, and excluding anyone with a risk score of 20% or higher
and then including remaining patients’ cardiovascular risk
score in each propensity score model and matching and re-
running the main analysis. Additional post hoc sensitivity
analyses were undertaken to examine the association be-
tween treatment and mortality by using standard multivari-
ate adjustment instead of propensity score matching.
Results
A total of 108 844 patients were potentially eligible for inclu-
sion in the analysis, including 19 143 patients prescribed treat-
ment in the 12 months before the index date (eFigure 1 in the
Supplement). A total of 19 143 treated patients (mean [SD] age,
54.7 [11.8] years; 10 705 [55.9%] women; 10 629 [55.5%] white)
were matched to 19 143 similar untreated patients (mean [SD]
age, 54.9 [12.2] years; 10 631 [55.5%] female; 10 654 [55.7%]
white), giving a total sample population for the main analysis
of 38 286 patients followed up for a median of 5.8 years (inter-
quartile range, 2.6-9.0 years). The mean (SD) blood pressure be-
fore initiation of treatment was 146/89 (6/5) mm Hg (eTable 2
and eAppendix in the Supplement). There were statistically but
not clinically significant differences between the control and
treatment groups in pretreatment mean (SD) diastolic blood
pressure (88.5 [5.2] vs 88.7 [5.6] mm Hg; P = .002), cardiovas-
cular risk score (8.1% [6.6%] vs 7.9% [6.6%]; P = .008), and al-
cohol consumption (13.0 [14.9] vs 12.1 [15.0] units per week;
P = .001) (eTable 2 and eAppendix in the Supplement). A total
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of 7958 patients (41.6%) in the control group were prescribed
an antihypertensive drug at some point during follow-up (eTable
3 and eAppendix in the Supplement), but total treatment
duration among these patients was less than a third of that in
the exposed group (34 571 vs 104 695 treatment years).
Primary Outcome
A total of 1641 deaths were observed across the groups during
the follow-up period. Overall mortality was 4.08% (95% CI,
3.80%-4.37%) in the control group and 4.49% (95% CI,
4.20%-4.80%) in the treatment group, a risk difference of
0.41% (95% CI, 0.02%-0.85%). No significant difference was
found between groups in time to death (HR, 1.02; 95%
CI, 0.88-1.17; P = .81) (Table 2 and Figure 1).
Secondary Outcomes
No significant associations were observed between anti-
hypertensive treatment and CVD (HR, 1.09; 95% CI, 0.96-
1.25). Similarly there were no associations with stroke, MI, heart
failure, or non-MI acute ACS (Table 2 and Figure 1). There was
a significant association between baseline antihypertensive
treatment exposure and time to adverse events, including hy-
potension (HR, 1.69; 95% CI, 1.30-2.20; P < .001), syncope (HR,
1.28; 95% CI, 1.10-1.50; P = .002), electrolyte abnormalities
(HR, 1.72; 95% CI, 1.12-2.65; P = .01), and acute kidney injury
(HR, 1.37; 95% CI, 1.00-1.88; P = .048) but not with falls or bra-
dycardia (Table 2 and Figure 2). Numbers needed to harm for
treatment prescription were as high as 580 (95% CI, 253-361)
at 5 years and 111 (95% CI, 49-687) at 10 years for electrolyte
abnormalities and as low as 135 (95% CI, 77-385) at 5 years and
35 (95% CI, 20-100) at 10 years for syncope. Numbers needed
to harm at 10 years were 41 (95% CI, 24-93) for hypotension and
91 (95% CI, 39-14 552) for acute kidney injury (Table 2). Base-
line treatment exposure was not associated with the negative
control (time to cancer: HR, 1.01; 95% CI, 0.92-1.11; P = .79).
Subgroup and Sensitivity Analyses
No evidence of an association was observed between base-
line antihypertensive treatment and mortality or CVD by age,
systolic blood pressure, or antihypertensive drug class
(Figure 3). Sensitivity analyses adjusting the propensity score
model for baseline cardiovascular risk score revealed a signifi-
cant association between antihypertensive treatment and
non-MI ACS (HR, 0.54; 95% CI, 0.33-0.89; P = .02), whereas
the associations between treatment and electrolyte abnor-
malities (HR, 1.38; 95% CI, 0.93-2.05; P = .11) and acute kid-
ney injury were no longer significant (HR, 1.15; 95% CI, 0.85-
1.58; P = .37) (eTable 4 in the Supplement). Adjustment and
exclusion of individuals estimated to be at high risk of CVD
(>20% risk) produced similar results to the primary analysis
except for the association between treatment and acute kid-
ney injury, which was no longer significant (HR, 1.32; 95% CI,
0.93-1.89; P = .12). Analysis of the data using multivariate
adjustment, rather than propensity score matching, showed
a significant association between treatment and mortality, with
smaller CIs because of the larger sample size available (mul-
tivariate adjustment: HR, 1.10; 95% CI, 1.02-1.19; propensity
score matching: HR, 1.02; 95% CI, 0.88-1.17).
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 Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension Original Investigation Research

Table 2. Primary (Mortality) and Secondary Outcomes

No. Not Treated No. Treated NNH (95% CI)a

Outcome No Event Event No Event Event Hazard Ratio (95% CI) P Value 5 Years 10 Years
Treatment benefit
outcomes
Mortality 18 362 781 18 283 860 1.02 (0.88-1.17) .81 NA NA
Cardiovascular diseaseb 18 443 700 18 425 718 1.09 (0.95-1.25) .23 NA NA
Stroke 18 858 285 18 851 292 0.97 (0.78-1.21) .76 NA NA
MI 18 864 279 18 867 276 1.00 (0.80-1.25) .98 NA NA
Non-MI acute coronary 19 087 56 19 082 61 1.19 (0.74-1.91) .47 NA NA
syndrome
Heart failure 19 012 131 18 974 169 1.34 (0.96-1.86) .09 NA NA
Treatment harm outcomes
Hypotension 18 982 161 18 875 268 1.69 (1.30-2.20) <.001 219 (127-501) 41 (24-93)
Syncope 18 670 473 18 534 609 1.28 (1.10-1.50) .002 135 (77-385) 35 (20-100)
Bradycardia 19 067 76 19 040 103 1.11 (0.75-1.65) .59
Electrolyte 19 089 54 19 048 95 1.72 (1.12-2.65) .01 580 (253-3610) 111 (49-687)
abnormalities
Falls 19 104 39 19 098 45 1.15 (0.63-2.09) .65
Acute kidney injury 18 999 144 18 949 194 1.37 (1.00-1.88) .048 467 (198-75 225) 91 (39-14 552)
Cancer (negative control) 17 550 1593 17 464 1679 1.01 (0.92-1.11) .79 NA NA
Abbreviations: MI, myocardial infarction; NA, not applicable; NNH, number effect (ie, CIs do not cross 1).
needed to harm. b
Cardiovascular disease was defined as any code for fatal and nonfatal stroke,
a
The NNH was only estimated when there was a single direction of treatment MI, non-MI acute coronary syndrome, or heart failure.

Figure 1. Cumulative Hazard Plots Comparing Risk of Mortality and Cardiovascular Disease With Treatment Exposure

A Mortality B Cardiovascular disease

0.25 0.25
HR with treatment, 1.02 (95% CI, 0.88-1.17) HR with treatment, 1.09 (95% CI, 0.95-1.25)
0.20 0.20
Cumulative Hazard

Cumulative Hazard

Not treated
0.15 0.15 Treated

0.10 0.10

0.05 0.05

0 0
0 5 10 15 0 5 10 15
Time to Event, y Time to Event, y
No. at risk No. at risk
Not treated 19 143 10 751 3717 216 Not treated 19 143 10 557 3581 202
Treated 19 143 10 695 3788 206 Treated 19 143 10 448 3621 190

C Myocardial infraction D Stroke

0.25 0.25
HR with treatment, 1.00 (95% CI, 0.80-1.25) HR with treatment, 0.97 (95% CI, 0.78-1.21)
0.20 0.20
Cumulative Hazard

Cumulative Hazard

0.15 0.15

0.10 0.10

0.05 0.05

0 0
0 5 10 15 0 5 10 15
Time to Event, y Time to Event, y
No. at risk No. at risk
Not treated 19 143 10 598 3629 201 Not treated 19 143 10 692 3655 199
Treated 19 143 10 590 3726 196 Treated 19 143 10 601 3723 202

HR indicates hazard ratio.

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 Research Original Investigation Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension

Figure 2. Cumulative Hazard Plots Comparing Risk of Adverse Events With Treatment Exposure

A Hypotension B Syncope
0.25 0.25
HR with treatment, 1.69 (95% CI, 1.30-2.20) HR with treatment, 1.28 (95% CI, 1.10-1.50)
0.20 0.20
Cumulative Hazard

Cumulative Hazard
Not treated
0.15 0.15 Treated

0.10 0.10

0.05 0.05

0 0
0 5 10 15 0 5 10 15
Time to Event, y Time to Event, y
No. at risk No. at risk
Not treated 19 143 10 697 3592 207 Not treated 19 143 10 548 3564 219
Treated 19 143 10 594 3697 199 Treated 19 143 10 436 3605 198

C Acute kidney injury D Electrolyte abnormalities

0.25 0.25
HR with treatment, 1.37 (95% CI, 1.00-1.88) HR with treatment, 1.72 (95% CI, 1.12-2.65)
0.20 0.20
Cumulative Hazard

Cumulative Hazard
0.15 0.15

0.10 0.10

0.05 0.05

0 0
0 5 10 15 0 5 10 15
Time to Event, y Time to Event, y
No. at risk No. at risk
Not treated 19 143 10 693 3664 211 Not treated 19 143 10 766 3720 211
Treated 19 143 10 661 3760 199 Treated 19 143 10 654 3760 202

HR indicates hazard ratio.

individuals.20-22,29 Trials examining lower-risk populations are

Discussion
Summary of Findings
The present study examined electronic health records from
38 286 low-risk patients with mild hypertension and com-
pared rates of mortality and CVD between patients prescribed
treatment and those not prescribed treatment for a median fol-
low-up period of 5.8 years. No evidence of an association was
found between baseline exposure to antihypertensive treat-
ment and mortality or CVD. There was evidence to suggest that
baseline treatment exposure may be associated with an in-
creased risk of adverse events, with a number needed to harm
after 5 years of treatment of 135 for syncopal outcomes. This find-
ing does not seem particularly important in terms of number
needed to harm but, in the context of little evidence of benefit,
suggests that physicians should be cautious when initiating new
treatment in this population, particularly because such an
approach may affect millions of individuals.17,28
Comparison With Previous Literature
A number of previous trials have examined the efficacy of blood
pressure–lowering treatment among patients with mild hyper-
tension but predominately foc used on higher-risk
summarized in eTable 5 in the Supplement.19,30-34 In trials that
found a benefit with treatment, it can be argued that partici-
pants were not truly low risk as defined in clinical guidelines,30
and some trials included patients with moderate hypertension
(systolic blood pressure ≥160 mm Hg); thus, their findings are
not directly relevant here.19,32 Studies that examined a rel-
evant population found no associations between treatment and
cardiovascular events,31,33,34 consistent with the findings of the
present study.
A Cochrane review by Diao and colleagues29 examined
8912 patients from 4 clinical trials and found no significant re-
duction in mortality, coronary artery disease, stroke, or total
cardiovascular events with treatment. However, the authors
of that review and subsequent commentators12,29 pointed to
a lack of power in previous trials and meta-analyses to show
significant results. In contrast, the current study was suffi-
ciently powered to detect a treatment association but failed
to find one.
The meta-analysis by Brunström and Carlberg21 showed
benefit of treatment at lower blood pressures in patients with
a history of CVD and higher-risk primary prevention pa-
tients. The present study found no evidence of benefit with
treatment in lower-risk populations.

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 Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension Original Investigation Research

Figure 3. Subgroup Analyses by Age, Sex, Systolic Blood Pressure, and Prescribed Antihypertensive Medication for Mortality and Cardiovascular
Disease Outcomes

No. Not Treated No. Treated

Total No Total No HR Favors Favors P Value
Category Population Events Events Population Events Events (95% CI) Treatment No Treatment Interaction
Mortality
Sex
Males 8512 8097 415 8438 7986 452 1.03 (0.77-1.37)
.90
Females 10 631 10 265 366 10 705 10 297 408 1.06 (0.79-1.41)
Age, y
<65 14 331 13 992 339 14 570 14 161 409 0.94 (0.74-1.21)
.35
≥65 4812 4370 442 4573 4122 451 1.08 (0.71-1.62)
sBP, mm Hg
<150 14 705 14 170 535 14 309 13 705 604 1.12 (0.91-1.36)
.10
≥150 4438 4192 246 4834 4578 256 0.77 (0.50-1.20)
Drug
ACE Inhibitors 5627 5369 258 5627 5440 187 0.88 (0.67-1.16)
CCBs 3558 3424 134 3558 3416 142 1.19 (0.82-1.72)
.65
Thiazides 5100 4908 192 5100 4805 295 0.96 (0.74-1.24)
ß-Blockers 4031 3866 165 4031 3853 178 1.01 (0.75-1.38)

Cardiovascular disease
Sex
Males 8359 7952 407 8438 8025 413 0.95 (0.73-1.23)
.06
Females 10 784 10 491 293 10 705 10 400 305 1.34 (1.02-1.75)
Age, y
<65 14 473 14 096 377 14 570 14 179 391 1.08 (0.87-1.34)
.56
≥65 4670 4347 323 4573 4246 327 0.83 (0.54-1.27)
sBP, mm Hg
<150 14 702 14 133 569 14 309 13 705 604 1.19 (0.98-1.44)
.34
≥150 4441 4194 247 4834 4578 256 1.17 (0.75-1.82)
Drug
ACE Inhibitors 5627 5421 206 5627 5434 193 1.37 (1.04-1.80)
CCBs 3558 3414 144 3558 3461 97 0.80 (0.57-1.14)
.11
Thiazides 5100 4944 156 5100 4863 237 1.04 (0.80-1.34)
ß-Blockers 4031 3875 156 4031 3880 151 0.99 (0.74-1.32)

0 0.5 1.0 1.5 2.0

HR (95% CI)

There were insufficient data to examine subgroups by angiotensin II receptor CCBs, calcium channel blockers; HR, hazard ratio; and sBP, systolic blood
blockers, α blockers, other vasodilators, and centrally acting antihypertensives. pressure.
Error bars indicate 95% CIs. ACE indicates angiotensin-converting-enzyme;

Implications for Practice
The present data provide no evidence to suggest that new ACC/
AHA guidelines10 will reduce CVD events in low-risk patients
with mild hypertension. Even in sensitivity analyses adjusting
the propensity score for previous or imputed risk score, the ob-
served treatment benefit for cardiovascular outcomes was mini-
mal, with only non-MI ACS associated with a significant risk
reduction with treatment. Furthermore, we found that long-
term antihypertensive treatment in clinical practice was asso-
ciated with harm attributable to adverse events, such as hypo-
tension, syncope, electrolyte abnormalities, and acute kidney
injury, although electrolyte abnormalities and acute kidney in-
jury were sensitive to the definition of high risk used in the
sensitivity analyses. Physicians should therefore be cautious
when initiating new treatment in this population, and
patients should be made aware of the limited evidence of
efficacy for treatment in low-risk individuals. These findings
may be particularly relevant for younger patients with mild
hypertension, because as these individuals age, they are
likely to develop higher risk and moderate or severe hyper-
tension, for which the benefits of treatment are more
established.20-22,29
Strengths and Limitations
This nationally representative23 observational cohort study with
a prespecified analysis plan is the largest study, to our knowl-
edge, to examine the association between antihypertensive
treatment and mortality among patients with low-risk mild hy-
pertension. Despite this, CIs for estimates of benefit and harm
outcomes were relatively wide; therefore, a larger study would
be required to provide more precise results. Crossover between
treatment groups was observed in the study, reflecting the ob-
servational nature of the data. Those in the treatment group
were exposed to 3 times as many years of treatment than those
in the control group; thus, if crossover masked an association
with treatment, such an association would have been small.
Fewer events occurred for assessment of secondary out-
comes, which may have been affected by inadequate docu-

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 Research Original Investigation Benefits and Harms of Antihypertensive Treatment in Low-Risk Patients With Mild Hypertension

mentation in the electronic health records studied. Linked data
were used, which reduces the consequences of this limitation35;
however, this strategy is unlikely to mitigate them com-
pletely, particularly for outcomes such as falls, which may not
lead to hospitalization or reporting to a primary care physi-
cian. Arguably, events not leading to contact with medical ser-
vices are less likely to be important to an individual. Assess-
ment of secondary outcomes may also have been affected
by ascertainment bias (ie, people undergoing treatment are
more likely to report having adverse events), although the risk
of this bias was minimized by limiting the end point to those
who were hospitalized for a given event. Blood pressure dif-
ferences at follow-up were not examined because monitor-
ing strategies are likely to be dependent on whether people are
undergoing antihypertensive therapy, giving potentially mis-
leading results.
Propensity scores were used in the present analysis to bal-
ance measured confounders at the index date. Because these
are nonrandomized, observational data, the results may still
be biased because of unmeasured residual confounding. Can-
cer prevalence was found to be higher in the treatment group
at baseline, and although this was adjusted for in the main
analysis, we cannot rule out the possibility that other con-
founders existed, causing our treatment group to be higher risk
than those in the control group; this scenario might explain
the lack of evidence of treatment benefit. There may also have
been bias in recording of risk factors (used in the propensity
score model), although because people undergoing treat-
ment are more likely to have complete data, this would likely
have led to controls with higher risk than recorded, which
would have favored those undergoing treatment (ie, made
treatment appear to be more beneficial). Small absolute
differences were observed in diastolic blood pressure, esti-
mated cardiovascular risk, and alcohol consumption between
groups at baseline, which were statistically significant, as might
be expected given the large sample size, but not clinically sig-
nificant (ie, differences of <0.2 mm Hg in diastolic blood pres-
sure, <0.2% risk, and <1 unit per week of alcohol).
The current study made many comparisons without ad-
justment for multiple testing; therefore, caution is required
when interpreting the results. In particular, some subgroup
analyses suggested a possible association between treatment
and CVD in women and those taking angiotensin-converting
enzyme inhibitors, but these findings should be interpreted
carefully because no significant interaction effects were
observed. Patients included in the study cohort were fol-
lowed up for a median of 5.8 years. Although this is compa-
rable or longer than most previous trials,18,21 it is possible that
the benefits of treatment take longer to manifest in this low-
risk population and therefore may have become more evi-
dent had data been available to follow up patients for longer.
Data for BMI were missing for 42% of patients available for
analysis. Because BMI was considered to be an important po-
tential variable associated with treatment and unlikely to be
missing not at random, multiple imputation was deemed to
be appropriate to avoid significant loss of data in a complete
case analysis.
Exposure to antihypertensive treatment was based on pre-
scriptions issued by a physician in primary care, but it was not
possible to ascertain whether this prescription was subse-
quently filled or whether patients actually took the treatment
as prescribed. Finally, subgroup analyses were undertaken with
the sample cohort used in the primary analysis, and patients
were not rematched based on propensity score, meaning that
there was a small imbalance in the total numbers compared in
each subgroup for age, sex, and systolic blood pressure.
Conclusions
These observational data provide no evidence that antihyper-
tensive treatment is associated with reduced mortality or rates
of CVD among low-risk patients with mild hypertension. Such
data may be subject to bias from unmeasured confounding but
suggest that caution should be exercised when considering
treatment in this population.

ARTICLE INFORMATION
Accepted for Publication: July 18, 2018.
Published Online: October 29, 2018.
doi:10.1001/jamainternmed.2018.4684
Author Contributions: Dr Sheppard had full access
to all the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Sheppard, S. Stevens, R. Stevens, Mant, Hobbs,
McManus.
Drafting of the manuscript: Sheppard, Martin,
McManus.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Sheppard, S. Stevens,
R. Stevens.
Obtained funding: Sheppard, Hobbs, McManus.
Administrative, technical, or material support:
Sheppard, S. Stevens.
Supervision: R. Stevens, Martin, Hobbs, McManus.
Conflict of Interest Disclosures: Dr R. Stevens is a
member of the Clinical Practice Research Datalink's
Independent Scientific Advisory Committee but
was not involved in the approval of this study. No
other disclosures were reported.
Funding/Support: This work was funded by
Medical Research Council (MRC) Strategic Skills
Postdoctoral Fellowship MR/K022032/1 (Dr
Sheppard), a National Institute for Health Research
(NIHR) professorship (Dr Sheppard and Mr
McManus), and grant NIHR-RP-R2-12-015 from the
NIHR (Mr McManus). Dr Sheppard receives funding
from the NIHR Collaboration for Leadership in
Applied Health Research and Care Oxford at Oxford
Health National Health Service Foundation Trust
and the NIHR School for Primary Care Research
(SPCR). Mr Hobbs received support from the NIHR
as director of the NIHR SPCR, director of the NIHR
Collaboration for Leadership in Applied Health
Research and Care Oxford, theme leader of the
NIHR Oxford Biomedical Research Centre, and
member of the NIHR Oxford Diagnostic Evidence
Cooperative and from Harris Manchester College.
Role of the Funder/Sponsor: The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: The views and opinions expressed are
those of the authors and do not necessarily reflect
those of the MRC, NHS, NIHR, or the UK
Department of Health.
Additional Contributions: Blanca Gallego Luxan,
PhD, reviewed and commented on the study
protocol. She was not compensated for her work.
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