new england
journal of medicineThe

established in 1812

May 26, 2016vol. 374

no. 21

Blood-Pressure Lowering in Intermediate-Risk Persons
without Cardiovascular Disease
Eva M. Lonn, M.D., Jackie Bosch, Ph.D., Patricio López‑Jaramillo, M.D., Ph.D., Jun Zhu, M.D., Lisheng Liu, M.D.,
Prem Pais, M.D., Rafael Diaz, M.D., Denis Xavier, M.D., Karen Sliwa, M.D., Ph.D., Antonio Dans, M.D.,
Alvaro Avezum, M.D., Ph.D., Leopoldo S. Piegas, M.D., Ph.D., Katalin Keltai, M.D., Ph.D., Matyas Keltai, M.D., Ph.D.,
Irina Chazova, M.D., Ph.D., Ron J.G. Peters, M.D., Ph.D., Claes Held, M.D., Ph.D., Khalid Yusoff, M.D.,
Basil S. Lewis, M.D., Petr Jansky, M.D., Alexander Parkhomenko, M.D., Ph.D., Kamlesh Khunti, M.D., Ph.D.,
William D. Toff, M.D., Christopher M. Reid, Ph.D., John Varigos, B.Sc., Lawrence A. Leiter, M.D.,
Dora I. Molina, M.D., Robert McKelvie, M.D., Ph.D., Janice Pogue, Ph.D.,* Joanne Wilkinson, B.A.,
Hyejung Jung, M.Sc., Gilles Dagenais, M.D., and Salim Yusuf, M.B., B.S., D.Phil., for the HOPE-3 Investigators†​​

a bs t r ac t
BACKGROUND

Antihypertensive therapy reduces the risk of cardiovascular events among high-risk
persons and among those with a systolic blood pressure of 160 mm Hg or higher,
but its role in persons at intermediate risk and with lower blood pressure is unclear.
METHODS

In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants at intermediate risk who did not have cardiovascular disease to receive
either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a doseof 12.5 mg per day or placebo. The first coprimary outcome was the composite ofdeath from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke;
the second coprimary outcome additionally included resuscitated cardiac arrest,
heart failure, and revascularization. The median follow-up was 5.6 years.
RESULTS

The mean blood pressure of the participants at baseline was 138.1/81.9 mm Hg;
the decrease in blood pressure was 6.0/3.0 mm Hg greater in the active-treatmentgroup than in the placebo group. The first coprimary outcome occurred in 260 participants (4.1%) in the active-treatment group and in 279 (4.4%) in the placebogroup (hazard ratio, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40); thesecond coprimary outcome occurred in 312 participants (4.9%) and 328 participants (5.2%), respectively (hazard ratio, 0.95; 95% CI, 0.81 to 1.11; P = 0.51). In oneof the three prespecified hypothesis-based subgroups, participants in the subgroupfor the upper third of systolic blood pressure (>143.5 mm Hg) who were in theactive-treatment group had significantly lower rates of the first and second coprimary outcomes than those in the placebo group; effects were neutral in the middle
and lower thirds (P = 0.02 and P = 0.009, respectively, for trend in the two outcomes).

The authors’ affiliations are listed in the
Appendix. Address reprint requests to Dr.
Lonn at the Population Health ResearchInstitute and Hamilton Health Sciences,
237 Barton St. E., Hamilton ON L8L 2X2,
Canada, or at ­eva​.­lonn@​­phri​.­ca.
* Deceased.
†A complete list of the Heart Outcomes
Prevention Evaluation (HOPE)–3 trial
investigators is provided in the Supple‑
mentary Appendix, available at NEJM.org.
This article was published on April 2, 2016,
at NEJM.org.
N Engl J Med 2016;374:2009-20.
DOI: 10.1056/NEJMoa1600175
Copyright © 2016 Massachusetts Medical Society.

CONCLUSIONS

Therapy with candesartan at a dose of 16 mg per day plus hydrochlorothiazide at
a dose of 12.5 mg per day was not associated with a lower rate of major cardiovascular events than placebo among persons at intermediate risk who did not havecardiovascular disease. (Funded by the Canadian Institutes of Health Research andAstraZeneca; ClinicalTrials.gov number, NCT00468923.)
n engl j med 374;21

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T h e n e w e ng l a n d j o u r na l o f m e dic i n eHigh blood pressure is the leadingrisk factor for cardiovascular disease
globally1 and affects more than 1 billion
adults worldwide.2 Observational studies involving persons without cardiovascular disease show
a graded increase in risk at systolic blood-pressure levels above 115 mm Hg.3 It has been suggested that lowering blood pressure at any level
above this value will reduce the risk of cardiovascular events.4 Antihypertensive therapy has beenclearly shown to reduce the risk of cardiovascular disease among people with vascular or renal
disease, diabetes, or hypertension with end-organ
damage or, in the absence of these conditions,among persons with a systolic blood pressureof 160 mm Hg or higher.5-8 However, the role oftherapy in persons at intermediate risk (defined
as an annual risk of major cardiovascular eventsof approximately 1%) who do not have vasculardisease and who have a systolic blood pressureof less than 160 mm Hg (who represent the majority of middle-aged and older persons) remains
less clear. We evaluated this question in the Heart
Outcomes Prevention Evaluation (HOPE)–3 trial.

Me thods
Trial Design

We conducted this double-blind, randomized,
placebo-controlled trial at 228 centers in 21
countries, using a 2-by-2 factorial design. The
trial evaluated blood-pressure–lowering therapy
with a fixed-dose combination of an angiotensinreceptor blocker (ARB) and a thiazide diuretic,cholesterol-lowering therapy with a statin, andthe combination of both interventions in persons
at intermediate cardiovascular risk (Table S1 in
the Supplementary Appendix, available with thefull text of this article at NEJM.org).9 The resultsof the cholesterol-lowering analysis and theanalysis of the combination of blood-pressure
lowering and cholesterol lowering are reported
in accompanying articles in the Journal.10,11
The trial was designed by an international
steering committee of academic investigatorsand sponsored by AstraZeneca and the Canadian
Institutes of Health Research. AstraZeneca provided the trial drug, served as a single voting
member on the 24-member steering committee,
and had no other role in the trial. The Population Health Research Institute, McMaster University, Canada, coordinated data collection andmonitoring and conducted all statistical analy2010n engl j med 374;21

ses independent of the sponsors. Ethical approval
was obtained at all centers, and all the participants provided written informed consent. An
event-adjudication committee whose members
were unaware of the trial-group assignments reviewed primary and secondary outcome eventsand deaths. An independent data and safety
monitoring board reviewed the accumulating
data. The authors vouch for the accuracy andcompleteness of the data and all the analyses, aswell as for the fidelity of this report to the trial
protocol (available at NEJM.org). The first author
drafted the manuscript, and all the authors
made the decision, with approval from the steering committee, to submit the manuscript for
publication.
Trial Population

The trial included men 55 years of age or older
and women 65 years of age or older who had atleast one of the following cardiovascular risk
factors: elevated waist-to-hip ratio, history of low
concentration of high-density lipoprotein cholesterol, current or recent tobacco use, dysglycemia,
family history of premature coronary disease, andmild renal dysfunction; details of the eligibility
criteria are provided in Table S2 in the Supplementary Appendix. We also included women
60 years of age or older who had at least twosuch risk factors.9 We excluded persons withknown cardiovascular disease, clear indications orcontraindications to the trial drugs or angiotensin-converting–enzyme (ACE) inhibitors, moderate
or advanced renal dysfunction, or symptomatic
hypotension.
Fasting lipid, glucose, and creatinine levels
and blood pressure were measured before enrollment. However, participants were not selectedon the basis of history of either hypertension or
hyperlipidemia, and the trial did not mandate
strict blood-pressure or lipid levels for entry. Persons with a history of hypertension could beenrolled if the blood pressure was adequately
controlled (in the assessment of the recruiting
physician) with lifestyle or drugs other than an
ARB, ACE inhibitor, or thiazides. Recruiting
physicians were informed about local guidelines
regarding the prevention of cardiovascular disease (including guidelines for the managementof hypertension and dyslipidemia), and they used
local standards as an additional guide to determine trial eligibility, on the basis of the uncertainty principle.12
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Blood-Pressure Lowering in Intermediate-Risk Persons

Trial Procedures

Eligible participants entered a single-blind run-inphase, during which they received both active
treatments (for blood-pressure lowering and forcholesterol lowering) for 4 weeks. Serum creatinine, potassium, creatine kinase, and alanine
aminotransferase (or aspartate aminotransferase)levels were measured at 3 weeks. Participants
who adhered to the regimen (taking ≥80% of thetablets) and who did not have an unacceptablelevel of adverse events underwent randomization
with the use of a central concealed randomization procedure, stratified according to center.
Participants were randomly assigned to the dailyadministration of either a fixed-dose combination of candesartan at a dose of 16 mg and hydrochlorothiazide at a dose of 12.5 mg or placebo;
participants were also randomly assigned toreceive either rosuvastatin at a dose of 10 mg orplacebo.
All the participants received individualized
structured lifestyle advice, according to identified
needs. Follow-up visits occurred at 6 weeks and6 months after randomization and every 6 months
thereafter. Adherence to the regimen (as measured by pill count), safety, and trial outcomes
were evaluated at each visit. The blood pressure
was measured at each visit during the first year
and annually thereafter (average of two measurements after 5 minutes of quiet rest) with the useof a standardized protocol (see the Supplementary Appendix) and an automated measurement
system (Omron model HEM-711DLXCAN). Fasting blood samples were obtained at baselinefrom all the participants and during follow-up
from 10 to 20% of the participants (with representation across geographic and racial and ethnic
subgroups), and the samples were shipped forcentral storage and analyses of lipid levels andadditional markers (see the Supplementary Appendix).
Trial Outcomes

The two prespecified coprimary efficacy outcomes were the composite of death from cardiovascular causes, nonfatal myocardial infarction,or nonfatal stroke and the composite of these
events plus resuscitated cardiac arrest, heart failure, or revascularization. There were two secondary outcomes: the composite of events comprising the second coprimary outcome plus angina
with evidence of ischemia, and for the comparison of blood-pressure lowering, fatal or nonfataln engl j med 374;21

stroke. The secondary outcomes were modified
from the original trial protocol and were formally adopted by the steering committee without a protocol amendment on July 15, 2015, before unblinding on November 3, 2015.
Additional prespecified outcomes were total
mortality, the components of the coprimary andsecondary outcomes (stroke was a component of
the coprimary outcomes and also a distinct secondary outcome for the comparison of bloodpressure lowering), new-onset diabetes, cognitive
function (in participants ≥70 years of age), anderectile dysfunction in men. The latter two outcomes are not reported here. Event definitions
are provided in the Supplementary Appendix.
Renal dysfunction was a tertiary outcome inthe original trial protocol and was removed because of limitations of statistical power. The
main safety outcomes included cancer, myopathy, rhabdomyolysis, and hospitalization. In addition, we collected data on adverse events leading to temporary or permanent discontinuationof the trial regimens and on suspected unexpectedserious adverse reactions. Safety monitoring issummarized in the Supplementary Appendix.
Statistical Analysis

With an expected annual event rate of 1% for the
first coprimary outcome in the dual-placebogroup (i.e., the group of participants assigned toplacebo in both the comparison of blood-pressure lowering and the comparison of cholesterol
lowering), an average duration of follow-up of
5.5 years, cumulative nonadherence rates of
23%, drop-in rates of 11% (participants who
were projected to use open-label ARBs, ACE inhibitors, thiazides, or statins), and rates of loss
to follow-up of less than 1%, we estimated thata sample of 12,700 participants would provide
the trial with 80% power to detect a risk withcandesartan plus hydrochlorothiazide that was
at least 22.5% lower than the risk with placebo,
after the occurrence of at least 500 first and 600
second coprimary outcomes.9
The main analyses were performed according
to the intention-to-treat principle. Survival curves
were computed with the use of the Kaplan–Meierprocedure. A Cox proportional-hazards model,
stratified according to the opposite group of thefactorial design, was used to estimate treatment
effects and possible interactions and to evaluate
effects in subgroups. No significant interaction
between the two factorial treatments was obnejm.org

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T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 1. Characteristics of the Participants at Baseline.*
Candesartan +Hydrochlorothiazide(N = 6356)

Placebo(N = 6349)

Age — yr65.7±6.4

65.8±6.4

Female sex — no. (%)

2910 (45.8)2964 (46.7)

Elevated waist-to-hip ratio

5511 (86.7)

5523 (87.0)

Recent or current smoking

1782 (28.0)1742 (27.4)

Low concentration of HDL cholesterol

2297 (36.1)

2291 (36.1)

Impaired fasting glucose or impaired glucose tolerance799 (12.6)

817 (12.9)

Early diabetes mellitus

386 (6.1)

345 (5.4)

Family history of premature coronary heart disease

1668 (26.2)

1667 (26.3)

Early renal dysfunction

184 (2.9)

166 (2.6)

Hypertension

2398 (37.7)

2416 (38.1)

Systolic

138.2±14.7137.9±14.8

Diastolic82.0±9.481.8±9.3

Heart rate — beats/min

72.9±10.272.5±10.2

Body-mass index

27.1±4.827.1±4.7

Characteristic

Cardiovascular risk factor — no. (%)

Blood pressure — mm Hg

Waist-to-hip ratio

0.94±0.08

0.94±0.08

Total cholesterol — mg/dl†

201.4±42.6

201.5±41.7

LDL cholesterol — mg/dl†

127.4±36.5

128.3±35.6

HDL cholesterol — mg/dl†

44.9±13.944.8±13.7

Triglycerides — mg/dl†
MedianInterquartile range

127.4

128.3

92.9–180.5

92.9–175.2

95.4

95.4

87.0–106.2

86.4–106.0

Fasting plasma glucose — mg/dl
MedianInterquartile range
High-sensitivity C-reactive protein — mg/liter†
MedianInterquartile range

2.0

2.0

1.0–4.1

1.0–3.9

Serum creatinine — mg/dl

0.9±0.2

0.9±0.2

INTERHEART Risk Score‡

14.5±5.2

14.4±5.2

Chinese1844 (29.0)

1847 (29.1)

Hispanic

1739 (27.4)

1757 (27.7)

White1284 (20.2)

1262 (19.9)

South Asian932 (14.7)

922 (14.5)

Other Asian342 (5.4)354 (5.6)

Black

116 (1.8)

109 (1.7)

Other

99 (1.6)

98 (1.5)

Race or ethnic group — no. (%)§

2012

n engl j med 374;21

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Blood-Pressure Lowering in Intermediate-Risk Persons

Table 1. (Continued.)
Candesartan +Hydrochlorothiazide(N = 6356)

Placebo(N = 6349)

Aspirin

739 (11.6)

654 (10.3)

Beta-blocker

524 (8.2)

496 (7.8)

Calcium-channel blocker

928 (14.6)

957 (15.1)

Alpha-blocker

72 (1.1)

69 (1.1)

Nonthiazide diuretic

36 (0.6)

29 (0.5)

Aldosterone antagonist

6 (0.1)

11 (0.2)

Any blood-pressure-lowering drug

1388 (21.8)

1395 (22.0)

Oral hypoglycemic agent

176 (2.8)

161 (2.5)

Characteristic
Medication use — no. (%)*	Plus–minus values are means ±SD. There were no significant between-group differences, except for heart rate (P = 0.03)
and the use of aspirin (P = 0.02). Definitions for the cardiovascular risk factors are provided in Table S2 in the Supple‑
mentary Appendix. Data on blood pressure were missing for 2 participants in the placebo group, and data on central
core laboratory measurements of low-density lipoprotein (LDL) cholesterol concentration for 649 in the active-treat‑ment group and for 658 in the placebo group. Data on age and sex were complete. Data on other characteristics wereavailable for 99.7% or more of the trial participants, except that some laboratory variables measured at the central corelaboratory had rates of missing data similar to that for LDL cholesterol concentration. The body-mass index is theweight in kilograms divided by the square of the height in meters. To convert values for cholesterol to millimoles per li‑
ter, multiply by 0.0259. To convert values for triglycerides to millimoles per liter, multiply by 0.01129. To convert values
for glucose to millimoles per liter, multiply by 0.05551. To convert values for creatinine to micromoles per liter, multiply
by 88.4. HDL denotes high-density lipoprotein.
†	The measurements were made at the central core laboratory.
‡	The scale for the INTERHEART Risk Score14 ranges from 0 to 49; low cardiovascular risk corresponds to a score of 9 orless, medium risk to a score of 10 to 15, and high risk to a score of 16 or higher.
§	Race and ethnic group were self-reported.

served. Prespecified hypothesis-based subgroup
analyses were conducted according to thirds ofbaseline cardiovascular risk, of systolic bloodpressure, and of low-density lipoprotein (LDL)cholesterol concentration (with P values for trend),
with additional confirmatory prespecified subgroup analyses according to age, sex, diastolicblood pressure, waist-to-hip ratio, additional lipid
measurements, and race or ethnic group. A post
hoc recurrent-events analysis was performed withthe use of proportional-means models to describe
the effect on the risk of total cardiovascular
events.13
To preserve an overall type I error rate of 5%,
the first coprimary outcome was tested at a
P value of 0.04 and the second at a P value of
0.02 (considering an 80% overlap between the
coprimary outcomes). A nominal P value of lessthan 0.05 was used for all other analyses. Further details are provided in the Supplementary
Appendix.

n engl j med 374;21

R e sult s
Participants, Follow-up, and Medication Use

From April 2007 through November 2010, a totalof 14,682 participants entered the run-in phase(Fig. S1 in the Supplementary Appendix). Of
these, 12,705 participants (86.5%) underwent
randomization; 6356 participants were randomly
assigned to candesartan plus hydrochlorothiazide, and 6349 to placebo. The main reasonsthat participants did not undergo randomization
were an unwillingness to continue in the trial,
an adherence to the regimen of less than 80%,and side effects, the most common of whichwere abnormal laboratory values and hypotension.
The characteristics at baseline were similar in
the two trial groups (Table 1). The population
was racially and ethnically diverse, and the mean
age of the participants was 65.7 years. A total of
46.2% of the participants were women, 37.9%
reported a history of hypertension, and 21.9%

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T h e n e w e ng l a n d j o u r na l o f m e dic i n ewere taking antihypertensive agents (other thanARBs, ACE inhibitors, or thiazides).
The median follow-up was 5.6 years (interquartile range, 5.2 to 6.2). Vital status was ascertained in 12,587 participants (99.1%) at the endof the trial (Fig. S1 in the Supplementary Appendix). Among participants randomly assigned toactive therapy, 88.2% were taking the assigned
regimen at 1 year, 83.6% at 3 years, 75.0% at
5 years, and 76.8% at the end of the trial; thecorresponding rates in the placebo group were
87.9%, 83.4%, 74.5%, and 75.7%. Data on openlabel use of ARBs, ACE inhibitors, thiazides, andother blood-pressure-lowering drugs are provided
in Table S3 in the Supplementary Appendix.
Blood Pressure

Systolic Blood Pressure (mm Hg)

At baseline, the mean blood pressure in theentire trial population was 138.1/81.9 mm Hg.
The mean (±SD) systolic blood pressure was138.2±14.7 mm Hg in the active-treatment groupand 137.9±14.8 mm Hg in the placebo group.
The mean decreases from baseline during thetrial were 10.0±13.1 mm Hg in the active-treatment group and 4.0±12.9 mm Hg in the placebogroup (Fig. 1), and the average difference between the groups was 6.0±13.0 mm Hg.
The mean diastolic blood pressure at baseline
was 82.0±9.4 mm Hg in the active-treatment

140
Placebo135

130
Candesartan+hydrochlorothiazide

125
0

0

1

2

3

4

5

6

7

Years
No. at Risk
Candesartan+hydro- 6356
chlorothiazide
Placebo
6347

5907

5667

5446

5213

3862

1437

350

5879

5623

5442

5186

3822

1424

334

Figure 1. Systolic Blood Pressure over the Course of the Trial, According to
Trial Group.
I bars represent 95% confidence intervals.

2014

n engl j med 374;21

group and 81.8±9.3 mm Hg in the placebo group.
The mean decreases from baseline during thetrial were 5.7±8.2 mm Hg in the active-treatment group and 2.7±7.9 mm Hg in the placebogroup (Fig. S4 in the Supplementary Appendix),
and the average difference between the groups
was 3.0±8.0 mm Hg.
Clinical Outcomes

There were no significant differences between
the active-treatment group and the placebo groupin the incidence of the first coprimary outcome(260 [4.1%] and 279 [4.4%], respectively; hazard
ratio, 0.93; 95% confidence interval [CI], 0.79 to
1.10; P = 0.40) or the second coprimary outcome(312 [4.9%] and 328 [5.2%], respectively; hazard
ratio, 0.95; 95% CI, 0.81 to 1.11; P = 0.51). There
were also no significant between-group differences in the incidence of the secondary outcomes
and the components of the coprimary outcomes,
in total mortality, in the incidence of new-onset
diabetes, or in the post hoc outcome of total
cardiovascular events (Table 2 and Fig. 2, andFigs. S5 and S6 in the Supplementary Appendix).
In one of three prespecified hypothesis-based
subgroups, there were significant differences in
the prespecified subgroup analysis according tothirds of baseline systolic blood pressure for thetwo coprimary outcomes and the first secondary
outcome (P = 0.02 for trend for the first coprimary outcome, P = 0.009 for trend for the second
coprimary outcome, and P = 0.005 for trend forthe first secondary outcome) but not for thesecond secondary outcome of stroke (P = 0.22
for trend) (Fig. 3, and Fig. S11 in the Supplementary Appendix). Participants in the subgroup for the upper third of systolic blood pressure (>143.5 mm Hg; mean, 154.1±8.9 mm Hg)
who were in the active-treatment group had
nominally significantly lower rates than those in
the placebo group with respect to the first co­primary outcome (hazard ratio, 0.73; 95% CI,
0.56 to 0.94), the second coprimary outcome(hazard ratio, 0.76; 95% CI, 0.60 to 0.96), andthe first secondary outcome (hazard ratio, 0.72;
95% CI, 0.57 to 0.90). There were no significant
interactions among the other prespecified subgroups, including those according to thirds ofbaseline risk, LDL cholesterol concentration, or
diastolic blood pressure (Figs. S12 and S13
in the Supplementary Appendix).

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Blood-Pressure Lowering in Intermediate-Risk Persons

Table 2. Primary, Secondary, and Other Outcomes.*
Candesartan +Hydrochlorothiazide(N = 6356)

OutcomePlacebo(N = 6349)

Hazard Ratio(95% CI)P Value

Coprimary outcomes — no. (%)
First coprimary outcome

260 (4.1)

279 (4.4)

0.93 (0.79–1.10)

0.40

Second coprimary outcome

312 (4.9)328 (5.2)

0.95 (0.81–1.11)

0.51First secondary outcome†335 (5.3)

364 (5.7)

0.92 (0.79–1.06)

0.26

Fatal or nonfatal stroke

75 (1.2)

94 (1.5)0.80 (0.59–1.08)

0.14

Death from cardiovascular causes

155 (2.4)

170 (2.7)

0.91 (0.73–1.13)

0.40

Fatal or nonfatal myocardial infarction

52 (0.8)

62 (1.0)

0.84 (0.58–1.21)

0.34

Secondary outcomes — no. (%)

Components of the coprimary and secondary outcomes— no. (%)

Resuscitated cardiac arrest

2 (<0.1)

6 (0.1)0.33 (0.07–1.65)

0.18Heart failure

21 (0.3)

29 (0.5)

0.72 (0.41–1.27)

0.26

Revascularization‡

64 (1.0)74 (1.2)

0.86 (0.62–1.21)

0.39

Angina with objective evidence of ischemia†

51 (0.8)

69 (1.1)

0.74 (0.51–1.06)

0.10

Other outcomes
Death from any cause — no. (%)

342 (5.4)

349 (5.5)

0.98 (0.84–1.14)

0.78

236/5970 (4.0)

222/6004 (3.7)

1.07 (0.89–1.29)

0.46

319 (5.0)

331 (5.2)

0.96 (0.83–1.12)

0.63

No. of participants with ≥1 event

312

328

—

—

No. of participants with ≥2 events

59

98

—

—

New diagnosis of diabetes — no./total no. (%)
Hospitalization for cardiovascular causes — no. (%)§
First and recurrent events of the second coprimary
outcome¶No. of participants with ≥3 events
Total no. of events

5

17

—

—

380

446

0.87 (0.74–1.02)

0.09*	The first coprimary outcome was the composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke; the second copri‑
mary outcome was the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, heart
failure, or revascularization; and the first secondary outcome was the composite of cardiovascular death, nonfatal myocardial infarction,
nonfatal stroke, resuscitated cardiac arrest, heart failure, revascularization, or angina with objective evidence of ischemia.
†	This outcome was not specified in the trial protocol but was adopted by the steering committee before unblinding.
‡	Revascularization included coronary, cerebrovascular, and peripheral arterial revascularization.
§	Hospitalization for cardiovascular causes was a prespecified safety outcome.
¶	The analysis of recurrent events of the second coprimary outcome was a post hoc analysis that used a proportional-means model. The sec‑
ond coprimary outcome is shown because it comprises all events that were included in the first coprimary outcome as well as resuscitatedcardiac arrest, heart failure, and revascularization.

SafetyThere were no differences between the activetreatment group and the placebo group in therates of cancer, hospitalization for cardiovascular causes, hospitalization for noncardiovascularcauses, or death from noncardiovascular causes(Tables S6, S7, and S8 in the Supplementary Appendix). Permanent discontinuation of the trial
regimen occurred in 1552 participants (24.4%)
in the active-therapy group and in 1598 (25.2%) inn engl j med 374;21

the placebo group (P = 0.33) and was more common in the active-therapy group than in the placebo group owing to symptomatic hypotension,dizziness, or light-headedness (217 participants[3.4%] vs. 130 [2.0%], P<0.001) but not owing tosyncope (7 [0.1%] vs. 4 [0.1%], P = 0.55) or renal
dysfunction or abnormalities in the serum potassium level (32 [0.5%] vs. 20 [0.3%], P = 0.13)(Table S9 in the Supplementary Appendix). The
results for temporary discontinuation of the trial

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n engl j med 374;21

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4

4

4969
4970

5

5

2076
2075

6

6

522
488

7

7

0

0.0

0.2

0

4

6043
6043

Years

3

4

5051
5048

5

5

2114
2112

6

6

532
506

7

7

0.0

0.2

0.4

0

0

6293
6292

1

0.000

0.005

6155
6147

3

2

4

6038
6041

Years

3

4

5042
5045

5

5

2111
2115

6

6

534
505

6236
6236

2

1

6155
6146

3

2

4

6036
6037

Years

3

4

7

7

5044
5040

5

5

2103
2107

6

6

529
497

7

7

Candesartan+hydrochlorothiazide

Hazard ratio, 0.83 (95% CI, 0.58–1.19)
P=0.32
Placebo

6235
6234

2

1

Candesartan+hydrochlorothiazide

Placebo

Hazard ratio, 0.80 (95% CI, 0.59–1.08)
P=0.14

Figure 2. Cumulative Incidence of Major Cardiovascular Events, According to Trial Group.
Shown are the Kaplan–Meier curves for the second coprimary outcome, which was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal
stroke, resuscitated cardiac arrest, revascularization, or heart failure (Panel A), for fatal and nonfatal stroke (Panel B), for myocardial infarction (Panel C), and for coronary revascu‑
larization (Panel D). Coronary revascularization was not a prespecified outcome. Insets show the same data on an enlarged y axis.

6154
6155

3

2

0.015
0.8

0.010

0.020

0.6

0

6292
6291

1

0.000

0.005

1.0

Candesartan+hydrochlorothiazide 6356
Placebo
6349

6233
6239

2

1

D Coronary Revascularization

No. at Risk

0

6295
6289

1

0.00

Candesartan+hydrochlorothiazide

Hazard ratio, 0.84 (95% CI, 0.58–1.21)
P=0.34
Placebo

5968
5967

Years

3

Candesartan+hydrochlorothiazide 6356
Placebo
6349

0.0

0.2

0.4

0.005

0.010

0.015

0.8

0.6

0.020

1.0

6103
6096

3

2

No. at Risk

C Myocardial Infarction

6200
6198

2

1

0.4

0.010

0.015

0.8
0.6

0.020

1.0

Candesartan+hydrochlorothiazide 6356
Placebo
6349

6272
6270

1

0

Placebo

Candesartan+hydrochlorothiazide

Hazard ratio, 0.95 (95% CI, 0.81–1.11)
P=0.51

No. at Risk

0

0.00

0.02

0.04

0.06

0.08

0.10

B Stroke

Candesartan+hydrochlorothiazide 6356
Placebo6349

Cumulative Hazard Rate

No. at Risk

0.0

0.2

0.4

0.6

0.8

1.0

Revascularization, or Heart Failure

Cumulative Hazard Rate
Cumulative Hazard Rate

2016

Cumulative Hazard Rate

A Death from Cardiovascular Causes, Myocardial Infarction, Stroke, Cardiac Arrest,

T h e n e w e ng l a n d j o u r na l o f m e dic i n e

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Blood-Pressure Lowering in Intermediate-Risk Persons

A First Coprimary Outcome
Mean Systolic Difference
Blood
in Blood
Candesartan+
Pressure
Pressure Hydrochlorothiazide

Subgroupmm Hg
Overall
Systolic blood pressure≤131.5 mm Hg
131.6–143.5 mm Hg>143.5 mm Hg

Placebo

P Valuefor Trend

Hazard Ratio (95% CI)

no. of events/total no. of participants (%)

138.1

6.0/3.0260/6356 (4.1)

279/6349 (4.4)

0.93 (0.79–1.10)

122.2
137.6
154.1

6.1/3.1
5.6/2.7
5.8/3.070/2080 (3.4)
87/2120 (4.1)
103/2156 (4.8)

62/2122 (2.9)
81/2141 (3.8)
136/2084 (6.5)

1.16 (0.82–1.63)
1.08 (0.80–1.46)
0.73 (0.56–0.94)
0.5

1.0

—
0.02

2.0

Candesartan+ Placebo
Hydrochlorothiazide Better
BetterB Second Coprimary Outcome
Mean Systolic Difference
Blood
in Blood
Candesartan+
Pressure
Pressure Hydrochlorothiazide

Subgroupmm Hg
Overall
Systolic blood pressure≤131.5 mm Hg
131.6–143.5 mm Hg>143.5 mm Hg

Placebo

P Valuefor Trend

Hazard Ratio (95% CI)

no. of events/total no. of participants (%)

138.1

6.0/3.0

312/6356 (4.9)

328/6349 (5.2)

0.95 (0.81–1.11)

122.2
137.6
154.1

6.1/3.1
5.6/2.7
5.8/3.090/2080 (4.3)
99/2120 (4.7)
123/2156 (5.7)

74/2122 (3.5)
98/2141 (4.6)
156/2084 (7.5)

1.25 (0.92–1.70)
1.02 (0.77–1.34)
0.76 (0.60–0.96)
0.5

1.0

—
0.009

2.0

Candesartan+ Placebo
Hydrochlorothiazide Better
BetterFigure 3. Forest Plots, According to Subgroup of Systolic Blood Pressure for the Coprimary Outcomes.
The difference in blood pressure refers to the average difference of the systolic and diastolic blood pressures between the two groups
during the trial, with the active-treatment group having lower mean values. The first coprimary outcome (Panel A) was the composite ofdeath from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke; the second coprimary outcome (Panel B) was thecomposite of these events plus resuscitated cardiac arrest, heart failure, or revascularization. Measurements of the systolic blood pres‑sure at baseline were missing for two participants in the placebo group. The size of each square is proportional to the number of events.

regimen were similar to those for permanent
discontinuation (Table S10 in the Supplementary
Appendix). There were also no significant differences in the rates of serious unexpected suspected
adverse reactions (Table S11 in the Supplementary Appendix).

Discussion
In the HOPE-3 trial, treatment with candesartan
at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day over a period of
5.6 years lowered blood pressure by 6.0/3.0 mm Hgfrom baseline but did not result in a significantly
lower risk, as compared with placebo, of major
cardiovascular events in an intermediate-risk
population without cardiovascular disease andn engl j med 374;21

with very low rates of diabetes (5.8%) and mild
renal dysfunction (2.8%). The average bloodpressure of the participants at baseline was138.1/81.9 mm Hg, approximately one third of
the participants had a history of hypertension,and approximately 22% were taking antihypertensive agents. As compared with placebo, active
treatment was associated with a slightly higher
risk of symptomatic hypotension, dizziness andlight-headedness but not syncope, renal dysfunction, or other adverse events.
The Action to Control Cardiovascular Risk inDiabetes (ACCORD) and Systolic Blood Pressure
Intervention (SPRINT) trials15,16 are similar to
the HOPE-3 trial in that they also included participants with an average systolic blood pressurethat was considered to be in the high-normal
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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

range. However, the participants’ risk wasmuch higher in these two trials by design (yearly event rates in the control group of 2.1% in the
ACCORD trial and 2.2% in the SPRINT trial vs.
0.8% for the first coprimary outcome and 0.9%
for the second coprimary outcome in the HOPE-3
trial). These trials used complex treat-to-target
approaches, which resulted in greater loweringof blood pressure than was observed in the
HOPE-3 trial but also in higher rates of adverse
events.
Given the data from the ACCORD and SPRINT
trials,15,16 we cannot fully exclude the possibility
that greater reduction in blood pressure might
have been more effective in the HOPE-3 trial.
However, the Blood Pressure Lowering Treatment Trialists’ Collaboration reported an 18%
lower risk of major cardiovascular events among
persons at comparable baseline risk (5-year event
rate in the placebo group, 6.5%) with a reduction inblood pressure of 4.6/3.0 mm Hg from baseline butwith a systolic blood pressure of 155±21 mm Hg
at baseline.8 Thus, a higher systolic blood pressure at baseline may be decisive in determining
whether small reductions in blood pressure reduce risk.
There were significant trends toward a lower
risk of events at higher baseline systolic bloodpressure for the two coprimary outcomes and forthe first secondary outcome, with risks that were
nominally significantly lower by 24 to 28% in thesubgroup for the upper third of systolic blood pressure (>143.5 mm Hg; mean, 154.1±8.9 mm Hg).
By contrast, no benefit was observed in participants who had a baseline systolic blood pressureof 143.5 mm Hg or less and a suggestion ofharm for those in the lower-third subgroup(≤131.5 mm Hg; mean, 122.2±7.5 mm Hg). The
pattern for stroke differed, with no heterogeneity in the three subgroups that were defined according to baseline systolic blood pressure.
Blood-pressure differences between the trial
groups were similar across the three subgroupsof baseline systolic blood pressure. Therefore,
the observed subgroup findings are not related
to differences in the magnitude of blood-pressure lowering but rather to a differential effectin participants at different baseline blood-pressure levels. Although any subgroup analysis
should be interpreted with caution, the analysis
according to thirds of systolic blood pressure
was hypothesis-driven and prespecified, and the2018

n engl j med 374;21

benefits were consistent across prespecified outcomes and appear to be plausible in the context
of previously reported data.
Our findings contradict the “lower is better”
hypothesis that has been derived from epidemiologic studies,3 and our findings support the concept that a J-curve phenomenon exists for major
cardiovascular events, other than for stroke, inthis population. After correction for time-dependent regression dilution by averaging of all bloodpressure measurements in the placebo group overthe first year, the mean “usual” systolic bloodpressure thus calculated was 140.9±11.9 mm Hg in
the upper-third subgroup and 127.1±11.1 mm Hg
in the lower-third subgroup. Therefore, our data
are compatible with the hypothesis that treating
persons without cardiovascular disease who havea systolic blood pressure above approximately
140 mm Hg appears to be beneficial, but treatment would not be of benefit and may be evenharmful in persons with lower systolic bloodpressure levels.
Several meta-analyses have shown similar
reductions in relative risk across pretreatment
systolic blood-pressure levels ranging from lessthan 130 mm Hg to more than 180 mm Hg withthe use of various drugs, among persons withdiabetes and those without diabetes, and acrossvarious levels of risk, largely on the basis oftrials involving patients with vascular or renal
disease, diabetes, or entry systolic blood-pressurelevels of more than 150 mm Hg in primary prevention.5-8,17 Other meta-analyses of trials involving patients with diabetes showed no reductionin the risk of major cardiovascular events (except
possibly stroke) and a potential for harm in persons with a pretreatment systolic blood pressureof less than 140 mm Hg.18,19
There are insufficient data to guide decisions
about blood-pressure levels for the initiation ofantihypertensive agents in persons at low ormoderate cardiovascular risk who have mild uncomplicated hypertension.20 In previous trials,
most participants were already receiving antihypertensive agents before randomization or
their blood pressure was substantially higher
than our current definitions of grade 1 hypertension21-24; previous meta-analyses are also inconclusive.25,26 The uncertainty surrounding thisimportant question is reflected in recent U.S.
and European guidelines.27,28
This trial evaluated blood-pressure–lowering
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Blood-Pressure Lowering in Intermediate-Risk Persons

therapy with a fixed-dose combination of an significantly reduced the risk of cardiovascular
ARB and a thiazide, at relatively low doses, in events.
persons at intermediate risk who did not have
Supported by a grant (IR2-91038) from the Canadian Institutes
cardiovascular disease, among whom very few
of Health Research and by an unrestricted grant from AstraZeneca.
had diabetes or renal dysfunction and only apDisclosure forms provided by the authors are available withproximately one fifth were receiving antihyper- the full text of this article at NEJM.org.
We thank Gunnar Olsson, Steve Thomas, Russell Esterline,
tensive drugs before randomization. Our dataand Larrye Loss (all from AstraZeneca) for their efforts andindicate that in this population overall, there was support.
no significant benefit of blood-pressure lowerWe dedicate the HOPE-3 articles to the memory of two of ouring with the tested treatment. However, in one most valued colleagues — Prof. David Sackett, who was thechair of the data and safety monitoring board, and Dr. Janiceof the three subgroups of participants with un- Pogue, who was the head of statistics for this trial and the Popucomplicated mild hypertension, such therapy lation Health Research Institute.
Appendix
The authors’ affiliations are as follows: the Population Health Research Institute, Hamilton Health Sciences (E.M.L., J.B., R.M., J.P.,
J.W., H.J., S.Y.), the Department of Medicine (E.M.L., R.M., S.Y.), the School of Rehabilitation Science (J.B.), and the Department ofClinical Epidemiology and Biostatistics (J.P.), McMaster University, Hamilton, ON, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, University of Toronto, Toronto (L.A.L.), and Institut Universitaire deCardiologie et Pneumologie de Québec, Université Laval, Quebec, QC (G.D.) — all in Canada; Fundacion Oftalmológica de Santander
and Instituto Masira, Medical School, Universidad de Santander, Bucaramanga (P.L.-J.), and University of Caldas and Institución Prestadora de Salud Internistas de Caldas, Manizales (D.I.M.S.) — both in Colombia; Fu Wai Hospital, Chinese Academy of Medical Sciences
and Peking Union Medical College, Beijing (J.Z., L.L.); St. John’s Research Institute (P.P., D.X.) and St. John’s Medical College (D.X.),
Bangalore, India; Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D.); Hatter Institute for Cardiovascular Research in Africa,
Department of Medicine, University of Cape Town, Soweto Cardiovascular Research Group, Cape Town, South Africa (K.S.); College ofMedicine, University of the Philippines, Manila (A.D.); Dante Pazzanese Institute of Cardiology (A.A.) and HCor-Heart Hospital (L.S.P.)— both in São Paulo; Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary (K. Keltai, M.K.); Institute ofClinical Cardiology in the Russian Cardiology Research Complex, Moscow (I.C.); the Department of Cardiology, Academic Medical
Center, Amsterdam (R.J.G.P.); the Department of Medical Sciences, Cardiology, Clinical Research Center, Uppsala University, Uppsala,Sweden (C.H.); Universiti Teknologi Majlis Amansh Rakyat, Selayang, and University College Sedaya International University, Kuala
Lumpur (K.Y.) — both in Malaysia; Lady Davis Carmel Medical Center, Ruth and Bruce Rappaport School of Medicine, Technion–Israel
Institute of Technology, Haifa (B.S.L.); University Hospital Motol, Prague, Czech Republic (P.J.); Institute of Cardiology, Kiev, Ukraine(A.P.); Diabetes Research Centre (K. Khunti) and the Department of Cardiovascular Sciences (W.D.T.), University of Leicester, and the
National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital (W.D.T.) — both in
Leicester, United Kingdom; and Primary Care Diabetes and Vascular Medicine, Monash Centre of Cardiovascular Research and Education in Therapeutics (C.M.R.), and the Department of Epidemiology and Preventive Medicine (J.V.), Monash University, Melbourne, VIC,
and the School of Public Health, Curtin University, Perth, WA (C.M.R.) — both in Australia.
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