Circulation: 

Cardiovascular Quality and Outcomes Topic Review

Most Important Outcomes Research Papers on Hypertension

Ruijun Chen, BA; Kumar Dharmarajan, MD, MBA; Vivek T. Kulkarni, AB;
Natdanai Punnanithinont, MD, MPH; Aakriti Gupta, MBBS; Behnood Bikdeli, MD;
Purav S. Mody, MBBS; Isuru Ranasinghe, MBChB, MMed, PhD, for the Editor

The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize
the most important manuscripts, as selected by the Editor, which have published in the Circulation portfolio. The objective of this new series
is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, as
well as general cardiology audience. The studies included in this article represent the most significant research related to hypertension.
(Circ Cardiovasc Quality and Outcomes. 2013; 6:e26–e35.)

E ssential or primary hypertension, the world’s leading risk fac-

tor for global disease burden, is expected to cause more than
half of the estimated 17 million deaths per year resulting from car-
diovascular disease (CVD) worldwide.1 Defined as an elevation of
blood pressure (BP) beyond 140/90 mm Hg, hypertension is strongly
correlated with adverse outcomes such as stroke, ischemic heart
disease, heart failure, and end stage renal disease. The challenges
of managing hypertension and preventing the development of these
latter outcomes are unlikely to relent; the global burden of hyper-
tension is projected to increase by 60% to affect approximately 1.6
billion adults worldwide by 2025.2 In this month’s topic review in
Circulation: Cardiovascular Quality and Outcomes, we concentrate
on this highly prevalent condition.
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surrounding lifestyle modification, and the presence of highly effica-
cious anti-hypertensive therapies. Indeed, such persistent deficiencies
have fueled national initiatives such as the HealthyPeople 2020 and
the Million Hearts initiative to focus on improving awareness, treat-
ment, and, ultimately, outcomes of this common disorder.
We focus predominantly on these challenges in the following topic
review for Circulation: Cardiovascular Quality and Outcomes. We have
therefore included papers that evaluate the (1) epidemiology of diagno-
sis and management of hypertension, (2) specific interventions and treat-
ment programs for hypertension, and (3) health risks of hypertension.
Blood Pressure Targets Recommended by
Guidelines and Incidence of Cardiovascular

Considerable hurdles remain in overcoming the burden of hyper-

tension. First, the insidious nature in which hypertension devel-
ops means that hypertension is frequently undiagnosed, and early
detection prior to the development of end-organ damage remains
a challenge. Second, many patients appropriately diagnosed with
hypertension fail to achieve the treatment targets recommended by
guidelines. This highlights the considerable challenges in implement-
ing risk factor modification and appropriate adherence to antihy-
pertensive therapies long term. Third, uncertainty remains as to the
appropriate BP treatment target for high-risk patients. While a target
BP <140/90 mm Hg is generally recommended, a lower threshold of
<130/80 mm Hg is recommended for patients at high risk of CVD,
such as patients with diabetes.3 Whether such intensive BP lower-
ing leads to improved outcomes remains uncertain.4 Fourth, even
among patients who receive appropriate care, a proportion of patients
remains resistant to treatment despite multiple medications. These
patients with resistant hypertension carry substantial risk of adverse
events.5 The emergence of renal artery de-innervation may herald a
novel and effective procedural option to treat these patients.6
The challenges highlighted are pertinent to many populations.
Many low- and middle-income countries, most of which are in the
midst of the epidemiological transition, face rapidly increasing preva-
lence of hypertension in the context of limited healthcare resources. In
these countries, diagnosis and appropriate management of hyperten-
sion remains disconcertingly low.7 Developing innovative and cost-
effective solutions to improve hypertension diagnosis and control
thus remains a key priority.8 These issues are not limited to develop-
ing countries alone; less than 50% of the US patients have appro-
priate BP control9 despite good access to care, a wealth of evidence
and Renal Events in the Ongoing Telmisartan
Alone and in Combination With Ramipril Global
Endpoint Trial (ONTARGET)
Summary: Guidelines recommend treatment of hypertension when
BP exceeds 140/90 mm Hg or 130/80 mm Hg for patients at high risk
of cardiovascular (CV) events.3 However, whether this lower thresh-
old for treatment in patients at high risk necessarily leads to fewer CV
events is uncertain with a few studies suggesting no benefit or even
harm from the excessive lowering of BP.10,11 The Ongoing Telmisartan
Alone and in Combination with Ramipril Global Endpoint Trial
(ONTARGET) compared telmisartan with telmisartan plus ramipril
for treatment of hypertension with a median follow-up of 56 months
using a randomized control trial design.12 Using pooled data from this
study, the authors performed an observational analysis to compare
patients with an in-trial pre-event BP of <140/90 mm Hg with patients
with those who achieved an in-trial pre-event BP of <130/90 mm Hg.
The study findings show that a progressive increase in the propor-
tion of visits in which BP was reduced to <130/80 mm Hg, compared
to reduction to <140/90 mm Hg, was associated with a reduction in
the risk of stroke and renal events (defined as new onset of micro-
albuminuria or macroalbuminuria and return to normoalbuminuria
in albuminuric patients). In contrast, tighter BP control to <140/90
mmHg or <130/80 mmHg did not have any consistent effect on the
adjusted risk of myocardial infarction and heart failure. The compos-
ite of CV events was reduced by lowering BP to <140/90 mmHg, but
no additional benefit was observed with lowering to <130/80 mmHg.

Correspondence to The Editor, Circulation: Cardiovascular Quality and Outcomes Editorial Office, 560 Harrison Ave, Suite 502, Boston, MA 02118.
E-mail: circ@circulationjournal.org
© 2013 American Heart Association, Inc.
Circ Cardiovasc Qual Outcomes is available at http://circoutcomes.ahajournals.org DOI: 10.1161/CIRCOUTCOMES.113.000424

e26
 Chen et al   Important Papers on Hypertension   e27
Conclusions: Data from the ONTARGET study suggests that tightly
controlled BP <130/80 mmHg does not necessarily lower cardio-
vascular events compared to a target BP of <140/90mmHg, raising
debate as to the appropriateness of the targets recommended in cur-
rent guidelines.3 However, many patients fail to meet either of these
targets in clinical practice and achieving any form of BP control
remains a challenge. As indicated in this study, tight BP control does
have additional non-cardiac benefits including reducing the risk of
stroke and renal events, which are important endpoints from a patient
perspective. Furthermore in these high risk individuals, tighter BP
control <130/80 was not necessarily associated with adverse patients
outcomes and thus may be an appropriate goal for these patients.
These results must also be interpreted with caution; this study is a
non-randomized post-hoc observational analysis, subject to potential
bias, and is not a substitute for a well-designed randomized trial.13
Blood Pressure Targets in Subjects With
Type 2 Diabetes Mellitus/Impaired Fasting
Glucose: Observations From Traditional and
Bayesian Random-Effects Meta-Analyses of
Randomized Trials
Summary: Guidelines recommended aggressive lowering of BP in
patients with diabetes with a target BP <130/80 compared with a target
BP of <140/90 for the general population.14 Whether this leads to better
outcomes among diabetic patients has been debated. In this study, the
authors performed a meta-analysis of randomized clinical trials (RCTs)
from 1965 to 2010 of antihypertensive therapy in patients with type 2
diabetes mellitus or impaired fasting glucose/impaired glucose tolerance.
RCTs were included if they enrolled at least 100 patients who achieved
systolic BP (SBP) of ≤ 135 mm Hg in the intensive BP control group
and ≤ 140 mm Hg in the standard BP control group. Thirteen trials with
37 736 participants met the inclusion criteria. Intensive BP control was
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associated with a 10% reduction in all-cause mortality (odds ratio, 0.90;
95% CI 0.83 to 0.98) and a 17% reduction in stroke. A 20% increase in
serious adverse effects was noted with intensive BP control but with no
difference in other macrovascular and microvascular (cardiac, renal, and
retinal) events, as compared with standard BP control. Lowering of BP
below ≤130 mm Hg was associated with further reductions in stroke risk,
a trend which continued to a SBP of <120 mm Hg. However, lowering
of BP <130 mm Hg was associated with 40% increase in serious adverse
events and showed no benefit for other outcomes. The 10% reduction
in all-cause mortality was largely driven by trials that achieved a SBP
between 130–135 mm Hg.
Conclusions: Continued debate persists about the appropriate target
BP for hypertensive patients with diabetes. This meta-analysis sug-
gests a treatment goal of 130-135mm Hg is associated with better
outcomes compared to a target BP of <140/90 mm Hg. Lowering of
BP below <130/80 leads to reduced risk of stroke, at the expense of
increased adverse events, and showed no benefits with regard to other
micro or macrovascular events. As with most meta-analyses, there are
some limitations which should be considered when interpreting these
findings. Only 5 of the 13 trials were designed to specifically test a
strategy of intensive versus standard BP lowering. Furthermore, the
heterogeneity of the patient populations, comorbid conditions, and
variations in the treatments used are potential drawbacks. However,
despite these limitations, this study raises concerns about the current
guideline recommendation of universal lowering of BP <130/80 in all
diabetic patients to reduce cardiovascular risk.4
National Surveillance Definitions for Hypertension
Prevalence and Control Among Adults
Summary: Epidemiologic estimates of hypertension and hyperten-
sion control have been quite varied due to differences in cohort defi-
nitions and adjustment methodologies, even when the same data set
has been used. The authors sought to characterize this variation using
recent survey cycles of the National Health and Nutrition Examination
Surveys (NHANES) from 2003 to 2008. They identified 19 studies that
used various criteria for defining hypertension and hypertension con-
trol. Although the definition of hypertension was uniformly a systolic
blood pressure (SBP) ≥140mm Hg or a diastolic blood pressure (DBP)
≥90mm Hg, studies varied in: (1) the use of patient self-report to define
the presence of hypertension; (2) the inclusion of all individuals with
hypertension or just treated patients when assessing hypertension con-
trol; (3) the age range of included patients; (4) the decision to include
pregnant women; (5) report of crude versus age-adjusted rates; and
many other parameters. As a result of these differences, crude preva-
lence of hypertension among adults varied from 28.9% to 49.9%, and
age-adjusted prevalence varied from 28.9% to 32.1%. Crude hyperten-
sion control varied from 37% to 52.9%, and age-adjusted hypertension
control varied from 35.1% to 64%. Using standard surveillance defini-
tions proposed by the American Heart Association,15 the authors found
the age-standardized prevalence of hypertension to be 29.8% and rate
of hypertension control to be 45.8%.
Conclusions: The authors found significant variation in estimates of
hypertension prevalence and control in the current medical literature
even when using the same baseline data from NHANES because of dif-
ferent definitions. These findings demonstrate the need to standardize
definitions in epidemiologic surveys in order to permit valid compari-
sons between populations and calculation of trends over time. Readers
of the hypertension literature should be made aware that study defini-
tions and methodology can significantly influence epidemiologic esti-
mates. Although not tested in this study, it is possible that significant
variability in the definitions of hypertension and hypertension control
is also present in clinical trials. It may therefore be prudent to standard-
ize definitions of hypertension-related parameters for trials in a paral-
lel way to what has been done by the Bleeding Academic Research
Consortium16 and Valve Academic Research Consortium.17–19
Epidemiology of Diagnosis and Management of
Hypertension
Significant advances have been made in the diagnosis and man-
agement of hypertension as contemporary studies have increased
our understanding of the risk factors and the effectiveness of treat-
ments. Large clinical trials have screened for and confirmed the BP
lowering effects of weight loss, sodium reduction, dietary modi-
fication, exercise, and alcohol reduction.20–23 Such findings led to
the ongoing promotion of healthier lifestyles to protect against the
development of hypertension, achieved through enhanced public
understanding and community-based strategies sponsored by non-
profit and government organizations such as the National Heart,
Lung, and Blood Institute (NHLBI).24 Coincident with these life-
style changes which serve as both preventative measures and early
treatment of hypertension, extensive research has been performed
on drug development and optimal drug regimens, resulting in
multiple highly effective therapeutic options for the treatment of
hypertension.25 Clinical management has benefited from the rapid
testing of new treatment strategies and evolving guidelines which
are frequently updated to maximize positive outcomes for patients.
Additional studies have similarly guided the incorporation of
angiotensin converting enzyme inhibitors, angiotensin II receptor
antagonists, and calcium channel blockers into our treatment arse-
nal, optimized their use in different clinical scenarios, and identi-
fied combination therapy as both a highly necessary and effective
means of BP management.26–28
As a result of these advancements in the scientific literature, we
may expect to observe changes in the epidemiology and trends in
the awareness, treatment, and effective BP control of hypertensive
patients along with their associations with outcomes. Here, we
summarize a number of papers which investigate contemporary
 e28   Circ Cardiovasc Qual Outcomes   July 2013
epidemiology and trends over time in the diagnosis and management
of hypertension across a variety of patient populations.
Trends in Antihypertensive Medication Use and
Blood Pressure Control Among United States
Adults with Hypertension: The National Health
and Nutrition Examination Survey, 2001 to 2010
Summary: Previous research has suggested that rates of treatment
and control of hypertension in the US have been suboptimal. The
authors therefore examine recent trends in antihypertensive medica-
tion use and its impact on blood pressure control using the National
Health and Nutrition Examination Survey from 2001 to 2010. Blood
pressure control was defined as <140/90 mm Hg for the general popu-
lation and BP < 130 /80 mm Hg for patients with diabetes mellitus or
chronic kidney disease. The prevalence of antihypertensive medica-
tion use increased from 64% to 77% during this decade, and blood
pressure control rates improved from 29% to 47%. Antihypertensive
polytherapy regimens appeared to control blood pressure signifi-
cantly better than monotherapy regimens. The study also shows that
younger people, Mexican-Americans, and those without health insur-
ance were undertreated. In contrast, hypertension in older people,
non-Hispanic blacks, persons with diabetes mellitus, and persons
with chronic kidney disease was more likely to be controlled with
treatment.
Conclusions: The study is the most recent nationally representative
study to document trends of antihypertensive medication use and
disease-specific rates of blood pressure control. The authors found
encouraging evidence of improvement in blood pressure control in
the US adults during the past decade, which appears to have been
facilitated by increased use of combination therapy regimens in the
treated hypertensive population. However, disparities remain in blood
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pressure control among specific subpopulations such as younger per-
sons. Furthermore, despite these encouraging improvements, less than
one-half of the population appears to have adequate blood pressure
control, which presents substantial opportunities for improvement.9
Trends in Blood Pressure and Hypertension
Detection, Treatment, and Control 1980 to
2009: The Minnesota Heart Survey
Summary: Recent national preventative health initiatives such as
Healthy People 2020, have set high goals for improvement in the
detection, treatment, and control of hypertension. This study evalu-
ated trends in population blood pressure and hypertension detection,
treatment, and control using the Minnesota Heart Survey from 1980
to 2009. In total, 23 978 adults (11 192 men, 12 795 women) aged 25
to 74 years participated in six cross-sectional surveys taken 5 yearly,
representing the Minneapolis/St. Paul metropolitan area. Over the 30
year study period, systolic and diastolic blood pressures decreased
significantly over time for both men (SBP from 124.9 mm Hg to
121.1 mm Hg; DBP from 78.1 mm Hg to 75.5 mm Hg) and women
(SBP from 120.1 mm Hg to 114.7 mm Hg; DBP from 74.0 mm Hg to
70.6 mm Hg), with most of the differences occurring among treated
hypertensive patients (p<0.0001). There was also a dramatic increase
in the population who were aware, treated with medications, and
had their blood pressure controlled, accounting for 66% of men and
72% of women in the 2007–2009 survey. The number of individuals
with uncontrolled blood pressure (BP ≥140/90), irrespective of anti-
hypertensive therapy, declined from 20.3% to 5.8% for men and from
13.1% to 2.7% for women (p<0.0001). Stroke mortality trends from
1990–2009 declined in parallel with the observed decline in BP dur-
ing the study period.
Conclusions: This study shows that the diagnosis, treatment, and
control of hypertension have improved drastically from 1980 to 2009
in the Minneapolis/St. Paul region, with better levels of treatment
and control along with lower average blood pressures than observed
nationally.29 It is important to note that compared to the entire US,
survey population is 90% white, has one of the highest levels of health
insurance coverage, fewer people in poverty, and higher average edu-
cational levels. Despite these differences, these results demonstrate
that high levels of control are already possible in certain regions, pro-
viding support that in time, the Healthy People 2020 goal of having
61.2% of the hypertensive population aware, treated, and controlled
may be achievable nationwide.30,31
Blood Pressure Control Among US Veterans:
A Large Multiyear Analysis of Blood Pressure
Data from the Veterans Administration Health
Data Repository
Summary: Control of blood pressure among patients with hyperten-
sion has been associated with improved cardiovascular outcomes.
The authors sought to assess improvements in hypertension control
from 2000 to 2010 among a large cohort of hypertensive patients
treated at 15 Department of Veterans Affairs medical centers. The
main outcome measure was the percentage of hypertensive patients
with controlled blood pressure, which was defined as those patients
with ≥3 days of BP readings but no days with BP elevated. The aver-
age SBP during the 10 year period decreased from 143/77 mm Hg
in 2000 to 131/75 mm Hg in 2010. Correspondingly, the proportion
of patients with controlled blood pressures increased over time from
45.7% in 2000 to 76.3% in 2010. On average, control rates increased
by 3.0% per year. Improvement was similar across all age, sex, and
race groups. Interestingly, both systolic and diastolic blood pressures
were lower in the summer compared with the winter for the whole
period of the study, and blood pressure control rates were 6.8% better
during the summer months.
Conclusions: The authors found a steady improvement in blood
pressure control among US veterans over a 10-year period; control
did not significantly vary by patient age, sex, or race. The degree of
improvement in blood pressure control in this patient cohort greatly
outstrips that of the US in general, which was from 35% to 50% over
a similar time period.32 The source of this substantial difference is
unknown, though may relate to the implementation of electronic
medical records into the VA system that automatically notify doctors
of patients’ blood pressure elevation as well as significant outpatient
capacity in which to schedule frequent follow up appointments until
blood pressure is adequately controlled.33
Prevalence, Awareness, Treatment, and
Control of Hypertension Among Residents in
Guangdong Province, China, 2004 to 2007
Summary: Hypertension in China has become a major public health
problem, but little is known about trends in hypertension at the pro-
vincial level. Such provincial trends are important for identifying
areas of need and future public health planning in the context of lim-
ited national healthcare resources. This study described the trends in
the prevalence and rates of hypertension awareness, treatment, and
control in Guangdong Province, the most populous Chinese province.
Data were derived from the Guangdong Provincial Chronic Disease
Risk Factor Surveillance, a representative cross-sectional survey of
residents 18 to 69 years of age and compared 7633 participants in
2004 with 6447 participants in 2007. During this period, the age-
standardized prevalence of hypertension increased from 12.2% to
15.4% (p<0.001), with the greatest increase in the rural population.
Hypertension awareness and treatment was poor and did not dif-
fer significantly (25.6% to 25.8%; 21.7% to 22.2%, respectively).
Hypertension control was rarely achieved and in fact worsened from
7.1% to 4.5% (p<0.01). Over the study period, mean body mass
 Chen et al   Important Papers on Hypertension   e29
index, systolic and diastolic blood pressure, and mean waist circum-
ference all significantly increased (p<0.01).
Conclusions: Recent trends in Guangdong Province show that adverse
markers of health outcomes including blood pressures, body mass
index, and waist circumference have increased along with the preva-
lence of hypertension. However, awareness, treatment, and control
of hypertension are poor, remaining unchanged or worse, suggesting
that clinical care in the region has not improved to meet the increased
needs of the population. Similar findings have been shown from
national surveys which have indicated a prevalence of hypertension
at 17% to 27%, awareness at 24% to 45%, treatment at 28% to 78%,
and control at 8% to 19%.34,35 These national findings together with
the results of this study highlight the major challenges in detecting
and managing hypertension in China, as they lag far behind the 77%
treated and 47% controlled seen in the US population.9 With num-
bers comparable to the lower end of the national spectrum or worse,
Guangdong Province may be an important underperforming region
which requires particular attention and resources in the future.7,36
Hypertension Control Among Patients Followed
by Cardiologists
Summary: Despite the high numbers of patients with hypertension
treated by cardiologists, most studies on hypertension control have
focused on primary care settings. This study evaluated hypertension
control rates of patients cared for longitudinally by cardiologist in the
cardiology clinics at Duke University Medical Center. It also assessed
physician-level variation in these control rates and clinician response
to elevated BP in the clinic. A total of 5979 patients with diagnosed
hypertension in 47 cardiologists’ clinics were included in the study
period from June 2009 to June 2010. The rate of sub-optimally
controlled BP ≥140/90 among these patients was 30.3% and varied
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across cardiologists’ clinics with a range from 16% to 44%. These
variations remained significant after risk adjustment for patient char-
acteristics. Cardiologists failed to document a response to a finding of
an elevated BP in the medical record in 38% of patients.
Conclusions: A large proportion of patients with hypertension seen
in cardiology clinics have suboptimally controlled BP which var-
ies widely across cardiologists and is often is not addressed during
the course of the clinic visit. These results may not be generalizable
since the study was performed at a single center and 98% of these
patients had health insurance. However, given the co-morbid effects
that hypertension has on a large number of cardiovascular diseases,
cardiologists should not overlook the importance of BP management
and need take on an active role, sharing responsibility for effective
control together with primary care providers.35,37
Trends in Mortality from All Causes and
Cardiovascular Disease Among Hypertensive
and Nonhypertensive Adults in the United States
Summary: Despite improvement in the identification and control of
hypertension over the past decades, relatively little is known about
trends in mortality among persons with hypertension in the United
States. This study aims to examine trends in all-cause and cardiovas-
cular mortality among persons with and without hypertension over the
past 4 decades. The authors used the data from the National Health
and Nutritional Examination Survey (NHANES) I Epidemiological
Follow-Up Study (1971 to 1975) and NHANES III Linked Mortality
Study (1988 to 1994). Follow up was for a mean of 17.5 and 14.2
years, respectively. Not surprisingly, the authors found higher mortal-
ity among hypertensive adults compared with nonhypertensive adults
in each cohort. Among hypertensive adults, adjusted mortality rate
from all causes decreased by 4.6 per 1,000 person-years and adjusted
mortality rate from CVD decreased by 3.6 per 1,000 person-years.
Among non-hypertensive adults, adjusted mortality rate from all
causes decreased by 4.2 per 1,000 person-years and the adjusted mor-
tality rate from CVD decreased by 2.6 per 1,000 person-years. Over
the study period, reduction in adjusted mortality was highest among
hypertensive men and hypertensive blacks and lowest among hyper-
tensive women, in particular.
Conclusions: Although both all-cause and cardiovascular mortality
declined significantly for adults with hypertension over the study
period, it is unclear whether these results are due to improved hyper-
tension control or rather reflect population wide-trends, as non-hyper-
tensive adults also experienced significant declines in mortality. In
addition, the reasons for greatest mortality reduction among hyperten-
sive men and blacks compared with hypertensive women is unknown
but may reflect the fact that compared with women and whites, men
and blacks with hypertension have higher absolute cardiovascular
risk and may therefore have greater opportunity for improvement.36,38
Interventions and Treatment Programs for
Hypertension
Despite the demonstrated efficacy of lifestyle changes and pharmaceu-
tical agents in lowering blood pressure, hypertension remains poorly
controlled in many populations and practice settings due to ineffective
implementation of prevention and treatment strategies. On the other
hand, even among patients receiving intensive pharmacotherapy, some
patients’ hypertension remains resistant to treatment. Regardless of the
cause, patients with suboptimally controlled hypertension remain at
elevated risk for cardiovascular events, and efforts should be directed
towards improving hypertension control in these patients.
In the following section, we review research aimed at improving
hypertension control by implementing standardized prevention and
treatment strategies across various practice settings—including phar-
macist-led interventions,39,40 educational programs in Pakistan,8 and
dietary protein supplementation41—as well as the Symplicity HTN-2
trial of renal denervation for drug-resistant hypertension.42
A Pharmacist-Led, American Heart Association
Heart360 Web-Enabled Home Blood Pressure
Monitoring Program
Summary: Home blood pressure monitoring (HBPM) is a promis-
ing modality for improving blood pressure control in patients with
hypertension. In this study, the authors conducted a randomized, con-
trolled trial to evaluate a HBPM program utilizing the American Heart
Association’s Heart360 web application, a free tool to help patients
and providers monitor cardiovascular risk factors. Adult patients in the
Kaiser Permanente system with BPs above goal (BP ≥140/90 mm Hg
or ≥130/80 mm Hg for patients with diabetes mellitus (DM) or chronic
kidney disease (CKD) were randomized to a HBPM group or a usual
care group. Patients in the usual care group (n=173) received written
educational materials and instructions to follow up with their physi-
cians. Patients in the HBPM group (n=175) additionally received a
home BP monitor, pharmacist-led instruction in proper use, assistance
with the Heart360 website, and instructions on how to upload their
home BP readings to the site. These patients then took ≥ 3 BP measure-
ments weekly. For patients in the HBPM group, clinical pharmacists
made medication adjustments as needed and communicated via tele-
phone or e-mail. The 2 groups did not differ in their demographic char-
acteristics or their initial BP readings. After 6 months, the proportion of
patients with achieving BP goal was 54.1% in the HBPM group com-
pared with 35.4% in the usual care group (adjusted risk ratio (aRR), 1.5;
95% confidence interval (CI), 1.2–1.9). In the subset of patients with
DM or CKD, the difference was even larger (51.7% v. 21.9%; aRR, 2.5;
95% CI, 1.6–3.8). Patients in the HBPM group also experienced signifi-
cantly larger drops in SBP (20.7 mm Hg versus 8.2 mm Hg) and DBP
(10.5 mm Hg versus 4.8 mm Hg) compared with the usual care group.
 e30   Circ Cardiovasc Qual Outcomes   July 2013
There was no difference between the groups in the number of clinic vis-
its, emergency department visits, or hospitalizations, but patients in the
HBPM group had significantly more telephone and e-mail encounters
and a larger fraction reported being very or completely satisfied with
their hypertension care than those in the usual care group.
Conclusions: This study shows promise that a pharmacist-led HBPM
program can substantially improve BP control in a diverse group
of patients in routine clinical practice, including those with DM or
CKD. Free online tools such as the Heart360 website (https://www.
heart360.org/) may facilitate these efforts. Nevertheless, substantial
resources may be required to effect these changes. Most impor-
tantly, substantial time and interaction from clinical pharmacists was
required to implement the study protocol, and it is difficult to distin-
guish the effects of home monitoring itself from the effects of phar-
macist intervention.39
Improving Blood Pressure Control Through
a Clinical Pharmacist Outreach Program in
Patients With Diabetes Mellitus in 2 High-
Performing Health Systems: The Adherence
and Intensification of Medications Cluster
Randomized, Controlled Pragmatic Trial
Summary: This study evaluated the real-world viability of the
Adherence and Intensification of Medications (AIM) intervention, a
multifaceted strategy to improve medication adherence, in improv-
ing blood pressure control among patients with diabetes mellitus
(DM). Diabetic patients with poor BP control and poor refill adher-
ence were enrolled from 3 urban VA facilities in the Midwest and 2
Kaiser Permanente facilities in California. These patients were then
randomized to either an AIM intervention group—which consisted
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of pharmacist-led motivational interviewing, medication adherence
assessment, and changes to BP medications when appropriate—or
a usual care group, with no staff contact. The AIM intervention has
been described in detail elsewhere in the literature.43 The primary out-
come was the change in SBP measurements at 6 months after the 14
month intervention period. There were no demographic or clinical
differences between the intervention group (n=1797) and the usual
care group (n=2303) at the time of randomization. At 3 months after
the intervention period, mean SBP in the intervention group had
dropped 9.7 mm Hg versus 7.2 mm Hg in the control group, a differ-
ence of 2.4 mm Hg (p<0.0001). However, at 6 months after the inter-
vention period, the decline in SBP was not different in the invention
group (8.9 mm Hg) compared to the usual care group (9.0 mm Hg).
Conclusions: This pharmacist-led intervention aimed at improving
BP control in patients with DM failed to show sustained improve-
ment of SBP compared with usual care. As the authors acknowledge,
the VA and Kaiser Permanente health systems are already “high-
performing” with respect to BP control, in that more than 80% of
patients are currently at goal. Thus, targeted interventions such as the
AIM intervention may be more efficacious in populations for whom
baseline control is poor, while the marginal benefit of such interven-
tions in high-performing practices may be minimal.40
Cost-Effectiveness of Community-Based
Strategies for Blood Pressure Control in a Low-
Income Developing Country: Findings from a
Cluster-Randomized, Factorial-Controlled Trial
Summary: Studies of cost effectiveness of interventions to reduce
BP in low and middle income countries are limited in number. In
this study, the authors performed a cost-effectiveness analysis of the
Control of Blood Pressure and Risk Attenuation (COBRA) trial, which
evaluated community based strategies to reduce BP by randomizing
1341 hypertensive subjects in 12 randomly selected communities in
Karachi, Pakistan, to 3 intervention programs: (1) home health edu-
cation (HHE) by community health workers focusing on risk factor
modification (2) training of general practitioners (GP) in guideline-
based BP management, and (3) combined HHE and GP training. The
comparator was no intervention (usual care). The primary results of
this study showed that the combined intervention (HHE and GP train-
ing) was associated with greater medication adherence and led to the
most significant decline in SBP (10.8 mm Hg reduction, 95% CI 8.9 to
12.8 mm Hg) at 2 years.44 The cost-effectiveness considered the cost of
the medications, costs to the patient in the health care received and the
lifestyle changes advised, and losses in productivity. The results show
that the combined intervention was the most cost-effective, with an
incremental cost-effectiveness ratio (ICER) of US$23 (95% CI, 6–99)
per 1 mm Hg reduction in systolic BP compared with usual care. This
estimate translated to an incremental per-capita cost of $0.43 per 1
mm Hg reduction in SBP and an estimated US$1226 per CV disease
related disability-adjusted life-year (DALY) averted from a societal
perspective (or $0.49 per-capita cost per DALY averted).
Conclusions: This well conducted cost-effectiveness analyses, con-
ducted from a societal perspective, suggest community based inter-
ventions are both effective and affordable in Pakistan. The reported
ICER, per capita cost, and cost per DALY averted fall within the
accepted ranges qualifying it to be cost-effective for developing
countries, as set by the World Health Organization and other agen-
cies.45,46 These findings have broad implications for other low and
middle income countries facing the constant challenge of how best to
care for people with high BP in the context of the rapidly increasing
prevalence of hypertension and limited healthcare resources.8
Effect of Dietary Protein Supplementation on
Blood Pressure: A Randomized, Controlled Trial
Summary: Dietary modification is recommended for the prevention and
treatment of hypertension. Previous observational data have suggested
that increasing dietary intake of vegetable protein leads to lowering of
blood pressure47 although this has not been evaluated in a randomized
fashion. In this study, the authors evaluated whether the intake of veg-
etable protein (40 g soy protein/day) or animal protein (milk protein
40g/day) compared to placebo (40g/day carbohydrate supplementation)
leads to a short-term reduction in BP using a randomized double-blind
cross-over design. Patients with SBP of 120-159 mm Hg and DBP of
80-95 mm Hg were included. Patients on anti-hypertensive therapy were
excluded. The study results show that in the 352 patients randomized,
compared with controls, soy and milk protein supplementation was
associated with 2.0 mm Hg (95% CI 3.2 to 0.7 mm Hg, p=0.002) and 2.3
mm Hg (95% CI 3.7 to 1.0 mm Hg, p=0.0007) reduction in SBP, respec-
tively, with no change in DBP over the 8 week trial period. No signifi-
cant difference in the magnitude of BP reduction was observed between
soy and milk protein. Other markers such as weight, body mass index,
blood glucose, total cholesterol, and LDL levels were unchanged with
the exception of HDL, which was increased with soy protein intake.
Conclusions: This clinical trial provides intriguing data that sug-
gest dietary modification with soy or milk protein may lead to a
statistically and clinical significant reduction in SBP, but not DBP,
in the short term. These findings must be interpreted with cau-
tion as these observations are yet to be replicated. Furthermore, it
remains to be seen whether the BP reduction can be sustained long-
term with improvements cardiovascular outcomes and whether the
reduction in BP will extend to patients with more severe hyper-
tension or those already receiving anti-hypertensive therapy.
Nevertheless, this well designed study provides promising early
evidence for dietary modification of protein as a viable population
strategy for lowering systolic hypertension for primary and second-
ary prevention.41
 Chen et al   Important Papers on Hypertension   e31
Renal Sympathetic Denervation for Treatment of
Drug-Resistant Hypertension: One-Year Results
From the Symplicity HTN-2 Randomized,
Controlled Trial
Summary: The randomized Symplicity HTN-2 trial demonstrated
that catheter-based renal denervation significantly lowered blood pres-
sure 6 months post-procedure among patients with treatment-resistant
hypertension (defined as a baseline SBP ≥160mm Hg and use of at
least 3 anti-hypertension medications). This study reports on 1-year
follow up of initial trial patients as well as 6-month follow up of control
patients allowed to cross-over to catheter denervation. At 12 months
post-procedure, the mean fall in office SBP in the initial renal denerva-
tion group (n=47, 28.1 mm Hg; 95% CI, 35.4 to 20.7; p<0.001 versus
initial baseline BP) was similar to the 6-month fall (31.7 mm Hg; 95%
CI, 38.3 to 25.0; p=0.16 versus 6-month change). The mean SBP of
the crossover group 6 months post-procedure was significantly low-
ered (from 190.0±19.6 to 166.3±24.7 mm Hg; change, -23.7±27.5;
p<0.001). In the crossover group, there was 1 renal artery dissection
during guide catheter insertion, before denervation, and 1 hypotensive
episode, which resolved with intravenous fluids.
Conclusions: In patients with treatment-resistant hypertension,
renal denervation appears to be relatively safe and result in a sig-
nificant drop in blood pressure both 6 and 12 months post-procedure.
However, limitations with trial design of Symplicity HTN-2 pre-
clude the ability to make strong recommendations in favor of renal
denervation. Methodological shortcomings include the use of clinic
blood pressure readings rather than 24 hour monitoring as the pri-
mary endpoint, lack of blinding of patients and staff measuring blood
pressure to treatment allocation, and absence of a sham renal dener-
vation procedure among control patients. Although incompletely
Downloaded from http://ahajournals.org by on April 19, 2019
recorded, ambulatory blood pressure readings from Symplicity 2 did
indeed show lower benefit as compared with clinic readings. These
limitations will be addressed in the ongoing Symplicity HTN-3 trial.
Futhermore, outcomes data showing an improvement in cardiovascu-
lar and other relevent endpoints are needed prior to the widespread
adoption of this novel approach.42
Health Risks of Hypertension
At a population level, hypertension is the most important risk factor
for premature cardiovascular disease. On a global basis, hypertension
accounts for approximately 50% of all strokes and ischemic cardiac
events.48 The risks for both of these outcomes increase progressively
with incremental rises in both systolic and diastolic blood pressure
above 115/75 mm Hg.49 Similarly, progressive increases in pulse pres-
sure (difference between systolic and diastolic blood pressures) are
likewise associated with heightened cardiovascular risk.50
Harms of hypertension are also seen among specific sub-popula-
tions of patients. For example, for patients with chronic kidney dis-
ease, hypertension can further damage the kidney and accelerate the
progression of a variety of underlying renal diseases.51,52 In addition,
hypertension during pregnancy, when severe, can result in complica-
tions to the fetus and mother such as an elevated incidence of preterm
delivery, small for gestational age infants, and abruptio placentae.53
Gestational hypertension is also associated with an increased risk of
chronic hypertension later in life.54
It is critical, however, to interpret the potential harms of hyperten-
sion in the context of a patient’s overall risk profile for CVD. The
presence of other risk factors such as hyperlipidemia, cigarette smok-
ing, diabetes, and elevated age can greatly increase the risks asso-
ciated with even mild hypertension, while in the absence of these
factors, elevated blood pressure may be associated with only a mini-
mal increase in absolute cardiovascular risk.55 In addition, knowledge
of a patient’s lifelong exposure to elevated blood pressure may help
further refine cardiovascular risk assessment.56,57
In the following section, we review research relating to cardiovas-
cular, cerebrovascular, and cognitive harms associated with hyper-
tension.5,58,59 We also present research related to risk in specific
populations such as pregnant women and the elderly.60,61
Incidence and Prognosis of Resistant
Hypertension in Hypertensive Patients
Summary: Patients with treatment-resistant hypertension constitute
a high-risk subset for cardiovascular complications such as myo-
cardial infarction and stroke. However, the incidence and prognosis
of this condition are largely unknown. Using patient data collected
from 2002 to 2006 in the Kaiser Permanente Colorado and Northern
California healthcare systems, the authors of this retrospective
cohort study identified 205 750 patients who were started on anti-
hypertensive treatment for newly diagnosed hypertension. Patients
were followed up for the development of resistant hypertension
based on AHA criteria of failure to achieve goal BP despite use of ≥3
antihypertensive medications. Within a median of 1.5 years from ini-
tial treatment, 1.9% of patients developed resistant hypertension (0.7
cases per 100 person-years of follow-up). These patients were more
often men, were older, and had higher rates of diabetes mellitus than
patients who were responsive to treatment. Over 3.8 years of median
follow-up, cardiovascular event rates (composite endpoint of death
or incident cardiovascular events including myocardial infarction,
heart failure, stroke, or chronic kidney disease) were significantly
higher in those with resistant hypertension (unadjusted 18.0% versus
13.5%, p<0.001). After adjustment for patient and clinical charac-
teristics, resistant hypertension was associated with a higher risk of
cardiovascular events (hazard ratio, 1.47; 95% CI, 1.33–1.62).
Conclusions: Using rigorous longitudinal follow-up data, the authors
of this study showed that resistant hypertension is common and have
significant adverse outcomes; 1 in 50 newly diagnosed hypertensive
patients become resistant to treatment within a median of 1.5 years of
treatment initiation and have approximately 50% higher risk of car-
diovascular events. This suggests the need to guide our efforts toward
improving recognition, management and outcomes of patients with
resistant hypertension. Numerous questions about this condition still
remain that may relate to its optimal medical and surgical management,
role of renin profiling, and cost effectiveness of various treatment meth-
ods. The Ongoing Prevention and Treatment of Resistant Hypertension
With Algorithm Guided Therapy (PATHWAY)62 and the Resistant
Arterial Hypertension Cohort Study (RAHyCo)63 studies would help
answer some of the fundamental questions still outstanding.5
Visit-to-Visit Blood Pressure Variability,
Carotid Atherosclerosis, and Cardiovascular
Events in the European Lacidipine Study on
Atherosclerosis
Summary: The authors sought to investigate whether visit-to-visit
blood pressure variability in patients treated for mild to moderate
hypertension was important in avoiding cardiovascular events and
preventing or delaying progression of end organ damage. The authors
pooled data (n= 2784 patients) from the European Lacidipine Study
on Atherosclerosis (ELSA), a randomized, double-blind 4-year trial
of the effect of lacidipine or atenolol on echocardiographic carotid
intima-media thickness.64 Visit-to-visit BP variability was assessed
by the coefficient of variation or the standard deviation (SD) of the
mean of the on-treatment SBP obtained at 6-month intervals (clinic
BP) and 12-month intervals (ambulatory or 24-hour BP), respectively.
The outcomes of interest included the impact of variability on carotid
intima-media thickness, major cardiovascular events (including fatal
and nonfatal myocardial infarctions, stroke and cardiovascular death),
minor cardiovascular events (hospitalized heart failure, angina, atrial
fibrillation, and claudication) and death from any cause. The results
 e32   Circ Cardiovasc Qual Outcomes   July 2013
show that the intima-media thickness increased progressively from the
lowest to highest quartile of mean on-treatment clinic or 24-hour SBP
(adjusted P for trend=0.046 and 0.048) but not along similar quartiles
of SBP coefficient of variation or SD. In a multivariable logistic regres-
sion model, mean clinic BP (odds ratio 1.03; 95% CI, 1.01–1.05) and
24-h clinic BP (odds ratio 1.04; 95% CI, 1.02–1.07) but not variability,
was associated with reduced incidence of cardiovascular outcomes.
Conclusions: The authors demonstrate that in patients with mild to
moderate hypertension, the mean reduction in blood pressure is prog-
nostically important in improving cardiovascular outcomes such as
stroke, myocardial infarction or mortality. In contrast, the variation in
blood pressures has no effect on pertinent cardiovascular outcomes.
These findings differ from recent studies that have suggested high
BP variability leads to adverse CV outcomes, especially stroke.65–67
The ELSA trial recruited predominantly disease free individuals,
had shorter duration of follow-up, with lower CV events compared
to other trials. Furthermore, methods of ascertaining BP and patient
adherence to medications differed between trials. These differences
may explain the differing results observed. Thus this study reinforces
that the primary goal of blood pressure control should be a reduction
in mean blood pressure. Benefit from additional therapy to control the
variability in BP remains uncertain at present.58
Hypertension, White Matter Hyperintensities,
and Concurrent Impairments in Mobility,
Cognition, and Mood: The Cardiovascular
Health Study
Summary: Hypertensive individuals are at increased risk of demen-
tia, depression and physical disability; however the co-occurrence
of impairment in these domains has not been examined previously.
Downloaded from http://ahajournals.org by on April 19, 2019
The authors investigated the association between hypertension and
concurrent impairments in mobility, cognition, and mood; the role
of brain white matter hyperintensities (WMH) in mediating this
association; and the impact of these impairments on disability and
mortality in elderly hypertensive individuals. They measured blood
pressure, gait speed, digit symbol substitution test, and the Center
for Epidemiological Studies Depression Scale yearly (1992–1999) on
4700 participants in the Cardiovascular Health Study (age: 74.7, 58%
women, 17% blacks, 68% hypertension). Using latent profile analysis
at baseline, they found that 498 (11%) subjects had concurrent impair-
ments and 3086 (66%) were intact on all 3 measures. Between 1992
and 1999, 651 (21%) became impaired in all 3 domains. Hypertensive
individuals were more likely to be impaired at baseline (odds ratio
1.23, 95% CI 1.04 to 1.42) and become impaired during the follow-
up (hazard ratio 1.3, 95% CI 1.02 to 1.66). A greater degree of WMH
was associated with impairments in the 3 domains and mediated the
association with hypertension (p=0.19 for hypertension after adjust-
ing for WMH in the model, 21% hazard ratio change). Impairments
in the 3 domains increased subsequent disability with hypertension
(p<0.0001). Mortality was also increased in impaired hypertensive
individuals when compared with unimpaired hypertensive individu-
als (hazard ratio 1.10, 95% CI 1.04 to 1.17, p=0.004).
Conclusions: Although hypertension has been previously linked to
decline in performance in the domains of cognitive function, mood,
and gait individually, this study demonstrates that these symptoms
tend to cluster in hypertensive patients and may constitute a hyper-
tension-specific triad. Moreover, WMH appears to fall in the causal
pathway and suggests that hypertension may affect brain function
even in the absence of clinical stroke or other cardiovascular compli-
cations and warrants the assessment of these domains as a routine part
of management of hypertension in older adults. This is particularly
important as impairment in these domains was associated with higher
risk of subsequent disability and mortality in this study.59
Elevated Blood Pressure in Pregnancy and
Subsequent Chronic Disease Risk
Summary: Preeclampsia/eclampsia is strongly associated with
increased CVD risk, but the effects of other forms of hypertension
during pregnancy on CVD risk are not well established. The authors
evaluated the prognostic importance of any form of hypertension dur-
ing pregnancy on the future CVD risk using the Northern Finland
Birth Cohort 1966 that included all births in the year 1966 with a
mean follow-up of 39.4 years. Blood pressure measurements and
clinical data were determined from prenatal care records and ques-
tionnaires for 10 314 women. Patients were classified into 7 mutu-
ally exclusive hypertensive disorders based on guideline definitions
(isolated systolic hypertension, isolated diastolic hypertension, iso-
lated systolic/diastolic hypertension with proteinuria, gestational
hypertension, eclampsia/pre-eclampsia, chronic hypertension, and
chronic hypertension with superimposed eclampsia/preeclampsia).
The results show that most forms of hypertension during pregnancy
(except isolated systolic/diastolic hypertension with proteinuria)
were associated with an elevated risk of CVD events when com-
pared with normotensive women. In order of increasing hazard ratios,
higher risk was found in isolated systolic hypertension (1.14), iso-
lated diastolic hypertension (1.18), preeclampsia/eclampsia (1.40),
gestational hypertension (1.45), chronic hypertension (1.66), super-
imposed preeclampsia/eclampsia (2.06). New onset hypertension
during pregnancy was also associated with a marked increase in
risk of developing future hypertension. Results were similar among
women without known risk factors for CVD, such as smoking, over-
weight/obesity, advanced age, and diabetes mellitus.
Conclusions: This study highlights the importance of hypertension
during pregnancy on future cardiovascular risk in addition to tradition-
ally known risk factors such as preeclampsia/eclampsia. These results
are highly relevant given that cardiovascular disease has been recog-
nized as the leading cause of death in women in the United States.
Since pregnancy seems to unmask patients at high risk of developing
hypertension and other CVD long-term, patients who develop hyper-
tension during pregnancy should be counseled on appropriate lifestyle
modification to prevent future hypertension and CVD as well as to
undertake intermittent BP monitoring for early detection.60
Impact of Blood Pressure and Blood Pressure
Change During Middle Age on the Remaining
Lifetime Risk for Cardiovascular Disease: The
Cardiovascular Lifetime Risk Pooling Project
Summary: Prior studies have evaluated the lifetime risk (LTR) of
CVD by hypertensive status at set points in time (index age) but
have failed to examine if changes in BP alter the LTR of CVD. In
this study, using data from the Cardiovascular Lifetime Risk Pooling
Project,68 the authors examined how changes in BP during middle
age affect LTR for CVD, defined as fatal coronary heart disease,
hospitalized myocardial infarction, non-hospitalized myocardial
infarction, and stroke. From 55 years of age, 61 585 men and women
were followed up for 700 000 person-years for development of CVD
events. The study results show that from 55 years of age onward,
the remaining LTR for CVD was 52.5% (95% CI, 51.3–53.7) for
men and 39.9% (95% CI, 38.7–41.0) for women. LTR for CVD was
higher for blacks and increased with increasing BP at index age.
Individuals who maintained or decreased their BP to normal levels
(<120/80) had the lowest remaining LTR for CVD (22% for women,
41% for men). In contrast, individuals who had or developed hyper-
tension by 55 years of age had the highest LTR of CVD (42% for
women, 69% for men).
Conclusions: The findings of this study suggest the presence of a
dose-response effect for the length of time at high BP levels and risk
 Chen et al   Important Papers on Hypertension   e33
of adverse cardiac events. These study findings re-iterates the impor-
tance of maintaining a blood pressure within normal limits for pre-
vention of hypertension which minimizes the LTR of cardiovascular
disease. Furthermore, these findings are relevant to secondary pre-
vention efforts as lowering of BP to normal levels in a person with
established hypertension also leads to a reduction in risk of CVD.61
Disclosures
Dr Dharmarajan is supported by grant HL007854 from the National
Heart, Lung, and Blood Institute; he is also supported as a Centers
of Excellence Scholar in Geriatric Medicine at Yale by the John
A. Hartford Foundation and the American Federation for Aging
Research. Dr Ranasinghe is supported by a research fellowship from
the Australian National Health and Medical Research Council with
cofunding by the National Heart Foundation of Australia. The other
authors report no conflicts.
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