REVIEW

Controversies in Hypertension II: The Optimal

Target Blood Pressure
Edward J. Filippone, MD,a Andrew J. Foy, MD,b Gerald V. Naccarelli, MDb
a
Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA;
b
Department of Medicine, Penn State University Heart and Vascular Institute, Penn State Milton S. Hershey Medical Center and College of
Medicine, Hershey, Penn.

ABSTRACT

The optimal target blood pressure in the treatment of hypertension is undefined. Whether more intense
therapy is better than standard, typically <140/90 mm Hg, is controversial. The most recent American
guidelines recommend ≤130/80 mm Hg for essentially all adults. There have been at least 28 trials target-
ing more versus less intensive therapy, including 13 aimed at reducing cardiovascular events and mortal-
ity, 11 restricted to patients with chronic kidney disease, and 4 with surrogate endpoints. We review these
trials in a narrative fashion due to significant heterogeneity in targets chosen, populations studied, and pri-
mary endpoints. Most were negative, although some showed significant benefit to more intense therapy.
When determining the optimal pressure for an individual patient, additional factors should be considered,
including age, frailty, polypharmacy, baseline blood pressure, and the diastolic blood pressure J-curve.
We discuss these modifying factors in detail. Whereas the tenet “lower is better” is generally true, one size
does not fit all, and blood pressure control must be individualized.
Ó 2022 Elsevier Inc. All rights reserved.  The American Journal of Medicine (2022) 135:1168−1177

KEY WORDS: Antihypertensive therapy; Hypertension; SPRINT

INTRODUCTION recommend a target pressure of <130/80 for all adults with

Hypertension remains a leading cause of death1 with a log-
linear relationship between usual blood pressure and cardio-
vascular mortality.2,3 Antihypertensive treatment reduces
cardiovascular events compared to placebo or no treat-
ment.4-6 What remains controversial is whether more inten-
sive pressure lowering is better than standard therapy,
typically defined as less than 140/90 (all pressures in mm
Hg). The recommended threshold pressure for the initiation
of treatment and the target on treatment have fluctuated
over time with subtle differences between international
guidelines (Table 1).7 The most recent American College
of Cardiology/American Heart Association Guidelines
Funding: None.
Conflicts of Interest: EJF reports serving on the speakers bureau for
AstraZeneca. AJF reports none. GVN reports serving as a consultant to
Sanofi, Glaxo Smith Kline, Acesion, and Milestone.
Authorship: All authors had access to the data and a role in writing
this manuscript.
Requests for reprints should be addressed to Edward J. Filippone, 2228
South Broad St., Philadelphia, PA, 19145.
E-mail address: edward.filippone@jefferson.edu
higher risk and consider it reasonable even without such
risk.8 The 2018 European Guidelines make an age distinc-
tion,9 and the Kidney Disease: Improving Global Outcomes
(KDIGO) consortium’s 2021 guidelines recommend a tar-
get of <120/80.10 Herein we review the literature on ran-
domized controlled trials comparing more intense versus
standard therapy (targeting trials) along with studies
addressing potential mitigating factors.
TARGETING TRIALS AND CARDIOVASCULAR
MORBIDITY AND MORTALITY
There are 13 trials comparing more intensive with less
intensive antihypertensive therapy reporting on cardiovas-
cular events and mortality11-23 (Table 2). Ten studies in
adults24-33 and 1 pediatric study34 are restricted to patients
with kidney disease (Table 3). Four trials reported interme-
diate endpoints.35-38
Review of the trials in Table 2 does not provide a clear
answer to whether more intensive therapy is beneficial,
because most had negative primary endpoints. There is

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https://doi.org/10.1016/j.amjmed.2022.05.009

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Filippone et al Optimal Target Blood Pressure 1169

significant heterogeneity in the populations studied and in TARGETING TRIALS AND CHRONIC KIDNEY
the targets chosen. These trials are discussed in detail in the DISEASE
Supplementary Materials, available There have been 11 targeting trials
online. restricted to patients with kidney dis-
The landmark Systolic Blood ease24-34 (Table 3). None of the 10
Pressure Intervention Trial CLINICAL SIGNIFICANCE adult studies showed a significant
(SPRINT) provided the most com- benefit of intensive control on
pelling evidence for more intensive  The optimal target blood pressure in decrease in kidney function or in
therapy comparing systolic pres- the treatment of adult hypertension is hard renal endpoints, although the 1
sures of <120 to <140 with signifi- uncertain and is not the same for all pediatric study was positive. Suba-
cant reduction of the primary patients. nalyses restricted to patients with
endpoint and mortality. Patients in  Factors potentially modifying the kidney disease from 2 trials in
SPRINT generally had pressure intensity of therapy include age, Table 2 revealed no significant bene-
measurement unattended by office fit on either progression of kidney
frailty, and polypharmacy.
staff39 removing the “white coat” 43,44
 More intensive antihypertensive ther- disease or cardiovascular events.
effect.40 Some have suggested that
the targets would be higher if pres- apy does not appear to slow the pro- In contrast, a prespecified subanaly-
sis of SPRINT participants with kid-
sures were obtained in the usual gression of chronic kidney disease.
attended fashion.39,41 However, post  The diastolic J-curve remains contro- ney disease revealed 45a significant
reduction of mortality. There was
hoc evaluation of clinical sites versial but may bear consideration if no difference in rate of change of
revealed that unattended pressure obstructive coronary artery disease and estimated glomerular filtration rates
measurement was not universal a very low diastolic pressure coexist. or hard renal endpoints.
because approximately one-third
had attended measurements.42

Table 1 Thresholds for Initiation of Antihypertensive Drug Therapy and Targets for Drug Treatment of Confirmed Hypertension
GuidelineYear Threshold for Initiation of Drug Therapy Targets of Drug Therapy
American College of Cardiology/American ≥ 140/90* for all < 130/80
Heart Association 130-139/80-89 if CV disease or 10-year CV
(ACC/AHA 2017) disease risk ≥ 10%
American College of Physicians/American SBP > 150 if > 60 years old SBP < 150 if > 60 years old
Academy of Family Practice Guidelines SBP > 140 if > 60 years old with history of SBP < 140 if > 60 years old with history of
for Adults aged 60 years or more stroke or TIA or CV risk stroke or TIA or high CV risk
(ACP/AAFP 2017)
European Society of Cardiology/European ≥ 160/100 in all patients < 140/90 in all patients
Society of Hypertension 140-159/90-99 if high risk or if lifestyle <130/80 if <140/90 well tolerated
(ESC/ESH 2018) modification fails 130-140/< 80 if > 65 years old
Hypertension (Canada ≥ 160/100 in low-risk patients < 140/90 in all patients
2018) ≥ 130/80 if high-risk < 130/80 if DM
≥ 130/80 if DM < 120 SBP in high risk
≥ 140/90 in all others
National Institute for Health and Clinical ≥ 160/100 < 140/90 if aged < 80 years
Excellence ≥ 140-159/90-99 if TOD, DM, CKD, or < 150/90 if aged > 80 years
(NICE 2019) 10-year CV disease risk ≥ 10%
> 150/90 if aged > 80 years should be
considered
International Society of Hypertension ≥ 160/100 in all patients Essential:
(ISH 2020) 140-159/90-99 if high risk or if lifestyle > 20/10 reduction, ideally to < 140/90
modification fails Optimal:
< 130/80 if tolerated (< 65 years old)
<140/90 if tolerated (≥ 65 years old)
Kidney Disease Improving Global Outcomes Not specified SBP < 120
(KDIGO 2021) Presumably SBP > 120 Except pediatric patients and those on
dialysis or with transplantation
CKD = chronic kidney disease; CV = cardiovascular; DBP = diastolic blood pressure; DM = diabetes mellitus; SBP = systolic blood pressure; TIA = transient
ischemic attack; TOD = target organ damage.
*All blood pressures in mm Hg.

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 1170
Table 2 Trials Targeting More Intensive Blood Pressure Control Versus Standard Control in Adult Patients with Primary Cardiovascular Endpoints
Trial/year Patients Intensive Standard Achieved BP Primary CV Primary Secondary Endpoints Comments
Target Target Difference Endpoint Result
BBB Study11 2127 DBP ≤ 80 DBP 90-100 DBP 7-7.5 lower CV events NS — AEs lower with intensive therapy
1994 Hypertension over 4 y
UKPDS 3812 1148 < 150/85 < 180/105 SBP/DBP 10/5 First clinical EP Sig reduction Reduced death related to Standard target high, so many
P = .0046 DM P = .019
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1998 Hypertension lower over 8.4 y related to DM patients were untreated

Type 2 DM
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HOT13 18,790 DBP ≤ 80 DBP ≤ 85 DBP 81 vs 83 vs 85 Stroke, MI, CV NS — Significant reduction in primary EP in
1998 Hypertension DBP ≤ 90 death 1501 with DM
JATOS14 4418 SBP < 140 SBP 140-160 SBP/DBP 10/3 Composite CV dis- NS Total mortality NS No difference AEs
2008 Hypertension lower over 2 y ease and kidney Significant interaction with age
failure
Cardio-Sis15 1111 SBP < 130 SBP < 140 SBP/DBP 4/1.5 Rate of LVH Sig reduction CVEs reduced No difference in side effects
2009 Hypertension lower over 2 y OR 0.63 HR 0.5
(P = .013) P = .003
VALISH16 3260 SBP < 140/90 SBP ≥ 140-<150 SBP/DBP 5.4/1.7 Composite CVEs NS Individual components No sig interactions with various sub-
2010 ISH lower over 3 y NS groups
No difference AEs
ACCORD-BP17 4733 SBP < 120 SBP < 140 SBP 14 lower over MI, stroke, CV NS Sig reduction of stroke Primary EP trended positive:
2010 Type 2 DM 4.7 y death HR 0.59, P = .01 HR 0.88, P = .20
More SAEs with strict control:
3.3% vs 1.3%, P < .001
HOMED-BP18 2012 3518 <125/<80 125-134/80-84 SBP/DBP 1.4/3.8 MI, stroke, CV NS Broader CV EP NS 5-y risk lowest if SBP ≤ 131.6
Hypertension lower over 5.3 y death
SPS319 3020 SBP < 130 SBP 130-149 SBP 11 lower over Reduction of all NS MI + vascular death: NS Primary EP trended positive:

The American Journal of Medicine, Vol 135, No 10, October 2022

2013 Recent lacunar 3.7 y strokes ICH sig less: HR 0.81, P = .08
stroke HR 0.37, P = .03 No significant difference in SAEs
Wei20 724 ≤ 140/90 ≤ 150/90 SBP/DBP 14/6 MI, stroke, CV 11% vs 19% Total mortality: decreased Long-term variability in SBP associ-
2013 Hypertension lower over 4 y death P = .004 42% ated with events
P = .001
CV mortality: decreased
50% P = .002
SPRINT21 9361 SBP < 120 SBP < 140 SBP 13 lower over MI, other ACS, HR 0.75 Total mortality: More SAEs with strict control:
2015 Hypertension 3.6 y stroke, HF, CV P < .001 HR 0.73, P = .003 4.7% vs 2.5%,
death HR 1.88, P < .001
Trial stopped early
PAST-BP22 529 SBP < 130 SBP < 140 SBP 2.9 lower over Change in SBP P = .03 Major CV events: NS No difference in mortality
2016 Prior stroke/TIA 1y over 1 y NS trend for more emergency hospital
admissions in intensive arm (13%
vs 8%)
STEP23 8511 SBP 110-<130 SBP 130-<150 SBP/DBP 9.2/2.8 Stroke, ACS, ADHF, HR 0.74 Individual components: Hypotension significantly high-
2021 Hypertension over 3.34 y coronary revas- P = .007 significant for stroke, er:3.4% vs 2.6%, P = .03
cularization ACS, ADHF NS difference in renal outcomes
AFib, CVD
ACCORD = Action to Control Cardiovascular Risk in Diabetes; Afib = atrial fibrillation; ACS = acute coronary syndrome; ADHF = acute decompensated heart failure; AE = adverse events; BBB = Behandla Blodtryck
Battre (Treat Blood Pressure Better); BP = blood pressure; Cardio-Sis = Studio Italiano Sugli Effetti CARDIOvascolari del Controllo della Pressione Arteriosa SIStolica; CV = cardiovascular; CVD = cardiovascular
death; CVE = cardiovascular events; DBP = diastolic blood pressure; DM = diabetes mellitus; EP = endpoint; HF = heart failure; HOMED-BP = Hypertension Objective Treatment Based on Measurement by Electrical
Devices of Blood Pressure; HOT = Hypertension Optimal Treatment; HR = hazard ratio; ISH = isolated systolic hypertension; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive
Patients; LVH = left ventricular hypertrophy; MI = myocardial infarction; NS = nonsignificant; OR = odds ratio; PAST-BP = Prevention After Stroke-Blood Pressure; SAE = serious adverse events; SBP = systolic blood
pressure; SPS3 = Secondary Prevention of Small Subcortical Strokes; SPRINT = Systolic Blood Pressure Intervention Trial; STEP = Strategy of Blood Pressure Intervention in Elderly Hypertensive Patients;
TIA = transient ischemic attack; UKPDS = United Kingdom Prospective Diabetes Study; VALISH = Valsartan in Elderly Isolated Systolic Hypertension Study.
 Filippone et al
Table 3 Trials Targeting More Intensive Blood Pressure Control Versus Standard Control in Adult Patients with Kidney Disease
Trial/year Patients Intense Target Standard Target Kidney Function Primary Endpoint Primary result Secondary Results Comments
24
MDRD 840 MAP 92 mm Hg MAP 107 mm Hg Iothalamate GFR Rate of change of GFR NS No difference in ESKD or Significant interac-
1994 GFR 13-55 death tion with protein-
No DM uria 85% Caucasian
Toto25 77 DBP 65-80 DBP 85-95 Iothalamate GFR Rate of change of GFR NS No difference 50% loss GFR, Small trial
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Optimal Target Blood Pressure

1995 Hypertension- ESKD, death 75% AA
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attributed
nephropathy
Lewis26 129 MAP ≤ 92 MAP 100-107 Iothalamate Rate of change of GFR NS Significantly lower Uprotein Similar adverse events
1999 Type 1 DM GFR, Clcreat 95% Caucasian
Creatinine < 4
ABCD-hypertensive27 470 DBP < 75 DBP 80-89 Clcreat Rate of change of NS No difference in urinary pro- Decrease in mortality
2000 Type 2 DM Clcreat tein progression with intense ther-
apy (5.5% vs 10.7%,
P = .037)
ABCD-normotensive28 480 Decrease DBP DBP 80-90 Clcreat Rate of change of NS Reduced progression Uprotein, Decrease in stroke
2002 Type 2 DM of 10 Clcreat less retinopathy with intensive ther-
progression apy (1.7% vs 5.4%,
P = .03)
Schrier29 75 <120/80 135-140/85-90 Clcreat Decrease in LVMI P < .01 No difference in rate of Small trial.
2002 ADPKD/LVH change of Clcreat
AASK30 1,094 MAP ≤ 92 MAP 102-107 Iothalamate GFR Rate of change of GFR NS No difference in composite 100% AA
2002 Hypertension- (GFR reduction ≥ 50%, No difference in CV
attributed ESKD, death) endpoints
nephropathy
REIN-231 338 SBP/DBP DBP < 90 Clcreat ESKD NS No difference in Clcreat decline No difference in pro-
2005 Nondiabetic pro- < 130/80 teinuria or mortality
teinuric
nephropathy
ABCD-2V32 129 DBP < 75 DBP 80-90 Clcreat Change in UAE Reduced No difference in Clcreat decline 75% of standard
2006 Type 2 DM P = .007 group received only
placebo vs 6%
intensive
ESCAPE34 385 pediatric 24-h MAP < 50th 24-h MAP 50th - eGFR 50% decrease in eGFR Reduced No difference in eGFR decline Significant interac-
2009 percentile 90th percentile (Schwartz or ESKD HR 0.65 tion with cause of
formula) P = -.02 CKD (0.009)
HALT-PKD33 558 SBP/DBP SBP/DBP eGFR Change in total kidney Reduced No difference in eGFR decline More dizziness and
2014 Hypertensive 95/60-110/75 120/70-130/80 (CKD-EPI) volume P = .006 Reduced LVMI P < .001) light-headedness
ADPKD Reduced UAE (P < .001) (P = .002)
AA = African American; AASK = African American Study of Kidney Disease and Hypertension; ABCD = Appropriate Blood Pressure Control in Diabetes Trials; ADPKD = autosomal dominant polycystic kidney dis-
ease; CKD = chronic kidney disease; CKD-EPI = chronic kidney disease epidemiology collaboration; Clcreat = creatinine clearance; CV = cardiovascular; DBP = diastolic blood pressure; DM = diabetes mellitus;
ESCAPE = Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CKD in Pediatric Patients; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; GFR = glomerular
filtration rate; HALT-PKD = HALT Progression of Polycystic Kidney Disease; HR = hazard ratio; LVH = left ventricular hypertrophy; LVMI = left ventricular mass index; MAP = mean arterial pressure;
MDRD = Modification of Diet in Renal Disease Study; NS = nonsignificant; SBP = systolic blood pressure; REIN = Ramipril Efficacy in Nephropathy Trial; UAE = urine albumin excretion; Uprotein = urine protein.

1171
1172
META-ANALYSES OF TARGETING TRIALS
Meta-analyses of targeting trials provided conflicting
results. Lv et al46 found significant reductions of major car-
diovascular events, myocardial infarction, stroke, and end-
stage kidney disease but not mortality. The positive results
were in line with those expected for the given pressure
decrease.2 Similarly, Xie et al47 found significant reduc-
tions for major events, myocardial infarction, and stroke,
although not for mortality or kidney failure.
These analyses cannot define a specific target. Bangalore
et al48 performed a network meta-analysis allowing for indi-
rect comparisons of different targets not directly compared.
Both the greatest benefit and the greatest increase in adverse
events were found with systolic pressure <120. Combining
safety and efficacy, <130 had the greatest balance.
In contrast, several Cochrane reviews found no benefit to
more intense therapy. Arguedas et al49 found no significant
reduction in cardiovascular events or total mortality. How-
ever, myocardial infarction and heart failure were signifi-
cantly reduced. A review restricted to patients with diabetes
found no significant benefit for myocardial infarction,
stroke, or heart failure but a trend for reduced overall mor-
tality.50 A review restricted to patients with existing cardio-
vascular disease found no significant difference in mortality
or cardiovascular events.51
Meta-analyses of trials restricted to patients with kidney
disease (Table 3) have also shown conflicting results. Ana-
lyzing all 11 trials, Lv et al52 found a significant reduction
in a composite kidney outcome; excluding the pediatric
study did not change results. There was no effect on cardio-
vascular events or mortality. In contrast, Tsai et al53 found
no significant benefit on renal endpoints but did find a sig-
nificant reduction of all-cause mortality when restricted to
patients without diabetes. Malhotra et al54 analyzed 7 pri-
mary kidney trials and 10 trials of the general hypertensive
population with extractable data on patients with kidney
disease and found more intensive control resulted in a sig-
nificantly lower risk of all-cause mortality. In an individual
patient data meta-analysis of 4 trials, Aggarwal et al55 com-
pared intensive control (<130/80) with standard control
(<140/90) in 4564 patients with kidney disease (2509 inten-
sive) and found no significant benefit on overall mortality or
total cardiovascular events.
MITIGATING FACTORS
Several factors may mitigate intensification of therapy
(Table 4). Chronologic age is controversial, as exemplified
Table 4 Mitigating Factors
Age
Frailty
Polypharmacy
Adherence
Baseline Blood Pressure
Percent Reduction of Blood Pressure
The Diastolic Blood Pressure J-curve
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The American Journal of Medicine, Vol 135, No 10, October 2022
by disparities in published guidelines (Table 1).8,9,56-59
Although the proportional increase in risk of cardiovascular
mortality for increasing pressure in observational analyses
is double for those aged 40-49 years compared to those 80-
89 years, the absolute increase in risk is greater in the older
age group due to a much higher absolute risk.2,3 These
observational data extend to pressure differences induced
by active treatment.60 Although proportional reductions in
cardiovascular morbidity and mortality were less in those
aged older than 85 years compared to participants younger
than age 55, absolute risk reductions were larger.
The Hypertension in the Very Elderly Trial (HYVET)
showed significant reductions by active treatment versus
placebo in death from stroke and overall mortality in hyper-
tensive patients aged ≥ 80 years,61 proving treatment is
beneficial. Targeting trials have also been performed in the
elderly, including a prespecified substudy of SPRINT.62
Three trials targeted systolic pressure <140 for the intensive
group,14,16,20 another trial 110 to <130,23 and SPRINT
<120. The 4 non-SPRINT trials were in Asian populations
(2 Japan, 2 China). Two were positive, whereas the 3 trials
targeting <140 as intensive were negative. A meta-analysis
of 4 showed significant benefit to intensive therapy on
major cardiovascular events and mortality but an increased
risk for kidney failure.63 Importantly, meta-regression
showed that the benefit in reduction of cardiovascular
events and mortality was proportional to the mean differ-
ence in systolic pressure, suggesting lower is better (at least
<140) when applied to elderly patients healthy enough to
be enrolled in a trial.
FRAILTY
A major modifying factor of chronologic age is coexisting
frailty, defined as a lack of physiologic reserve resulting in
enhanced susceptibility to stressors. It is not synonymous
with either comorbidity or disability, although comorbidity
contributes to frailty and frailty contributes to disability.
There are at least 67 proposed definitions of frailty;64,65
however, the most used ones are the frailty phenotype and
indices related to deficit accumulation. The frailty pheno-
type consists of 5 criteria: unintentional weight loss,
exhaustion, reduced hand-grip strength, slow walking
speed, and low physical activity.66 The presence of 3 or
more of the 5 defines frailty and having 2 defines intermedi-
ate frailty.
In deficit accumulation indices (each termed a frailty
index), deficits accumulate as patients age. These consist of
symptoms, signs, laboratory abnormalities, comorbid con-
ditions, disabilities, and psychosocial aspects.67 To be con-
sidered a potential deficit, a factor should increase with age,
not saturate in the population at an early age, and associate
with adverse outcomes.67,68 There are 100 or more possible
deficits, but at least 30 should be included and cover a range
of systems. No individual deficit is required, and all are
considered equally. Each is assigned a value between 0 (no
deficit) and 1 (deficit present). The values are added and
Filippone et al Optimal Target Blood Pressure
divided by the number of factors to give a score between 0
and 1. Frailty is generally defined as a score >0.2. Although
specific components of published frailty indices may differ,
they are generally considered comparable.
Warwick et al69 found no interaction of frailty with the
positive treatment effect of HYVET because both frail and
fit patients benefitted. Williamson et al62 found no significant
interaction of frailty with the benefit of intensive treatment
in elderly SPRINT participants. However, patients ineligible
for these trials may have a different risk-to-benefit ratio for
intensification of therapy. Application of trial eligibility crite-
ria to national surveys showed that 72% of the 59 million
adults qualifying for intensification of antihypertensive ther-
apy by current guidelines would be trial ineligible.70 The
major reasons for exclusions in the older populations were
multimorbidity and reduced life expectancy.71
The results of observational studies concerning frailty
conflict with the trial data presented. In a 2019 meta-analy-
sis of 9 observational studies involving 21,906 community-
dwelling adults aged 65 years and older, Todd et al72 found
no mortality benefit to systolic pressure <140 in those with
documented frailty, but there was a benefit in its absence.
Masoli et al73 studied 415,980 UK adults 75 years or
older and compared all-cause mortality to median pressure
over 3 years modified by frailty. In those aged 85 years and
older, mortality was significantly reduced for all systolic
pressures ≥140 (versus 130-139), including even >180, and
was also increased for <130 regardless of the degree of
frailty. In the group aged 75-84 years, no pressure ≥140 was
associated with increased mortality in the presence of moder-
ate/severe frailty (index >0.24) but was at ≥170 only in the
nonfrail group. Including only patients with no decline in
pressure over the 2 years prior to enrollment, consistent
results obtained, excluding a bias resulting from the reported
decline in the last 2 years of life.74 However, despite the
mortality benefits with higher pressure, cardiovascular events
were increased with pressure ≥150 in both age groups.
Similarly, Kremer et al75 followed 1170 community-
dwelling German adults aged > 65 years and assessed the
relationship between systolic pressure and all-cause mortal-
ity modified by frailty. In nonfrail participants, a J-shaped
relationship obtained with significantly increased mortality
below 110 and a trend for above 160. For 251 frail partici-
pants, all pressures >130 trended toward reduced mortality.
In our opinion, chronological age per se should not mod-
ify intensity. However, all elderly should be evaluated for
frailty. Available tools include the “FRAIL” scale,76 the
frailty phenotype outlined previously, and others easily
available online.77 In the presence of moderate or severe
frailty, modification of intensity is reasonable.
POLYPHARMACY AND MEDICATION ADHERENCE
The prescription of multiple medications, termed polyphar-
macy, is common in the elderly. Although consensus has
not occurred, the most common definitions include 5 or
more medications.78 Polypharmacy increases the chance
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1173
for adverse events related to drug-drug interactions and
reduced clearance in the elderly. Analyzing 193 commu-
nity-dwelling, hypertensive African Americans, Bazargan
et al79 found that nearly 50% had inappropriate medication
use. Laville et al80 studied 3033 elderly patients with kidney
disease prescribed a median of 8 medications. Adverse
events were significantly more common if >10 versus <5
medications were prescribed. In another study of 28,411
hospital admissions, 187 were the result of severe adverse
drug reactions, and the number of medications was indepen-
dently associated with such admissions.81
The other downside to polypharmacy is enhanced
nonadherence, a major cause of suspected resistant
hypertension.82,83 Adherence is traditionally defined
with a cutoff of 80% and can be assessed indirectly
(diaries, prescription refill rate, or pill counts) or directly
(supervision or by measurement of drug or metabolite in
serum or urine by high-pressure liquid chromatography
with tandem mass spectrometry).84 Direct methods are
more sensitive85 and combinations may be used. For
example, in patients referred to a hypertension clinic,
only 36.4% of 55 self-reported adherent patients were
confirmed adherent by liquid chromatography.86
Importantly, nonadherence can be directly linked to pill
burden. Analyzing 1348 hypertensive patients from 2 Euro-
pean countries, Gupta et al87 performed liquid chromatogra-
phy to assess adherence. Each increase in the number of
medications led to an average increase in nonadherence by
85% and 77% in the 2 populations (P < .001), and nonad-
herence ranged from 35%-40% in patients prescribed 3
antihypertensive medications to 60%-80% in those pre-
scribed 5. None of the patients admitted to nonadherence.88
Nonadherence is associated with adverse outcomes. In a
meta-analysis of studies addressing adherence of antihyper-
tensive medications, Chowdry et al89 demonstrated that the
relative risks for both mortality and any cardiovascular disease
were significantly reduced with good adherence versus poor.
BASELINE BLOOD PRESSURE AND PERCENT
REDUCTION
It remains uncertain whether the main benefit is derived
from lowering pressure from baseline versus achieving a
final target level independent of baseline with a dearth of
data to answer this question. An analysis of 1474 patients
with resistant hypertension followed for 9 years with serial
ambulatory pressure monitoring revealed J- or U-shaped
curves between percentage of pressure reduction and most
outcomes, suggesting that after a certain point greater
reductions from baseline are potentially deleterious.90
In a tabular meta-analysis of 123 studies, Ettehad et al91
found proportional reductions in cardiovascular events and
mortality regardless of baseline pressure, including baseline
systolic pressure <130, suggesting the drop from baseline is
more important than a specific achieved target. Similarly,
an individual patient data meta-analysis found that a reduc-
tion of systolic pressure of 5 was associated with a 10%
1174
reduction of cardiovascular events at all baseline levels,
including <120. In both studies meta-regression revealed
that reduction in events was directly proportional to reduc-
tion of pressure. It remains uncertain whether reduction
from baseline is more important than achieving specific tar-
gets and whether excessive reduction may be harmful. Fur-
thermore, overall cardiovascular risk may be more
important than the actual pressure levels in determining
intensification of therapy.
THE DIASTOLIC BLOOD PRESSURE J-CURVE
As diastolic pressure drops below a threshold, cardiovascu-
lar events, especially myocardial infarction, increase, the
so-called J-curve.92 First described more than 40 years
ago,93,94 this phenomenon has been demonstrated in both
observational studies and trials.95 It becomes a major issue
when attempting to attain more stringent systolic control,
especially in the elderly who tend to have low diastolic and
widened pulse pressures. The J-curve clearly exists, but the
cause remains controversial. Patients with obstructive coro-
nary disease appear most at risk because the coronaries fill
in diastole. Alternatively (not mutually exclusively), the J-
curve may be a manifestation of reverse causation because
either severe comorbidity or diseased vasculature may
cause both the low diastolic pressure and the subsequent
adverse events.
The CLARIFY investigators observationally analyzed
22,672 adults with hypertension and stable coronary dis-
ease.96 A steep, J-shaped curve existed for both average
systolic and diastolic pressures and the primary outcome
(ie, cardiovascular death, myocardial infarction, or stroke),
including individual components except for stroke. The J-
shaped relationship persisted if restricted to those with the
lowest pulse pressure (45-64).
In the International Verapamil-Trandolapril Study of
hypertensive patients with coronary disease,97 a significant
J-shaped relationship was found between mean on-treat-
ment diastolic pressure and the primary outcome (ie, total
mortality, myocardial infarction, and stroke) and all-cause
death.98 A significant interaction with revascularization
was noted because only those not revascularized maintained
a significant J-curve whereas those revascularized did not.
Similarly, in the Eplerenone Post-Acute Myocardial Infarc-
tion Heart Failure Efficacy and Survival Study of 6642
patients with myocardial infarction and heart failure, analy-
ses of the 45% that had coronary reperfusion showed no J-
curve, whereas the 55% without revascularization did.99 In
our opinion, excessive lowering of diastolic pressure should
be a consideration in those with documented coronary dis-
ease when intensifying therapy with very low baseline pres-
sure (eg, <60).
DISCUSSION
As a generalization, the lower the pressure, the better. How-
ever, a corollary should be not at all costs and not necessar-
ily to the same target in all patients. The guideline target of
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The American Journal of Medicine, Vol 135, No 10, October 2022
<130/80 is reasonable for most adults. In approaching the
individual patient, however, the mitigating factors dis-
cussed previously should be considered. Chronologic age is
not necessarily a deterrent; however, in the elderly, frailty
should be assessed, and if present, a more aggressive
approach can be mitigated. Equally important is polyphar-
macy, especially in the elderly, for fear of both drug-drug
interactions and promotion of nonadherence. In the pres-
ence of apparent treatment resistance, or if no response
occurs with addition of medications, formal testing for
adherence should proceed.
The baseline pressure should be considered. In those
with higher baseline pressure on multiple antihypertensives,
a higher final pressure may be acceptable to avoid further
polypharmacy issues. As a corollary, those with lower base-
line pressure may derive benefit from therapy even if
already below target, especially if at higher cardiovascular
risk. The J-curve remains controversial. A very low dia-
stolic pressure (<60) should prompt consideration of either
tolerating a systolic pressure above target or proceeding
with revascularization in the presence of significant
obstructive coronary disease; however, we acknowledge
that randomized trials are needed to address this issue.
The Kidney Disease: Improving Global Outcomes target
of <120/80 for all patients with kidney disease is derived
from Systolic Blood Pressure Intervention Trial-Chronic
Kidney Disease (SPRINT-CKD) substudy. However, most
patients with kidney disease would be excluded from
SPRNT (ie, diabetes, proteinuria, polycystic disease, esti-
mated glomerular filtration rate <20) limiting external
validity. In our opinion, more data are required to support
this target.
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SUPPLEMENTARY DATA
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.amjmed.2022.05.009.
1177.e1
SUPPLEMENTARY MATERIALS
There are 13 randomized controlled trials comparing more
intensive with less intensive antihypertensive therapy in the
general hypertensive population or specific subsets report-
ing on cardiovascular events and mortality as primary end-
points. Ten additional studies in adults and 1 pediatric
study are restricted to patients with kidney disease. Four
more trials reported only intermediate endpoints. Herein we
discuss these 28 trials.
Trials with Cardiovascular Morbidity and
Mortality as Primary Endpoints
The Bahandla Blodtryck Battre (BBB) Study was a multi-
center randomized controlled trial of 2227 Swedish hyper-
tensive adults with diastolic blood pressure (DBP) of 90-
100 mm Hg randomized to either intensive therapy (DBP ≤
80 mm Hg) or unchanged therapy and followed for over
4 years.11 There was no difference in cardiovascular mor-
bidity or mortality between the groups.
The UK Prospective Diabetes Study (UKPDS) was the
first targeting trial to show a benefit to more intensive ther-
apy in 1148 hypertensive diabetics randomized to blood
pressure <150/85 versus <180/105.12 Significant reductions
occurred in any diabetes-related endpoint, deaths from dia-
betes mellitus (DM), strokes, and microvascular complica-
tions. However, the standard target is unacceptably high by
current standards; about 50% of the standard group were
left untreated at initiation and about 20% were not treated
at all throughout the trial.
The largest study to date, the Hypertension Optimal
Treatment (HOT) trial, randomized 18,790 patients into 1
of 3 groups based on DBP: ≤90, ≤85, and ≤80.13 There
was no significant benefit on major cardiovascular (CV)
events, but unfortunately there was relatively little separa-
tion of achieved DBP: 85, 83, and 81, respectively. How-
ever, when restricted to the 1501 patients with DM there
was significant reduction.
Similarly negative were 2 trials in elderly Asian popula-
tions targeting systolic blood pressure (SBP). In the Japa-
nese Trial to Assess Optimal Systolic Blood Pressure
(JATOS), 4418 elderly (65-85 years old) hypertensive
patients were randomized to intensive therapy (SBP < 140)
or standard therapy (140 to <160) and followed for
2 years.14 For a difference of 9.7 in SBP, there was no dif-
ference in the primary endpoint (CV disease and renal fail-
ure, P = .99) or total mortality (P = .22). In the Valsartan in
Elderly Isolated Systolic Hypertension Study (VALISH),
3260 elderly (70-84 years old) Japanese with isolated sys-
tolic hypertension were randomized to SBP < 140 versus
≥140 to <150 and followed for 3 years.16 There was no sig-
nificant difference in the primary endpoint (hazard ratio
[HR] 0.89, P = .38) for a mean BP difference of 5.4/1.7
(SBP/DBP).
In the Cardio-Sis trial, 1111 nondiabetic Italian adults
with SBP ≥ 150 mm Hg were randomized to SBP <130
versus <140 mm Hg and followed for 2 years.15 For a
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The American Journal of Medicine, Vol 135, No 10, October 2022
between-group difference of 3.8/1.5 mm Hg, the rate of
electrocardiographic left ventricular hypertrophy (the pri-
mary endpoint) was significantly lower with more intensive
therapy (odds ratio of 0.63, 95% confidence interval [CI]
0.43-0.91, P = .013). The composite CV endpoint was also
significantly reduced (HR 0.50, 95% CI 0.31-0.79, P =
0.003).
There were 3 trials funded by the National Institutes
of Health in different populations: the Action to Control
Cardiovascular Risk in Diabetes-Blood Pressure
(ACCORD-BP) trial,17 the Secondary Prevention of
Small Subcortical Strokes (SPS3) trial,19 and the Sys-
tolic Blood Pressure Intervention Trial (SPRINT).21 In
ACCORD-BP, 4733 participants with DM were random-
ized to SBP <120 versus <140 mm Hg and followed for
4 years. The primary endpoint, myocardial infarction
(MI), stroke, or CV death was not significantly reduced
despite a mean SBP difference of 14.2, although there
was a trend (HR 0.88, P = 2.0). Stroke was significantly
reduced (HR 0.59, P = .01). Serious adverse events
(SAE) were significantly more common with intensive
therapy (3.3% versus 1.3%, P < .001). It has been
argued that the trial was underpowered because the
annual event rate of the primary endpoint was only
2.09% in the standard arm despite the a priori assump-
tion of 4% used for power calculations.
The landmark SPRINT provided the most compelling
evidence for more intensive therapy in a randomized con-
trolled trial of 9361 patients older than the age of 50 with
increased CV risk but no DM or prior stroke; SBP <120
was compared to <140. The primary endpoint of CV events
or CV mortality was significantly reduced with intensive
therapy (HR 0.75) as was all-cause mortality (HR 0.73).
The trial was halted early after 3.6 years of a planned 5-
year follow-up. Treatment-related SAE were significantly
more common with intensive therapy.
In SPS3, 3020 patients with recent, lacunar infarcts
defined by magnetic resonance imaging were randomized
to SBP <130 versus 130-149 and followed for 3.7 years.
Despite a mean SBP difference of 9 mm Hg after 1 year,
there was no significant difference in the primary endpoint
of reduction in all strokes, although like ACCORD-BP, the
trend was positive for more intensive therapy (HR 0.81,
P = .8). Also trending positive were reductions in disabling
or fatal strokes (HR 0.81, P = .32) and a composite of MI or
CV death (HR 0.83, P = .32). Intracranial hemorrhages
were significantly reduced (HR 0.37, P = .03) with no
increase in SAEs.
In the Hypertension Objective Treatment Based on Mea-
surement by Electrical Devices of Blood Pressure
(HOMED-BP) trial, 5518 Japanese patients with untreated
BP of 135-179/85-119 mm Hg were randomized to more
intense (<125/<80 mm Hg) or less intense (125-134/80-
84 mm Hg) antihypertensive therapy and followed for
5.3 years.18 Despite a small but significant difference in
home BP (SBP 1.3 mm Hg, P = .018; DBP 0.8 mm Hg,
P = .020), there was no difference in the primary endpoint
Filippone et al Optimal Target Blood Pressure
(CV death, MI, or stroke) with more intense therapy (HR
1.02, P = .94).
Wei et al20 randomized 724 Chinese hypertensive
patients aged >70 years to more intense (≤140/90 mm Hg)
or standard therapy (≤150/90 mm Hg) with a 4-year fol-
low-up. For a difference of 14/5.9 mm Hg, total mortality
and CV mortality were significantly reduced by 41.7% and
50.3%, respectively.
In the Prevention After Stroke-Blood Pressure (PAST-
BP) trial, 529 English patients with stroke or transient
ischemic attack and BP ≥125 mm Hg were randomized to
more intense (<130 mm Hg) or standard (<140 mm Hg)
therapy and followed for 12 months.22 Despite a small but
significant difference in SBP (2.9 mm Hg, P = .03), there
was no significant difference in major CV events (ie, stroke,
MI, or CV death; HR 0.19, P = .36).
In the Strategy of Blood Pressure Intervention in Elderly
Hypertensive Patients (STEP) trial, 8511 hypertensive Chi-
nese patients aged 60-80 were randomized to SBP of 110 to
<130 versus 130 to <150 and followed for 3.34 years.23
For a mean SBP difference of 9.2, there was significant
reduction of the primary endpoint (ie, stroke, acute coro-
nary syndrome, acute decompensated congestive heart fail-
ure, coronary revascularization, atrial fibrillation, and CV
death) with HR 0.74, P = .007. The individual components
stroke, acute coronary syndrome, and acute decompensated
congestive heart failure were also significantly reduced.
There was no difference in renal outcomes. Hypotension
was significantly more frequent with intensive therapy
(3.4% vs 2.6%, P = .03).
Overall, a clear picture has not emerged that more inten-
sive therapy is superior to standard therapy in preventing
CV events and mortality. Most of the trials were negative
for their primary endpoints. The 3 most positive were
UKPDS38, SPRINT, and STEP. UKPDS38 can be criti-
cized because of the unacceptably high target in the stan-
dard arm (180/105) and the fact that a significant minority
in the standard arm were not treated at all due to the high
target. The method of measurement in SPRINT has raised
controversy because most patients had BP measured alone
without office personnel being present. Such pressures may
have been higher if attended suggesting the targets would
be higher if BP was attained in the usual fashion. STEP
included only elderly Chinese patients, which restricts
external validity. Certainly, an optimal pressure applicable
to all patients cannot be determined from these trials given
the heterogeneity of populations studied and targets.
There are 4 additional targeting trials that only reported
intermediate or other endpoints. Ichihara et al35 randomized
140 patients to 12 months of intense control (<130/85) or
standard control (<140/90) and compared changes in aortic
pulse wave velocity, which decreased only in the inten-
sively treated group. Solomon et al36 randomized 228
patients with diastolic dysfunction to SBP <130 or to <140
and found no difference in the improvement of myocardial
relaxation between the 2 groups after 24 weeks. Parkash
et al37 randomized 184 participants undergoing catheter
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1177.e2
ablation for atrial fibrillation to BP <120/80 versus <140/
90 and found no difference in the rate of recurrence of atrial
arrythmias after 6 months. Markus et al38 randomized 111
patients with lacunar infarcts to SBP <125 versus 130-140
and found no difference in white matter diffusion tensor
imaging after 2 years. None of these 4 trials reported CV
events or mortality.
Trials in Patients with Chronic Kidney Disease
Eleven studies were restricted to patients with chronic kid-
ney disease (CKD), most of which had primary kidney end-
points. Some did report on CV events and mortality. In the
Modification of Diet in Renal Disease Study (MDRD), 855
patients with CKD were randomized to more intense (mean
arterial pressure [MAP] 92 mm Hg) or standard therapy
(MAP 107 mm Hg) and followed for 2.2 years.24 For a
mean MAP difference of 4.7 mm Hg in rate of decline of
glomerular filtration rate (GFR), there was a significant
interaction with baseline urinary protein (P = .01).
Two trials involved patients with presumed hyperten-
sion-associated nephropathy. Toto et al25 randomized 77
patients with presumed hypertensive nephropathy to DBP
of 65-80 mm hg versus 85-95 mm Hg with approximately
41 months of follow-up. For a mean DBP difference of
7 mm hg, there was no significant difference in the slope of
decline of GFR or in the composite endpoint (50% reduc-
tion in GFR or end-stage kidney disease [ESKD]). The
African American Study of kidney Disease and Hyperten-
sion (AASK) was the largest trial restricted to patients with
CKD (hypertension-attributed CKD) and compared intense
control (MAP < 92 mm HG) with standard control (MAP
102-107 mm Hg) in 1094 participants.30 Three antihyper-
tensive medications (ie, metoprolol, amlodipine, and rami-
pril) were also compared in a 2 £ 3 design. For a mean
SBP/DBP difference of 13/7 mm Hg, there was no change
in the rate of measured GFR decline, the primary endpoint,
or in the composite clinical outcome (50% reduction in
GFR, ESKD, or death).
Lewis et al26 randomized 129 patients with type 1 DM to
MAP ≤ 92 mm hg versus 102-107 mm Hg with a minimum
2-year follow-up. For a mean difference of 6 mm Hg in
MAP, there was no significant difference in rate of decline
of GFR, although there was significant reduction of protein-
uria.
Three trials were completed in patients with type 2 DM.
In the Appropriate Control of Blood Pressure in Diabetes
Trial (ABCD), 470 patients with type 2 DM and DBP
>90 mm Hg were randomized to a DBP <75 mm Hg versus
DBP 80-90 mm Hg and followed for 5 years.27 For a mean
difference of 5/3 mm Hg (SBP/DBP), there was no signifi-
cant difference in creatinine clearance, although death was
significantly reduced (5.5% vs 10.7%, P = .037). There was
no difference in CV endpoints.
In the ABCD-Normotensive Trial, 480 patients with type
2 DM and DBP 80-90 mm Hg were randomized to a
decrease in DBP of 10 mm hg versus DBP of 80-90 mm Hg
1177.e3
and followed for 5.3 years.28 For a mean SBP/DBP differ-
ence of 9/6 mm Hg, there was no difference in rate of
change of creatinine clearance, although there was signifi-
cant reduction in progression of albuminuria (ie, normoal-
buminuria to microalbuminuria, P = .012;
microalbuminuria to overt albuminuria, P = .028) and
reduced incidence of stroke (P = .03).
In the ADCD-2V Trial, 129 patients with type 2 DM and
BP <140/90 mm Hg were randomized to DBP <75 mm Hg
versus no therapy until SBP >140 mm Hg or DBP >90 mm
Hg and followed for 1.9 years.32 For a mean SBP/DBP dif-
ference of 6/5 mm Hg, there was no significant difference
in rate of change of creatinine clearance, although albumin-
uria was significantly reduced.
Two studies were performed in patients with autosomal
dominant polycystic kidney disease (ADPKD). Schrier
et al29 randomized 75 patients with ADPKD to more intense
therapy (<120/80 mm Hg) versus standard control (135-
140/85-90 mm Hg) with a 7-year follow-up. For a mean
MAP difference of 11 mm Hg, there was significant greater
reduction in left ventricular mass index, the primary end-
point. There was no difference in creatinine clearance
between groups. In the HALT-PKD Trial, 558 patients with
hypertension and ADPKD were randomized to intense BP
control (95-110/60-75 mm Hg) or standard control (120-
130/70-80 mm Hg) and followed for 96 months.33 For a
SBP/DBP difference of 13.4/9.3 mm Hg at 96 months, par-
ticipants in the more intensive group had 14.2% slower
annual increase in total kidney volume, the primary end-
point (P = .006). There was no significant difference in rate
of change of GFR, but urinary albumin was significantly
reduced compared to standard control. There was no signifi-
cant difference in CV events or mortality.
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The American Journal of Medicine, Vol 135, No 10, October 2022
The Ramipril Efficacy in Nephropathy-2 trial (REIN-2)
randomized 338 patients with nondiabetic proteinuric
nephropathies on baseline angiotensin-converting enzyme-
inhibition to more intense (SBP/DBP <130/80 mm Hg) ver-
sus standard therapy (DBP <90 mm Hg) with a median fol-
low-up of 19 months.31 There was no difference in the
primary endpoint, progression to ESKD (HR 1.00, 95% CI
0.61-1.64, P = .99) with a mean SBP/DBP difference of
4.1/2.8 mm Hg. There was no difference in rate of change
of creatinine clearance as well.
One trial was restricted to pediatric patients. In the
Effect of Strict Blood Pressure Control and ACE Inhibition
on the Progression of CRF in Pediatric Patients Trial
(ESCAPE), 385 patients were randomized to more intense
therapy (24-hour MAP below the 50th percentile) versus
less intense therapy (MAP in the 50th-90th percentile).34
More intense therapy significantly reduced the primary end-
point of 50% decline of GFR or ESKD (HR 0.65, 95% CI
0.44-0.94, P = .02). The MAP differed between groups by
2.7 to 3.9 mm Hg on yearly 24-hour monitoring (all signifi-
cant). There was a significant interaction (P = .009) with
the benefit of intensive therapy on the primary endpoint and
the cause of CKD: HR for glomerulopathies 0.32, 95% CI
0.14-0.73, HR for hypoplasia-dysplasia 0.58, 0.35-0.97,
and HR for all others 1.23, 0.56-2.72.
Except for the pediatric study, the trials were invariably
negative in the ability of more intense therapy to slow the
progression of CKD, whether determined by measured GFR,
estimated GFR, or creatinine clearance. The major causes of
CKD were well represented, including type 2 DM, hyperten-
sion attributed CKD, ADPKD, and proteinuric nephropathy.
There is no proof to date that more intense antihypertensive
therapy will slow the progression of CKD in adults.