INTRODUCTION
- In the United States, 75% of persons older than 75 years
have hypertension, for whom cardiovascular disease complications are a leading
cause of disability, morbidity, and mortality
- European guideline
committees have recommended treatment
initiation only above 160 mm Hg for
persons aged 80 years or older
- US guideline, a
report from the panel appointed to the Eighth Joint National Committee (JNC 8),
recommended a SBP treatment target of
150 mm Hg for adults aged 60 years or older.
- However, a report from a minority of the members argued to retain the previously recommended
SBP treatment goal of 140 mm Hg, highlighting
the lack of consensus
- Whether treatment
targets should consider factors such as frailty or functional status is also
unknown
- Observational
studies have noted differential associations among elevated blood pressure
(BP) and cardiovascular disease, stroke, and mortality risk when analyses are
stratified according to measures of functional status.
- A recent secondary analysis of the Systolic Hypertension in the Elderly Program showed that the benefit of antihypertensive therapy was
limited to participants without a self-reported physical ability limitation.
- In contrast, analyses from the Hypertension in the Very Elderly Trial (HYVET) showed a consistent benefit with antihypertensive
therapy on outcomes irrespective of frailty status.
The Systolic Blood Pressure Intervention Trial (SPRINT) recently
reported that participants assigned to an intensive SBP treatment target of
less than 120 mm Hg vs the standard SBP treatment goal of less than140mmHg had a
25% lower relative risk of major cardiovascular events and death, and a 27% lower
relative risk of death from any cause.
- This trial was specifically funded to enhance recruitment
of a prespecified subgroup of adults aged 75 years or older, and the study
protocol (appears in Supplement 1) also included measures of functional status
and frailty.
- This article details results for the prespecified subgroup
of adults aged 75 years or older with hypertension.
OBJECTIVE
To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP
targets in persons aged 75 years or
older with hypertension but without diabetes.
METHODOLOGY
Population
Inclusion:
- Increased risk for cardiovascular disease (based on a clinical
or subclinical cardiovascular disease, chronic kidney disease [CKD], a 10-year
Framingham General cardiovascular disease risk ≥15%, or age ≥75 years).
Exclusion:
- had type 2 diabetes, a history of stroke, symptomatic
heart failure within the past 6 months or reduced left ventricular ejection
fraction (<35%), a clinical diagnosis of or treatment for dementia, an
expected survival of less than 3 years, unintentional weight loss (>10% of
body weight) during the preceding 6 months, an SBP of less than 110 mm Hg following
1 minute of standing, or resided in a nursing home.
Study Measurements
- Sociodemographic data were collected at baseline, whereas both
clinical and laboratory data were obtained at baseline and every 3 months
- Race and ethnicity information was obtained via
self-report.
- Blood pressure was determined using the mean of 3 properly
sized automated cuff readings, taken 1 minute apart after 5 minutes of quiet
rest without staff in the room.
- Gait speed was
measured via a timed 4-m walk performed
twice at the participant’s usual pace from a standing start.
- The use of an assistive device was permitted if typically used
by the participant to walk short distances.
- The faster of the 2
gait speeds (measured in meters/second) was used in the analysis.
- Frailty status
at randomization was quantified using a previously reported 37-item frailty index.
Clinical Outcomes
- A committee unaware of treatment assignment adjudicated the
protocol-specified clinical outcomes.
- The primary
cardiovascular disease outcome was a composite of: nonfatal myocardial infarction,
acute coronary syndrome not resulting in a myocardial infarction, nonfatal
stroke, nonfatal acute decompensated heart failure, and death from cardiovascular
causes.
- Secondary outcomes:
all-cause mortality and the composite of the SPRINT primary outcome and
all-cause mortality.
- The primary renal
disease outcome was assessed in participants with CKD at baseline (estimated glomerular filtration rate [eGFR]
<60 ml/min/1.73 m2 based on the 4-variable
Modification of Diet in Renal Disease equation). It was
based on the composite incidence of either a decrease in eGFR of 50% or greater (confirmed by subsequent
laboratory test ≥90 days later) or the development of
end-stage renal disease requiring long-term dialysis or transplantation.
- Secondary renal
disease outcome (assessed in participants without CKD at baseline) was based on incidence of a decrease in eGFR from 30% or greater at
baseline to a value less than 60 mL/min/1.73 m2 (also confirmed
by a subsequent test ≥90 days later).
Definition of Serious
Adverse Events
- Serious adverse events (SAEs) were defined as events that were
fatal or life threatening, resulted in significant or persistent disability,
required hospitalization or resulted in prolonged hospitalization, or medical
events that the investigator judged to be a significant hazard or harm to the
participant and required medical or surgical intervention to prevent any of
these.
- The following conditions of interest were reported as
adverse events if they were evaluated in an emergency department: hypotension, syncope, injurious falls,
electrolyte abnormalities, and bradycardia.
- Episodes of acute
kidney injury (or acute renal failure) were monitored if they led to hospitalization
and were reported in the hospital discharge summary.
Statistical Analysis
- Power to detect
a 25% treatment effect for the primary outcome within the subgroup of
participants aged 75 years or older was estimated assuming an enrollment of
3250.With a 2-year recruitment period, maximum follow-up of 6 years, and annual
loss to follow-up of 2%, power was estimated to be 81.9%, assuming an event rate of 3.25%per year in the standard
treatment group (Appendix B in Supplement 1).
- Linear-mixed models
with an unstructured covariance matrix, assuming independence across
participants, were used to model
longitudinal differences in SBP between treatment groups
- Fixed effects
in the model were BP at randomization
and a treatment group indicator.
- The time to first
occurrence of the primary composite outcome,
all-cause mortality, primary composite outcome plus all-cause mortality, SAEs,
and loss to follow-up or withdrawing consent were compared between the 2 randomized groups using Cox proportional hazards regression models with the baseline hazard
function stratified by clinic site (participants were recruited at 100
clinics).
- Follow-up time
was censored on the date of last event ascertainment on or before August 20, 2015, the date on
which the National Heart, Lung, and Blood Institute director decided to stop
the intervention.
- Exploratory
secondary analyses were conducted to examine
modification of the treatment effect by
frailty status and gait speed.
- Neither frailty status nor gait speed was a prespecified subgroup
in the trial protocol.
We fit separate Cox regression models:
- for frailty status
classified as fit (frailty index ≤0.10),
less fit (frailty index >0.10 to ≤0.21), or frail (frailty index >0.21), and
- for gait speed classified
as 0.8m/s or greater (normal walker), less than 0.8 m/s (slow walker), or
missing.
- Interactions between treatment group, frailty status, and
gait speed were formally tested by including interaction terms within a Cox
regression model (ie, using likelihood ratio tests to compare with a model that
did not allow the treatment effect to vary by frailty status or gait speed).
- For the primary cardiovascular disease composite outcome, sensitivity analyses accounting for the
competing risk of death were conducted using the sub-distribution hazard model
of Fine and Gray.
- All hypothesis tests were 2-sided at the 5%level of
significance
- Additional analyses
compared the total burden of SAEs between the randomized groups (allowing
for recurrent events) using the mean cumulative count estimator (standard
errors computed using bootstrap resampling).
- Hazard ratios (HRs) were computed to compare the
randomized groups using the gap-time
formation of the Prentice, Williams, and Peterson recurrent events regression model.
- All analyses were performed using SAS version 9.4 (SAS
Institute Inc) and the R Statistical Computing Environment (http://www.r-project.org)
RESULTS
Baseline
characteristics and Study Retention
- The treatment
groups were similar for most characteristics with the exception of frailty status and aspirin use (Table 1).
- Overall, 815 participants (30.9%) were classified as frail
and 1456 (55.2%) as less fit (Table 1).
- A total of 2510 (95.2%) participants provided complete follow-up
data.
- In the intensive treatment group, 440 participants (33.4%)
were classified as frail compared with 375 participants (28.4%) in the standard
treatment group.
- A total of 740 participants (28.1%) were classified as
slow walkers (<0.8m/s).
- There was no baseline treatment group difference in the proportion
of participants classified as slow walkers or in performance on the Montreal
Cognitive Assessment screening test
- Even though participants who were less fit, frail, or with
reduced gait speed exhibited higher rates of loss to follow-up or withdrawal of
consent, there were no significant differences between the treatment groups for
frailty or low gait speed (eTable 1 in Supplement 2).
- The frequency at which participants discontinued the
intervention but continued follow-up was 6.2% in the intensive treatment group
vs 6.4% in the standard treatment group (P = .87).
Blood Pressure Levels
Throughout follow-up,
Mean SBP:
- Intensive treatment group: 123.4 mm Hg
- Standard treatment group: 134.8 mm Hg
- Between group difference: 11.4 mg (95% CI, 10.8-11.9 mm
Hg)
Mean Diastolic BP:
- Intensive treatment group: 62.0 mm Hg
- Standard treatment group: 67.2 mm Hg
- On average, participants in the intensive treatment group required 1 more medication to reach the
achieved lower BP (eTable 2 and eFigure 1 in Supplement 2).
- Within the intensive treatment group, mean SBP during follow-up was higher for participants classified as less fit or frail compared with those
considered fit.
- Differences in mean
SBP by treatment group differed by frailty status (P = .01), with frail participants exhibiting smaller inter-treatment
group differences (10.8 mm Hg) compared with less fit participants (11.3 mm Hg)
and fit participants (13.5 mm Hg).
- Treatment group differences in SBP were similar across subgroups defined by gait
speed.
Clinical Outcome
- A primary composite
outcome event was observed for 102 participants (2.59% per year) in the
intensive treatment group and for 148 participants (3.85% per year) in the
standard treatment group (HR, 0.66 [95%
CI, 0.51-0.85]; Table 3).
- Results were similar for all-cause mortality (there were 73 deaths in the intensive
treatment group and 107 deaths in the standard treatment group; HR, 0.67 [95% CI, 0.49-0.91]).
- Inference for the primary outcome was unchanged when non-cardiovascular
disease death was treated as a competing risk (HR, 0.66 [95% CI, 0.52-0.85]).
- At 3.14 years,
the number needed to treat (NNT)
estimate for the primary outcome was 27
(95% CI, 19-61) and for all-cause
mortality was 41 (95% CI, 27-145).
- In participants without CKD at the time of
randomization, more participants in
the intensive treatment group compared with the standard treatment group experienced the secondary CKD outcome
(a 30% decrease in eGFR from baseline to an eGFR <60 mL/min/1.73 m2 [1.70%
vs 0.58% per year, respectively]; HR, 3.14 [95% CI, 1.66-6.37]).
- There were no
significant treatment group differences in the primary renal outcome in
those with baseline CKD; however, power
to detect differences was limited
due to low numbers of events.
Exploratory Subgroup
Analyses
- Results stratified by baseline frailty status showed higher
event rates with increasing frailty in both treatment groups (Table 4 and Figure 2).
- However, within each frailty stratum, absolute event rates
were lower for the intensive treatment group (P = .84 for interaction).
- Results were similar when participants were stratified by
gait speed (P = .85 for interaction), with the HRs in favor of the
intensive treatment group in each gait speed stratum (eFigure 2 in Supplement 2).
Serious Adverse
Events (SAEs)
- Detailed information regarding SAEs appears in eTable 3
and eTable 4 in Supplement 2.
- In the intensive treatment group, SAEs occurred in 637
participants (48.4%) compared with 637 participants (48.3%) in the standard
treatment group (HR, 0.99 [95% CI, 0.89-1.11]; P = .90).
- The absolute rate
of SAEs was higher but was not statistically significantly different in the
intensive treatment group for hypotension (2.4%vs 1.4% in the standard treatment
group;
For each specific SAE:
- Hypotension: 2.4% (intensive group) vs 1.4% (standard
group) (HR, 1.71 [95% CI, 0.97-3.09])
- Syncope: 3.0% (intensive group) vs 2.4% (standard group) (HR,
1.23 [95% CI, 0.76-2.00])
- Electrolyte abnormalities: 4.0% (intensive group) vs 2.7%
(standard group) (HR, 1.51 [95% CI, 0.99-2.33])
- Acute kidney injury: 5.5% (intensive group) vs 4.0%
(standard group) (HR, 1.41 [95% CI, 0.98-2.04])
- Injurious falls: 4.9% (intensive group) vs 5.5% (standard
group) (HR, 0.91 [95% CI, 0.65-1.29])
[Note from ZYL: To see
whether the group differences are significant, we look at the 95% confidence
interval (CI) of the hazard ratio (HR): If the CI pass did not pass through the
value ‘1’, then it is significant; if the CI passed through value ‘1’, then it
is not significant (The reason why we look at ‘1’ is because ‘1’ means null
effect in ratio).
From the results, all
of the CI of the serious adverse events reported passed through the value ‘1’,
therefore the serious adverse events between groups were not significantly
difference. However, it must be noted that there is a trend that the intensive
group had more hypotension, electrolyte abnormalities and acute kidney injury
(the lower CI is very near to 1)
- Even though the SAE
rates were higher with greater frailty or slower walking speed, these rates
were not statistically different by
treatment group when stratified by frailty status or gait speed.
DISCUSSION
Main Findings
- These results extend and detail the main SPRINT study
findings in community-dwelling persons aged 75 years or older, demonstrating
that a treatment goal for SBP of <120 mm Hg reduced incident cardiovascular
disease by 33% (from 3.85% to 2.59% per year) and total mortality by 32% (from 2.63%
to 1.78% per year)
- Number needed to treat: strategy of intensive BP control
for 3.14 years would be expected to prevent 1 primary outcome event for every
27 persons treated and 1 death from any cause for every
41 persons treated.
- These estimates are lower than those from the overall
results of the trial due to the higher event rate in persons aged 75 years or
older.
- Exploratory analysis also suggested that the benefit of
intensive BP control was consistent among persons in this age range who were
frail or had reduced gait speed.
Serious Adverse Events
- The overall SAE rate was comparable by treatment group, including
among the most frail participants.
- There were no differences in the number of participants
experiencing injurious falls or in the prevalence of orthostatic hypotension
measured at study visits – complement results from other trials demonstrating
improved BP control reduces risk for orthostatic hypotension and has no effect
on risk for injurious falls
Limitations
- Randomization was not stratified by categories of age
- Did not enroll older adults residing in nursing homes,
persons with type 2 diabetes or prevalent stroke (because of concurrent BP lowering
trials) and individuals with symptomatic heart failure due to protocol
differences required to maintain BP control in this condition – cannot be
generalized to these groups of patients. Individuals with these conditions also
represent a subset of older persons at increased risk for falls.
Exploratory Analysis
- No other chronic conditions were excluded from this trial,
and the frailty index applied in this study combined with the assessment of
gait speed contribute to assessing possible effect modification by comorbidity
and functional status.
- In exploratory analyses, there was no evidence of heterogeneity for the cardiovascular benefit of
intensive BP management by frailty or gait speed.
- However, these analyses should be interpreted cautiously.
- The analyses were not prespecified in the trial protocol and
were possibly underpowered because SPRINT was designed to consider only the
ability to detect a treatment effect in participants aged 75 years or older as
a whole
Representativeness of
the trial participants
- Despite excluding some chronic conditions, 30.9% of
participants aged 75 years or older in this trial were categorized as frail at
baseline, and the distribution of frailty status parallels that estimated for
ambulatory, community living populations of similar age.
- In addition, the proportion of US adults aged 75 years or
older who have hypertension and meet the study entry criteria has been
estimated to represent 64% of that population using the 2007-2012 National
Health and Nutrition Surveys (approximately 5.8 million individuals).
- Therefore, participants aged 75 years or older in this
trial are representative of a
sizeable fraction of adults in this age group with hypertension
Compare with the HYVET
Trial
- Randomized 3845 patients aged 80 years or older within
Europe and Asia (mean age, 83 years [3 years older than SPRINT]; mean entry
SBP, 173mmHg [31 mm Hg higher than SPRINT]) to either therapy with indapamide, with
or without the angiotensin-converting enzyme inhibitor perindopril, or placebo
with an SBP treatment goal of <150 mm Hg.
- The 2-year between-group SBP difference was 15 mm Hg (the
active treatment group achieved a mean SBP of 143mm Hg, slightly higher than
the SPRINT baseline SBP).
- Similar to SPRINT, HYVET was terminated early (at a median
follow-up time of 1.8 years) due to significant reductions in the incidence
rate of total mortality.
- A retrospective analysis of the HYVET population conducted
to determine its frailty status identified that (1) the cohort’s frailty status
was similar to that of community living populations of similar age and (2) the
treatment benefits were similar even in the most frail participants.
- Taken together, current results from SPRINT also reinforce and extend
HYVET’s conclusions that risk reductions in cardiovascular disease
events and mortality from high BP treatment are evident regardless of frailty status
SAEs related to Acute
Kidney Injury
- Among all participants aged 75 years or older, the SAEs
related to acute kidney injury occurred more
frequently in the intensive treatment group (72 participants [5.5%] vs 53
participants [4.0%] in the standard treatment group).
- The differences in adverse renal outcomes may be related to a reversible intrarenal
hemodynamic effect of the reduction in BP and more frequent use of diuretics,
angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers
in the intensive treatment group.
- Although there is
no evidence of permanent kidney injury associated with the lower BP goal, the
possibility of long-term adverse renal
outcomes cannot be excluded and requires longer-term follow-up
Implications of the
study
- Considering the high prevalence of hypertension among older
persons, patients and their physicians may be inclined to underestimate the
burden of hypertension or the benefits of lowering BP, resulting in under-treatment.
- On average, the benefits
that resulted from intensive therapy required treatment with 1 additional
antihypertensive drug and additional early visits for dose titration and
monitoring.
- Future analyses of SPRINT data may be helpful to better
define the burden, costs, and benefits of intensive BP control.
- However, the present results have substantial implications
for the future of intensive BP therapy in older adults because of this
condition’s high prevalence, the high absolute risk for cardiovascular disease
complications from elevated BP, and the devastating consequences of such events
on the independent function of older people
CONCLUSIONS
- Among ambulatory adults aged 75 years or older, treating
to an SBP target of less than 120 mm Hg compared with an SBP target of less
than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal
major cardiovascular events and death from any cause
- The overall serious adverse events rate was comparable by treatment group, including among the most frail participants.
- The overall serious adverse events rate was comparable by treatment group, including among the most frail participants.
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