SPRINT Commentary
SPRINT
What Remains Unanswered and Where Do We Go From Here?
Daniel W. Jones, Lyssa Weatherly, John E. Hall
T he Systolic Blood Pressure Intervention Trial (SPRINT)
main results were recently published and presented at the
American Heart Association Scientific Sessions.1 These data
provide insight into the important question of the most appro-
priate treatment goal for systolic blood pressure (BP). The
results of this study will have a large and lasting impact on the
management of patients with hypertension. The study answers
a critical question, but important questions remain.
The large over-riding question remaining from the SPRINT
trial is this: How generalizable are the results? The J-curve
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relationship between systolic BP and risk is present in every
individual and every group.2 What has been uncertain is where
the inflection point on the J curve is and how the J curve rela-
tionship is impacted by chronic hypertension, age, diabetes
mellitus, chronic kidney disease, and atherosclerotic disease
leading to stroke and heart disease. The SPRINT has answered
some of these questions, but some remain unanswered.
Perhaps, the most important question coming from the
SPRINT involves a group of patients not included in the trial:
patients with diabetes mellitus. A few years earlier, the Action
to Control Cardiovascular Risk in Diabetes (ACCORD) study3
was done to determine the appropriate goal systolic BP for
patients with diabetes mellitus. ACCORD did not demonstrate
a benefit for a systolic BP goal of 120 versus 140 mmHg.
On the basis of those results, most current guidelines call for
lowering BP to the range of 135 to 140 mmHg in diabetic
patients.4,5 If the interpretation of the ACCORD results is cor-
rect, is the reason for lower BP goals leading to better results
in SPRINT related to the influence of diabetes mellitus on
the vasculature? Could diabetes mellitus have some negative
influence on arteriolar function and blood flow autoregulation
that shifts the J curve or the pressure/flow relationship.6 We
know that blood flow is related to BP and that flow in organs,
such as the brain, heart, and kidneys, remains relatively con-
stant over a wide range of BPs in healthy people without target
organ injury. But there is a precipitous decrease in flow when
BP reaches a critical low point. Some speculate that arterio-
lar dysfunction with hampered autoregulation in diabetics
might account for the difference in results for SPRINT and
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Departments of Medicine (D.W.J., L.W.) and Physiology and
Biophysics (J.E.H.), University of Mississippi Medical Center, Jackson.
Correspondence to Daniel W. Jones, Department of Medicine,
University of Mississippi Medical Center, Jackson, MS 39056. E-mail
danjones@olemiss.edu
(Hypertension. 2016;67:261-262.
DOI: 10.1161/HYPERTENSIONAHA.115.06723.)
2015 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.115.06723
261
ACCORD. And some argue that the unexpected difference
in outcomes might be related to the ACCORD study design.6
ACCORD had lower event rates than initially predicted
because of a lower cardiovascular risk profile in participants.
The exclusion of participants aged >80 years led to a younger
group of patients in ACCORD than in SPRINT. The mean age
for ACCORD was 62 years and for SPRINT was 68 years.1,3
Participants in the BP arm were also at lower risk because
patients with dyslipidemia were assigned to the lipid arm and
excluded from the BP arm.3 Finally, because of the use of met-
formin in the treatment of diabetes mellitus, participants with
a serum creatinine concentration >1.5 mg/dL were excluded.3
Another significant difference in the design of the SPRINT
and ACCORD studies was the use of diuretics. The treat-
ment regimen for hypertension in the ACCORD study often
used hydrochlorthiazide,3 and the SPRINT study primar-
ily used chlorthalidone.1 And the complexity of the factorial
study design in ACCORD may have made it less likely that
a statistically significant difference could be demonstrated.3
Another study addressing the issue of goal BP in treating
diabetic patients with a different study design might need to
be considered. Because of the issues previously noted, the
ACCORD study was not sufficiently powered to detect a sig-
nificant 20% reduction in the primary outcome in the more
intensively treated group. Support for this consideration is the
finding in ACCORD of a 40% reduction in stroke in the inten-
sively treated group.3 A related question on diabetes mellitus
is the recommendation for the upcoming American College of
Cardiology/American Heart Association guidelines for treat-
ment of diabetic patients with hypertension. Should the goal
systolic BP be 140, 135, 130, or 120 mm Hg? Adequate evi-
dence to guide this recommendation will not be available for
the upcoming set of guidelines. The recommendation will be
based on expert opinion. It is reassuring that adverse events
in ACCORD were low for both randomized groups.3 So one
might argue that risk for harm for a systolic BP goal of 120
mmHg might be low.
Other questions in need of further study include goal BP
for patients with preserved ejection fraction heart failure and
for patients with low ejection fraction heart failure. Another
interesting question that arises from SPRINT is whether to per-
form more clinical trials in patients with untreated systolic BP
from 120 to 140 mmHg. Would it be prudent to evaluate that
patient population again to determine whether there is a benefit
of drug treatment to a lower systolic BP? Previous studies may
have demonstrated no benefit because overall risk was low in
this patient group.7 Or might it be similar to ACCORD in that
that power of the study design may have been insufficient to
demonstrate benefit? Important unanswered questions unre-
lated to goal BP but important in hypertension management
include issues related to obesity and precision medicine. Will
 262HypertensionFebruary 2016
we discover meaningful ways to prevent and manage obesity
that will lead to dramatic changes in the prevalence of high BP?
The development of new science and new therapies for hyper-
tension over the past 50 years offers hope that science will
yield similar good options for obesity management. Fifty years
ago what was available to manage hypertension were a small
number of mostly undesirable drugs and lifestyle recommen-
dations that were difficult to implement. That is pretty much
where we are today in obesity knowledge and management.
Also the growing investment in precision medicine may
offer opportunities to refine optimal BP management includ-
ing goal BP for individuals or more narrowly defined groups.
Where do we go from here? Certainly, the SPRINT
results should be considered by the writing committee for the
upcoming American College of Cardiology/American Heart
Association BP guidelines. The most critical decision relates
to the treatment goal for systolic BP, including goal systolic BP
for subgroups such as patients with diabetes mellitus, patients
<50 years, and those with untreated systolic BP of 120 to 140
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mmHg. Given that SPRINT only included patients with, or at
high risk for, cardiovascular disease, the committee might con-
sider whether treatment recommendations should be based on
global cardiovascular risk rather than BP alone. The writing
committee may also want to consider implications for classifica-
tion of BP. We should increase efforts in hypertension research
including basic science, translational science, clinical trials,
and population science. The impact of the results of SPRINT,
Systolic Hypertension in the Elderly Program (SHEP), and the
Antihypertensive and Lipid Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT) should encourage funders and
investigators to continue the use of high-quality, event-based,
randomized clinical trials. Research should include expanded
use of better BP measurements, including improved methods
for ambulatory BP measurements. We need to better under-
stand the risk associated with various components of BP, such
as variability, nighttime dipping, and pulse pressure. We should
consider whether clinical trial results could be improved if we
had more accurate and more complete BP measurements.
We should consider how we might address the question of
whether treatment to 120/80 mmHg early in life prevents the
intermediate end points that may predict later target organ injury
or earlier intermediates such as albuminuria and vascular stiff-
ness. We should continue and increase efforts in hypertension-
related research including obesity and precision medicine. We
should continue efforts to better implement what we know now
including lifestyle therapy with a strong focus on prevention in
early childhood and on improving the food and physical activity
environment. This includes consideration of the use of regula-
tion. And we should not fail to pause momentarily to appreciate
the progress in the field of hypertension including the remark-
able results of the SPRINT. The investigators, the National
Institutes of Health, and participants of the SPRINT are com-
mended and congratulated for this important contribution.
Disclosures
None.
References
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 SPRINT: What Remains Unanswered and Where Do We Go From Here?
Daniel W. Jones, Lyssa Weatherly and John E. Hall

Hypertension. 2016;67:261-262; originally published online November 9, 2015;

doi: 10.1161/HYPERTENSIONAHA.115.06723
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