1. Michael Nguyen, PharmD Candidate 2017 (MCPHS University)
A Randomized Trail of Intensive versus Standard Blood-Pressure Control
The SPRINT trial
Journal Club
BACKGROUND – THE STUDY QUESTION?
Background  Hypertension stage 1 is defined by JNC 7 as multiple proper readings of blood pressure >
140/90
 Hypertension stage 2 is defined by JNC 7 “” > 160/100
 Hypertension is highly prevalent in the US especially those > 60 years’ old
 For patients > 50 years of age, isolated systolic hypertension is the most common form.
 It is well known that elevated systolic blood pressure is a greater risk predictor for coronary
events,stroke, HF and ESRD vs. diastolic blood pressure
 Previous trials have shown that treatment of hypertension reduces the risk of cardiovascular
disease outcomes including
 Stroke
 MI
 and HF
 We know that reducing blood pressure is beneficial in cardiovascular outcomes but yet we do
not know how low we should go.
 Several trials have tried to unravel this answer prior but more information is required
 With JNC 8 being released at the end of 2013 with much controversy,the new guidelines
lacked of endorsement from major organizations like the NHLBI, AHA and ACC
 This just shows that even the experts disagree on what the goals should be.
JNC 8 (Dec. 2013) holds the definition of hypertension as > 140/90. What changed were the goals.
The goals are generally <140/<90 for all patients except for those who are greater than 60 years of
age. The latter group having a goal of <150/<90. The guidelines also included population specific
drug selection too (i.e. thiazides for African Americans)
JNC 7 (2003) NHLBI endorsed goals are more stringent than those seen in JNC 8. Clinicians are
encouraged to treat most patients to a goal of <140/90. Those with diabetes or CKD are encouraged
to have a goal of <130/80.
ADA standards ofcare lists their goal as <140/<90 which is consistent with JNC 8. However, the
ADA guidelines also recognizes that a lower goal of <130/<80 may be appropriate for patients who
are younger, had albuminuria or have HTN with one or more additional ASCVD risk factor
(smoker, LDL > 190, higher age)
Previous trials  Verdeccia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure
in non-diabetic patients with hypertension (cardio-sis): an open-label randomized trial.
Lancet 2009; 374:525-33
 Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in
type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85
 Benavate OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patient with recent lacunar
stroke: the SPS3 randomized trial. Lancet 2013;382:507-15
Why this study?  The purpose of this study is to provide additional clarity on which blood pressure goals have
greater cardiovascular and mortality benefit
 GENERAL STUDY OVERVIEW
Title/Citation  The SPRINT Research Group. "A randomized trial of intensive versus standard blood-pressure
control". The New England Journal of Medicine. 2015. 373(22):2103-2116.
Funding  The National Institutes of Health
Null Hypothesis  Lower systolic blood pressure goal of <120 mmHg is no different at reducing clinical
cardiovascular events when compared to the standard goal of <140 mmHg
Trial design  Open-label, Randomized control trial
 Enrollment November 2010 – March 2013
 Planned average follow-up was to be 5 years
 August 20, 2015, NHLBI stopped the trial due to overwhelming results  3.26 years median
follow-up of the planned 5 years.

2. Objectives  To provide data that a more intensive systolic blood pressure goal of <120 mmHg will have a
greater cardiovascular benefit versus the standard goal of <140 mmHg
 METHODS (only list pertinent trial info in this section:refer to trial for further details)
Inclusion criteria  50 years old +
 Systolic blood pressure
1) SBP: 130 – 180 mm Hg on 0 or 1 medication
2) SBP: 130 – 170 mm Hg on up to 2 medications
3) SBP: 130 – 160 mm Hg on up to 3 medications
4) SBP: 130 – 150 mm Hg on up to 4 medications
 An increased risk for cardiovascular events
 Defined as one or more of the following
1. Clinical OR subclinical cardiovascular disease excluding stroke
a. Clinical CVD
i. Previous MI, PCI, CABG, carotidendarterectomy, carotidstenting
ii. PAD with revascularization
iii. ACS with or without restingECGchange, ECGchanges on graded
exercise test, or positive cardiac imagingstudy
iv. At least 50% diameterstenosis of coronary,carotidor lower extremity
artery
v. Abdominal aortic aneurism > 5 cm without repair
b. Subclinical CVD
i. Coronaryarterycalciumscore> 400 Agatstonunits withinthe past 2 years
ii. ABI < 0.9 within the past 2 years
iii. Left ventricular hypertrophyby ECGreading, echo or othercardiac
imagingprocedure withinthe past 2 years
2. Chronic kidney disease with an eGFR of 20-49 mL/min/ 1.73 m2 excluding
polycystic kidney disease
a. Calculated with MDRD not CG equation with the latest lab value
(within the past 6 months)
3. Framingham Risk Score of greater than 15%
4. Age > 75
Exclusion criteria  An indication for a specific BP lowering medication that a person is not taking and the person
has not been documented to be intolerant of the medication class. (i.e. if the patient had an
MI and was non-compliant with their beta-blocker)
 This is a pre-screening criterion – if the PCP manages to get the patient on the proper
meds for their disease,then the patient may be considered for screening if SBP falls in
appropriate range
 Known secondary cause ofhypertension that causes concern regarding safety of the protocol
 One-minute standing SBP < 110 mmHg (does not apply to wheelchair bound patients)
 Proteinuria (based on a measurement within the past 6 months)
 24-hour urinary protein excretion > 1 gram / day
 Or if measurement is not available, 24-hour urinary albumin excretion > 600 mg / day
 Or spot urine protein/creatinine ratio > 1 g/g creatinine
 Or spot urine albumin/creatinine ratio > 600 mg/g creatinine
 Or urine dipstick > 2+
 Arm circumference too large or too small to allow for blood pressure measurement
 Diabetes Mellitus
 History of Stroke
 Diagnosis of polycystic kidney disease
 Glomerulonephritis with or likely to be treated with immunosuppressive therapy
 eGFR < 20 or ESRD
 Cardiovascular event or procedure or hospitalization for unstable angina within the past 3
months
 Symptomatic heart failure within the past 6 months or LVEF < 35%
 Life expectancy < 3 years
 Poor adherence (judged by the clinic team)
 Failure to obtain consent form
 Currently participating in anotherclinical trial (intervention study)
 Living in the same household of someone already in SPRINT trial
 Any organ transplant
 Unintentional weight loss > 10 % in the last 6 months

3.  Pregnancy, currently trying to become pregnant, or of child-bearing potential AND not using
birth control
Interventions  Intensive-treatment group
 Target SBP < 120
 Standard-treatment group
 Target SBP 135-139
 Drugs were provided to participants at NO COST
 Prescribers were encouraged but NOT MANDATED to use drug classes with strong evidence
for reduction in cardiovascular outcomes
1. Thiazide diuretics (encouraged as first line agents)particularly chlorthalidone
2. Loop diuretics (encouraged for patients with advanced kidney disease)
3. Beta-blockers (encouraged for those with CAD)
4. Amlodipine was the preferred calcium channelblocker
5. Azilsartan and Azilsartan/chlorthalidone were donated by Takeda Pharmaceuticals and
Arbor Pharmaceuticals.
 Life style modification was encouraged for all participants (however, was not measured)
Follow up  Monthly for the first 3 months
 Every 3 months thereafter
 Medications were adjusted on a monthly basis to reach target goals
 Blood pressure measurement and dose adjustment
 Use of an automated blood pressure cuff (model 907, Omron healthcare)
 Patient was quietly seated prior to measurement for 5 minutes
 Dose adjustments were based on a mean of 3 blood pressure readings
 A structured interview was used in both groups to assess self-reported cardiovascular disease
outcomes (prevent ascertainment bias)
 The study was ended early after the data and safety monitoring board noted that the primary
outcome exceeded the monitoring boundary at two consecutive points
 The study ended early on August 10, 2015 for a median follow-up of 3.26 years of the planned
5 years.
Endpoints (separate as
primary and secondary)
 Primary Endpoint
 Composite outcome of
1. Myocardial infarction
2. Acute Coronary syndrome not resulting in MI
3. Stroke
4. Acute decompensated heart failure
5. Or death from cardiovascular causes
 Secondary endpoints
 The individual components of the composite primary endpoint
 Death from any cause
 Composite endpoint of the primary endpoint PLUS death from any cause
 Renal outcomes for patients WITH CKD at baseline
 Definedas: a composite ofdecrease in eGFR of 50% ormore OR the development ofESRD requiring
long-termdialysis or kidney transplant
 Renal outcomes for patients WITHOUT CKD at baseline
 Definedas: a decrease in eGFR of 30% or moreOR to a value of < 60 ml/min/1.73m2
 Renal outcome for all participants
 Incident albuminuria = a doublingof the ratioof urinaryalbumin (mg)tocreatinine (g) from less than
10 at baseline to > 10 during follow-up
 Serious adverse events
 Events that were fatal orlife-threatening, that resultedin clinicallysignificant orpersistent disability,
that requiredor prolongeda hospitalization,or that were judgedby the investigator to represent a
clinically significant hazardor harm to theparticipant that might require medical or surgical
intervention to prevent oneof the otherevents listedabove.
Statistical analyses  Planned study

4.  2-year recruitment period
 Planned 5-year follow-up
 Maximum follow-up = 6 years
 Anticipated loss to follow-up of 2% per year
 Enrollment target of 9250 participants
 Power of 88.7% to detect 20% effect with respect to primary outcome
 Assuming an event rate of 2.2% in the standard-treatment group
The study ended early on August 10, 2015 for a median follow-up of 3.26 years of the planned 5
years.
 Data Analysis
 INTENT TO TREAT for all randomized participants
 Time to first occurrence to primary outcome event
 Analyzed with Cox proportional-hazards regression with 2-sided tests at 5% level
 Interactions between treatment effect and pre-specified subgroups
 Analyzed with likelihood-ratio test for interactions with the use of Hommel-
adjusted P values
 Interim analysis performed for each meeting of the data and safety monitoring board
 Sequential stopping boundaries defined with Lan-DeMets method with O’Brien-
Flemming-type spending function
 Sensitivity analysis for the competing risk of death
 Fine-Gray model was used.
 RESULTS
Enrollment  14,692 patients were assessed foreligibility
 9361 participants enrolled between November 2010 and March 2013
Randomization
 4678 – intensive-treatment group
 4683 – standard-treatment group
489 lost in intensive treatment (10.4%)
497 lost in standard treatment (10.6%)
All randomized participants were included in analysis (ITT)
Patient Baseline
characteristics
 See table 1 for full data
Notable differences between groups (intensive group vs.standard group)
 SBP >132 to < 145 mmHg (31.8% vs. 33.1%)
 Ratio of urinary albumin (mg) to creatinine (g) (44.1+178.7 vs. 41.1+152.9)
 Urine Albumin (mg/dL) / Urine Creatinine (g/dL) = UACR in mg/g≈ Albumin excretionin mg/day
 Albuminuria is present when UACR is greater than30mg/gandis a marker forCKD
 It seems that there were more patients with CKD in the intensive treatment group
 Fasting triglycerides (mg/dL) (124.8+85.8 vs. 127.1+95.0)
 Statin use - no./total no. (42.6% vs.44.7%)
 Aspirin use – no/total no. (52.6% vs.50.4%)
 Current smoker (13.7% vs.12.8%)
Investigators claim that there were NO SIGNIFICANT differences between the two groups
EXCEPT for STATIN USE
Primary Outcomes
 244 (1.65% per year) in intensive treatment group
 319 (2.19% per year) in standard treatment group
 Hazard ratio – 0.75
 95% CI – 0.64 to 0.89
 P < 0.001
Secondary Outcomes  Acute decompensated heart failure

5.  62 (0.41% per year) in intensive group
 100 (0.67% per year) in standard group
 Hazard ratio – 0.62
 95% CI – 0.45 – 0.84
 P = 0.002
 Death from cardiovascular causes
 37 (0.25% per year) in intensive group
 65 (0.43% per year) in standard group
 Hazard ratio – 0.57
 95% CI – 0.38 - 0.85
 P = 0.005
 Death from any cause
 115 (1.03% per year) in intensive group
 210 (1.40% per year) in standard group
 Hazard ratio – 0.73
 95% CI – 0.6 -0.9
 P =0.003
 Composite endpoint of the primary endpoint PLUS death from any cause
 332 (2.25% per year) in intensive group
 423 (2.90% per year) in standard group
 Hazard ratio – 0.78
 95% CI – 0.67 – 0.90
 P < 0.001
Non-significant outcomes (see tablet 2 for details on risks)
 Myocardial infarction
 Acute Coronary syndrome not resulting in MI
 Stroke
Other results  Average systolic blood pressure at year 1
 Intensive group – 121.4 mmHg
 Standard group – 136.2 mmHg
 Difference in average of 14.8 mmHg
 Average diastolic blood pressure at year 1
 Intensive group – 68.7 mmHg
 Standard group – 76.3 mmHg
 Average systolic blood pressure throughout 3.6-year follow-up
 Intensive group – 121.5 mmHg
 Standard group – 143.6 mmHg
 Average number of blood pressure medications for
 Intensive group – 2.8
 Standard group – 1.8
 Renal outcomes for patients without CKD at baseline
 127 (1.21% per year) in intensive group
 37 (0.35% per year) in standard group
 Hazard ratio – 3.49
 95% CI – 2.44 – 5.10
 P < 0.001
Non-significant renal outcomes (see table 2 for details on risks)
 Renal outcomes for patients with CKD at baseline
 Incident Albuminuria for patients with CKD at baseline or patients without CKD at baseline

6. Sub-group analysis for Primary outcome (see figure 4 forest plot)
In regards to intense-treatment
 Patients with No CKD at baseline benefited more than those with CKD at baseline
 Patients > 75 years old benefitted more than those < 75 years old
 Males benefitted more than females
 Non-blacks benefitted more than blacks
 Patients with no previous cardiovascular disease at baseline benefitted more than those who did
 Patients with lower systolic blood pressure at baseline (particularly those with SBP < 132) had
benefitted more than those with higher SBP at baseline
Adverse events
 Serious adverse events were generally more prevalent in the intensive treatment arm (hazard
ratio 1.04, P = 0.25)
 Hypotension,syncope,electrolyte abnormalities, and AKI were significantly greater in
the intensive treatment group. All of these were also primary or secondary diagnosis
for ER visits with a greater prevalence in the intensive group too.
 There was no statistical difference in injurious fall (falls that required ED evaluation or
resulted in hospitalization)
 There was not statistical difference in bradycardia
 Orthostatic Hypotension alone (without dizziness) was greater in the standard treatment group
with 18.3% prevalence vs.16.6% prevalence in the intensive treatment arm
AUTHORS’ CONCLUSIONS
The authors claim that this is one of the first trials that is powered enough to provide evidence that a target
less than that of an SBP <150 may have benefit in elderly patients.
The authors conclude that targeting a systolic blood pressure of less than 120 mmHg, as compared with less
than 140 mmHg in patients at high risk for cardiovascular events but without diabetes resulted in lower rates
of fatal and nonfatal major cardiovascular disease and death from any cause.
It’s important to note that the intensive-therapy group had a greater incidence of sever adverse events which
were significant.
GENERALIZABILITY/CRITIQUE/DISCUSSION
Study Design  The study was an open-label randomized control trial
 The study by nature could not have been blinded because investigators had to monitor
blood pressures
 The NIH funded the study.Generally, studies funded with tax payer dollars have low funding
bias
 According to the authors,the only statisticaldifference in baseline characteristics was statin use
 The standard-treatment group had more statin users relative to the intensive-treatment
group
 If this were a confounder, the standard-treatment group would have had a lower
incidence of cardiovascular events (which it did not)
 The randomization process was not disclosed but based on baseline characteristics, the
participants seemed to be well randomized.

7. Population  The authors begin with a background that clearly justifies why they are studying in this
population. (a majority of patients who have high blood pressure and are at risk of CVD
are 60 years and older). It has been shown that SBP reduction has cardiovascular benefits
but the goal is still uncertain.
 In regards to baseline characteristics – there were no statistically significant differences except
for statin use.
 MDRD may underestimate eGFR compared to CG especially in patients with eGFR of
> 90
 Framingham risk score was used instead of the ASCVD risk calculator
 This is probably because the ASCVD risk calculator was not yet available. It was
released in 2013 when the SPRINT trial recruitment process began in November
2010
 Additionally, one of the exclusion criteria is diabetes (the major difference in the
newer CVD risk calculator and the older one)
 The inclusion criteria included those who had high SBP that could be managed with non-acute
pharmacological therapy and those who are at risk for primary or secondary CVD episodes
 The exclusion criteria were properly set to reduce confounding,protect participants (those with
excessive SBP or are symptomatically hypotensive)and prevent breach in study protocol
(adherence).
 In the inpatient setting (especially in Lahey) a majority of patients who are admitted are elderly
and may have some form of kidney injury. These patients may benefit from the results of
this study.However, the study excluded diabetics, patients with a history of stroke and
those with ESRD, meaning the data cannot be generalized to these specific populations
which is quite prevalent.
Intervention  Older trials from the 20th century3-4 targeted blood pressure at <150 mmHg in elderly patients
 Newer studies such as JATOS and Cardio-sis6-7 were not adequately powered although they
target lower SBP goals.
 The standard treatment is reflective of current guidelines (JNC 7)
 The interventions of intensive treatment (<120 mmHg) and standard treatment (<140 mmHg)
are appropriate
 It is notable that the drug therapy regimen was not mandated by the clinical centers .
 However, this is appropriate due to variability in pharmacological response in patients.
 Also, each patient may require a different cocktail of medications based on co-morbidities as
mentioned by the authors.
 The supplementary documents provide a detailed protocol for treating patients to reach their
goal and when to step down therapy (page 24-35 in supplementary documents)
Endpoints
 The Primary endpoint is appropriate to show superiority of cardiovascular benefit over the
standard treatment group and reflects the study hypothesis.
 Secondary endpoints include all-cause mortality and individual components of the primary
endpoint.
 These provide a deeperanalysis of potential benefits of the intensive-therapy vs.
standard therapy
 In addition, the renal outcomes provided a measurement of potential harm of intensive-
therapy vs. standard therapy

8. Statistics  Nominal and continuous data were assessed properly and displayed properly as either
percentages or averages with standard deviations
 The study exceeded its enrollment requirements to power the study at 88.7% to detect 20%
effect with respect to primary outcome
 The statistical tests were appropriate to the best of my knowledge. Cox-regression model was
properly used to produce hazard ratios and detect time-to-event
 The authors gave the results in relative ratios. Nevertheless, they also provided number needed
to treat for the primary outcome
ARR
- Primary outcome = 1.6% absolute risk reduction (6.8-5.2)
- All-cause mortality = 1.2% absolute risk reduction (4.5 – 3.3)
NNT (my calculations were slightly different)
- Primary outcome = 61 patients
- All-cause mortality = 90 patients
Subgroup analysis
 Benefit in the female, CKD at baseline, and black populations were probably not detected
because of low participants in the study with these baseline characteristics. Thus not
powering the study enough to detect a difference.
 It is interesting that the study had more patients < 75 years old yet the group that benefitted
more was the > 75-year-old group
Results  The results were printed clearly on tables and charts and mentioned throughout the discussion.
The supplemental material includes a plethora of additional data.
 The results are clinically meaningful. The results give clinicians a lower potential goal when
treating patients with hypertension.
 The authors conclude that Lower blood pressure goal of < 120 is more beneficial … But they
never achieved that goal!
 This has several implications
1. The blood pressure difference of 10.1 mmHg can have a large impact on
cardiovascular events
2. Achieving a blood pressure goal this low can be difficult (average 2.8 medications to
achieve mean SBP of 121.5 mmHg)
3. Truly achieving this blood pressure goal can intensify the side-effects that were
already seen when the investigators failed to reach their own goal.
 It is interesting that there was no statistical difference in incidence of injurious fall or
bradycardia.
 It would have been nice to for the investigators to measure all falls (not just injurious
ones)
 I found it surprising that patients who were in the standard therapy group had a higher incidence
of orthostatic hypotension without dizziness vs. intensive therapy group.
 Benefit in the female, CKD at baseline, and black populations were probably not detected
because of lower number of participants in the study with these baseline characteristics.
(thus not powering the study enough to detect a difference in these populations).
 It is interesting that the study had more patients < 75 years old yet the group that benefitted
more was the > 75-year-old group

9. Leader’s Conclusion
In my conclusion, this data brings forth a major change in practice. The SPRINT trial is not applicable to everyone and I
would not generalize it to all hypertensive patients. Until further data is available, it may be prudent to apply the intensive
goal to older patients who are at risk of cardiovascular disease.
However, with the greater incidence of adverse events in the intensive group, especially those that older patients are already
susceptible to, I would have to weigh the risks of pushing such a harsh goal on a patient. Although the authors claim that
the cardiovascular benefits are more apparent in the intensive-treatment group, the risk of injury due to adverse events
seems very high to me.
To support my concern, the study was stopped early. If the study continued, I would believe that the incidence of adverse
events would have been greater in the study. The authors say that a goal of < 120 is superior but I have to be skeptical of
this goal because the authors themselves did not achieve this goal in the majority of the intensive-treatment group. If the
authors used an average of 3.8 drugs to truly reach the goal of <120 mmHg, I believe adverse events would grow even
greater.
In conclusion, I do not believe that a SBP goal of < 120 mmHg is appropriate for everyone. Although this study was
performed mostly in elderly patients, I would use extra caution when pushing the goal that low. I understand that there are
clear cardiovascular benefits but as my patient’s systolic blood pressure dips below 135 mmHg, I would proceed with
caution and only proceed if the patient tolerates.
References:
1. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report. JAMA 2003:289:2560-72
2. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults:
Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
doi:10.1001/jama.2013.284427.
3. Staessen JA, Fagard R, Thijs L, et al. Randomized double-blind comparison of placebo and active treatment for older patients
with isolated systolic hypertension.Lancet 1997:354:1291-7
4. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated
systolic hypertension:final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-
64American Diabetes Association.Standards of medical care in diabetes—2016. Diabetes Care 2016;39(suppl 1):S1-S106
5. Verdeccia P, Staessen JA, Angeli F, et al. Usual versus tight control of systolic blood pressure in non-diabetic patients with
hypertension (cardio-sis): an open-label randomized trial. Lancet 2009; 374:525-33
6. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive
patients (JATOS). Hypertens Res 2008;31:2115-27
7. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl
J Med 2010;362:1575-85
8. Benavate OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patient with recent lacunar stroke: the SPS3 randomized
trial. Lancet 2013;382:507-15