SPRINT

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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.
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Clinical Question

In patients at high risk for CVD but who do not have a history of stroke or diabetes, does intensive BP control (target SBP <120 mm Hg) yield superior CV outcomes compared to standard treatment (target SBP 135-139 mm Hg)?

Bottom Line

In patients at high risk for CVD but who do not have a history of stroke or diabetes, intensive BP control (target SBP <120 mm Hg) improved CV outcomes and overall survival compared to standard therapy (target SBP 135-139 mm Hg), while modestly increasing the risk of some serious adverse events.

Major Points

Systolic hypertension (SBP ≥140 mm Hg) and prehypertension (SBP 120-139 mm Hg) are risk factors for myriad diseases including CAD, CKD, and stroke.[1][2][3] Treatment conventions and guideline statements have called for the treatment of hypertension to a target SBP of <140 mm Hg, but no large trial had demonstrated this in a well-designed, randomized fashion, and it has been largely unknown whether more intensive therapy would be more efficacious. ACCORD BP (2010) demonstrated that among patients with diabetes, intensive therapy (target SBP <120 mm Hg) yielded no improvement in CV outcomes compared to standard therapy (target SBP <140 mm Hg). Similarly, SPS3-BP [4] found no reduction in the risk of recurrent stroke in patients with recent lacunar stroke randomized to intensive (target SBP <130 mm Hg) versus conventional therapy (target SBP 130-150 mm Hg). But what of patients without known CVD or CVD risk equivalents such as diabetes? That is, it be that intensive therapy could benefit high-risk patients who haven't already had complications of CVD such as stroke?

The 2015 Systolic Blood Pressure Intervention Trial (SPRINT) studied 9,361 non-diabetic patients ≥50 years of age without a history of prior stroke who were at elevated risk for CV events. Patients were randomized to intensive BP control targeting SBP <120 mm Hg or to standard therapy targeting SBP 135-139 mm Hg. This open-label trial was powered to detect a 20% effect difference in the primary composite outcome of MI, ACS without MI, stroke, acute HF, or CV death, assuming an event rate of 2.2% per year in the standard arm, and an average follow-up of 5 years. The choice of antihypertensive was left to investigator discretion, with a preference for first-line thiazide, beta-blockers for patients with CAD, etc. Despite the planned follow-up of 5 years, the trial was stopped short after just 3 years when an interim analysis demonstrated the superiority of intensive therapy compared to the standard of care. Intensive BP control was associated with fewer primary outcome events (5.2% vs. 6.8%; P<0.001; NNT 63) and a reduction in all-cause mortality (3.3% vs. 4.5%; P=0.003; NNT 83). There was no difference in the composite endpoint of all serious adverse events, but the intensive therapy arm was associated with more non-orthostatic hypotension, syncope, electrolyte abnormalities, and AKI.

Given that SPRINT was so recently published, it is certain to incite controversy; but its impact on patient care is yet to be determined. Multiple questions remain unanswered about the implications of widespread intensive BP therapy among adults. One such concern is the potential for complications from hypotension and end-organ hypoperfusion in patients treated to intensive BP targets. For example, intracranial hypoperfusion has been linked to cognitive decline in the elderly,[5] which may be worsened by lower BP targets, although SPRINT was likely too short to detect a meaningful change in cognitive status. Similarly, AKI is associated with excess mortality[6] and occurred more frequently in the intensive therapy group. Intensive BP control was associated with a higher pill burden, and polypharmacy has been associated with poor outcomes particularly in the elderly.[7] Further follow-up and identification of subgroups more likely to benefit from intensive control is needed.

Guidelines

As of November 2015, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, open-label, randomized controlled trial
  • N=9,361 patients without diabetes or stroke at elevated CV risk
    • Intensive, target SBP <120 mm Hg (n=4,678)
    • Standard, target SBP 135-139 mm Hg (n=4,683)
  • Setting: 102 sites in the US and Puerto Rico
  • Enrollment: 2010-2013
  • Median follow-up: 3.26 years (stopped prematurely; goal 5 years)
  • Analysis: Intention-to-treat
  • Primary outcome: First occurrence of MI, ACS, stroke, HF, or CV mortality

Population

Inclusion Criteria

  • Age ≥50 years
  • SBP (mmHg) in a range:
    • 130-180 on ≤1 medication
    • 130-170 on ≤2 medications
    • 130-160 on ≤3 medications
    • 130-150 on ≤4 medications
  • ≥1 of the following CVD risk criteria:
    • Clinical CVD (non-stroke):
      • Prior MI, PCI, CABG, CEA, or carotid stenting
      • Revascularized PAD
      • ACS ± EKG changes, EKG changes on a stress test, or ischemic findings on other cardiac imaging
      • ≥50% stenosis of coronary, carotid, or LE artery, or
      • AAA ≥5 cm
    • Subclinical CVD:
      • Carotid artery calcium score ≥400 in prior 2 years
      • ABI ≤0.90 in prior 2 years, or
      • LVH on EKG, echocardiogram, or other imaging in prior 2 years
    • CKD: eGFR 20-59 mL/min/1.73 m2 on MDRD in prior 6 months
    • Framingham estimated 10-year CVD risk ≥15% in prior 12 months
    • Age ≥75 years

Exclusion Criteria

  • DM
  • Stroke
  • Not on disease-appropriate antihypertensives (eg, beta blocker and recent MI)
  • Secondary cause of hypertension
  • If able to stand, 1 min standing SBP <110
  • Proteinuria in any of the following ranges:
    • ≥1g/day urine protein
    • ≥600 mg/day urine albumin
    • Spot protein:creatinine ≥1g protein/g creatinine
    • Spot albumin:creatinine ≥600 mg/g creatinine
    • Urine dipstick ≥2+ protein if none of the above are available
  • Polycystic kidney disease
  • Glomerulonephritis
  • eGFR < 20 mL/min/1.73 m2
  • CV event, procedure, or UA hospitalization in prior 3 months
  • Symptomatic HF in prior 6 mo
  • LVEF <35%
  • Life-limiting illness
  • Poor adherence
  • Organ transplant
  • Unintentional weight loss >10% in prior 6 months
  • Pregnancy

Baseline Characteristics

From the intensive group

  • Demographics: Age 68 years, female 36%
    • Race/ethnicity: Black 31%, non-Hispanic black 29%, Hispanic 11%, Non-Hispanic white 58%, other 2%
  • Criterion for increased CV risk:
    • CVD: 20%
      • Clinical: 17%
      • Subclinical CV disease: 5%
    • CKD: 28%
    • Framingham 10-year risk >15%: 61% (avg risk 20%)
    • Age ≥75 years: 28%
  • Body measurements: BP 140/78 mmHg, BMI 30 kg/m2
    • SBP: ≤132 mmHg 34%, 132-145 mmHg 32%, ≥145 mmHg 34%
  • Laboratory: Serum creatinine 1.07 mg/dl (eGFR 72 mL/min/1.73 m2), urine albumin:creatinine 44 mg/g, Tchol 190 mg/dL, HDL 53 mg/dL, TG 125 mg/dL, fasting glucose 99 mg/dL
  • Medications: Statin 43%, ASA 52%, antihypertensives 1.8/patient (none 9%)
  • Smoking status: Never 44%, former 42%, current 14%

Interventions

  • Patients randomized in an open label fashion to a group:
    • Intensive - Target SBP <120 mm Hg
    • Standard - Target SBP 135-139 mm Hg
  • Antihypertensives were encouraged per standard practice:
    • Thiazide diuretics (primarily chlorthalidone) were encouraged as first-line agents
    • Loop diuretics were encouraged for those with CKD
    • Beta-blockers were encouraged for those with CAD
  • Lifestyle modifications were encouraged
  • Study medications were provided free of cost to participants

Outcomes

Comparisons are intensive vs. standard therapy groups.

Primary Outcome

First ACS, stroke, HF, or CV death
5.2% vs. 6.8% (HR 0.75; 95% CI 0.64-0.89; P<0.001; NNT 63)

Secondary Outcomes

MI
2.1% vs. 2.5% (HR 0.83; 95% CI 0.64-1.09; P=0.19)
ACS without MI
0.9% vs. 0.9% (HR 1.00; 95% CI 0.64-1.55; P=0.99)
Stroke
1.3% vs. 1.5% (HR 0.89; 95% CI 0.62-1.25; P=0.50)
HF
1.3% vs. 2.1% (HR 0.62; 95% CI 0.45-0.84; P=0.002; NNT 125)
CV mortality
0.8% vs. 1.4% (HR 0.57; 95% CI 0.38-0.85; P=0.005; NNT 167)
All-cause mortality
3.3% vs. 4.5% (HR 0.73; 95% CI 0.60-0.90; P=0.003; NNT 83)
Composite of primary outcome or all-cause mortality
7.1% vs. 9.0% (HR 0.78; 95% CI 0.67-0.90; P<0.001; NNT 53)
Of those with CKD at baseline
≥50% reduction in GFR, long-term HD, or renal transplant: 1.1% vs. 1.1% (HR 0.89; 95% CI 0.42-1.87; P=0.76)
≥50% reduction in GFR: 0.8% vs. 0.8% (HR 0.87; 95% CI 0.36-2.07; P=0.75)
Long-term HD: 0.5% vs. 0.8% (HR 0.57; 95% CI 0.19-2.54; P=0.27)
Renal transplant: none
New albuminuria: 9.3% vs. 11.8% (HR 0.72; 95% CI 0.48-1.07; P=0.11)
Above defined as doubling of albumin:creatinine ratio from <10 to >10 mg albumin/g creatinine.
Of those without CKD at baseline
≥30% reduction in GFR to <60 mL/min/1.73 m2: 3.8% vs. 1.1% (HR 3.49; 95% CI 2.44-5.10; P<0.001; NNH 37)
New albuminuria: 6.2% vs. 7.4% (HR 0.81; 95% CI 0.63-1.04; P=0.10)

Additional Outcomes

BP at year 1
SBP: 121.4 vs. 136.2 mmHg
DBP: 68.7 vs. 76.3 mmHg
Number of antihypertensives
2.8 vs. 1.8
None: 2.7% vs. 11.3%
1: 10.5% vs. 31.1%
2: 30.5% vs. 33.3%
3: 31.8% vs. 17.2%
≥4: 24.3% vs. 6.9%
Breakdown of medication utilization is presented on page 30 of the supplementary appendix.[8]

Subgroup Analysis

There was no significant interaction for the primary outcome by CKD at baseline, age, sex, race, prior CVD, or SBP.

Adverse Events

Serious adverse event (SAE)
38.3% vs. 37.1% (HR 1.04; P=0.25)
Hypotension: 2.4% vs. 1.4% (HR 1.67; P=0.001; NNH 100)
Syncope: 2.3% vs. 1.7% (HR 1.33; P=0.05; NNH 167)
Bradycardia: 1.9% vs. 1.6% (HR 1.19; P=0.28)
Electrolyte abnormality: 3.1% vs. 2.3% (HR 1.35; P=0.02; NNH 125)
Fall with injury: 2.2% vs. 2.3% (HR 0.95; P=0.71)
AKI/ARF: 4.1% vs. 2.5% (HR 1.66; P<0.001; NNH 63)
SAE possibly or definitely associated with the intervention 4.7% vs. 2.5% (HR 1.88; P<0.001; NNH 45)
Above is from page 33 of supplemental appendix.[8]
SAE or ED visit
Hypotension: 3.4% vs. 2.0% (HR 1.70; P<0.001; NNH 71)
Syncope: 3.5% vs. 2.4% (HR 1.44; P=0.003; NNH 91)
Bradycardia: 2.2% vs. 1.8% (HR 1.25; P=0.13)
Electrolyte abnormality: 3.8% vs. 2.8% (HR 1.38; P=0.006; NNH 100)
Fall with injury: 7.1% vs. 7.1% (HR 1.00; P=0.97)
AKI/ARF: 4.4% vs. 2.6% (HR 1.71; P<0.001; NNH 56)
Laboratory abnormality
Na <130 mmol/L: 3.8% vs. 2.1% (HR 1.76; P<0.001; NNH 59)
Na >150 mmol/L: 0.1% vs. 0% (HR not given; P=0.02; NNH 1,000)
K <3 mmol/L: 2.4% vs. 1.6% (HR 1.50; P=0.006; NNH 125)
K >5.5 mmol/L: 3.8% vs. 3.7% (HR 1.00; P=0.97)
Orthostatic hypotension
16.6% vs. 18.3% (HR 0.88; P=0.01; NNT 59)
With dizziness: 1.3% vs. 1.5% (HR 0.85; P=0.35)

Criticisms

  • Early cessation of trials is associated with introduction of bias, including overestimation of effect sizes[9]
  • No enrollment of those in nursing homes or assisted living facilities
  • Low rate of ASA and statin use[10]
  • Cognitive outcomes not presented here

Funding

  • NIH (NHLBI, NIDDKD, NINDS, NIA)

Further Reading

  1. Hsia J, et al. "Prehypertension and cardiovascular disease risk in the Women's Health Initiative." Circulation. 2007;115(7):855-860.
  2. Stamler J, et al. "Blood pressure, systolic and diastolic, and cardiovascular risks. US population data." Archives of Internal Medicine. 1993;153(5):598-615.
  3. Law MR, et al. "Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies." BMJ. 2009;338;b1665.
  4. SPS3 Study Group. "Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial." The Lancet. 2013;382(9891):507-515
  5. Roman GC. "Brain hypoperfusion: a critical factor in vascular dementia." Neurological Research.. 2004;26(5):454-458.
  6. Ympa YP, et al. "Has mortality from acute renal failure decreased? A systematic review of the literature." American Journal of Medicine. 2005;118(8):827-832.
  7. Hajjar ER, et al. "Polypharmacy in elderly patients." American Journal of Geriatric pharmacotherapy. 2007;5(4):345-351.
  8. 8.0 8.1 Supplemental Appendix
  9. Bassler D, et al. "Stopping randomized trials early for benefit and estimation of treatment effects: Systematic review and meta-regression analysis." JAMA. 2010;303(12):1180-1187.
  10. Perkovic V and Rodgers A. "Editorial: Redefining blood-pressure targets -- SPRINT starts the marathon." The New England Journal of Medicine. epub 2015-11-09.