SPRINT - Targeting a systolic BP <120 vs <140

in

The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. NEJM 2015;373:2103-16.

Bottom line:

  • In patients with initial SBP 130-180 mm Hg, targeting SBP <120 vs 135-139 mm Hg reduces the risk of death (NNT 84), CV events (NNT 63; primarily from fewer CV deaths & new cases of HF) over 3.3 years.

  • Targeting this lower target results in prescribing of 1 additional BP med & an increase in a number of adverse events related to BP meds, including syncope (NNH 91), AKI (NNH 56) & electrolyte abnormalities (NNH 100) versus the "standard" target.

 

Patients (n=9361)

  • Included
    • Age >50 y
    • SBP 130-180 mm Hg (upper limit lower with higher # of BP meds pre-enrolment)
    • High CV risk, defined as 1 or more of:
      • Age 75+ y
      • Clinical CVD other than stroke (prior ACS, PCI, CABG, carotid endarterectomy, carotid stenting, PAD with revascularization, stenosis >50% of coronary, carotid or lower-extremity artery, AAA 5+ cm with or without repair)
      • Subclinical CVD (CAC >400 units, ABI <0.9, LVH) in past 2 years
      • Framingham risk score 15% or more over 10 y
      • CKD (stable eGFR 20-59 in past 6 months)
  • Key exclusion
    • Prior stroke
    • Diabetes
    • Symptomatic HF with EF <35%
    • CV event or procedure, or hospitalization for unstable angina within 3 months
    • SBP <110 mm Hg after 1 min of standing 
    • Indication for specific BP med that pt is not taking
    • Renal
      • ESRD or eGFR <20
      • Proteinuria defined as: 24h urinary protein excretion >1 g, 24h urinary albumin excretion 600+ mg, spot urine PCR 1+ g/g, spot urine ACR 600+ mg/g, urine dipstick 2+ protein
      • PCKD
      • Glomerulonephritis
    • Any organ transplant
  • Typical study patient
    • Age 67.9 y (75+ 28%)
    • Female 36%
    • CV risk criterion met
      • Clinical CVD 17%
      • Subclinical CVD 5%
      • FRS 15%+ 61%
      • Race: Black 30%, Hispanic 10%, white 58%, other 2%
      • BP 140/78 mm Hg
      • eGFR 72
      • Mean FRS 20%
      • Meds
        • Mean # of BP meds 1.8
        • ASA 51%
        • Statin 44%

Interventions

  • BP med adjustments based on automated office BP (AOBP) using Omron device based on average of 3 measurements while sitting after 5 min of quiet rest
  • I: Intensive therapy (target SBP <120 mm Hg, with secondary target of DBP <90 mm Hg)
    • At randomization, started on combo of 2-3 BP meds including a thiazide, ACEI or ARB, & CCB (or other agents for compelling indication, e.g. beta-blocker post-MI)
    • Mean AOBP SBP during follow-up: 121.5 mm Hg
    • Mean # of BP meds during follow-up: 2.8
  • C: Standard therapy (target SBP 135-139 mm Hg, with secondary target of DBP <90 mm Hg)
    • At randomization, converted to SPRINT formulary
    • If SBP <130 x1 visit or <135 x2 visits, BP meds changed to increase SBP back into 135-140 range
    • Mean AOBP SBP during follow-up: 134.6 mm Hg
    • Mean # of BP meds during follow-up: 1.8
  • Agents used in each class as part of SPRINT formulary: Thiazide (chlorthalidone 12.5-25 mg), ACEI (lisinopril 5-40 mg), ARB (azilsartan 40-80 mg, losartan 25-100 mg), beta-blocker (atenolol 25-100 mg, metoprolol tartrate 50-100 mg), CCB (amlodipine 2.5-10 mg, diltiazem 120-540 mg), other classes
  • The control group required a very tight SBP range (135-139 mm Hg), which may have resulted in frequent medication adjustments & resulting visits to maintain this target (these data have not yet been reported)

Results @ median follow-up 3.3 years

  • BP meds used at last visit (full list included in study's supplemental appendix)
    • Thiazide 55% vs 33%
    • ACEI or ARB 77% vs 55%
    • Beta-blocker 41% vs 31%
    • CCB 57% vs 35%
  • Mean AOBP SBP difference at year 1: ~15 mm Hg
  • Death: 3.3% vs 4.5% (NNT 84), hazard ratio (HR) 0.73 (95% confidence interval 0.60-0.90)
  • Serious adverse event: 38.3% vs 37.1%, p=0.25
  • Primary outcome (composite of CV death, ACS, stroke, acute decompensated HF): 5.2% vs 6.8% (NNT 63), HR 0.75 (0.64-0.89)
    • CV death: 0.8% vs 1.4%, HR 0.57 (0.38-0.85)
    • HF: 1.3% vs 2.1%, HR 0.62 (0.45-0.84)
    • MI: 2.1% vs 2.5%, HR 0.83 (0.64-1.09)
    • Stroke: 1.3% vs 1.5%, HR 0.89 (0.63-1.25)
  • Renal event
    • Prior CKD (eGFR decreased >50%, development of ESRD requiring long-term dialysis or kidney transplant): 1.1% in both groups
    • No prior CKD (eGFR decreased >30% to <60 mL/min/1.73 m2): 3.8% vs 1.1% (NNH 37), HR 3.49 (2.44-5.10)
    • Subgroup analyses demonstrated no significant subgroup differences
  • Events leading to ED visit, hospitalization, death, or resulting in persistent disability:
    • Injurious fall: 7.1% in both groups
    • Syncope: 3.5% vs 2.4% (NNH 91)
    • Hypotension: 3.4% vs 2.0% (NNH 72)
    • Bradycardia: 2.2% vs 1.8%
    • Electrolyte abnormality 3.8% vs 2.8% (NNH 100)
    • AKI: 4.4% vs 2.6% (NNH 56)
  • Orthostatic hypotension with dizziness: 1.3% vs 1.5% (asymptomatic: 16.6% vs 18.3%)

Generalizability

  • Population caveats
    • Specifically excluded patients with diabetes & stroke due to ongoing BP-target trials at time of SPRINT design (ACCORD-BP for diabetes & SPS3 for lacunar stroke)
      • Therefore, results of SPRINT not directly applicable to patients with diabetes or stroke, but must consider SPRINT in interpretation of both ACCORD-BP & SPS3
    • Excluded patients with symptomatic HFrEF; these patients should be treated to achieve maximally-tolerated doses of HFrEF-modifying drugs as previously reviewed
    • >75% of SPRINT patients had no CVD at baseline (primary prevention), so the absolute risk reduction reported in SPRINT mainly applies to this "lower risk" population, & absolute benefits are likely greater for patients at higher baseline CV risk
  • Intervention caveats
    • The SPRINT treatment protocols encouraged use of interventions with greatest evidence base, i.e. thiazides recommended as 1st-line, & chlorthalidone (not hydrochlorothiazide) included on formulary
      • Absolute benefit of intensive BP control may therefore vary based on agents used in practice. Clinicians should strive to use these proven agents

Internal validity

  • Low risk of allocation, attrition, & selective outcome reporting biases
    • Random sequence generation & allocation concealment
    • Loss-to-follow-up minimal (~3%), analyzed by intention-to-treat
    • Reported (or in process of gathering & publishing) all clinically-important outcomes of interest
  • Unclear risk of performance & detection bias
    • Outcome adjudicator blinded, but patients and clinicians aware of allocated treatment group. Overall, likely low-risk due to protocolized intervention for each group & clearly-defined outcome definitions with objective criteria
  • Early truncation unlikely to introduce significant bias due to large number of primary outcome events (>500) & valid, pre-defined stopping rules

Additional publications of SPRINT

  • Clinicians are reasonably cautious with BP lowering in very elderly patients, particularly in those who are frail. The SPRINT investigators explored the efficacy and safety of intensive SBP lowering in the 28% of patients in SPRINT 75+ years old at baseline
    • In these 2636 patients with a mean age of 80 y, results were largely consistent with those seen in the overall SPRINT population, with greater absolute benefits due to age-related increases in baseline risk:
      • Efficacy: Reduced primary outcome (NNT 27), death (NNT 41), and HF
      • Safety: No increase in serious adverse events (HR 0.99, 0.89-1.11), injurious falls; non-statistically significant increases in syncope (NNH 167), symptomatic orthostatic hypotension (NNH 167), electrolyte abnormalities and AKI
    • Among those aged 75+ years, efficacy outcomes did not differ based on frailty status or gait speed 
    • A further analysis of patients 75+ years old in SPRINT found that intensive versus standard BP lowering had no impact on gait speed or progression to mobility limitation
      • In other words, intensive BP lowering in SPRINT did not inadvertently result in an increase in frailty or disability due to hypotension-related falls, fractures, gait instability or lightheadedness

Other studies

  • ACCORD BP (low target SBP in diabetes):
    • Open-label RCT of 4733 type 2 diabetics with baseline SBP 130-180 mm Hg, A1c 7.5% or more & high CV risk (40+ y with CVD or 55+ y with atherosclerosis, albuminuria, LVH, or 2+ other CV risk factors) randomized to target SBP <120 or <140 mm Hg
    • Mean achieved SBP 119 vs 133 mm Hg (mean difference 14 mm Hg) using a mean of 3.4 & 2.1 BP meds, respectively
    • At mean 5 y, no statistically significant difference in death (HR 1.07, 0.85-1.35) or primary outcome (CV death, MI, stroke; HR 0.88, 0.73-1.06), but statistically significant reduction in stroke (NNT 91; HR 0.59, 0.39-0.89)
    • Subgroup analysis by assignment to intensive vs standard glycemic control (stratified at baseline) suggested that target SBP <120 mm Hg beneficial on primary outcome in patients assigned to standard glycemic control (p=0.08 for interaction)
    • Bottom line of ACCORD BP: Does not rule out clinically important benefit of lower SBP target (especially considering interaction with harmful intensive glycemic control of ACCORD)
  • SPS3 (low target SBP post-stroke):
    • Open-label RCT of 3020 patients with symptomatic lacunar stroke within past 6 months randomized to target SBP <130 or 130-149 mm Hg
    • Mean achieved SBP 127 vs 138 mm Hg (mean difference 11 mm Hg) using mean 2.4 vs 1.8 BP meds, respectively
    • At mean 3.7 y, no statistically significant difference in stroke (HR 0.81, 0.64-1.03), MI/vascular death (HR 0.84, 0.68-1.04) or serious adverse events (HR 1.53, 0.80-2.93)
    • Bottom line of SPS3: Does not rule out clinically important benefit of lower SBP target
  • Conflicting results between low vs standard BP target in other studies of overall HTN population
    • HOT (low target diastolic BP in overall HTN population):
      • Open-label RCT of 18,790 patients with baseline diastolic BP 100-115 mm Hg (baseline BP 170/105 mm Hg) randomized to target DBP <80, <85, or <90
      • Mean achieved SBP 140 vs 141 vs 144 mm Hg (mean SBP difference 4 mm Hg between DBP <80 and <90 groups)
        • Standard BP med step-wise process: Step 1 (felodipine), step 2 (ACEI or beta-blocker), step 3 (increase felodipine), step 4 (increase ACEI/BB), step 5 (add diuretic)
      • At mean 3.8 years, no difference between groups in primary outcome or individual CV outcomes in overall population
      • Investigators performed subgroup analysis in patients with diabetes (without appropriately performing a test for interaction to assess for a subgroup effect of diabetes vs no diabetes)
        • Identified a lower risk of the primary outcome & CV mortality, but not MI or stroke, with a target DBP <80 vs <90 in diabetes
      • Bottom line of HOT: No reduction in CV events with a lower target DBP using the aforementioned 5-step regimen; HOT diabetic subgroup effect is questionable at best
    • Cardio-Sis (target SBP <130 in HTN with 1 other CV risk factor)
      • Open-label RCT of 1111 patients with baseline SBP >150 randomized to target SBP <130 vs 140 mm Hg 
      • Mean achieved SBP 132 vs 136 mm Hg (mean SBP difference 4 mm Hg)
      • At 2 years, reduction in patients with new-onset LVH (primary outcome), as well as a broad CV composite outcome (death, MI, angina, coronary revascularization, stroke/TIA, AF, HF admission; NNT 22, RRR 50%)