SPS3-BP

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SPS3 Study Group. "Blood-pressure targets in patients with recent lacunar stroke". The Lancet. 2013. 382(9891):507-515.
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Clinical Question

In patients with a recent lacunar stroke, does lower-target BP control (target SBP <130 mm Hg) reduce incident stroke when compared to higher-target BP control (target SBP 140-150 mmHg)?

Bottom Line

Among patients with a recent lacunar stroke (here, small subcortical stroke or S3), lower-target BP control (target SBP <130 mm Hg) does not reduce incident stroke when compared to higher-target BP control (target SBP 140-150 mmHg). However, there was a non-significant trend towards benefit (P=0.08).

Major Points

Lacunar strokes are infarcts <20 mm in diameter located in territories classically supplied by cerebral small vessels (40–200 μm in diameter) such as the centrum semiovale, corona radiata, internal capsule, thalamus or ventral pons.[1] Hypertension is a well-recognized risk factor for the development of both ischemic and hemorrhagic strokes and is one of the only modifiable risk factors of cerebral small vessel disease,[2] a process associated with lacunar strokes, deep intra-cerebral hemorrhages, and vascular dementia. Because of the close association of cerebral small vessel disease with hypertension, there is particular interest in determining whether stricter BP control after lacunar strokes would prevent subsequent strokes.

It has long been suspected that patients classified as having pre-hypertension may also benefit from blood pressure lowering therapies. For example, a post-hoc subgroup analysis from the PROGRESS trial breaking down risk reduction by baseline SBP (≥160, 140–159, 120–139, or <120 mmHg) found benefits in lowering blood pressure in patients with SBP in the pre-hypertensive range (RRRs 39%, 31%, 14%, and 0% for each group listed above respectively).[3]

Published in 2013, the Secondary Prevention of Small Subcortical Strokes (SPS3) blood pressure arm randomized 3,020 individuals with recent small subcortical strokes (S3s) or subcortical TIAs with MRI evidence to higher-target (SBP 130-150 mmHg; mean achieved at 1 year=138 mmHg) or lower-target (SBP <130 mmHg; mean achieved at 1 year=127 mmHg) BP control. With 3.7 years of follow-up, there was no difference in the primary outcome of incident stroke, though there was a non-significant trend towards benefit with lower BP targets (2.77% vs. 2.25%; P=0.08). The lower BP target was generally well-tolerated.

The evidence of benefit was compelling enough to trigger a revision of the AHA/ASA Stroke prevention guidelines to urge clinicians to consider targeting a SBP <130mmHg for patients who have had a recent lacunar stroke. This is a controversial recommendation as there is conflicting evidence from the PRoFESS trial[4] suggesting that SBP <120 mmHg is associated with increased risk of recurrent strokes in patients who recently had a non-cardioembolic stroke. There are several meta-analyses prior to SPS3 offering mixed conclusion, with one concluding stricter BP control (SBP<130 vs. SBP 130-140) offered no stroke risk reduction in patients with established cardiovascular disease[5] while two others concluding blood pressure reduction down to 115/75 continued to offer benefit for stroke risk reduction. [6][7]

Guidelines

AHA/ASA Stroke prevention if stroke/TIA (2014, adapted)[8]

  • Start BP therapy in previously untreated patients with ischemic stroke or TIA if post-event BP ≥140/≥90 mmHg after several days (Class I; Level of Evidence B).
    • Initiation of therapy if BP <140/<90 mmHg is of uncertain benefit (Class IIb; Level of Evidence C).
  • Restart BP therapy in those with ischemic stroke or TIA previously treated for HTN (after the first several days) to reduce recurrent stroke and prevention of other vascular events (Class I; Level of Evidence A).
  • Target BP level or reduction from pretreatment baseline are unclear and should be individualized; it is reasonable to target <140/<90 mmHg (Class IIa; Level of Evidence B). If recent lacunar stroke, it might be reasonable to target an SBP of <130 mmHg (Class IIb; Level of Evidence B).
  • Lifestyle modifications to reduce BP are reasonable part of a comprehensive antihypertensive therapy, including salt restriction, weight loss, high intake of fruit, vegetables, and low-fat dairy products, regular aerobic activity, and limited EtOH consumption (Class IIa; Level of Evidence C).
  • The optimal drug regimen to achieve the recommended level of reductions is unclear but diuretics or diuretics+ACE-inhibitors is useful (Class I; Level of Evidence A).
    • The choice of specific drugs and targets should be individualized (Class IIa; Level of Evidence B).

Design

  • Multicenter, open label, 2x2 factorial, randomized controlled trial
  • N=3,020
    • Higher-target, SBP 130-150 mm Hg (n=1,519)
    • Lower-target, SBP <130 mm Hg (n=1,501)
Participants were also randomized to dual antiplatelet therapy or aspirin monotherapy, which is reported in a separate publication.[9]
  • Setting: 81 centers in North America, Latin America, and Spain
  • Enrollment: 2003-2011
  • Mean follow-up: 3.7 years
  • Analysis: Intention-to-treat
  • Primary outcome: Incident stroke

Population

Inclusion Criteria

Full details are presented elsewhere.[10]

  • Adults ≥30 years with hypertension or normotension
  • ≥1 lacunar stroke clinical syndromes lasting >24 hrs or subcortical TIA with corresponding lesion on DWI in prior 6 months but randomized ≥2 weeks after event
  • Absence of signs or symptoms of cortical dysfunction (eg, aphasia, apraxia, agnosia, agraphia, homonymous visual field defect)
  • No ipsilateral cervical carotid stenosis ≥50% if hemispheric
  • No major-risk cardioembolic sources requiring anticoagulation or other specific therapy. Minor-risk cardioembolic sources will be permitted if anticoagulation is not prescribed by the patient's primary care physician.
  • MRI evidence of small subcortical stroke (S3; ≤2.0 cm in diameter) corresponding to the qualifying event (required for all brainstem events) OR multiple S3s and absence of cortical stroke and large subcortical stroke (recent or remote)

Exclusion Criteria

  • Disabling stroke (Modified Rankin Scale ≥4)
  • Prior ICH (except traumatic) or hemorrhagic stroke
  • Age <30 years
  • High risk of bleeding (eg, recurrent GI or GU bleeding, active peptic ulcer disease, etc)
  • Anticipated requirement for long-term use of anticoagulants (eg, recurrent DVT) or other antiplatelets
  • Prior cortical or retinal stroke or TIA (diagnosed either clinically or by neuroimaging)
  • Prior ipsilateral carotid endarterectomy or stent
  • GFR <40
  • Intolerance or contraindications to aspirin or clopidogrel (eg, thrombocytopenia, prolonged INR)
  • An age and education adjusted Folstein MMSE score <24
  • Medical contraindication to MRI
  • Pregnancy or women of child-bearing potential not on contraception
  • Unable or unwilling to provide informed consent
  • Unlikely to be compliant with therapy/unwilling to return for frequent clinic visits
  • Patients concurrently participating in another investigational study
  • Other likely cause of stroke (eg, dissection, vasculitis, prothrombotic diathesis, drug abuse)

Baseline Characteristics

From the higher target group (n=1519)

  • Demographics: Age 63 years, male sex 65%
    • Race or ethnicity: White 50%, Black 17%, Hispanic 31%, other 3%
    • Region: North America 65%, Latin America 23%, Spain 12%
  • BP: 144/79 mmHg
  • BMI: 29 kg/m2
  • PMH: HTN 75%, DM 36%, ischemic heart disease 11%, stroke or TIA 14%
  • Current tobacco smoker: 20%
  • Qualifying event: Ischemic stroke 99%, TIA 1%
  • Number of antihypertensive medications at study entry: 1.7

Interventions

  • Patients were randomized to a group:
    • Higher-target group: SBP target 130-149 mmHg
    • Lower-target group: SBP target <130 mmHg
  • Clinicians directed the antihypertensive regimen

Outcomes

Comparisons are higher-target group vs. lower-target group groups.

Primary Outcome

Incident stroke
2.77% vs. 2.25% (HR 0.81; 95% CI 0.64–1.03; P=0.08)

Secondary Outcomes

Stroke subtype
Ischemic strokes or unknown: 2.4% vs. 2.0% (HR 0.84; 95% CI 0.66–1.09; P=0.19)
ICH: 0.38% vs. 0.23% (HR 0.61; 95% CI 0.31–1.22; P=0.16)
Intracerebral hemorrhages: 0.29% vs. 0.11% (HR 0.37; 95% CI 0.15–0.95; P=0.03)
SDH or epidural hemorrhage: 0.091% vs. 0.11% (HR 1.18; 95% CI 0.36–3.88; P=0.78)
Other ICH: 0.036% vs. 0.072% (HR 1.97; 95% CI 0.36–10.74; P=0.43)
Disabling or fatal: 0.89% vs. 0.72% (HR 0.81; 95% CI 0.53–1.23; P=0.32)
Disabling defined as mRS ≥3 after 3–6 months.
MI
0.70% vs. 0.62% (HR 0.88; 95% CI 0.56–1.39; P=0.59)
Major vascular event
3.46% vs. 2.91% (HR 0.84; 95% CI 0.68–1.04; P=0.10)
All-cause mortality
1.74% vs. 1.80% (HR 1.03; 95% CI 0.79–1.35; P=0.82)
Vascular mortality: 0.70% vs. 0.61% (HR 0.86; 0.55–1.35; P=0.52)
Non-vascular mortality: 0.60% vs. 0.68% (HR 1.12; 0.71–1.76; P=0.62)
Unknown cause of death: 0.43% vs. 0.51% (HR 1.18; 0.69–2.00; P=0.55)

Additional Outcomes

Average SBP at 1 year
138 mmHg (95% CI 137–139) vs. 127 mmHg (95% CI 126–128)
Within target BP range: 75% vs. 65%
Mean number of antihypertensives at 1 year
1.8 vs. 2.4 (P<0.0001)
Drug classes at 1 year
Thiazides: 43% vs. 58% (P<0.0001)
ACE inhibitor/ARB: 63% vs. 80% (P<0.0001)
Calcium-channel blockers: 30% vs. 43% (P<0.0001)
β blockers: 25% vs. 31% (P=0.0008)
Other: 9% vs. 11% (P=0.051)
Mean number of antihypertensive medication at final visit
1.8 vs. 2.4 (P<0.0001)
Drug classes at final visit
Thiazides: 38% vs. 54% (P<0.0001)
ACE inhibitor/ARB: 60% vs. 78% (P<0.0001)
Calcium-channel blockers: 39% vs. 43% (P<0.0001)
β blockers: 28% vs. 35% (P<0.0001)
Other: 11% vs. 14% (P=0.042)
Statins used during follow-up
84% vs. 85%

Subgroup Analysis

There was no significant interaction for the primary outcome by age (≥65 or <65), sex, history of diabetes, race, region of residence/recruitment center, or baseline SBP.

Adverse Events

Serious adverse event (SAE) related to hypotension
Any: 0.26% vs. 0.40% (HR 1.53; 95% CI 0.80–2.93; P=0.20)
Orthostatic syncope: 0.09% vs. 0.19% (HR 2.18; 95% CI 0.76–6.27; P=0.14)
Stroke associated with hypotension: 0.02% vs. 0.03% (HR 2.00; 95% CI 0.18–22.09; P=0.57)
Myocardial infarction associated with hypotension: 0 vs. 0
Fall with injury: 0% vs. 0.052%
Other: 0.19% vs. 0.15% (HR 0.82; 95% CI 0.34–1.97; P=0.65)
Side effects potentially related to BP management
Unsteadiness when standing: 24% vs. 26% (HR 1.09; 95% CI 0.92–1.29; P=0.31)
Blurred vision when standing: 7% vs. 6% (HR 0.82; 95% CI 0.61–1.11; P=0.19)
Dizziness when standing up: 21% vs. 22% (HR 1.10; 95% CI 0.92–1.31; P=0.30)
Light-headedness when standing: 16% vs. 15% (HR 0.94; 95% CI 0.77–1.15; P=0.54)
Palpitations when standing: 0.4% vs. 0.4% (HR 0.86; 95% CI 0.48–1.55; P=0.62)
Cognitive outcomes by Cognitive Abilities Screening Instrument Assessed Annually (reported separately)[11]
Changes in CASI z-scores over time did not differ between assigned blood pressure control groups, P=0.5

Criticisms

  • Possible underpowering given the lower-than-predicted observed stroke rate[12]
  • Not blinded
  • Although more aggressive BP targets were associated with a statistically significant reduction in intracerebral hemorrhage, the ARR was 0.18% which yield a NNT of 556 over 4 years which is of limited clinical relevance
  • There is some recent evidence suggesting over aggressive treatment of blood pressure may adversely impact cognitive outcomes in the elderly. Cognitive outcomes for the SPS3 trial was not reported with this paper but can be found separately.
  • Patient population in SPS3 is younger than many other stroke trials (mean age 63) and excluded patients with large vessel disease (>50% carotid stenosis) which limits the applicability of the conclusion of this trial to many patients typically seen for secondary stroke prevention [13]

Funding

National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS)

Further Reading

  1. Bailey EL et al. Pathology of lacunar ischemic stroke in humans--a systematic review. Brain Pathol. 2012. 22:583-91.
  2. Staals J et al. Stroke subtype, vascular risk factors, and total MRI brain small-vessel disease burden. Neurology 2014. 83:1228-34.
  3. Arima H et al. Lower target blood pressures are safe and effective for the prevention of recurrent stroke: the PROGRESS trial. J. Hypertens. 2006. 24:1201-8.
  4. Ovbiagele B et al. Level of systolic blood pressure within the normal range and risk of recurrent stroke. JAMA 2011. 306:2137-44.
  5. Lee M et al. Does achieving an intensive versus usual blood pressure level prevent stroke?. Ann. Neurol. 2012. 71:133-40.
  6. Lewington S et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002. 360:1903-13.
  7. 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.
  8. Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.
  9. Benavente OR et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N. Engl. J. Med. 2012. 367:817-25.
  10. Benavente OR et al. The Secondary Prevention of Small Subcortical Strokes (SPS3) study. Int J Stroke 2011. 6:164-75.
  11. Pearce LA et al. Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial. Lancet Neurol 2014. 13:1177-85.
  12. Hankey GJ & An optimum blood pressure target after lacunar stroke?. Lancet 2013. 382:482-4.
  13. Castilla-Guerra L & del Carmen Fernandez-Moreno M Lessons from the SPS3 trial. Lancet 2014. 383:512.