Comment

1162 www.thelancet.com/neurology Vol 13 December 2014

Blood pressure control after stroke: too little, too late, or too soon to tell?

Cognitive decline is among the most feared and common changes in late life, and prevention of cognitive decline in any population is a worthy goal. In The Lancet Neurology, Lesly Pearce and colleagues1 report results of a prespecifi ed secondary outcome analysis of cognitive function from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, which compared aspirin plus clopidogrel with aspirin plus placebo, and high goal (130–149 mm Hg) with low goal (<130 mm Hg) blood pressure targets, in a factorial design. The primary results2,3 from this well designed trial showed no benefi t of dual antiplatelet treatment on the primary endpoint (prevention of recurrent stroke) and an unexpected increase in mortality associated with use of dual antiplatelet treatment. A non-signifi cant fi nding (p=0·08) suggested that the lower blood pressure target might be associated with a reduction in recurrent stroke.

In this secondary analysis,1 the investigators report that neither dual antiplatelet treatment nor the lower blood pressure target were associated with a diff erence in the secondary endpoint of change in cognitive function during up to 5 years of follow-up (median 3 years, IQR 1·0–4·9), as assessed by the Cognitive Abilities Screening Instrument (p=0·858 and p=0·520, respectively). This result is perhaps unsurprising, since there was no signifi cant reduction in recurrent stroke, based on the assumption that the main mechanism by which lower blood pressure might prevent cognitive decline is by prevention of subsequent stroke.

However, these negative results should not lead to the conclusion that blood pressure does not aff ect cognition. Indeed, recent evidence suggests that such a conclusion would be wrong. Results from the Atherosclerosis Risk in Communities (ARIC) study,4 for example, show that midlife hypertension is associated with later cognitive decline. Several other studies have also shown an association between history of hypertension and risk of dementia or cognitive decline,5 but the ARIC study4 showed more specifi cally that the association with cognitive decline in late life was stronger with hypertension documented at midlife (<55 years) than with hypertension documented at older ages (>70 years). Although studies of blood pressure treatment have generally not shown a reduction in incidence of dementia or an improvement in cognitive outcomes,6 one possible explanation for these negative results is that the eff ects of treatment might not be realised for a decade or more.4 Alternatively, treatment might need to be started before substantial damage to the cerebral vessels has occurred for a signifi cant eff ect to be seen. When treatment is started too late, after substantial cerebrovascular stenosis, lowering blood pressure might even have a negative eff ect.

In one double-blind, placebo-controlled trial7 of blood pressure reduction in individuals older than 80 years, there was a signifi cant U-shaped association between achieved diastolic blood pressure and incident dementia, with high incidences of dementia at the lowest and highest achieved blood pressures in the treatment group. The investigators noted no diff erence in incidence of dementia between the placebo and treatment groups, but an increased risk of dementia was associated with wider achieved pulse pressure in both groups. Likewise, in a large longitudinal study of healthy individuals,8 cross-sectional results across several assessments over time revealed moderated U-shaped and J-shaped associations between blood pressure and results of several cognitive tests.

The reported associations between cognitive decline and both low and high blood pressures have been noted in individuals without stroke, and it seems plausible that similar associations might be apparent after acute stroke. A meta-analysis9 of 37 acute stroke trials identifi ed a

Published OnlineOctober 24, 2014

http://dx.doi.org/10.1016/S1474-4422(14)70180-2

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Comment

www.thelancet.com/neurology Vol 13 December 2014 1163

Acute stroke often causes immobility, which predisposes to deep vein thrombosis and pulmonary embolism and these can be fatal or disabling. Low-dose subcutaneous anticoagulation with heparins and heparinoids reduces the risk of venous thromboembolism, but the benefi t is off set by haemorrhagic complications.1 Even targeting anticoagulation to patients at high risk of venous thromboembolism and low risk of bleeding does not add value because patients at high risk of venous thromboembolism (eg, increased severity of stroke) are

also at high risk of bleeding.2,3 Application of graduated compression stockings to the legs is a physical method for the prevention of deep vein thrombosis in patients undergoing surgery, but it was ineff ective in immobile patients with acute stroke in the CLOTS (Clots in Legs Or sTockings after Stroke) trials 1 and 2.4,5

Intermittent pneumatic compression (IPC) is another physical method for the prevention of deep vein thrombosis in patients undergoing surgery. In 2013, according to the results of the CLOTS 3 trial, IPC, through

U-shaped or J-shaped association between outcome of acute stroke (defi ned as death or dependency) and on-treatment blood pressure change—ie, large decreases or increases in blood pressure were associated with worse outcomes of acute stroke, although cognitive outcomes were not assessed.9 In fact, in rare cases or very small trials of acute stroke caused by large vessel stenosis, in which acute cognitive defi cits are due to regional hypoperfusion beyond the infarct, temporary blood pressure elevation (with fl uids or pressors) has resulted in improvement in cognitive function.10–12 Such cases of large vessel stenosis might represent the low end of the J-shaped association—ie, patients who have a poor outcome with a reduction in blood pressure after acute stroke.

The absence of an identifi ed link between blood pressure and cognition in the SPS3 trial has several possible explanations. The intervention might not have aff ected cognition because there was no signifi cant reduction in subsequent stroke. Alternatively, the intervention might have been started too late—it might be necessary to treat blood pressure before clinically signifi cant small vessel disease (before stroke) to prevent cognitive decline. Or, it might be too soon (ie, the follow-up too short) for eff ects on cognition to be identifi ed. Neuroprotective eff ects of blood pressure lowering on cognitive function, especially in the context of small vessel disease, might only be realised many years from the start of the intervention. Finally, a J-shaped or U-shaped association between blood pressure change and cognition might be identifi ed by additional analyses, although such associations are more likely to be identifi ed after acute strokes caused by large vessel stenosis than after acute lacunar strokes (as investigated in SPS3). So,

despite the negative results of this study, investigators should continue to measure cognitive outcomes of stroke, and continue to investigate positive long-term eff ects of lowering blood pressure, preferably before, but also after lacunar stroke.

Argye E HillisDepartment of Neurology, Johns Hopkins Hospital, Baltimore, MD 21287, USAargye@jhmi.edu

I declare no competing interests.

1 Pearce LA, McClure LA, Anderson DC, et al, for the SPS3 Investigators. Eff ects 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; published online Oct 24. http://dx.doi.org/10.1016/S1474-4422(14)70224-8.

2 The SPS3 Study Group. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013; 382: 507–15.

3 The SPS3 Investigators. Eff ects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012; 367: 817–25.

4 Alonso A, Mosley TH Jr, Gottesman RF, Catellier D, Sharrett AR, Coresh J. Risk of dementia hospitalisation associated with cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities (ARIC) study. J Neurol Neurosurg Psychiatry 2009; 80: 1194–201.

5 Starr JM. Blood pressure and cognitive decline in the elderly. Curr Opin Nephrol Hypertens 1999; 8: 347–51.

6 McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst Rev 2009; 4: CD004034.

7 Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358: 1887–98.

8 Waldstein SR, Giggey PP, Thayer JF, Zonderman AB. Nonlinear relations of blood pressure to cognitive function: the Baltimore Longitudinal Study of Aging. Hypertension 2005; 45: 374–79.

9 Geeganage CM, Bath PM. Relationship between therapeutic changes in blood pressure and outcomes in acute stroke: a metaregression. Hypertension 2009; 54: 775–81.

10 Olsen TS, Bruhn P, Oberg RG. Cortical hypoperfusion as a possible cause of ‘subcortical aphasia’. Brain 1986; 109: 393–410.

11 Hillis AE, Ulatowski JA, Barker PB, et al. A pilot randomized trial of induced blood pressure elevation: eff ects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003; 16: 236–46.

12 Hillis AE, Kane A, Tuffi ash E, et al. Reperfusion of specifi c brain regions by raising blood pressure restores selective language functions in subacute stroke. Brain Lang 2001; 79: 495–510.

Published OnlineOctober 31, 2014http://dx.doi.org/10.1016/S1474-4422(14)70263-7

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Intermittent pneumatic compression after stroke