Secondary prevention after ischaemic stroke: the ASPIRE-S study

This study reveals suboptimal control of many risk factors post IS despite the availability
of evidence-based therapies and clear guidelines for secondary prevention. This cohort
was at high-risk for recurrent stroke, with prevalent baseline risk factors, two-thirds
over the age of 65 years, and one-quarter having previous stroke. These findings raise
concern for health professionals and should prompt more intensive management of risk
factors.

Studies have shown an association between TC, LDL and elevated TG with IS risk, especially
among atherosclerotic and lacunar stroke subtypes 21]. Although mean lipid levels recorded at 6 months were not excessively high, many
results were not at target. Only three-quarters of our cohort had TC at target (4.5 mmol/L)
with a similar proportion (77 %) having LDL at target (2.5 mmol/L). However, these
results compare favourably with those from EUROASPIRE III (49 and 55 % respectively
at target) 8] and with results from the stroke-specific module of EUROASPIRE III 10], likely due to the higher uptake of lipid-lowering medications in our group. Outside
the trial setting, there is currently no published data available on the adequacy
of control of lipid levels specific to IS. Although the optimal LDL level for secondary
stroke prevention is unclear, there is evidence from the SPARCL study that tight control
(1.8 mmol/L; achieved by only 44 % of our cohort) reduces recurrent IS risk by one
quarter 22] and European guidelines now advise this target for high-risk patients 15].

Diabetes is independently related to a greater risk of IS (adjusted risk ratio, 2.26)
23]. For diabetic patients in ASPIRE-S with suboptimal control (HbA1c???7, 28 %), it
is unknown (without access to patient notes at follow-up) whether the treating physician
opted for less strict control in light of poorly tolerated hypoglycaemic episodes
in some patients. Optimal target HbA1c levels in diabetic patients still remain the
subject of much debate, and in most cases is individualised to particular patient
characteristics 24]. Only 1.5 % of non-diabetic patients had FG ?7 mmol/L. Four percent of patients had
FG within the impaired fasting glucose range (?6.1 mmol/L), but this rose to almost
10 % when the latest American Diabetes Association definition (?5.6 mmol/L) was applied
16]. Diagnoses were not made on the basis of a single FG level in ASPIRE-S but it is
known that early dietary and lifestyle modifications can delay or prevent the development
of diabetes in patients with impaired FG 25].

The prevalence of obesity in the developed world has substantially increased over
time 26]. Results from the Physician’s Health Study reported a significant increase in the
relative risk of stroke with each unit increase of BMI, independent of the effects
of other stroke risk factors 27]. Over two-thirds of our cohort had a BMI of ?25 kg/m
²
with one quarter being classified as obese. These levels are higher than those reported
in the general Irish population (overweight 39 % and obese 18 %) 28] and likely contribute to other stroke/cardiovascular risk factors such as hypertension,
hyperlipidaemia and diabetes. Two-thirds of participants had abdominal obesity. These
results suggest that a more active role for sustained professional support and motivation
in achieving successful weight reduction post stroke is needed, including (repeated)
clear advice on weight loss from health professionals, which positively impacts on
weight loss behaviour 29]. Although multiple successful weight reduction interventions are available, the ability
of patients post stroke to engage in vigorous exercise programmes may be limited.
Studies to explore the effectiveness of interventions such as group education or dietary
changes for weight loss specifically after stroke are limited. The first randomized-controlled
trial to evaluate the efficacy and safety of a weight management intervention in stroke
survivors using the SystemCHANGEâ„¢ approach is currently underway 30].

The INTERSTROKE study reported a doubling in the risk for IS in current smokers (OR
2.09, 1.75–2.51) 3]. Although smoking rates are reportedly decreasing over time 2], 16 % were still smoking in our cohort at 6 months. This reflects a smoking cessation
rate of 41 % (compared with 81 % in the Irish subgroup of EUROASPIRE III and 40 %
in the stroke-specific module) 8], 10]. Although physician advice to stop smoking is the most important first step in the
cessation process, this advice must be reiterated and reinforced by all health professionals
31]. Multiple pharmacotherapies for tobacco dependence have been shown to increase smoking
cessation rates 32], and behavioural interventions can further increase the success of smoking cessation
33].

Although the mean BP reading was not excessively elevated, only 37 % of patients had
BP ?140/90 (similar to EUROASPIRE stroke module; 38 %). Such poor control of BP may
reflect a lack of focus on secondary preventive initiatives for patients after stroke.
The proportion at target was lower amongst patients with a previous diagnosis of hypertension
and amongst those on anti-hypertensive therapy, reflecting the difficulty in treating
hypertension in clinical practice. Recent European guidelines 5], 15] suggest a lower BP target of ?130/80 in patients after IS, where tolerated. Only
16 % of our cohort achieved this target at 6 months and this proportion dropped to
13 % amongst those on anti-hypertensive therapy. Although these results reflect a
single reading in patients, they are a reminder that better management of BP is required
after IS including greater up-titration of medication dosages and use of multiple
medication regimens in addition to lifestyle advice.

Ambulatory BP monitoring (reflecting multiple measurements) is known to provide a
more accurate measure of BP control 34]. This is one of the first studies to describe ambulatory BP control post acute stroke
and results clearly demonstrate greater overall BP control, compared with office readings.
Better control of daytime (versus nightime) readings may reflect the timing of administration
of antihypertensive medications (usually in the morning) which impacts on circadian
control 35]. It may also reflect lack of attention placed by physicians on nightime BP control.
Nightime BP control has been strongly linked to an increased risk of cardiovascular
disease in multiple studies, including the Dublin outcome study of 5292 participants
36], which reported a relative hazard ratio (for cardiovascular mortality) of 1.21 for
each 10-mm Hg increase in nightime systolic BP. This increased risk remained significant
in older patients 36], 37].

Most IS patients are prescribed a combination of cardiovascular medications and this
multi-factorial approach to secondary stroke prevention can result in a substantial
reduction (of up to 80 %) in future stroke risk 38]. Although prescription rates of anti-thrombotic and lipid-lowering medications in
our cohort were high, the prescription of anti-hypertensive medications appeared suboptimal.
Despite positive findings from the pivotal PROGRESS study 39], a minority of patients in ASPIRE-S were on dual ACE I and diuretic therapy. However,
a significant proportion of patients had hypertension (58 %), atrial fibrillation
(40 %) and/or heart disease (30 %) at baseline and were likely already established
on appropriate medications with anti-hypertensive effects (such as beta-blockers or
CCBs) prior to their stroke.

This study has many strengths including its prospective design, large sample size,
high rate of follow-up, in-hospital assessment of patients to verify eligibility for
inclusion and a standardised follow-up assessment at 6 months modelled on previous
robust EUROASPIRE surveys. There is little information in the stroke literature on
the adequacy of secondary prevention after IS and much of the findings from ASPIRE-S
are therefore novel. The recent EUROASPIRE III stroke-specific module (including four
countries) reported some comparable findings but was retrospective, excluded IS patients
over 80, had a broader follow-up period (6–36 months), used self-reported definitions
of vascular risk factors and unhealthy lifestyle habits, did not include ambulatory
BP monitoring and had limited generalizability.

Limitations

The majority of the findings from ASPIRE-S are novel within the Irish stroke setting
(and further afield), but there are some limitations to this study. Participants were
recruited over 12 months as a representative (not consecutive) sample of ischaemic
stroke patients in North Dublin. However, no attempt was made to be selective in any
way and this cohort compares favourably in many ways with that recruited in 2006 as
part of the North Dublin Population Stroke Study (NDPSS) 11]. Although the ASPIRE-S sample of three hospitals reflects the north Dublin population
well, results may not be representative of the population nationally. It may be that
the burden of cardiovascular risk factors is particularly high in north Dublin. Higher
prevalence of cardiovascular risk factors has previously been linked with social disadvantage
40], 41] and the north Dublin population includes several communities where social disadvantage
is common. Furthermore, although ASPIRE-S has a large overall sample size, the statistical
significance of some results may have been limited by small numbers within sub-cohorts.