Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials

Background

Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated.

Methods

Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6–12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline.

Findings

We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32–0·55, p<0·0001) and disabling or fatal ischaemic stroke by about 70% (36 of 8452 vs 110 of 7326; 0·29, 0·20–0·42, p<0·0001), with greatest benefit noted in patients presenting with TIA or minor stroke (at 0–2 weeks, two of 6691 participants in the aspirin group with TIA or minor stroke had a disabling or fatal ischaemic stroke vs 23 of 5726 in the control group, HR 0·07, 95% CI 0·02–0·31, p=0·0004; at 0–6 weeks, 14 vs 60 participants, 0·19, 0·11–0·34, p<0·0001). The effect of aspirin on early recurrent ischaemic stroke was due partly to a substantial reduction in severity (mRS shift analysis odds ratio [OR] 0·42, 0·26–0·70, p=0·0007). These effects were independent of dose, patient characteristics, or aetiology of TIA or stroke. Some further reduction in risk of ischaemic stroke accrued for aspirin only versus control from 6–12 weeks, but there was no benefit after 12 weeks (stroke risk OR 0·97, 0·84–1·12, p=0·67; severity mRS shift OR 1·00, 0·77–1·29, p=0·97). By contrast, dipyridamole plus aspirin versus aspirin alone had no effect on risk or severity of recurrent ischaemic stroke within 12 weeks (OR 0·90, 95% CI 0·65–1·25, p=0·53; mRS shift OR 0·90, 0·37–1·72, p=0·99), but dipyridamole did reduce risk thereafter (0·76, 0·63–0·92, p=0·005), particularly of disabling or fatal ischaemic stroke (0·64, 0·49–0·84, p=0·0010). We pooled data for 40 531 participants from three trials of aspirin versus control in major acute stroke. The reduction in risk of recurrent ischaemic stroke at 14 days was most evident in patients with less severe baseline deficits, and was substantial by the second day after starting treatment (2–3 day HR 0·37, 95% CI 0·25–0·57, p<0·0001).

Interpretation

Our findings confirm that medical treatment substantially reduces the risk of early recurrent stroke after TIA and minor stroke and identify aspirin as the key intervention. The considerable early benefit from aspirin warrants public education about self-administration after possible TIA. The previously unrecognised effect of aspirin on severity of early recurrent stroke, the diminishing benefit with longer-term use, and the contrasting time course of effects of dipyridamole have implications for understanding mechanisms of action.

Funding

Wellcome Trust, the National Institute of Health Research (NIHR) Biomedical Research Centre, Oxford.

Lancet Volume 388, No. 10042, p365–375, 23 July 2016

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Improving the transition from primary care for people with neurological conditions

A report from the Neurological Alliance finds that GPs in England lack confidence in the care for people with neurological conditions.

GPs expressed doubts about the ability of local services and systems to manage neurology patients effectively and concern over unnecessary delays. The report sets out eight recommendations aimed at improving the primary care pathway for people with neurological conditions, including a call for the development of a “watch list” of the ten signs and symptoms GPs should be aware of during patient interactions in primary care settings.

Read the full report here

Long-term evidence for the effect of pay-for-performance in primary care on mortality in the UK: a population study

Background

Introduced in 2004, the UK’s Quality and Outcomes Framework (QOF) is the world’s largest primary care pay-for-performance programme. We tested whether the QOF was associated with reduced population mortality.

Methods

We used population-level mortality statistics between 1994 and 2010 for the UK and other high-income countries that were not exposed to pay-for-performance. The primary outcome was age-adjusted and sex-adjusted mortality per 100 000 people for a composite outcome of chronic disorders that were targeted by the QOF. Secondary outcomes were age-adjusted and sex-adjusted mortality for ischaemic heart disease, cancer, and a composite of all non-targeted conditions. For each study outcome, we created a so-called synthetic UK as a weighted combination of comparison countries. We then estimated difference-in-differences models to test whether mortality fell more in the UK than in the synthetic UK after the QOF.

Findings

Introduction of the QOF was not significantly associated with changes in population mortality for the composite outcome (−3·68 per 100 000 population [95% CI −8·16 to 0·80]; p=0·107), ischaemic heart disease (−2·21 per 100 000 [–6·86 to 2·44]; p=0·357), cancer (0·28 per 100 000 [–0·99 to 1·55]; p=0·679), or all non-targeted conditions (11·60 per 100 000 [–3·91 to 27·11]; p=0·143).

Interpretation

Although we noted small mortality reductions for a composite outcome of targeted disorders, the QOF was not associated with significant changes in mortality. Our findings have implications for the probable effects of similar programmes on population health outcomes. The relation between incentives and mortality needs to be assessed in specific disease domains.

Funding

None.

Volume 388, No. 10041, p268–274, 16 July 2016

Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes A Meta-analysis

Importance  Numerous glucose-lowering drugs are used to treat type 2 diabetes.

Objective  To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin.

Data Sources  Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016.

Study Selection  Randomized clinical trials of 24 weeks’ or longer duration.

Data Extraction and Synthesis  Random-effects network meta-analysis.

Main Outcomes and Measures  The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A1c (HbA1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight.

Results  A total of 301 clinical trials (1 417 367 patient-months) were included; 177 trials (56 598 patients) of drugs given as monotherapy; 109 trials (53 030 patients) of drugs added to metformin (dual therapy); and 29 trials (10 598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, −22% [−27% to −18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, −10% [95% CI, −18% to −2%]).

Conclusions and Relevance  Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.

JAMA. 2016;316(3):313-324.

Risk of hypoglycaemia in users of sulphonylureas compared with metformin in relation to renal function and sulphonylurea metabolite group: population based cohort study

Objective To determine the association between use of sulphonylureas and risk of hypoglycaemia in relation to renal function and sulphonylurea metabolic group compared with use of metformin.

Design Population based cohort study using routinely collected data from general practices in England.

Setting Clinical Practice Research Datalink (CPRD) database, 2004-12.

Participants 120 803 new users of a non-insulin antidiabetic agent with at least one prescription and aged 18 years or more. The first prescription defined start of follow-up. Patients were followed until the end of data collection, a record for hypoglycaemia, or a blood glucose level of less than 3.0 mmol/L.

Main outcome measures Associations between sulphonylurea dose, renal impairment, type of sulphonylurea used, and risk of hypoglycaemia, were determined using Cox proportional hazard models. Adjustments were made for age, sex, lifestyle, comorbidity, and drug use.

Results The risk of hypoglycaemia in current users of sulphonylureas only was significantly increased compared with current users of metformin only (adjusted hazard ratio 2.50, 95% confidence interval 2.23 to 2.82). The higher risk in current users of sulphonylureas only was further increased in patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 (4.96, 3.76 to 6.55). The risk of hypoglycaemia was also significantly higher in patients with a high sulphonylurea dose (3.12, 2.68 to 3.62) and in current users of glibenclamide (7.48, 4.89 to 11.44). Gliclazide, the sulphonylurea of first choice, showed a similar risk of hypoglycaemia compared with other sulphonylureas.

Conclusions Sulphonylurea treatment in patients with a renal function of less than 30 mL/min/1.73 m2should be considered with caution. Moreover, an increased risk of hypoglycaemic events was observed among all users of sulphonylureas. This contrasts with several guidelines that recommend gliclazide as first choice sulphonylurea, and therefore requires further investigation.

BMJ 2016;354:i3625

Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care

Objective To assess associations between risks of cardiovascular disease, heart failure, and all cause mortality and different diabetes drugs in people with type 2 diabetes, particularly newer agents, including gliptins and thiazolidinediones (glitazones).

Design Open cohort study.

Setting 1243 general practices contributing data to the QResearch database in England.

Participants 469 688 people with type 2 diabetes aged 25-84 years between 1 April 2007 and 31 January 2015.

Exposures Diabetes drugs (glitazones, gliptins, metformin, sulphonylureas, insulin, other) alone and in combination.

Main outcome measure First recorded diagnoses of cardiovascular disease, heart failure, and all cause mortality recorded on the patients’ primary care, mortality, or hospital record. Cox proportional hazards models were used to estimate hazard ratios for diabetes treatments, adjusting for potential confounders.

Results During follow-up, 21 308 patients (4.5%) received prescriptions for glitazones and 32 533 (6.9%) received prescriptions for gliptins. Compared with non-use, gliptins were significantly associated with an 18% decreased risk of all cause mortality, a 14% decreased risk of heart failure, and no significant change in risk of cardiovascular disease; corresponding values for glitazones were significantly decreased risks of 23% for all cause mortality, 26% for heart failure, and 25% for cardiovascular disease. Compared with no current treatment, there were no significant associations between monotherapy with gliptins and risk of any complications. Dual treatment with gliptins and metformin was associated with a decreased risk of all three outcomes (reductions of 38% for heart failure, 33% for cardiovascular disease, and 48% for all cause mortality). Triple treatment with metformin, sulphonylureas, and gliptins was associated with a decreased risk of all three outcomes (reductions of 40% for heart failure, 30% for cardiovascular disease, and 51% for all cause mortality). Compared with no current treatment, monotherapy with glitazone was associated with a 50% decreased risk of heart failure, and dual treatment with glitazones and metformin was associated with a decreased risk of all three outcomes (reductions of 50% for heart failure, 54% for cardiovascular disease, and 45% for all cause mortality); dual treatment with glitazones and sulphonylureas was associated with risk reductions of 35% for heart failure and 25% for cardiovascular disease; triple treatment with metformin, sulphonylureas, and glitazones was associated with decreased risks of all three outcomes (reductions of 46% for heart failure, 41% for cardiovascular disease, and 56% for all cause mortality).

Conclusions There are clinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality between different diabetes drugs alone and in combination. Overall, use of gliptins or glitazones was associated with decreased risks of heart failure, cardiovascular disease, and all cause mortality compared with non-use of these drugs. These results, which do not account for levels of adherence or dosage information and which are subject to confounding by indication, might have implications for prescribing of diabetes drugs.

BMJ 2016;354:i3477

Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records

Objective To determine whether the incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre’s syndrome is higher in general practices that prescribe fewer antibiotics for self limiting respiratory tract infections (RTIs).

Design Cohort study.

Setting 610 UK general practices from the UK Clinical Practice Research Datalink.

Participants Registered patients with 45.5 million person years of follow-up from 2005 to 2014.

Exposures Standardised proportion of RTI consultations with antibiotics prescribed for each general practice, and rate of antibiotic prescriptions for RTIs per 1000 registered patients.

Main outcome measures Incidence of pneumonia, peritonsillar abscess, mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre’s syndrome, adjusting for age group, sex, region, deprivation fifth, RTI consultation rate, and general practice.

Results From 2005 to 2014 the proportion of RTI consultations with antibiotics prescribed decreased from 53.9% to 50.5% in men and from 54.5% to 51.5% in women. From 2005 to 2014, new episodes of meningitis, mastoiditis, and peritonsillar abscess decreased annually by 5.3%, 4.6%, and 1.0%, respectively, whereas new episodes of pneumonia increased by 0.4%. Age and sex standardised incidences for pneumonia and peritonsillar abscess were higher for practices in the lowest fourth of antibiotic prescribing compared with the highest fourth. The adjusted relative risk increases for a 10% reduction in antibiotic prescribing were 12.8% (95% confidence interval 7.8% to 17.5%, P<0.001) for pneumonia and 9.9% (5.6% to 14.0%, P<0.001) for peritonsillar abscess. If a general practice with an average list size of 7000 patients reduces the proportion of RTI consultations with antibiotics prescribed by 10%, then it might observe 1.1 (95% confidence interval 0.6 to 1.5) more cases of pneumonia each year and 0.9 (0.5 to 1.3) more cases of peritonsillar abscess each decade. Mastoiditis, empyema, meningitis, intracranial abscess, and Lemierre’s syndrome were similar in frequency at low prescribing and high prescribing practices.

Conclusions General practices that adopt a policy to reduce antibiotic prescribing for RTIs might expect a slight increase in the incidence of treatable pneumonia and peritonsillar abscess. No increase is likely in mastoiditis, empyema, bacterial meningitis, intracranial abscess, or Lemierre’s syndrome. Even a substantial reduction in antibiotic prescribing was predicted to be associated with only a small increase in numbers of cases observed overall, but caution might be required in subgroups at higher risk of pneumonia.

BMJ 2016;354:i3410