Emma Heeley

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage

BACKGROUND Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. METHODS We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physicians choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. RESULTS Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. CONCLUSIONS In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial

BACKGROUND There is much uncertainty about the effects of early lowering of elevated blood pressure (BP) after acute intracerebral haemorrhage (ICH). Our aim was to assess the safety and efficiency of this treatment, as a run-in phase to a larger trial. METHODS Patients who had acute spontaneous ICH diagnosed by CT within 6 h of onset, elevated systolic BP (150-220 mm Hg), and no definite indication or contraindication to treatment were randomly assigned to early intensive lowering of BP (target systolic BP 140 mm Hg; n=203) or standard guideline-based management of BP (target systolic BP 180 mm Hg; n=201). The primary efficacy endpoint was proportional change in haematoma volume at 24 h; secondary efficacy outcomes included other measurements of haematoma volume. Safety and clinical outcomes were assessed for up to 90 days. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00226096. FINDINGS Baseline characteristics of patients were similar between groups, but mean haematoma volumes were smaller in the guideline group (12.7 mL, SD 11.6) than in the intensive group (14.2 mL, SD 14.5). From randomisation to 1 h, mean systolic BP was 153 mm Hg in the intensive group and 167 mm Hg in the guideline group (difference 13.3 mm Hg, 95% CI 8.9-17.6 mm Hg; p<0.0001); from 1 h to 24 h, BP was 146 mm Hg in the intensive group and 157 mm Hg in the guideline group (10.8 mm Hg, 95% CI 7.7-13.9 mm Hg; p<0.0001). Mean proportional haematoma growth was 36.3% in the guideline group and 13.7% in the intensive group (difference 22.6%, 95% CI 0.6-44.5%; p=0.04) at 24 h. After adjustment for initial haematoma volume and time from onset to CT, median haematoma growth differed between the groups with p=0.06; the absolute difference in volume between groups was 1.7 mL (95% CI -0.5 to 3.9, p=0.13). Relative risk of haematoma growth >or=33% or >or=12.5 mL was 36% lower (95% CI 0-59%, p=0.05) in the intensive group than in the guideline group. The absolute risk reduction was 8% (95% CI -1.0 to 17%, p=0.05). Intensive BP-lowering treatment did not alter the risks of adverse events or secondary clinical outcomes at 90 days. INTERPRETATION Early intensive BP-lowering treatment is clinically feasible, well tolerated, and seems to reduce haematoma growth in ICH. A large randomised trial is needed to define the effects on clinical outcomes across a broad range of patients with ICH. FUNDING National Health and Medical Research Council of Australia.

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea

BACKGROUND Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).

Effects of Early Intensive Blood Pressure-Lowering Treatment on the Growth of Hematoma and Perihematomal Edema in Acute Intracerebral Hemorrhage: The Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT)

Background and Purpose— The Intensive Blood Pressure Reduction In Acute Cerebral Haemorrhage Trial (INTERACT) study suggests that early intensive blood pressure (BP) lowering can attenuate hematoma growth at 24 hours after intracerebral hemorrhage. The present analyses aimed to determine the effects of treatment on hematoma and perihematomal edema over 72 hours. Methods— INTERACT included 404 patients with CT-confirmed intracerebral hemorrhage, elevated systolic BP (150 to 220 mm Hg), and capacity to start BP-lowering treatment within 6 hours of intracerebral hemorrhage. Patients were randomly assigned to an intensive (target systolic BP 140 mmHg) or standard guideline-based management of BP (target systolic BP 180 mm Hg) using routine intravenous agents. Baseline and repeat CTs (24 and 72 hours) were performed using standardized techniques with digital images analyzed centrally. Outcomes were increases in hematoma and perihematomal edema volumes over 72 hours. Results— Overall, 296 patients had all 3 CT scans available for the hematoma and 270 for the edema analyses. Mean systolic BP was 11.7 mm Hg lower in the intensive group than in the guideline group during 1 to 24 hours. Adjusted mean absolute increases in hematoma volumes (mL) at 24 and 72 hours were 2.40 and 0.15 in the guideline group compared with −0.74 and −2.31 in the intensive group, respectively, an overall difference of 2.80 (95% CI, 1.04 to 4.56; P=0.002). Adjusted mean absolute increases in edema volumes (mL) at 24 and 72 hours were 6.27 and 10.02 in the guideline group compared with 4.19 and 7.34 in the intensive group, respectively, for an overall difference of 2.38 (95% CI, −0.45 to 5.22; P=0.10). Conclusion— Early intensive BP-lowering treatment attenuated hematoma growth over 72 hours in intracerebral hemorrhage. There were no appreciable effects on perihematomal edema.

Chronic atrial fibrillation: Incidence, prevalence, and prediction of stroke using the Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2) risk stratification scheme

BACKGROUND The aim of the study is to estimate the incidence and prevalence of chronic AF (cAF) in the United Kingdom and test the accuracy of the CHADS2 score for stroke prediction. METHODS The General Practice Research Database was used to identify patients aged 40+ years diagnosed with cAF and control patients. Harrells C-statistic was used to test possible improvements in CHADS2. RESULTS The study population included 51,807 cAF patients. The incidence of cAF increased by age and was higher in men than women. The prevalence of cAF has increased over time. The excess 5-year risk for stroke in cAF patients correlated well with CHADS2 as follows: score 0, 1.9% (95% CI 1.6-2.1); 1, 3.0% (95% CI 2.7-3.3); 2, 4.7% (95% CI 4.3-5.1); 3, 7.2% (95% CI 6.6-7.9); 4, 10.5% (95% CI 9.4-11.5); 5, 13.9% (95% CI 12.2-15.5); and 6, 15.8% (95% CI 13.5-18.1). Adding sex, the extension of age categories and reweighing of established risk factors improved CHADS2 accuracy (C-statistic 0.68-0.72). Applying the reclassification resulted in a substantial number of patients changing stroke risk category. CONCLUSION Atrial fibrillation is a prevalent and growing problem, which significantly increases the risk of ischemic stroke. The CHADS2 score is a good predictor of the stroke risk but could be improved.

The Second (Main) Phase of an Open, Randomised, Multicentre Study to Investigate the Effectiveness of an Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (Interact2)

Rationale: The INTERACT pilot study demonstrated the feasibility of the protocol, safety of early intensive blood pressure lowering and effects on haematoma expansion within 6h of onset of intracerebral haemorrhage. This article describes the design of the second, main phase, INTERACT2. Aims: To compare the effects of a management strategy of early intensive blood pressure lowering with a more conservative guideline-based blood pressure management policy in patients with acute intracerebral hemorrhage. Design: INTERACT2 is a prospective, randomized, open label, assessor-blinded end-point (PROBE). Patients with a systolic blood pressure greater than 150 mmHg and no definite indication for or contraindication to blood pressure-lowering treatment are centrally randomised to either of two treatment groups within 6h onset of intracerebral haemorrhage. Those allocated to intensive blood pressure lowering will receive primarily intravenous, hypotensive agents to achieve a systolic blood pressure target of <140 mmHg within 1 h of randomisation and to maintain this level for up to 7 days in hospital. The control group will receive blood pressure-lowering treatment to a target systolic blood pressure of < 180 mmHg. Both groups are to receive similar acute stroke unit care, therapy and active management. Oral antihypertensive therapy is recommended in patients before hospital discharge with a long-term systolic blood pressure goal of 140 mmHg according to secondary stroke prevention guidelines. A projected 2800 subjects are to be enrolled from approximately 140 centres worldwide to provide 90% power (α 0·05) to detect a 14% difference in the risk of death and dependency between the groups, which equates to one or more cases of a poor outcome prevented in every 15 patients treated. Study outcomes: The primary outcome is the combined end-point of death and dependency according to the modified Rankin Scale at 90 days. The secondary outcomes are the separate components of the primary end-point in patients treated <4 hours of ICH onset, grades of physical function on the modified Rankin Scale, health-related quality of life on the EuroQoL, recurrent stroke and other vascular events, days of hospitalisation, requirement for permanent residential care and unexpected serious adverse events. The study is registered under NCT00716079, ISRCTN73916115 and ACTRN12608000362392.

Significance of perihematomal edema in acute intracerebral hemorrhage: The INTERACT trial

Background: Uncertainty surrounds the effects of cerebral edema on outcomes in intracerebral hemorrhage (ICH). Methods: We used data from the INTERACT trial to determine the predictors and prognostic significance of “perihematomal” edema over 72 hours after ICH. INTERACT included 404 patients with CT-confirmed ICH and elevated systolic blood pressure (BP) (150–220 mm Hg) who had the capacity to commence BP lowering treatment within 6 hours of ICH. Baseline and repeat CT (24 and 72 hours) were performed using standardized techniques, with digital images analyzed centrally. Predictors of growth in edema were determined using generalized estimating equations, and its effects on clinical outcomes were estimated using a logistic regression model. Results: Overall, 270 patients had 3 sequential CT scans available for analyses. At baseline, there was a highly significant correlation between hematoma and perihematomal edema volumes (r2 = 0.45). Lower systolic BP and baseline hematoma volume were independently associated with absolute increase in perihematomal edema volume. History of hypertension, baseline hematoma volume, and earlier time from onset to CT were independently associated with relative increase in edema volume. Both absolute and relative increases in perihematomal edema growth were significantly associated with death or dependency at 90 days after adjustment for age, gender, and randomized treatment, but not when additionally adjusted for baseline hematoma volume. Conclusions: The degree of, and growth in, perihematomal edema are strongly related to the size of the underlying hematoma of acute intracerebral hemorrhage, and do not appear to have a major independent effect in determining the outcome from this condition.

Role of health insurance in averting economic hardship in families after acute stroke in China

Background and Purpose— Stroke is a major health burden in China, but there are limited data on its economic effects on households. We aimed to examine the economic impact of stroke and to assess the influence of health insurance. Methods— In a nationwide, prospective, 62-hospital registry study of acute stroke in China, we recorded information on patient demographics, clinical features, socioeconomic factors, management, and costs of medical care. Information on out-of-pocket health expenses was obtained in surviving patients at 3- and 12-month follow-up. Catastrophic healthcare payments, defined as ≥30% of total household annual income, were estimated from reported household annual income. Results— Among 4739 3-month survivors of stroke with outcome data, average hospital and medication costs were 16 525 Chinese Yuan Renminbi (US

Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial

2361) and out-of-pocket costs were 14 478 Chinese Yuan Renminbi (US

Hematoma growth and outcomes in intracerebral hemorrhage The INTERACT1 study

2068). Overall, 3384 (71%) patients had experienced catastrophic out-of-pocket expenditure. Workers without health insurance were 7 times (OR, 6.9; 95% CI, 4.6 to 10.3) more likely to experience catastrophic payments than workers with insurance. Health insurance also protected against catastrophic payments in patients who were either retired or not working (no insurance: OR, 4.7; 95% CI, 3.1 to 7.2; OR, 1.82; 95% CI, 1.3 to 2.6, respectively). Conclusions— Because healthcare costs are high relative to income in China, families face considerable economic hardship after stroke. Health insurance protects families against catastrophic healthcare payments, thus highlighting the need to accelerate the ongoing process of building a comprehensive healthcare system in both urban and rural settings in China.