Chamila Geeganage

Dual or Mono Antiplatelet Therapy for Patients With Acute Ischemic Stroke or Transient Ischemic Attack Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background and Purpose— Antiplatelets are recommended for patients with acute noncardioembolic stroke or transient ischemic attack. We compared the safety and efficacy of dual versus mono antiplatelet therapy in patients with acute ischemic stroke or transient ischemic attack. Methods— Completed randomized controlled trials of dual versus mono antiplatelet therapy in patients with acute (⩽3 days) ischemic stroke/transient ischemic attack were identified using electronic bibliographic searches. The primary outcome was recurrent stroke (ischemic, hemorrhagic, unknown; fatal, nonfatal). Comparison of binary outcomes between treatment groups was analyzed with random effect models and described using risk ratios (95% CI). Results— Twelve completed randomized trials involving 3766 patients were included. In comparison with mono antiplatelet therapy, dual therapy (aspirin+dipyridamole and aspirin+clopidogrel) significantly reduced stroke recurrence, dual 58 (3.3%) versus mono 91 (5.0%; risk ratio, 0.67; 95% CI, 0.49–0.93); composite vascular event (stroke, myocardial infarction, vascular death), dual 74 (4.4%) versus mono 106 (6%; risk ratio, 0.75; 95% CI, 0.56–0.99); and the combination of stroke, transient ischemic attack, acute coronary syndrome, and all death, dual 100 (1.7%) versus mono 136 (9.1%; risk ratio, 0.71; 95% CI, 0.56–0.91); dual therapy was also associated with a nonsignificant trend to increase major bleeding, dual 15 (0.9%) versus mono 6 (0.4%; risk ratio, 2.09; 95% CI, 0.86–5.06). Conclusions— Dual antiplatelet therapy appears to be safe and effective in reducing stroke recurrence and combined vascular events in patients with acute ischemic stroke or transient ischemic attack as compared with mono therapy. These results need to be tested in prospective studies.

Relationship Between Therapeutic Changes in Blood Pressure and Outcomes in Acute Stroke: A Metaregression

Both low and high blood pressures (BPs) during the acute phase of stroke are associated independently with a poor outcome. Several small clinical trials have involved the alteration of BP, and this study assessed the relationship between change in BP and functional outcome. Randomized, controlled trials of interventions that would be expected, on pharmacological grounds, to alter BP in patients within 1 week of the onset of acute ischemic or hemorrhagic stroke were sought using electronic searches. Data were collected on BP and clinical outcome. The relationship between the differences in on-treatment BP and odds ratios for outcomes was assessed using meta-regression. Thirty-seven trials involving 9008 patients were included. A U- or J-shaped relationship was found among on-treatment BP difference and early death, death at the end of 90-day follow-up, and combined death or dependency at the end of follow-up. Although outcomes were not significantly reduced at any level of change in BP, the lowest odds occurred at the following times: early death (odds ratio: 0.87; 95% CI: 0.54 to 1.23), 8.1 mm Hg; death at the end of follow-up (odds-ratio: 0.96; 95% CI: 0.31 to 1.65), 14.4 mm Hg; and combined death or dependency at the end of follow-up (odds ratio: 0.95; 95% CI: 0.11 to 1.72), 14.6 mm Hg. Although large falls or increases in BP are associated with a worse outcome, modest reductions may reduce death and combine death or dependency, although the CIs are wide and compatible with an overall benefit or hazard.

Relationship Between Baseline Blood Pressure Parameters (Including Mean Pressure, Pulse Pressure, and Variability) and Early Outcome After Stroke Data From the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST)

Background and Purpose— High blood pressure (BP) in acute stroke is associated independently with a poor outcome. Recent evidence suggests that other hemodynamic parameters may also be associated with outcomes following stroke. Methods— The relationship between baseline BP, heart rate, and other hemodynamic parameters, and early outcomes were assessed using data from TAIST trial. Results— Death or neurological deterioration at day 10 was associated, both in unadjusted and adjusted analyses, with systolic BP (adjusted OR, 1.02; 95% CI, 1.01–1.03), mean arterial pressure (OR, 1.02; 95% CI, 1.01–1.04), pulse pressure (OR, 1.02; 95% CI, 1.01–1.03), and BP variability (OR, 1.03; 95% CI, 1.01–1.05). Similar relationships were noted for deterioration alone, and recurrent stroke. Conclusions— Early death or neurologic deterioration, deterioration, and recurrent stroke are associated independently with high systolic BP, mean arterial pressure, pulse pressure, and BP variability. These measures offer potential therapeutic targets for improving early outcome after acute ischemic stroke.

Triple antiplatelet therapy for preventing vascular events: a systematic review and meta-analysis

BackgroundDual antiplatelet therapy is usually superior to mono therapy in preventing recurrent vascular events (VEs). This systematic review assesses the safety and efficacy of triple antiplatelet therapy in comparison with dual therapy in reducing recurrent vascular events.MethodsCompleted randomized controlled trials investigating the effect of triple versus dual antiplatelet therapy in patients with ischaemic heart disease (IHD), cerebrovascular disease or peripheral vascular disease were identified using electronic bibliographic searches. Data were extracted on composite VEs, myocardial infarction (MI), stroke, death and bleeding and analysed with Cochrane Review Manager software. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random effects models.ResultsTwenty-five completed randomized trials (17,383 patients with IHD) were included which involving the use of intravenous (iv) GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), aspirin, clopidogrel and/or cilostazol. In comparison with aspirin-based therapy, triple therapy using an intravenous GP IIb/IIIa inhibitor significantly reduced composite VEs and MI in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) (VE: OR 0.69, 95% CI 0.55-0.86; MI: OR 0.70, 95% CI 0.56-0.88) and ST elevation myocardial infarction (STEMI) (VE: OR 0.39, 95% CI 0.30-0.51; MI: OR 0.26, 95% CI 0.17-0.38). A significant reduction in death was also noted in STEMI patients treated with GP IIb/IIIa based triple therapy (OR 0.69, 95% CI 0.49-0.99). Increased minor bleeding was noted in STEMI and elective percutaneous coronary intervention (PCI) patients treated with GP IIb/IIIa based triple therapy. Stroke events were too infrequent for us to be able to identify meaningful trends and no data were available for patients recruited into trials on the basis of stroke or peripheral vascular disease.ConclusionsTriple antiplatelet therapy based on iv GPIIb/IIIa inhibitors was more effective than aspirin-based dual therapy in reducing VEs in patients with acute coronary syndromes (STEMI and NSTEMI). Minor bleeding was increased among STEMI and elective PCI patients treated with a GP IIb/IIIa based triple therapy. In patients undergoing elective PCI, triple therapy had no beneficial effect and was associated with an 80% increase in transfusions and an eightfold increase in thrombocytopenia. Insufficient data exist for patients with prior ischaemic stroke and peripheral vascular disease and further research is needed in these groups of patients.

Clinical trials for preventing post stroke cognitive impairment.

Post stroke dementia (PSD) develops in up to 40% of patients and often co-exists with Alzheimers disease in the elderly. Unsurprisingly, the combination of stroke and dementia is associated with considerable morbidity and mortality, and is devastating to patients and carers. Limited trial evidence suggests that lowering high blood pressure reduces the development of cognitive decline, vascular dementia and PSD, although whether this relates to the magnitude of BP reduction or specific drug classes remains unclear. Biological plausibility and/or existing studies suggest that other types of drug treatments might also be effective, including choline esterase inhibitors, lipid lowering agents, antiplatelet agents, and selective serotonin reuptake inhibitors. Preventing cognitive decline and dementia post stroke is critical and large definitive trials are now needed.

Asymptomatic Hemorrhagic Transformation of Infarction and Its Relationship With Functional Outcome and Stroke Subtype Assessment From the Tinzaparin in Acute Ischaemic Stroke Trial

Background and Purpose— Asymptomatic hemorrhagic transformation of infarction (AHTI) is common, but its risk factors and relationship with functional outcome are poorly defined. Methods— The analyses used data from the Tinzapararin in Acute Ischaemic Stroke Trial, a randomized controlled trial assessing tinzaparin (low molecular weight heparin) versus aspirin in 1484 patients with acute ischemic stroke. CT head scans (baseline, day 10) were adjudicated for the presence of hemorrhagic transformation. Stroke subtype was classified according to modified Trial of Org 10172 in Acute Stroke Treatment (small vessel, large vessel, cardioembolic) and the Oxfordshire Community Stroke Project (total anterior, partial anterior, lacunar, and posterior circulatory syndromes). Modified Rankin scale and Barthel Index were measured at 3 and 6 months. Analyses were adjusted for age, sex, severity, blood pressure, infarct volume, and treatment. Symptomatic hemorrhage was excluded. Results— At day 10, AHTI did not differ between aspirin (300 mg; 32.8%) and medium-dose (100 IU/kg; 36.0%) and high-dose (175 IU/kg; 31.4%) tinzaparin groups (P=0.44). Relative to lacunar stroke, AHTI on follow-up CT was significantly increased in total anterior circulation syndrome (odds ratio, 11.5; 95% CI, 7.1 to 18.7) and partial anterior circulation syndrome (odds ratio, 7.2; 95% CI, 4.5 to 11.4) stroke. Similarly, relative to small vessel disease, AHTI was increased in large vessel (odds ratio, 15.1; 95% CI, 9.4 to 24.3) and cardioembolic (odds ratio, 14.1; 95% CI, 8.5 to 23.5) stroke. After adjustment for infarct volume, the presence of AHTI was not associated with outcome at 3 or 6 months as measured by the modified Rankin Scale and Barthel Index. Conclusions— AHTI is increased in ischemic stroke with cortical syndromes and of large vessel or cardioembolic etiology. Heparin does not increase AHTI. AHTI is not associated with functional outcome.

High Blood Pressure in Acute Ischaemic Stroke – Broadening Therapeutic Horizons

High blood pressure (BP) is present in 80% of patients with acute ischaemic stroke and is independently associated with poor outcome. Although this epidemiology suggests that BP should be lowered acutely, concerns about dysfunctional cerebral autoregulation suggest otherwise. Several small randomised trials have assessed cerebral blood flow with various antihypertensive classes and agents in acute ischaemic stroke. Overall, these studies showed no change in cerebral perfusion, although the numbers of studies and patients are limited and there are methodological problems with some trials. There are no large published randomised trials assessing outcome with BP lowering in acute stroke. Calcium channel blockers did not alter outcome after ischaemic stroke (29 trials, 7,665 patients). However, some trials, especially those testing intravenous calcium channel blockers (INWEST) or oral β-receptor antagonists (BEST) reported real or potential hazard. In contrast, oral candesartan reduced combined vascular events in 339 patients with ischaemic stroke (ACCESS) although it had no effect on disability. The CHHIPS trial found that death was reduced in patients randomised to active treatment (labetalol, lisinopril) as compared with placebo. Two larger trials reported that glucose-potassium-insulin therapy (GIST) or magnesium (IMAGES) lowered BP but had no effect on functional outcome. The INTERACT pilot trial studied patients with intracerebral haemorrhage and found that an intensive BP-lowering regime non-significantly reduced haematoma expansion. There are four large ongoing trials examining whether to continue or stop pre-stroke antihypertensive therapy (COSSACS, ENOS) or lower BP in acute stroke (ENOS, SCAST) or haemorrhage (INTERACT 2).

Use of Ordinal Outcomes in Vascular Prevention Trials Comparison With Binary Outcomes in Published Trials

Background and Purpose— Vascular prevention trials mostly count “yes/no” (binary) outcome events, eg, stroke/no stroke. Analysis of ordered categorical vascular events (eg, fatal stroke/nonfatal stroke/no stroke) is clinically relevant and could be more powerful statistically. Although this is not a novel idea in the statistical community, ordinal outcomes have not been applied to stroke prevention trials in the past. Methods— Summary data on stroke, myocardial infarction, combined vascular events, and bleeding were obtained by treatment group from published vascular prevention trials. Data were analyzed using 10 statistical approaches which allow comparison of 2 ordinal or binary treatment groups. The results for each statistical test for each trial were then compared using Friedman 2-way analysis of variance with multiple comparison procedures. Results— Across 85 trials (335 305 subjects) the test results differed substantially so that approaches which used the ordinal nature of stroke events (fatal/nonfatal/no stroke) were more efficient than those which combined the data to form 2 groups (P<0.0001). The most efficient tests were bootstrapping the difference in mean rank, Mann–Whitney U test, and ordinal logistic regression; 4- and 5-level data were more efficient still. Similar findings were obtained for myocardial infarction, combined vascular outcomes, and bleeding. The findings were consistent across different types, designs and sizes of trial, and for the different types of intervention. Conclusions— When analyzing vascular events from prevention trials, statistical tests which use ordered categorical data are more efficient and are more likely to yield reliable results than binary tests. This approach gives additional information on treatment effects by severity of event and will allow trials to be smaller.

Balance of symptomatic pulmonary embolism and symptomatic intracerebral hemorrhage with low-dose anticoagulation in recent ischemic stroke: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND The current consensus is that anticoagulation therapy has no role acutely in the management of ischemic stroke, although there is still debate for specific conditions, such as cerebral venous thrombosis and cervical dissection. In addition, anticoagulation is used in the prevention of venous thromboembolic events. We assess the balance between preventing symptomatic pulmonary embolism (sPE) and causing symptomatic intracerebral hemorrhage (sICH) in patients with recent stroke who were randomized to low-dose subcutaneous anticoagulation in trials. METHODS We systematically searched the Cochrane Library, Medline, Embase, and Science Citation Index for prospective randomized controlled trials assessing the effect of heparin and other antithrombotic therapies in patients with acute/early ischemic stroke. Included trials had to record information on pulmonary embolism and sICH. Risk ratios (RRs) were calculated for sICH per sPE for each trial using a random effects model. RESULTS We identified 15 trials of low-dose subcutaneous anticoagulation. The trials studied low molecular weight heparin, heparinoids, and unfractionated heparin. The ratio of sICH to sPE was increased with low molecular weight heparin (RR 2.1; 95% confidence interval [CI] 1.03-4.28), but was in approximated unity with heparinoids (RR 1.27; 95% CI 0.31-5.17) and unfractionated heparin (RR 0.99; 95% CI 0.65-1.52). CONCLUSIONS Prophylactic/low-dose heparin increased sICH by more than they reduced sPE in patients with recent ischemic stroke. Therefore, their routine acute use cannot be recommended, but they may still be relevant in patients at very high risk of PE (eg, morbid obesity, previous venous thromboembolism, and inherited thrombophilia) or if started later, although trials have not assessed these issues.

Determining the feasibility of ambulance-based randomised controlled trials in patients with ultra-acute stroke: Study protocol for the “Rapid Intervention with GTN in Hypertensive Stroke Trial” (RIGHT, ISRCTN66434824)

Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.