Interventions for basal cell carcinoma of the skin.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin malignancy in humans. BCCs are defined as slow-growing, locally invasive, malignant (but not life threatening), epidermal skin tumours which mainly affect white skinned people. The first line treatment is usually surgical excision, but numerous alternatives are available. OBJECTIVES: To assess the effects of treatments for basal cell carcinoma. SEARCH STRATEGY: We searched the Cochrane Database of Systematic Reviews (2002 issue 1) and Cochrane Controlled Trials Register (2002 issue 1), the Cochrane Skin Group Specialised Register (January 2002), MEDLINE (from 1966-2002), EMBASE (from 1980-2002), the Mega Register of Controlled trials and the National Research Register (2002 issue 1). In addition the cited references of all trials identified and key review articles were searched. Pharmaceutical companies were contacted where appropriate for reviews or unpublished trials. SELECTION CRITERIA: Inclusion criteria were adults with one or more histologically proven, primary basal cell carcinoma. The primary outcome measure was recurrence at 3- 5 years, measured clinically. The secondary outcome included early treatment failure within 6 months, measured histologically. Adverse effect of treatment was evaluated by reviewing aesthetic appearance (to patient and blinded observer) and pain during and after treatment. DATA COLLECTION AND ANALYSIS: Study selection and assessment of methodological quality were carried out by two independent reviewers. MAIN RESULTS: 19 studies (13 published and 6 abstracts) were identified which include 7 broad therapeutic categories. Only one RCT of surgery versus radiotherapy had primary outcome data at four years, which showed that there were significantly more persistent tumours and recurrences, measured histologically, in the radiotherapy group as compared to the surgery group, which translates to an odds ratio of 0.09 (95%CI, 0.01 to 0.67) in favour of surgery. Cryotherapy, although convenient and less expensive than surgery, showed no significant difference in recurrences at one year, measured clinically, when compared to surgery, OR 0.23 (0.01 to 6.78). However when radiotherapy was compared to cryotherapy there were significantly more recurrences at one year, measured histologically, in the cryotherapy group, this translates to an odds ratio of 14.80 (95%CI, 3.17 to 69) in favour of radiotherapy. Preliminary studies suggest a high success rate (87-88%) for imiquimod in the treatment of superficial BCC using a once-daily regimen for 6 weeks and a useful (76%) treatment response when treating nodular BCC for 12 weeks, when measured histologically. However this cream has not been compared to surgery. REVIEWER'S CONCLUSIONS: There has been very little good quality research on efficacy of the treatment modalities used. Most of the trials have looked only at BCCs in low risk areas. Surgery and radiotherapy appear to be the most effective treatments with surgery showing the lowest failure rates. Other treatments might have some use but few have been compared to surgery. Imiquimod emerged as a possible new treatment although it has not been compared to surgery or any other modality.

Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke.

BACKGROUND: Nitric oxide has several effects that may be beneficial in ischaemic stroke and useful in the management of high blood pressure in acute stroke. Some forms of nitric oxide synthase inhibition may also be beneficial. However, high concentrations of nitric oxide are likely to be toxic to brain tissue. OBJECTIVES: The objective of this review was to assess the effects of nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in people with acute stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched in March 2002), EMBASE (1980-March 2002), MEDLINE (1966-March 2002), and ISI Science Citation Indexes (1981-March 2002). We contacted drug companies and researchers in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in patients within one week of onset of confirmed stroke. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria. The data are given as weighted mean difference (WMD) or odds ratio (OR) with 95% confidence intervals (CI). MAIN RESULTS: Two small completed trials (127 patients) of transdermal glyceryl trinitrate (GTN), a nitric oxide donor, were found. GTN lowered 24 hour ambulatory systolic blood pressure by 7.9 mmHg (95% CI 0.1, 15.8) and increased heart rate (WMD 6.2 beats per minute, 95% CI 2.7, 9.8). Treatment with GTN was not associated with statistically significant effects on end-of-treatment death, or combined death or deterioration, or end-of-trial death, combined death or dependency, or combined death or institutionalisation. REVIEWER'S CONCLUSIONS: There is currently insufficient evidence from randomised trials on the effects of nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in patients with acute stroke to recommend their use. A large controlled trial of glyceryl trinitrate patches is underway.

Tirilazad for acute ischaemic stroke.

BACKGROUND: Tirilazad mesylate is neuroprotective in experimental models of ischaemic stroke suggesting it might be of benefit clinically. OBJECTIVES: To assess whether tirilazad mesylate is safe and effective at improving outcome in patients with acute ischaemic stroke. SEARCH STRATEGY: Trials of tirilazad were identified from searches of the Cochrane Stroke Group Specialised Trials Register (last searched: May 2001) and the Cochrane Controlled Trials Register (CENTRAL/CCTR). In addition, we contacted the Pharmacia & Upjohn company, the manufacturer of tirilazad, to identify unpublished studies and further information. SELECTION CRITERIA: Truly and quasi-randomised unconfounded placebo or open controlled trials of tirilazad administered within 24 hours onset of suspected or proven acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and QTc were extracted by treatment group from published data and company reports. MAIN RESULTS: Six trials (four published, two unpublished) assessing tirilazad in 1757 patients with presumed acute ischaemic stroke were identified; all were double-blind and placebo-controlled in design. Tirilazad did not alter early case fatality (odds ratio, OR 1.11, 95% confidence intervals, 95% CI 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). Tirilazad increased the odds of being dead or disabled by about one fifth, though the result was only just statistically significant; the odds ratios were similar whether the expanded Barthel Index or Glasgow Outcome Scale were used to assess outcome (OR 1.23, 95% CI 1.01 to 1.51; OR 1.23, 95% CI 1.01 to 1.50 respectively). Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (EBI) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a non-significant worse outcome was also seen in patients with mild-moderate stroke (OR 1.40, 95% CI 0.99 to 1.98). REVIEWER'S CONCLUSIONS: Tirilazad mesylate increased the combined end-point of 'death or disability' by about one-fifth, but did not alter case fatality, when given to patients with acute ischaemic stroke. Although further trials of tirilazad are now not warranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischaemic stroke.

The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke.

BACKGROUND AND PURPOSE: Hypertension is a common medical complication in acute stroke and is associated with a poor outcome. However, no large trials have assessed the effect of lowering blood pressure (BP) on outcome, and it remains unclear how BP should be managed in acute stroke. We assessed, in a double-blind randomised controlled trial, whether the nitric oxide (NO) donor glyceryl trinitrate (GTN, a known systemic and cerebral vasodilator), would lower BP and alter platelet function. METHODS: Thirty-seven patients with recent (< 5 days) ischaemic or haemorrhagic stroke were randomised by minimisation to 12 days of daily treatment with transdermal GTN or matching placebo patches. Twenty-four-hour ambulatory BP was measured before and during GTN treatment at days 0, 1 and 8. Platelet aggregation and expression of adhesion molecules were assessed at the same time points. Functional outcome (Rankin scale) and case fatality were assessed at 3 months. Analysis was by intention-to-treat. RESULTS: GTN significantly lowered BP by 13.0/5.2 mm Hg at day 1 and 9.3/5.0 mm Hg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to GTN was developing. Non-significant falls of 0.9/0.6 and 3.8/0.0 mm Hg occurred at days 1 and 8, respectively, in the placebo group. GTN had no effect on heart rate, or platelet aggregation or expression of platelet adhesion molecules, including glycoproteins Ia, Ib, IIIa and P-selectin. Additionally, GTN did not alter case fatality or dependency, although the study was not powered for these outcomes. CONCLUSIONS: Transdermal GTN, an NO donor, lowered BP by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke. However, GTN had no effect on platelet aggregation or expression of adhesion molecules. Since NO donors increase cerebral blood flow in patients with acute ischaemic stroke, GTN may be an appropriate drug for testing the effect of lowering BP on functional outcome.

Low-molecular-weight heparins and heparinoids in acute ischemic stroke : a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Low-molecular-weight heparins and heparinoids (LMWHs) are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism and acute coronary syndromes. We performed a systematic review of randomized controlled trials (RCTs) to examine the safety and efficacy of LMWH in acute ischemic stroke. METHODS: Randomized, controlled, and nonconfounded trials of LMWH in acute ischemic stroke were identified from the Cochrane Library (version 2, 1999), previous systematic reviews, and a review of publication quality relating to acute stroke trials. The authors each independently extracted data by treatment group and assessed trial quality using Cochrane Collaboration criteria. RESULTS: Eleven completed RCTs involving 3048 patients were identified; data were available from 10 of these. Four trials explicitly excluded patients with presumed cardioembolic stroke. Treatment with LMWH was associated with significant reductions in prospectively identified deep vein thrombosis (OR 0.27, 95% CI 0.08 to 0.96) and symptomatic pulmonary embolism (OR 0.34, 95% CI 0.17 to 0.69) and with increased major extracranial hemorrhage (OR 2.17, 95% 1.10 to 4.28). Nonsignificant increases in end-of-treatment (OR 1.20, 95% CI 0.86 to 1.69) and end-of-trial (OR 1.05, 95% CI 0.83 to 1.32) case fatality and symptomatic intracranial hemorrhage (OR 1.77, 95% CI 0. 95 to 3.31) were observed. End-of-trial death and disability was nonsignificantly reduced (OR 0.87, 95% CI 0.72 to 1.06). CONCLUSIONS: ++LMWHs reduce venous thromboembolic events in patients with acute ischemic stroke and increase the risk of extracranial bleeding. A nonsignificant reduction in combined death and disability and nonsignificant increases in case fatality and symptomatic intracranial hemorrhage were also observed. On the basis of the current evidence, LMWH should not be used in the routine management of patients with ischemic stroke.

Pentoxifylline, propentofylline and pentifylline for acute ischaemic stroke.

BACKGROUND: Methylxanthine derivatives are vasodilators. They also inhibit platelet aggregation and thromboxane A2 synthesis, decrease the release of free radicals and may be neuroprotective. OBJECTIVES: The objective of this review was to assess the effect of intravenous or oral methylxanthines (pentoxifylline, propentofylline, or pentifylline) in patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register, Medline (from 1965), Embase (from 1981), ISI (from 1981) and the Ottawa stroke trials registry. We contacted drug companies. SELECTION CRITERIA: Randomised trials comparing pentoxifylline, propentofylline or pentifylline with placebo or control in patients with definite or presumed acute ischaemic stroke. Trials were included if treatment was started within one week of stroke onset. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria. Trial quality was assessed. MAIN RESULTS: Five trials were included. Four trials tested pentoxifylline in 763 people, and one tested propentofylline in 30 people. No trials of pentifylline were found. Early death (within four weeks) occurred in 34 of 408 patients given a methylxanthine drug compared with 49 of 385 given placebo (odds ratio 0.64, 95% confidence interval 0.41 to 1.02). This non-significant trend to less deaths was due mainly to one pentoxifylline trial that found a highly significant reduction in early deaths. Two trials reported early death or disability and found a non-significant reduction (odds ratio 0.49, 95% confidence interval 0.20 to 1.20). Late death (beyond four weeks) was reported in the propentofylline trial involving 30 patients, with no difference between treatment and placebo (odds ratio 0.70, 95% confidence interval 0.13 to 3.68). Data for neurological impairment and disability were not in a form suitable for analysis. Data on quality of life, stroke recurrence, thromboembolism and bleeding were not reported. REVIEWER'S CONCLUSIONS: There is not enough evidence to assess the effectiveness and safety of methylxanthines after acute ischaemic stroke.

Prostacyclin and analogues for acute ischaemic stroke.

BACKGROUND: Prostacyclin is an agent with a number of effects on platelets, blood vessels and nerve cells which might improve outcome after acute ischaemic stroke. OBJECTIVES: The objective of this review was to assess the effect of prostacyclin or analogues on survival in people with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched: March 1999), Medline (from 1965), Embase (from 1980) and ISI (from 1981). We contacted drug companies. SELECTION CRITERIA: Randomised trials comparing prostacyclin or analogues with placebo or control. Trials where people were entered within one week of stroke onset were included. DATA COLLECTION AND ANALYSIS: Trial quality was assessed. MAIN RESULTS: Five trials involving 191 people were included. Six early deaths (within four weeks) occurred with prostacyclin and nine with placebo (odds ratio of 0.63, 95% confidence interval 0.22 to 1.85). One trial of 32 patients reported late deaths (by 10 to 18 months) in 50% of patients in each group. REVIEWER'S CONCLUSIONS: Too few patients have been studied in randomised trials to allow conclusions to be drawn about the effect of prostacyclin treatment on survival of people with acute stroke.

Theophylline, aminophylline, caffeine and analogues for acute ischaemic stroke.

BACKGROUND: Theophylline causes potent cerebral vasoconstriction which decreases blood flow in the non-ischaemic areas of the brain and increases collateral blood flow surrounding the ischaemic region. OBJECTIVES: The objective of this review was to assess the effect of theophylline and its analogues (aminophylline and caffeine) in people with confirmed or presumed acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched: March 1999), Medline (from 1965), Embase (from 1980), and ISI (from 1981). We contacted drug companies. SELECTION CRITERIA: Randomised trials of theophylline or an analogue compound compared with placebo or control in people with confirmed or presumed acute ischaemic stroke. Trials were included if treatment was started within one week of stroke onset. DATA COLLECTION AND ANALYSIS: Three reviewers applied the inclusion criteria, assessed trial quality and extracted data. MAIN RESULTS: Two trials involving 119 patients were included. Trial quality was good. Both of the trials tested aminophylline. Analysis was by intention-to-treat where possible. No difference was shown in early death (within four weeks) between aminophylline and placebo (odds ratio 1.12, 95% confidence interval 0.49 to 2.56). There was no significant difference for early mortality and deterioration (odds ratio 0.87, 95% confidence interval 0.41 to 1.88). Death or disability was not reduced by treatment based on 73 patients in one trial (odds ratio 0.64, 95% confidence interval 0.24 to 1.68). Data for late mortality and disability were not in a form suitable for analysis. No data on quality of life were available. REVIEWER'S CONCLUSIONS: There is not enough evidence to assess whether theophylline or its analogues reduce mortality or morbidity, or are safe, in people with acute ischaemic stroke.

Interventions for dysphagia in acute stroke.

BACKGROUND: It is unclear how dysphagic patients should be fed and treated after acute stroke. OBJECTIVES: The objective of this review was to assess the effect of different management strategies for dysphagic stroke patients, in particular how and when to feed, whether to supplement nutritional intake, and how and whether to treat dysphagia. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register, Medline, Embase, ISI, and existing review articles. We contacted researchers in the field and equipment manufacturers. Date of the most recent searches: March 1999. SELECTION CRITERIA: Unconfounded truly or quasi randomised controlled trials in dysphagic patients with acute/subacute (within 3 months) stroke. DATA COLLECTION AND ANALYSIS: Three reviewers independently applied the trial inclusion criteria. Two reviewers assessed trial quality and extracted the data. MAIN RESULTS: Percutaneous endoscopic gastrostomy (PEG) versus nasogastric tube (NGT) feeding: two trials (49 patients) suggest that PEG reduces end-of-trial case fatality (Peto Odds Ratio, OR 0.28, 95% CI 0.09 to 0.89) and treatment failures (OR 0.10, 95% CI 0.02 to 0.52), and improves nutritional status, assessed as weight (Weighted Men Difference, WMD +4.1 kg, 95% CI -4.3 to +12.5), mid-arm circumference (WMD +2.2 cm, 95% CI -0.5 to +4.9) or serum albumin (WMD + 7.0 g/l, 95% CI +4.9 to +9.1) as compared with NGT feeding; two larger studies are ongoing. Timing of feeding: no completed trials; one large study is ongoing. Swallowing therapy for dysphagia: two trials (85 patients) suggest that formal swallowing therapy does not significantly reduce end-of-trial dysphagia rates (OR 0.55, 95% CI 0.18 to 1.66). Drug therapy for dysphagia: one trial (17 patients); nifedipine did not alter end-of-trial case fatality or the frequency of dysphagia. Nutritional supplementation: one trial (42 patients) found a non-significant trend to a lower case fatality, and significantly increased energy and protein intake; one large trial is ongoing and data is awaited from two other studies. Fluid supplementation: one trial (20 patients) found that supplementation did not alter the time to resolution of dysphagia. REVIEWER'S CONCLUSIONS: Too few studies have been performed, and these have involved too few patients. PEG feeding may improve outcome and nutrition as compared with NGT feeding. Further research is required to assess how and when patients are fed, and the effect of swallowing or drug therapy on dysphagia.

Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute ischaemic stroke.

BACKGROUND: Nitric oxide has several effects that may be beneficial in ischaemic stroke and useful in the management of hypertension in acute stroke. Some forms of nitric oxide synthase inhibition may also be beneficial. However, high concentrations of nitric oxide are likely to be toxic to brain tissue. OBJECTIVES: The objective of this review was to assess the effects of nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in people with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (July 1997), Medline (for trials from 1965), Embase (from 1980) and ISI (from 1981). We contacted drug companies and researchers in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials comparing nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in patients within one week of onset of confirmed ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria. MAIN RESULTS: No completed trials were found. One small placebo-controlled trial of glyceryl trinitrate patches is underway. REVIEWER'S CONCLUSIONS: There is currently no evidence from randomised trials on the effects of nitric oxide donors, L-arginine, or nitric oxide synthase-inhibitors in patients with acute ischaemic stroke.

Quality of full and final publications reporting acute stroke trials: a systematic review.

BACKGROUND AND PURPOSE: Several studies have shown that the quality of reporting of trials throughout medicine is variable and often poor. We report on the quality of the final reports of randomized controlled trials (RCTs) of drug therapies assessed in acute stroke. METHODS: English-language reports published up to the end of 1996 relating to completed RCTs in acute stroke were identified from electronic searches of the Cochrane Stroke Review Group database of stroke trials and the Cochrane Controlled Trials Register (CD-ROM issue 1, 1997, of the Cochrane Library). Report quality was assessed with the 33 criteria of the CONSORT statement and 53 additional factors relevant to acute stroke or trials in general. Trial quality was also assessed with a 7-point scale. RESULTS: Up to 1996, 114 RCTs were published which involved 20 536 patients (median, 80; range, 16 to 1267 per trial); 39 (35.5%) of these were published in Stroke. The median total report quality was 40/86 (range, 15 to 61) for all criteria and 19/33 (range, 9 to 29) for the CONSORT criteria alone. Although adequate information was given in the introduction and discussion sections of most reports, insufficient details were given on methods, assignment of patients to treatment groups, statistical analyses, the prevalence of risk factors, and assessment of outcomes. Report quality has improved between 1956 and 1996 (Spearman correlation coefficient [rs], 0.575; 95% confidence interval [CI], 0. 439 to 0.685) and was superior in large trials (rs=0.434; 95% CI, 0. 274 to 0.571). Although report quality was related to trial quality (rs=0.675; 95% CI, 0.563 to 0.763), it was not related to journal impact factor (rs=0.170; 95% CI, -0.015 to 0.344). Trials with a positive outcome tended to be less well reported than those with a neutral or negative outcome (rs=-0.192; 95% CI, -0.351 to -0.011). CONCLUSIONS: The overall quality of study reports for parallel group RCTs in acute stroke is poor but appears to be improving with time and in parallel with an increase in trial size. Reports often lack detailed information on the methods of randomization, concealment of allocation, and statistical analysis, all factors which can, if undertaken poorly, affect trial results and validity. It is vital that future trials are adequately reported; we believe that authors should follow the CONSORT guidelines and that referees and editors should ensure this happens.