A wealth of data supports the use of cholesterol-lowering statin medications for secondary prevention in patients with myocardial infarction. Patients in these trials have demonstrated not only a reduction in secondary cardiovascular events, but also a decreased risk of subsequent stroke and transient ischemic attack (TIA) in subgroup analyses. However, it still remains unclear if initiation of a statin after initial stroke or TIA will effectively prevent secondary cerebrovascular events. A recently published large trial attempted to address this issue and guide clinicians who are considering statin therapy in their patients who present with stroke or TIA.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial enrolled 4731 adults who suffered an ischemic or hemorrhagic stroke or TIA, diagnosed by a neurologist, one to six months prior to study entry. Patients with atrial fibrillation or proven cardiac sources of embolus were excluded, hoping to focus on a more atherosclerotic stroke population. Patients with known coronary heart disease were also excluded. Patients with an LDL level at baseline of 100 to 190 mg/dL were randomized in a double-blind fashion to 80 mg of atorvastatin daily or placebo with a primary end point of nonfatal or fatal stroke. The two study groups had similar LDL levels at study entry and did not have significant differences in their use of antiplatelet medications, antihypertensives, or warfarin throughout the course of the trial.

After a median follow up of nearly 5 years, the atorvastatin group demonstrated a 16.0% relative reduction in risk of subsequent nonfatal or fatal stroke (hazard ratio, 0.84; CI, 95%, interval, 0.71 to 0.99; p = .03). The number needed to treat with atorvastatin for 5 years to prevent one recurrent stroke was 46 patients (CI, 95%: 24 to 243 patients). Secondary end point analysis revealed a significant reduction in the combined risk of stroke and TIA (hazard ratio, 0.77; CI, 95%, interval, 0.67 to 0.88; p < .001) as well as in cardiovascular events such as myocardial infarction. There were no significant mortality differences between the two groups.

The number of patients in each group lost to follow up was similar as were the rates of serious adverse events. There were only five cases of rhabdomyolysis in the trial, and three occurred in patients assigned to the placebo group. Persistent transaminase elevation (defined as greater than three times normal) was more frequent in the statin group than in the placebo group (2.2% versus 0.5%, p < .001), but there were no episodes of liver failure observed in any of the patients in the trial.

Of the 88 patients experiencing at least one hemorrhagic stroke during the study, 55 were in the statin group and 33 were in the placebo group. Although this trial was not powered adequately to detect a difference in hemorrhage rates, these results agree with some previous studies that have revealed an increase in hemorrhagic stroke in patients with low LDL levels on statin therapy.

This well-designed randomized trial demonstrates that treating stroke or TIA patients with high-dose atorvastatin reduces the risk of recurrent stroke or TIA. The study population was limited to patients without known coronary artery disease and with baseline LDL levels of 100 to 190 mg/dL. The data support the view of stroke and TIA as coronary heart disease equivalents necessitating appropriate aggressive treatment of atherosclerotic risk factors such as hypercholesterolemia.

A few questions remain for clinicians deciding how best to treat patients with stroke and TIA. First, the dose and type of statin used in this trial was extremely high, and it is not clear if lower doses or alternative statin medications would have the same effect. Second, the relationship between low LDL levels and hemorrhagic stroke remains unclear. It is possible that statins alone or their lipid-lowering effects increase the risk of hemorrhagic stroke in some patients; until this is studied further, patients with hemorrhagic stroke should perhaps not have their LDL levels lowered to extremely low values, and they might not be ideal candidates for high-dose statin therapy. Finally, although the adverse event profile in this study was favorable in the treatment group, concerns regarding statin-induced myopathy and neuropathy remain, especially when statins are given at these high doses. Despite these limitations, this important study likely will change practice and now makes initiation of statin therapy standard-of-care in most patients with stroke or TIA.

Clinical Question:
Does metformin lead to weight loss for obese children and adolescents?

Bottom Line:
Metformin therapy for obese insulin-resistant pediatric patients results in significant improvement in body composition and fasting insulin. Although improvement in Si was noted in many individuals, Si was a less useful parameter for analysis of group data, possibly because of effects of variable compliance and changing Si during puberty.

Reference:
Srinivasan S, Ambler GR, Baur LA, et al Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: Improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006;91:2074-2080.

Study Design:
Cross-over trial (randomized)

Synopsis:
Participants were obese 9- to 18-year-olds (13 boys, 15 girls) who were treated in an endocrine clinic. All had clinical evidence of insulin resistance, but did not meet the criteria for diabetes. Patients were randomized (double-blinded) to metformin 1g twice daily or placebo for 6 months. This was followed by a 6-month crossover to the other treatment, with a 2-week washout period in between. There were equal numbers of children at Tanner stages 1 and 2 as at Tanner stages 3 to 5 at study entry. Mean body mass index (BMI) was 35. Standardized information on exercise and healthy eating was given to all patients. Four patients dropped out during the study; none because of medication side effects. At the end of the active treatment period significant benefits were observed for weight, BMI, abdominal circumference, and fasting insulin levels. The mean sizes of treatment effects at the end of the 6-month period of active therapy compared with placebo were weight loss of 4.35 kg, BMI decrease of 1.3, waist circumference decrease of 2.8 cm, and fasting insulin decrease of 2 mU/L. Data were not presented to calculate a number needed to treat.

Clinical Question:
Does metformin slow the progression of puberty and increase the adult height of girls with history of low birth weight and early-normal onset of puberty?

Bottom Line:
Metformin treatment for 36 months in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls.

Reference:
Ibanez L, Valls C, Ong K, Dunger DB, de Zegher F. Metformin therapy during puberty delays menarche, prolongs pubertal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty. J Clin Endocrinol Metabol 2006;91:2068-2073.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Hyperinsulinemia and insulin resistance in girls with history of LBW is thought to play a role in early onset of puberty. This study conducted in Spain enrolled 22 girls with history of LBW and onset of puberty in the early-normal age range of 8 to 9 years. LBW was defined as less than 1.5 standard deviation (SD) score for gestational age, which is less than 2.8 kg at term for the corresponding population. Onset of puberty was defined as Tanner stage 2 breast development, and had to occur at age 8 years or 9 years and within 1 year prior to enrollment in the study. Additional criteria for enrollment included height at enrollment of at least 1 SD above mid-parental height for chronological age and bone age of at least 1 SD above chronological age. Girls were excluded if they had personal or family history of diabetes or precocious puberty, signs of androgen excess, evidence of thyroid dysfunction, glucose intolerance, or were taking a medication that could affect gonadal function or carbohydrate metabolism. Treatment consisted of once-daily metformin 850 mg at dinnertime or no treatment. Assessments were made at 6-month intervals for a 36-month treatment period, and for an additional 6 months after the treatment stopped. Treated girls had a mean height gain of 3.5 cm more than untreated girls by the study’s conclusion (19.5 cm vs 16.0 cm; P < .01). Since treated girls still had a higher height velocity in the final observation interval, it is expected that adult height gains will be even greater. Treated girls also had a longer time to menarche by a mean of 1 year (3 yearsr vs 2 years; P < .01) and a leaner body composition. Treatment was well tolerated and there were no cases of abnormality of liver function or kidney function during the study.

Clinical Question:
In patients with type 2 diabetes, does fenofibrate prevent coronary events?

Bottom Line:
Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.

Reference:
Keech A, Simes RJ, Barter P, et al, for the FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. They did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481). Vital status was confirmed on all but 22 patients. Averaged over the 5 years’ study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects.

Omega-3 fatty acids are purported to reduce the risk of cancer. Studies have reported mixed results.

OBJECTIVE:
To synthesize published and unpublished evidence to determine estimates of the effect of omega-3 fatty acids on cancer risk in prospective cohort studies.

DATA SOURCES:
Articles published from 1966 to October 2005 identified through MEDLINE, PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CAB Health; unpublished literature sought through letters to experts in the neutraceutical industry.

STUDY SELECTION:
A total of 38 articles with a description of effects of consumption of omega-3 fatty acids on tumor incidence, prospective cohort study design, human study population; and description of effect of omega-3 among groups with different levels of exposure in the cohort were included. Two reviewers independently reviewed articles using structured abstraction forms; disagreements were resolved by consensus.

DATA EXTRACTION:
Two reviewers independently abstracted detailed data about the incidence of cancer, the type of cancer, the number and characteristics of the patients, details on the exposure to omega-3 fatty acids, and the elapsed time between the intervention and outcome measurements. Data about the methodological quality of the study were also abstracted.

DATA SYNTHESIS:
Across 20 cohorts from 7 countries for 11 different types of cancer and using up to 6 different ways to categorize omega-3 fatty acid consumption, 65 estimates of the association between omega-3 fatty acid consumption were reported. Among these, only 8 were statistically significant. The high degree of heterogeneity across these studies precluded pooling of data. For breast cancer 1 significant estimate was for increased risk (incidence risk ratio [IRR], 1.47; 95% confidence interval [CI], 1.10-1.98) and 3 were for decreased risk (RR, 0.68-0.72); 7 other estimates did not show a significant association. For colorectal cancer, there was 1 estimate of decreased risk (RR, 0.49; 95% CI, 0.27-0.89) and 17 estimates without association. For lung cancer one of the significant associations was for increased cancer risk (IRR, 3.0; 95% CI, 1.2-7.3), the other was for decreased risk (RR, 0.32; 95% CI, 0.13-0.76), and 4 other estimates were not significant. For prostate cancer, there was 1 estimate of decreased risk (RR, 0.43; 95% CI, 0.22-0.83) and 1 of increased risk (RR, 1.98; 95% CI, 1.34-2.93) for advanced prostate cancer; 15 other estimates did not show a significant association. The study that assessed skin cancer found an increased risk (RR, 1.13; 95% CI, 1.01-1.27). No significant associations between omega-3 fatty acid consumption and cancer incidence were found for aerodigestive cancer, bladder cancer, lymphoma, ovarian cancer, pancreatic cancer, or stomach cancer.

CONCLUSIONS:
A large body of literature spanning numerous cohorts from many countries and with different demographic characteristics does not provide evidence to suggest a significant association between omega-3 fatty acids and cancer incidence. Dietary supplementation with omega-3 fatty acids is unlikely to prevent cancer.

Reference:
JAMA. 2006 Jan 25;295(4):403-15.

Clinical Question:
Is silver nitrate a safe, effective way to relieve the pain of apthous stomatitis?

Bottom Line:
The results of our study showed that one application of silver nitrate can decrease the severity of pain in aphthous ulceration without significantly shortening or prolonging healing time. We did not observe any side-effects in our study. The effect is rapid and lasts for the duration of the lesion. The treatment is simple and cost-effective in patients with infrequent recurrences.

Reference:
Alidaee MR, Taheri A, Mansoori P, Ghodsi SZ. Silver nitrate cautery in aphthous stomatitis: a randomized controlled trial. Br J Dermatol 2005;153:521-25.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Aphthous stomatitis is a painful, recurrent disease of the oral mucous membrane. Silver nitrate sticks have been used for a long time to provide pain relief for the duration of an aphthous ulceration, with only one application. Silver nitrate causes chemical cauterization and increases the depth of injury. To study the effect of chemical cautery with silver nitrate in reducing pain of aphthous ulceration and to determine if this treatment shortens or prolongs healing. In a randomized, patient-blinded, placebo-controlled study, 97 patients with painful minor oral aphthous ulceration were randomized to receive silver nitrate cautery or placebo. The severity of pain was rated on a three-category scale (severe, mild, none) and was recorded each day until the seventh day after the procedure. The lesion size was recorded at the time of the procedure and on the seventh day afterwards. In the treatment group, the ulcer was gently painted with a silver nitrate stick until it turned white. In the placebo group, the ulcer was gently painted with a placebo stick. In the treatment group, 33 of 47 patients (70%) evaluated and in the placebo group, four of 38 patients (11%) evaluated had reduction in severity of pain 1 day after the procedure. The difference was statistically significant (P < 0.001). On the seventh day after the procedure, the ulcers were completely re-epithelialized in 39 patients (83%) in the treatment group and in 34 patients (89%) in the placebo group. The difference was not statistically significant (P = 0.39).