Significant Relative Risk Reduction Research Articles

Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2)

The objective of this prevention programme was to study whether combining pioglitazone with lifestyle modification would enhance the efficacy of lifestyle modification in preventing type 2 diabetes in Asian Indians with impaired glucose tolerance. In a community-based, placebo-controlled 3 year prospective study, 407 participants with impaired glucose tolerance (mean age 45.3 +/- 6.2 years, mean BMI 25.9 +/- 3.3 kg/m(2)) were sequentially grouped to receive either: lifestyle modification plus pioglitazone, 30 mg (n = 204) or lifestyle modification plus placebo (n = 203). The participants and investigators were blinded to the assignment. The primary outcome was development of diabetes. At baseline, both groups had similar demographic, anthropometric and biochemical characteristics. At year 3, the response rate was 90.2%. The cumulative incidence of diabetes was 29.8% with pioglitazone and 31.6% with placebo (unadjusted HR 1.084 [95% CI 0.753-1.560], p = 0.665). Normoglycaemia was achieved in 40.9% and 32.3% of participants receiving pioglitazone and placebo, respectively (p = 0.109). In pioglitazone group, two deaths and two non-fatal hospitalisations occurred due to cardiac problems; in the placebo group there were two occurrences of cardiac disease. Despite good adherence to lifestyle modification and drug therapy, no additional effect of pioglitazone was seen above that achieved with placebo. The effectiveness of the intervention in both groups was comparable with that of lifestyle modification alone, as reported from the Indian Diabetes Prevention Programme-1. The results are at variance with studies that showed significant relative risk reduction in conversion to diabetes with pioglitazone in Americans with IGT. An ethnicity-related difference in the action of pioglitazone in non-diabetic participants may be one explanation. ClinicalTrials.gov NCT00276497 FUNDING: This study was funded by the India Diabetes Research Foundation.

Invasive management and late clinical outcomes in contemporary Australian management of acute coronary syndromes: observations from the ACACIA registry

TO THE EDITOR: The work presented by Chew and colleagues in setting up and using the Acute Coronary Syndrome Prospective Audit (ACACIA) is an important and influential initiative. It has the potential to provide a strong evidence base for the design and delivery of cardiac services in Australia. Their article and the accompanying editorial by Scott highlighted the difficulty in determining treatment benefit from uncontrolled observational studies. Among the unreported and possibly significant confounders underpinning the association between acute invasive care and the 47% improved 12-month survival in patients treated for acute coronary syndrome is participation in post-event secondary-prevention cardiac rehabilitation. A contemporary systematic review of randomised controlled trials of cardiac rehabilitation reported a significant relative risk reduction in all-cause mortality of 20% (95% CI, 7%–32%) over a median follow-up of 12 months. Despite this evidence and the long-term policy of the World Health Organization that cardiac rehabilitation should be available to all patients with cardiovascular disease, this secondary-prevention intervention is largely underused, and those who do attend are generally at lower risk of recurrent coronary events than those who do not. Further, secondary-prevention cardiac-rehabilitation programs are cost-effective relative to other coronary interventions and, along with proven cardioprotective pharmacotherapy and acute invasive care, should be given priority as part of an optimal treatment and management strategy for secondary prevention. The completion of cardiac rehabilitation or other forms of secondary prevention by ACACIA patients may have favourably impacted upon the marked improvement in 12-month survival seen in the ACACIA cohort. Chew and colleagues identified the fact that patients who underwent invasive therapies were also more likely to be treated according to bestpractice guidelines. It may be that this same group were also more likely to be referred to cardiac-rehabilitation and secondary-prevention programs. It would be of great interest to know if attendance in cardiac-rehabilitation and secondary-prevention programs was recorded in the ACACIA registry and, if so, why those results were not incorporated.

The effect of dyslipidemic drugs on mortality: A meta-analysis.

Most of the previously published meta-analyses include studies exploring the effect of statins, rather than all dyslipidemic drugs, on mortality. We explored the overall effect of all dyslipidemic drugs on coronary artery disease mortality, cardio-vascular disease mortality and all-cause mortality. A meta-analysis of all randomized controlled trials that were published before February 2006 was carried out. Data sources were published articles in bibliographic electronic databases and medical journals. The article selection criteria included all randomized placebo-controlled trials of at least one year duration and those which measured at least one of the following clinical endpoints: coronary artery disease mortality, cardio-vascular mortality or all-cause mortality. Information on sample size, follow up period, drug used, and clinical outcomes was abstracted independently by two authors. Disagreements were resolved by consensus. The meta-analysis (19 trials, 59033 patients) showed a significant relative risk reduction of coronary artery disease mortality of 23% (P<0.00001), cardiovascular disease mortality of 19% (P<0.00001) and all-cause mortality of 14% (P<0.0001), without any significant heterogeneity and inconsistency between the trials. It was concluded from this meta-analyses that dyslipidemic drugs are indeed highly effective medicines and confer benefit to patients, in terms of primary and secondary prevention of coronary artery disease.

Response to Letters Regarding Article, “Optimal Medical Therapy With or Without Percutaneous Coronary Intervention to Reduce Ischemic Burden: Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Nuclear Substudy”

On behalf of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Investigators, we wish to thank Drs Joshi, Tarantini, and colleagues for their letters to the editor regarding our article.1 Many excellent comments were made that serve to clarify the COURAGE nuclear substudy. It is important to note that this study was devised to compare treatment effectiveness using nuclear quantification of ischemia as a surrogate outcome. The design of the substudy was based on the prognostic findings from observational registries of tens of thousands of patients undergoing stress myocardial perfusion single photon emission computed tomography (SPECT).2–4 Importantly, no published data were available previously to suggest that significant relative risk reduction would be seen in patients with ischemia reduction. Therefore, this study was not powered to examine differences in prognosis but was designed to determine whether percutaneous coronary intervention (PCI) resulted in a greater reduction of objective ischemia than did optimal medical therapy alone, extending prior, small series that found serial changes in …

Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes

Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained. Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories. Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02). The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837.)

The Effect of Electronic Prescribing on Medication Errors and Adverse Drug Events: A Systematic Review

The objective of this systematic review is to analyse the relative risk reduction on medication error and adverse drug events (ADE) by computerized physician order entry systems (CPOE). We included controlled field studies and pretest-posttest studies, evaluating all types of CPOE systems, drugs and clinical settings. We present the results in evidence tables, calculate the risk ratio with 95% confidence interval and perform subgroup analyses for categorical factors, such as the level of care, patient group, type of drug, type of system, functionality of the system, comparison group type, study design, and the method for detecting errors. Of the 25 studies that analysed the effects on the medication error rate, 23 showed a significant relative risk reduction of 13% to 99%. Six of the nine studies that analysed the effects on potential ADEs showed a significant relative risk reduction of 35% to 98%. Four of the seven studies that analysed the effect on ADEs showed a significant relative risk reduction of 30% to 84%. Reporting quality and study quality was often insufficient to exclude major sources of bias. Studies on home-grown systems, studies comparing electronic prescribing to handwriting prescribing, and studies using manual chart review to detect errors seem to show a higher relative risk reduction than other studies. Concluding, it seems that electronic prescribing can reduce the risk for medication errors and ADE. However, studies differ substantially in their setting, design, quality, and results. To further improve the evidence-base of health informatics, more randomized controlled trials (RCTs) are needed, especially to cover a wider range of clinical and geographic settings. In addition, reporting quality of health informatics evaluation studies has to be substantially improved.

The effect of losartan on hemoglobin concentration and renal outcome in diabetic nephropathy of type 2 diabetes

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can decrease hemoglobin, causing anemia and this may be an independent risk factor for chronic kidney disease progression. We studied the relationship between a decline in hemoglobin and outcome in 1513 patients with type 2 diabetes and kidney disease by a post hoc analysis of the RENAAL Study (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) with an average follow-up of 3.4 years. The relationship between baseline and year-1 hemoglobin and treatment on end-stage renal disease (ESRD) and ESRD or death was evaluated using multivariate Cox models (covariates: baseline hemoglobin, proteinuria, serum albumin, serum creatinine, and year-1 hemoglobin). Compared with placebo, losartan treatment was associated with a significant decrease of hemoglobin, with the largest between-group difference at 1 year. After adjustment, there were significant relative risk reductions for losartan compared with placebo for ESRD and for ESRD or death regardless of the baseline hemoglobin even in those patients with a baseline hemoglobin below 120 g l(-1). Hence, the renoprotective properties of losartan were maintained despite a significant lowering of the hemoglobin concentration.

Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics

Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the beta1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.

Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.

Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Etidronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. To assess the efficacy of etidronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. Women receiving at least one year of etidronate for postmenopausal osteoporosis were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. Study selection and data abstraction was done in duplicate. Meta-analysis of fracture outcomes was performed with data presented as relative risks and a relative change greater than 15% was considered clinically important. Study quality was assessed through the reporting of allocation concealment, blinding and withdrawals. Eleven studies representing a total of 1248 patients were included in the review.A significant 41% relative risk reduction (RRR) in vertebral fractures across eight studies (RR 0.59, 95% CI 0.36 to 0.96) was found. The six secondary prevention trials demonstrated a significant RRR of 47% in vertebral fractures (RR 0.53, 95% CI 0.32 to 0.87) and a 5% absolute risk reduction (ARR); compared with the pooled result for the two primary prevention trials (RR 3.03, 95% CI 0.32 to 28.44), which was not significant. There were no statistically significant risk reductions for non-vertebral (RR 0.98, 95% CI 0.68 to 1.42), hip (RR 1.20, 95% CI 0.37 to 3.88) or wrist fractures (RR 0.87, 95% CI: 0.32 to 2.36). For adverse events, no statistically significant differences were found in the included studies. However, observational data has led to concerns regarding potential risk for upper gastrointestinal injury. Etidronate, at 400 mg per day, demonstrated a statistically significant and clinically important benefit in the secondary prevention of vertebral fractures. No statistically significant reductions in vertebral fractures were observed when it was used for primary prevention. In addition, no statistically significant reductions in non-vertebral, hip, or wrist fractures were found, regardless of whether etidronate was used for primary or secondary prevention. The level of evidence for all outcomes is Silver (www.cochranemsk.org.).

Beneficial effects of aggressive low-density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study

Objective:To examine by secondary analysis of the Treating to New Targets (TNT) study whether the benefits of intensive versus standard levels of lipid lowering are equally applicable to women.Methods:A total...

The Cochrane Library and trachoma: an overview of reviews

AbstractBackground:Trachoma is the leading infectious cause of blindness worldwide. Active trachoma is caused by the bacterium Chlamydia trachomatis. Recurrent infection over many years may lead to scarring of the conjunctiva, entropion, trachomatous trichiasis and corneal opacity.Objective:To summarize Cochrane reviews that assess the effect of SAFE strategy (surgery, antibiotics, face washing and environmental change) for trachoma in developing countries.Methods:The Cochrane Database of Systematic Reviews was searched for any intervention to prevent or treat trachoma. Data was extracted in duplicate and analyzed.Main Results:There were four systematic reviews addressing trachoma, all of which met the inclusion criteria. There was some evidence that the prevalence of active trachoma was reduced by the use of antibiotics. At three months, six of nine trials found a significant reduction in relative risk of active trachoma in the intervention groups. At 12 months, only three of six studies found a significant reduction. Oral azithromycin performed better than topical tetracycline at clearing infection at three months, but not at resolving clinical signs. There is evidence that face washing in combination with topical tetracycline antibiotics can reduce the prevalence of severe trachoma compared to face washing alone. Insecticide spray as a fly control measure significantly reduced trachoma and health education may be effective in reducing active trachoma.Full thickness incision of the tarsal plate was found to be the most successful type of surgery for trichiasis. Tarsal rotation surgery was also found to be more effective than non‐surgical techniques for minor trichiasis. This surgery was equally effective when performed by appropriate trained ophthalmic nurses and ophthalmologists and also when conducted in a health centre or village setting.Authors' Conclusions:There are no clinical trials of the full SAFE strategy for trachoma control on blindness prevention, or on reducing active trachoma, or ocular Chlamydia trachomatis infection. However, there is some evidence that separately supports each of the components of SAFE: surgery, antibiotics, facial cleanliness, and environmental improvements. Programmatically, continued delivery of the full SAFE strategy is warranted and can be expected to have a positive impact on the control of blinding trachoma. Copyright © 2007 The Cochrane Collaboration. Published by John Wiley &amp; Sons, Ltd. The Cochrane Collaboration

Poster 150: Effect of Once-Yearly Infusion of 5mg of Zoledronic Acid in Postmenopausal Women With Osteoporosis: The HORIZON-Pivotal Fracture Trial

Objective: To evaluate once-yearly 5mg of zoledronic acid (ZOL) to decrease fracture risk in women with postmenopausal osteoporosis (PMO). Design: Multinational, 3-year, randomized, double-blind, placebo-controlled trial. Setting: 240 clinical centers in 27 countries. Participants: 7736 women with PMO (age range, 65−89y). Intervention: Once-yearly 5mg infusion of ZOL. Main Outcome Measure: New morphometric vertebral fractures and hip fractures at 3 years. Results: A 5mg treatment of ZOL resulted in significant relative risk reductions in morphometric vertebral fracture of 70% versus placebo (3.3% vs 10.9%; 95% confidence interval (CI), 62%−76%) and in hip fracture of 41% versus placebo (1.4% vs 2.5%; 95% CI, 17%−58%).

Reducing the Risk for Breast Cancer Recurrence After Completion of Tamoxifen Treatment in Postmenopausal Women

Background: In postmenopausal women with hormone-sensitive early stage breast cancer, the risk for relapse persists after 5 years of treatment with adjuvant tamoxifen. Because tamoxifen is not indicated for adjuvant therapy beyond 5 years, the need for another therapy in the extended adjuvant setting to reduce late recurrence risk is clear. The National Cancer Institute of Canada Clinical Trials Group MA.17 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-33 trial found that extended adjuvant therapy with an aromatase inhibitor (AI) (eg, letrozole, exemestane, or anastrozole) rendered additional benefit in postmenopausal women with hormone receptor-positive breast cancer. The MA.17 trial was unblinded at the first interim analysis (median follow-up, 2.4 years) due to a significant reduction in relative risk for recurrence ( P < 0.001). Following the publication of the final analysis, several other MA.17 trial analyses and a postblinding analysis were also conducted. Recent data on the NSABP B-33 trial, which investigated exemestane in the extended adjuvant setting, and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 6a, which evaluated anastrozole in the extended adjuvant setting, have also been reported. Objective: The goal of this article was to provide a current review of the MA.17 and NSABP B-33 resuits, together with additional data, to determine the benefit and tolerability of extended adjuvant AI therapy and the potential benefits of late extended adjuvant therapy with AIs after a prolonged (≤5 years) period after the completion of tamoxifen treatment. Methods: A literature search was performed. PubMed and MEDLINE were searched for descriptions of clinical trials published from 1990 to 2007 using the terms breast cancer, extended adjuvant, aromatase inhibitor, anastrozole, exemestane, and letrozole. Abstracts from several oncology meetings held between 2001 and 2007 also were searched to extract relevant data (disease-free survival [DFS], overall survival [OS]). Results: In MA.17 at 30 months, postmenopausal patients with early stage breast cancer who received extended adjuvant letrozole (n = 2593) experienced a significant (42%) improvement in DFS regardless of nodal status ( P < 0.001), and there was a significant (39%) improvement in as in node-positive patients ( P = 0.04), compared with placebo. At median follow-up (54 months), a postunblinding analysis found that patients who were switched to letrozole after a prolonged period (up to 5 years) after discontinuation of tamoxifen experienced a 69% improvement in DFS ( P < 0.001), a 72% improvement in distant DFS ( P = 0.002), and a 47% improvement in as ( P = 0.05) compared with patients who elected to continue with no treatment at trial unblinding. Results from 2 other extended adjuvant trials, the NSABP B-33, investigating exemestane in the extended setting (relapse-free survival, P = 0.03; no significant improvement in DFS or as), and the smaller ABCSG 6a, also support a benefit of extended adjuvant AI therapy. Conclusions: Current evidence supports the use of letrozole and perhaps exemestane in the extended adjuvant setting, while data on anastrozole are emerging. Based on the results from this review, initiation of letrozole treatment following a prolonged interval after completion of 5 years of tamoxifen treatment might be beneficial.

Comorbidity with ADHD Decreases Response to Pharmacotherapy in Children and Adolescents with Acute Mania: Evidence from a Metaanalysis

To assess whether comorbid attention-deficit hyperactivity disorder (ADHD) influences response to treatment in young patients with acute mania. We conducted a metaanalysis of 5 open trials of 100, 35, 41, 60, and 37 children and adolescents. The pooled group included 273 children and adolescents with bipolar disorder (BD), divided into 2 subgroups: those with (n = 132), and those without (n = 141), ADHD comorbidity. There was a moderate and significant reduction in relative risk (RR) favouring treatment response in children and adolescents with BD but without ADHD comorbidity (RR 0.822; 95% CI, 0.69 to 0.97; P = 0.021). The negative effect of ADHD comorbidity on treatment response was more significant in studies including adolescents only or subjects with BD I only. These findings suggest that children and adolescents with BD and ADHD tend to be less responsive to drugs used in treatment of acute mania.

Effects of perindopril on long-term clinical outcome of patients with coronary artery disease and preserved left ventricular function

Background The EUROPA trial has demonstrated that an ACE inhibitor perindopril, was able to significantly decrease the risk of major cardiac events in patients with stable coronary heart disease without apparent heart failure. Aim To assess the long-term clinical outcome of patients with stable coronary heart disease and preserved left ventricular function (left ventricular ejection fraction (LVEF ≥ 40%). Methods A retrospective evaluation of LVEF was performed in the EUROPA study population. Among the 12,218 patients of EUROPA, we identified 7096 (58%) patients who had LVEF measurement before randomization. The measurements were obtained mainly by echocardiography in 5214 cases (73%) or by angiography in 1470 cases (21%). Two groups of patients were studied: 6878 (97 %) patients with LVEF ≥ 40% (3429 received 8 mg of perindopril and 3449 received a placebo) and 218 patients (3%) with a LVEF < 40% (111 received perindopril and 107 a placebo). Results The baseline characteristics of patients with documented LVEF were similar to the whole EUROPA population in terms of demographics, medical history, physical examination (heart rate, blood pressure), and medications at screening. The mean LVEF of this population was 57.0 ± 10.4%. In patients ( n = 6878) with preserved LV function (LVEF ≥ 40%), there was a significant relative risk reduction of 16% of the primary endpoint (a composite of cardiovascular death, non-fatal myocardial infarction and resuscitated cardiac arrest) in the group treated with perindopril (8.3%) in comparison to the group treated with placebo (9.8%): Hazard ratio (HR) = 0.84 [95% CI: 0.72–0.99] p = 0.033). Similar results were obtained for the first secondary endpoint (total mortality, non-fatal myocardial infarction, hospital admission for unstable angina and cardiac arrest with successful resuscitation): HR = 0.85 [95% CI: 0.76–0.96] p = 0.008, for cardiovascular mortality and non-fatal MI: HR = 0.84 [95% CI: 0.72–0.99] p = 0.036. Similar benefits were observed in patients with an LVEF ≥ 40% and a history of previous myocardial infarction and in patients with an LVEF < 40%. Conclusions LVEF was documented in 58% of the EUROPA study population and only 3% had an impaired LV function, confirming that EUROPA patients did not have asymptomatic LV dysfunction. Results in patients with preserved LV function are consistent with those of the whole EUROPA study population and perindopril 8 mg is beneficial in the broad spectrum of patients with stable coronary artery disease without evidence of heart failure.

Abstract 4192: Tissue ACE Inhibitors for Secondary Prevention of Adverse Cardiovascular Events in Patients with Preserved Left Ventricular Function: A Pooled Meta-Analysis

Introduction: Although the role of angiotensin converting enzyme (ACE) inhibitors in patients with depressed left ventricular function is well established, their role in patients with preserved ventricular function is uncertain. We conducted a meta-analysis of recent clinical trials to evaluate the role of tissue ACE inhibitors in secondary prevention of cardiovascular disease in patients with preserved left ventricular function. Study Selection: Randomized placebo-controlled clinical trials of at least 12 months duration, conducted in patients who had experienced an acute cardiovascular event or were at high risk for cardiovascular events. Data Synthesis and Analysis: A total of 31,555 patients from 4 selected trials were analyzed. Relative risk estimations were made using pooled data from the 4 trials. Statistical significance was determined using the Chi-square test (two-sided alpha error &lt;0.05). Results: When compared to placebo, the use of tissue ACE inhibitors was associated with significant relative risk reductions in all-cause mortality (p&lt;0.001), cardiovascular mortality (p&lt;0.001), fatal &amp; non-fatal myocardial infarction (p&lt;0.001) and stroke (p&lt;0.001), as well as hospitalization for congestive heart failure (p=0.001) &amp; occurrence of new-onset diabetes mellitus (p&lt;0.001). The need for invasive coronary revascularization was also reduced (p&lt;0.03), but the risk of hospitalization for angina was not significantly affected. Conclusion: Tissue ACE inhibitors decrease mortality and cardiovascular morbidity in high risk patients with cardiovascular disease and preserved left ventricular function in randomized placebo-controlled clinical trials.

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes: a subanalysis of Japanese patients from the RENAAL study

The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study has previously shown losartan to confer significant benefits to patients with type 2 diabetes and nephropathy. The original study of 1513 patients included 96 Japanese patients; the present study is a post-hoc analysis of the effects of losartan in this Japanese subpopulation. This double-blind, randomized study compared losartan (50 to 100 mg once daily) with placebo. The study medication was taken in addition to conventional antihypertensive treatment, and the mean follow-up period for the Japanese patients was 2.8 years. The primary endpoint was the composite of doubling of serum creatinine, endstage renal disease, or death. Secondary endpoints included changes in proteinuria levels. Safety was also evaluated. The primary composite endpoint was reached in fewer Japanese patients receiving losartan than placebo (50.0% versus 65.4%, respectively). The treatment effects of losartan were more robust when data were corrected for differences in proteinuria at baseline--a significant relative risk reduction of 45% with losartan (P=0.0397) was apparent. Treatment benefit exceeded that attributable to blood pressure changes alone. Levels of proteinuria were reduced with losartan compared with placebo, with an overall losartan treatment effect of 37.8% (P<0.001). Overall, losartan was similarly well tolerated in both the Japanese patients and the total population. In Japanese patients with type 2 diabetes and nephropathy, losartan offers renal protection and is generally well tolerated.

The Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: a comparison of first-line combination therapies

Although multidrug therapy is required in order to achieve good blood pressure control in many hypertensives, there are no studies directly comparing fixed-dose combinations as initial therapy. The Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial compares regimens of benazepril plus amlodipine versus benazepril plus hydrochlorothiazide, force-titrated to 40/10 and 40/25mg, respectively. A total of 12,600 high-risk hypertensives have been randomised and will be followed for 3 – 5years, during which cardiovascular events will be monitored. The investigators hypothesise that the benazepril plus amlodipine regimen will decrease cardiovascular events by 15% compared with benazepril plus hydrochlorothiazide. Recruitment began in 2003, and the trial is expected to end in 2008. The ACCOMPLISH trial shares important limitations with many other recent trials that will make it difficult to apply the results in clinical practice. These include the focus on high-risk hypertensive patients, in whom significant reductions in relative risk will translate into meaningful reductions in absolute risk: in lower-risk hypertensives with a low absolute risk, similar relative risk reductions may not be of great impact on the population disease burden. In ACCOMPLISH, as in most industry-sponsored clinical trials, the main goal appears to be market-driven: doses of drugs tested are not those available for clinical practice. The question asked, whether the combination of benazepril with either diuretic or dihydropyridine calcium channel blocker is more efficacious, is not a clinically compelling one. Finally, the univariate subgroup analyses proposed are unlikely to lead to an understanding of whether either combination has specific advantages for patients encountered clinically, most of whom have multiple risk factors. Thus, it appears that ACCOMPLISH, as with many recent pharmacological trials, will not greatly impact the treatment of hypertension.

Impact of counselling on careseeking behaviour in families with sick children: cluster randomised trial in rural India

Objective To assess whether training doctors in counselling improves careseeking behaviour in families with sick children.Design Pair matched, community randomised trial conducted in 12 primary health centres (six pairs). Doctors...

Long-term statin safety and efficacy in secondary prevention: can combination therapy improve outcomes?

The use of statins has been associated with substantial reductions in vascular morbidity and mortality. The Prospective Pravastatin Pooling Project (PPP) looked at the long-term safety and efficacy of statins in secondary prevention, based on pooled results from three key statin trials. PPP revealed a highly significant relative risk reduction in total mortality, and demonstrated that pravastatin has a similar incidence of muscle-related side effects as placebo. It has been speculated that treatment with statins in combination with other cardiovascular drugs may have a synergistic effect on reduction of cardiovascular complications. However, for ethical reasons, evidence can only ever be sought from sub-group analyses or meta-analyses of existing studies. Recent studies have focused on statins plus acetyl- salicylic acid (ASA, aspirin). Evidence suggests that a combination of statins with ASA provides a cardiovascular risk reduction that is superior to the respective monotherapy. Thus, statins effectively reduce further cardiovascular morbidity and mortality as well as total mortality in patients with manifest coronary artery disease (CAD) or at high risk, also they act in synergy with ASA and they are safe.