Prospective Randomized Open Blinded Endpoint Research Articles

Benefits of Aldosterone Receptor Antagonism in Chronic Kidney Disease (BARACK D) trial-a multi-centre, prospective, randomised, open, blinded end-point, 36-month study of 2,616 patients within primary care with stage 3b chronic kidney disease to compare the efficacy of spironolactone 25mg once daily in addition to routine care on mortality and cardiovascular outcomes versus routine care alone: study protocol for a randomized

BackgroundChronic kidney disease (CKD) is common and increasing in prevalence. Cardiovascular disease (CVD) is a major cause of morbidity and death in CKD, though of a different phenotype to the general CVD population. Few therapies have proved effective in modifying the increased CVD risk or rate of renal decline in CKD. There are accumulating data that aldosterone receptor antagonists (ARA) may offer cardio-protection and delay renal impairment in patients with the CV phenotype in CKD. The use of ARA in CKD has therefore been increasingly advocated. However, no large study of ARA with renal or CVD outcomes is underway.MethodsThe study is a prospective randomised open blinded endpoint (PROBE) trial set in primary care where patients will mainly be identified by their GPs or from existing CKD lists. They will be invited if they have been formally diagnosed with CKD stage 3b or there is evidence of stage 3b CKD from blood results (eGFR 30–44 mL/min/1.73 m2) and fulfil the other inclusion/exclusion criteria. Patients will be randomised to either spironolactone 25 mg once daily in addition to routine care or routine care alone and followed-up for 36 months.DiscussionBARACK D is a PROBE trial to determine the effect of ARA on mortality and cardiovascular outcomes (onset or progression of CVD) in patients with stage 3b CKD.Trial registrationEudraCT: 2012-002672-13ISRTN: ISRCTN44522369

Impact of metformin on endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study.

IntroductionLarge prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury.MethodsTwenty-eight healthy volunteers (age 41±6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm.ResultsBaseline FMD did not differ between metformin pretreatment and no pretreatment (6.9±3.6% and 6.1±3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4±3.3% and 4.3±2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR.ConclusionA 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment.Trial Registration ClinicalTrials.gov NCT01610401

A prospective study comparing the efficacy and safety of two sublingual birch allergen preparations.

BackgroundSUBLIVAC FIX Birch (SUB-B) is a liquid oral preparation of Betula verrucosa pollen extract for the treatment of allergic rhinitis/rhinoconjuctivitis induced by birch pollen. The major allergen content of SUB-B and Staloral Birch (Stal-B) have been shown to be comparable. In order to compare the clinical efficacy and safety of both products, the present study was designed to investigate efficacy of treatment with SUB-B compared to Stal-B by means of reduction in allergy symptoms assessed by a titrated nasal provocation test (TNPT) in subjects suffering from IgE mediated allergy complaints triggered by birch pollen.MethodsA prospective, randomized, open, blinded endpoint (PROBE), controlled, single-centre study in 74 birch allergic adults was performed. Treatment consisted of either SUB-B (10,000 AUN/ml) or Stal-B (initial phase 10 I.R./ml and maintenance phase 300 I.R./ml) for 16–20 weeks at maintenance dose. The primary efficacy outcome was defined by the difference in change of the TNPT-threshold dose between the two treatment groups at baseline and after completion of treatment. Secondary outcomes included determination of birch pollen specific IgE and IgG levels, safety lab and ECG. During the first 30 days of treatment, subjects were requested to fill out a diary concerning compliance with study medication, occurrence of AEs and the use of concomitant medication.ResultsAnalysis of the primary efficacy parameter showed that the percentage of subjects showing a beneficial treatment effect was similar in both treatment groups, 33.3% for SUB-B vs. 31.4% for Stal-B in the intention to treat population. Evaluation of the immunologic response, showed that treatment with SUB-B and Stal-B induced similar increases (approximately 2 times) in IgE, IgG and IgG4 specific for Bet v 1.In total, 143 related adverse events (AEs) were reported. The majority of the AEs was of mild intensity. The same pattern of AEs was observed for both products. No clinically relevant changes in other safety parameters, such as safety laboratory parameters, vital signs, physical examination and ECGs were observed.ConclusionTaken together, treatment with both products was effective by means of reduction in allergic symptoms during a TNPT. In addition, safety analysis revealed a good tolerability of both SLIT extracts.

Italian guidelines on thrombolysis indications in ischaemic stroke have been revised after IST 3 trial and Cochrane Review: PROS

On 26th, 27th and 28th October 2012, a group of Italian neurologists and stroke physicians met in Vibo Valentia, to discuss the implications of IST 3 and updated Cochrane Systematic Review results on thrombolysis in acute ischaemic stroke [1, 2]. After careful examination of all the available evidence, some modifications of the current Italian guidelines were agreed to, which are as follows: Recommendation, Grade A: treatment with rt-PA (0.9 mg/kg) is indicated within 4.5 h from the beginning of symptoms of an ischaemic stroke, without any age limit. Treatment must be started as soon as possible after the stroke onset. Synthesis: both the IST 3 trial and Cochrane Systematic Review suggest that treatment could be effective up to 6 h. Single patient data meta-analysis of all rt-PA trials (which is ongoing) will offer a clarification of the possible interaction among age, severity and onset to treatment time. Text: exclusion criteria for thrombolysis: third criterium ‘‘severe stroke clinically (i.e. National Institute for Health Stroke Scale [25) or by neuroimaging’’. Note: this criterium should be abandoned after IST 3 results. Why were these important statements decided? The results of IST 3 are to be carefully analysed, and put in the context of the whole evidence on rt-PA treatment for cerebral ischaemia. IST 3 was a no profit, clinicians driven trial, with the aim of clarifying whether a promising therapy could be given to almost all the patients admitted to Stroke Units, despite age and severity of the neurological deficit. The randomisation was based on the uncertainty principle, a well-known concept, successfully used in many previous relevant large trials (i.e. IST, CLOTS, FOOD, ECST), that produces a high degree of external validity of the results. The trial was based on the PROBE (prospective, randomised, open blinded endpoint) method (after the first 300 patients were randomized in a blind fashion), which is the best available system to combine both correct methodology and feasibility of the study [3]. Central blind follow-up was secured, and this way to obtain outcome information has been validated many years prior [4, 5] and is the same used in many previous and current studies. As happens in many large trials, IST 3 lasted several years, during which new pieces of knowledge were made available in the field of stroke medicine, and of course they should have been taken into account by the IST 3 group. In fact, the original IST 3 protocol stated that the primary outcome was a dichotomized end point, based on Oxford Handicap Scale (OHS) at 6 months [that can be considered as the modified Rankin Scale (mRS)]: 0–2 vs 3–6, aiming at a 4 % absolute reduction of worse prognosis. However, when results of ECASS 3 [6] became available, it was clear that different dichotomizations could lead to different results: in fact, ECASS 3 results were not statistically significant when considering 0–2 vs 3–6 cut off, but definitely positive when considering 0–1 vs 2–6 cut off, and this very result prompted a modification of the European Guidelines, which was widely accepted by the stroke community (time limit moved from 3 to 4.5 h). As a matter of fact, ECASS 2 had given a statistically not significant result when considering 0–1 vs 2–6 cut off, but was significant if 0–2 vs 3–6 was taken into account. Therefore, we decided to add the 0–1 vs 2–6 endpoint to our outcome measures, to make our results comparable with those already produced. In the meantime, increasing evidence had become available on a new way to analyze stroke S. Ricci (&) S. Cenciarelli T. Mazzoli UO Neurologia, USL Umbria 1, Centro di Coordinamento IST 3 per l’ Italia, Ospedali di Citta di Castello e Branca, Citta di Castello, Italy e-mail: stefano.ricci@uslumbria1.it

Azelnidipine versus diuretic against albuminuria used in combination with angiotensin receptor blocker in hypertensive patients with diabetes

Purpose: A thiazide diuretic used in combination with an angiotensin converting enzyme inhibitor, benazepril, more effectively reduces urinary albumin as compared to amlodipine plus benazepril in patients with hypertension and diabetes. However, calcium channel blockers have diverse characteristics. The present study was designed to test the hypothesis that combining an angiotensin receptor blocker with either azelnidipine or a thiazide diuretic produced similar reductions in albuminuria in hypertensive diabetic patients for the same levels of blood pressure achieved. Methods: This was a 24-week prospective randomized open blinded endpoint study assessing the effects of azelnidipine versus those of a diuretic in combination with an angiotensin receptor blocker, olmesartan, on urinary albumin excretion in patients with hypertension and diabetes. Patients with hypertension, type 2 diabetes, and albuminuria (30–600 mg/g creatinine) under antihypertensive treatment (mean age, 67.0±7.6 years) were recruited. They were instructed to stop all antihypertensive treatment and take a combination of olmesartan (20 mg, daily) and amlodipine (5 mg, daily) for 12 weeks (run-in period). Then, patients were randomly assigned to receive either olmesartan plus azelnidipine (16 mg/day; n=71) or olmesartan plus trichlormethiazide (1 mg/day; n=72) for an additional 24 weeks, with the endpoint being urinary excretion of albumin. Results: At the time of randomization, the blood pressures was 135±12/75±10 and 135±12/76±9 mmHg and urinary albumin was 116.0 and 107.8 mg/g creatinine (geometric mean) in the azelnidipine and diuretic arms, respectively. Urinary albumin excretion was reduced to a similar extent in the azelnidipine (79.8 [95% confidence interval 66.4–96.0] mg/g creatinine) and diuretic regimen (89.7 [74.6–107.7] mg/g creatinine) after adjustment for baseline values, while glomerular filtration rate was reduced only in the diuretic group. There were no significant differences in blood pressure between the two arms throughout the treatment period (at 24 weeks 133±10/74±8 and 134±11/74±10 mmHg in the azelnidipine and diuretic regimens, respectively). Conclusion: Azelnidipine is equally effective as a thiazide diuretic in reducing urinary albumin when used in combination with olmesartan though the calcium channel blocker does not reduce glomerular filtration rate.

Left atrial dilatation as a predictive factor of beneficial response to carvedilol in patients with HFPEF: A finding from the Japanese Diastolic Heart Failure study (J-DHF)

Purpose: Therapeutic strategy for Heart Failure with Preserved Ejection Fraction (HFPEF) has not been established. Recently, the Japanese Diastolic Heart Failure Study (J-DHF), a multicenter, prospective, randomized, open, blinded endpoint (PROBE) trial to assess the effects of β-blocker, carvedilol, in HFPEF patients in Japan, has suggested beneficial effects of the standard-dose, not the low-dose, prescription of carvedilol in HFPEF patients. However, it is unclear whether any factor could predict the effects of the standard-dose carvedilol in HFPEF. Methods: Data from 245 HFPEF patients in J-DHF were evaluated to clarify demographic, clinical, echocardiographic and biological variables that are related to the primary outcome (a composite of cardiovascular death and unplanned hospitalization for heart failure) and another major outcome (a composite of cardiovascular death and unplanned hospitalization for any cardiovascular causes). We also analyzed the interaction between these clinically relevant factors and the response to standard-dose carvedilol in the proportional hazard model. Results: Aging, decreased body mass index, diabetes mellitus, history of hospitalization for heart failure, anemia, renal dysfunction, increased plasma B-type natriuretic peptide, left ventricular (LV) hypertrophy, and left atrial (LA) dilatation were prognostic factors for both clinical outcomes. In the patients with LA diameter ≥ 43.2mm (the median value), standard-dose carvedilol was associated with hazard ratio (HR) 0.263 (95% confidence interval (CI):0.080 to 0.859) for the primary outcome, but in those with LA diameter < 43.2mm, HR was 1.123 (95% CI:0.501 to 2.514). A p value for the interaction was 0.0462. For another major outcome, HR was 0.257 (95% CI:0.092 to 0.715) in the patients with LA diameter ≥ 43.2mm and 0.783 (95% CI:0.393 to 1.561) in those with LA diameter < 43.2mm, and a p value for the interaction was 0.0764. The other prognostic factors did not influence the response to standard-dose carvedilol. Conclusions: As LA dilatation is a sign of LV diastolic dysfunction, the current results suggest that the beneficial effects of standard-dose carvedilol are provided in HFPEF patients with advanced rather than modest diastolic dysfunction.

The Evening versus Morning Polypill Utilization Study: the TEMPUS rationale and design

In clinical practice, blood pressure (BP)-lowering agents are generally prescribed for use in the morning, whereas (short-acting) statins are recommended for use in the evening. There is evidence that the reduction in LDL cholesterol (LDL-c) achieved with short-acting statins is superior when taken in the evening and reported improvement in BP control when aspirin and BP-lowering agents are taken in the evening. However, it is unclear whether the additional reduction in LDL-c and BP is offset by a reduction in adherence, given that taking medication in the evening may be less typical or convenient. There is therefore uncertainty concerning the best timing of administration of a cardiovascular combination pill such as the polypill. The aim of TEMPUS (NCT01506505), a prospective randomized open blinded endpoint (PROBE) crossover trial, is to evaluate whether there is a difference in LDL-c levels or 24-hour ambulatory BP in individuals at increased risk of cardiovascular disease when the cardiovascular polypill is taken in the evening compared to the morning. An additional aim is to assess the effect of the polypill on LDL-c and BP compared to the administration of separate pills of identically dosed components of the polypill. In total 75 participants with established cardiovascular disease or an intermediate to high risk for cardiovascular disease are randomly allocated to the sequence of three different treatments of 6-8 weeks: (1) the cardiovascular polypill (aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg, and hydrochlorothiazide 12.5 mg) in the evening; (2) the polypill in the morning; and (3) the use of the identically dosed agents in separate pills taken at different time points during the day. The primary endpoint is the difference in LDL-c and mean 24-hour ambulatory systolic BP. Secondary outcomes are the difference in relative risk reduction, biochemistry, platelet function and pulse wave analysis, participants' adherence, and acceptability. TEMPUS will evaluate the effect of timing of the administration of a cardiovascular polypill on LDL-c and BP measurements in patients with an intermediate or high risk for cardiovascular disease.

Do open label blinded outcome studies of novel anticoagulants versus warfarin have equivalent validity to those carried out under double-blind conditions?

Recent anticoagulants for stroke prevention in AF have been tested in active comparator controlled studies versus warfarin using two designs: double-blind, double-dummy and prospective randomised, open blinded endpoint (PROBE). The former requires elaborate procedures to maintain blinding, while PROBE does not. Outcomes of double-blind and PROBE designed studies of novel anticoagulants for AF, focusing on warfarin controls, were explored. Major, Phase III warfarin-controlled trials for stroke prevention in AF were identified. Odds ratios (ORs) of key outcomes for active comparators versus VKA and event rates for VKA arms were compared between designs, in context of baseline demographics and inclusion criteria. Identified trials studied five novel anticoagulants in three each of PROBE and double-blind design. For ORs of results across studies and outcomes, there was little pattern differentiating the two designs. Among VKA-control subjects, event rates for the primary outcome (stroke or systemic embolism) in PROBE trials at 1.74 %/year (95% confidence interval: 1.54-1.95) was not significantly different from that in double-blind trials, at 1.88 (1.73-2.03). Among other outcomes, VKA-treated subjects in both trial designs had similar event rates, apart from higher all-cause mortality in ROCKET AF, and lower myocardial infarction rates among the PROBE study patients. Although there are differences in outcome between PROBE and double blind trials, they do not appear to be design-related. The exacting requirements of double-blinding in AF trials may not be necessary.

Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT)

IntroductionCyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects....

Specificity of the Cardiocerebral-Event Reductions in the Kyoto Heart and Jikei Heart Study

Specificity of the Cardiocerebral-Event Reductions in the Kyoto Heart and Jikei Heart Study The Kyoto Heart Study was a prospective randomized open blinded end-point (PROBE)-design trial, in which 3031 Japanese patients (mean, 66 years) with uncontrolled hypertension were randomized to either valsartan add-on or non-angiotensin receptor blocker (ARB) treatment.

Strategy for treating selective serotonin reuptake inhibitor-resistant social anxiety disorder in the clinical setting: a randomised controlled trial protocol of cognitive behavioural therapy in combination with conventional treatment

IntroductionPharmacotherapy and cognitive behavioural therapy (CBT) are consistently effective as first-line treatments for social anxiety disorders (SADs). Nevertheless, pharmacotherapy is often the first choice in clinical practice. In many countries,...

A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design

BackgroundSevere hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial.Methods/designThe study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year.DiscussionIn contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996.

Randomized Crossover Study of the Efficacy and Safety of Sevelamer Hydrochloride and Lanthanum Carbonate in Japanese Patients Undergoing Hemodialysis

Insufficient control of serum calcium and phosphate levels in patients undergoing hemodialysis is associated with increased mortality. As commonly used calcium-containing phosphate binders can cause arterial calcification, newly developed calcium-free phosphate binders, such as sevelamer hydrochloride (SH) and lanthanum carbonate (LC), have received much attention. We assessed the efficacy and safety of SH and LC treatment in Japanese patients undergoing hemodialysis in a prospective randomized open blinded endpoint (PROBE) crossover study. Forty-two patients were randomized to receive SH or LC for 13 weeks, with the dosages adjusted every 2 weeks, followed by treatment with the other drug for another 13 weeks. The average daily doses of SH and LC were 2971 ± 1464 mg and 945 ± 449 mg, respectively. The mean dosage ratio of SH to LC was 3.05, which was maintained throughout the treatment period. SH and LC were similarly effective at controlling serum calcium and phosphate levels in the majority of patients (78-93%). A few serious adverse events (AEs) involving the biliary system occurred during the LC treatment period, but they were not considered to be treatment-induced. Although the incidence of constipation, the most common treatment-related AE, was higher during the SH period (27% vs. 5%; P < 0.05), no difference was observed in total treatment-related AEs. This study demonstrates that SH and LC are comparable treatments for controlling serum phosphate and calcium levels, and that both compounds are safe and well-tolerated in Japanese patients undergoing hemodialysis.

Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

BackgroundIntravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics.ResultsThe initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials.ConclusionThe data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials.Trial registrationISRCTN25765518

Comparison the effects of antihypertensive agents on arterial structure and function with non-dependent blood pressure reduction

Objective: To compare the effects of antihypertensive agents on arterial structure and function with non-dependent blood pressure reduction. Methods: Sixty-six patients with essential hypertensive were assigned to by the prospective randomized open blinded end-point (PROBE) study, which were divided into two groups by 37 patients in the telmisartan plus amlodipine and 29 patients in the compound amiloride plus amlodipine group, respectively. We compared the beneficial effects of the two groups on arterial stiffness.

Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study

The objective was to assess the add-on effect of valsartan on top of the conventional treatment for high-risk hypertension in terms of the morbidity and mortality. The KYOTO HEART Study was of a multicentre, Prospective Randomised Open Blinded Endpoint (PROBE) design, and the primary endpoint was a composite of fatal and non-fatal cardiovascular events (clintrials.gov NCT00149227). A total of 3031 Japanese patients (43% female, mean 66 years) with uncontrolled hypertension were randomized to either valsartan add-on or non-ARB treatment. Median follow-up period was 3.27 years. In both groups, blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study. Compared with non-ARB arm, valsartan add-on arm had fewer primary endpoints (83 vs. 155; HR 0.55, 95% CI 0.42-0.72, P = 0.00001). Valsartan add-on treatment to improve blood pressure control prevented more cardiovascular events than conventional non-ARB treatment in high-risk hypertensive patients in Japan. These benefits cannot be entirely explained by a difference in blood pressure control.

Candesartan for cardiovascular prevention in Japanese hypertensive patients with coronary heart disease

validity. The HIJ-CREATE investigators recruited among selected hospitalized patients undergoing coronary angiography. Patients without stenotic coronary lesions were eligible for randomization in the presence of a history of coronary revascularization or coronary spasm. Of those screened, only 40.9% were enrolled. The trial was powered to detect a 20% reduction in the primary endpoint at a rate in the control group of 100 events per 1000 patientyears. The observed rate was only 67 events per 1000 patientyears and explains why the trial was underpowered. The primary endpoint included weak events, such as a clinically defined diagnosis of heart failure or growing aortic aneurysm without dissection. The daily dose of candesartan used in the HIJ-CREATE trial (range 4‐12 mg) was lower than in most other countries (8‐16 mg in hypertensive patients, and up to 32 mg in patients with heart failure). By the end of the trial, 23.0% of patients of the non-ARB group had crossed over to treatment with ARBs. Furthermore, the HIJ-CREATE trial had a prospective randomized open blinded endpoint (PROBE) design. 2 An independent and blinded endpoint committee adjudicated the endpoints. However, such a PROBE design does not protect against observer bias in the assessment and reporting of endpoints or side effects. Only reported endpoints and symptoms qualify for blinded validation. HIJ-CREATE was not a trial of differential cardiovascular outcomes on ARB vs. non-ARB treatment, but a comparison of candesartan with a number of unspecified ACEIs. 1 In the non-ARB group, the use of ACEIs increased from 38.0% at randomization to 70.5%. About half of the patients in both treatment groups were on treatment with calcium channel blockers or b-blockers. Only 10% of patients were on treatment with diuretics. The investigators reported that the incidence of side effects leading to discontinuation of medications was 5.7% on candesartan and 12.2% on non-ARB treatment. Not unexpectedly, cough

Third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke.

BackgroundIntravenous recombinant tissue plasminogen activator (rt-PA) is approved for use in selected patients with ischaemic stroke within 3 hours of symptom onset. IST-3 seeks to determine whether a wider range of patients may benefit.DesignInternational, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rt-PA in acute ischaemic stroke. Suitable patients must be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracerebral haemorrhage. With 1000 patients, the trial can detect a 7% absolute difference in the primary outcome. With3500 patients, it can detect a 4.0% absolute benefit & with 6000, (mostly treated between 3 & 6 hours), it can detect a 3% benefit.Trial proceduresPatients are entered into the trial by telephoning a fast, secure computerised central randomisation system or via a secure web interface. Repeat brain imaging must be performed at 24–48 hours. The scans are reviewed 'blind' by expert readers. The primary measure of outcome is the proportion of patients alive and independent (Modified Rankin 0–2) at six months (assessed via a postal questionnaire mailed directly to the patient). Secondary outcomes include: events within 7 days (death, recurrent stroke, symptomatic intracranial haemorrhage), outcome at six months (death, functional status, EuroQol).Trial registrationISRCTN25765518

Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure

BackgroundThe large clinical trials proved that Basal-Bolus (BB) insulin therapy was effective in the prevention of diabetic complications and their progression. However, BB therapy needs multiple insulin injections per a day. In this regard, a biphasic insulin analogue needs only twice-daily injections, and is able to correct postprandial hyperglycemia. Therefore it may achieve the blood glucose control as same as that of BB therapy and prevent the diabetic complications including macroangiopathy.MethodsIn PROBE (Prospective, Randomized, Open, Blinded-Endpoint) design, forty-two type 2 diabetic patients (male: 73.8%, median(inter quartile range) age: 64.5(56.8~71.0)years) with secondary failure of sulfonylurea (SU) were randomly assigned to BB therapy with a thrice-daily insulin aspart and once-daily basal insulin (BB group) or to conventional therapy with a twice-daily biphasic insulin analogue (30 Mix group), and were followed up for 6 months to compare changes in HbA1c, daily glycemic profile, intima-media thickness (IMT) of carotid artery, adiponectin levels, amounts of insulin used, and QOL between the two groups.ResultsAfter 6 months, HbA1c was significantly reduced in both groups compared to baseline (30 Mix; 9.3(8.1~11.3) → 7.4(6.9~8.7)%, p < 0.01, vs BB;8.9(7.7~10.0) → 6.9(6.2~7.3)%, p < 0.01), with no significant difference between the groups in percentage change in HbA1c (30 Mix; -14.7(-32.5~-7.5)% vs BB -17.8(-30.1~-11.1)%, p = 0.32). There was a significant decrease in daily glycemic profile at all points except dinner time in both groups compared to baseline. There was a significant increase in the amount of insulin used in the 30 Mix group after treatment compared to baseline (30 Mix;0.30(0.17~0.44) → 0.39(0.31~0.42) IU/kg, p = 0.01). There was no significant difference in IMT, BMI, QOL or adiponectin levels in either group compared to baseline.ConclusionBoth BB and 30 mix group produced comparable reductions in HbA1c in type 2 diabetic patients with secondary failure. There was no significant change in IMT as an indicator of early atherosclerotic changes between the two groups. The basal-bolus insulin therapy may not be necessarily needed if the type 2 diabetic patients have become secondary failure.Trial registrationCurrent Controlled Trials number, NCT00348231

When premature is not premature—the ASCOT studyThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

‘ Controversy is the Lifeblood of Science ’Sir George Pickering1 Almost 3 years ago, in the aftermath of the ALLHAT study,2 the New York Times was carrying the headlines ‘Older way to treat hypertension found best’.3 ALLHAT, the largest study ever done, showed no difference in primary outcome (coronary heart disease) among the three treatment arms but seemed to favour chlorthalidone over amlodipine or lisinopril with regard to some secondary endpoints. Clearly, these headlines will need to be amended in view of the recent premature termination of the ASCOT trial.4 The primary objective of ASCOT was to compare the effects on fatal and non-fatal coronary heart disease of a so-called ‘conventional’ treatment, i.e. a beta-blocker (atenolol), combined, if needed, with a thiazide diuretic, to a more contemporary regimen of a calcium antagonist (amlodipine) and, if needed, an ACE-inhibitor (perindopril). In a prospective randomized open-blinded endpoint design (PROBE), a total of 19 000 patients were randomized to the two antihypertensive strategies. The study was launched in 1997 and stopped about 1 year …