Primary Cardiovascular End Point Research Articles

CArdiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular ComoRbiditiES

Comprehensive safety evaluation of new drugs for noncardiac indications is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk such as gout. Febuxostat is a potent nonpurine selective inhibitor of xanthine oxidase approved for the treatment of gout. Long-term CV safety of febuxostat is being established in a randomized, allopurinol-controlled clinical study in patients with gout who have increased CV risk using an analytical approach that provides 90% power to meet a noninferiority margin of 1.3 for the hazard ratio (HR) (febuxostat relative to allopurinol). The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina requiring urgent coronary revascularization. Approximately 7,500 men and women with gout and CV disease are being recruited and will be followed up for up to 5 years postrandomization. The statistical plan for the trial uses a design that evaluates the HR of febuxostat to allopurinol based on the primary CV composite end point when there are a maximum of 624 CV events. Interim analyses will be conducted when approximately 25%, 50%, and 75% of events have occurred. At each analysis, if the upper 1-sided confidence limit of the HR is <1.3, the study will be stopped, and the noninferiority of febuxostat relative to allopurinol with regard to CV risk will be declared. The CARES trial will define the CV safety profile of febuxostat and allopurinol in gout patients at high risk for CV events.

Combination therapy for hypertension in the elderly: a sub-analysis of the Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) Trial

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; <140/90 mm Hg). We further evaluated the efficacy and safety of these combination therapies in older (65 years) and younger (<65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (153365 years old and 1760 <65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a β-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P=0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08-6.96; β-blocker vs. thiazide, P=0.022) for fatal and non-fatal stroke, and 2.47 (1.03-5.91; β-blocker vs. ARB, P=0.043) for new-onset diabetes. Thus, benidipine combined with an ARB, a β-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.

Treatment of Hypertriglyceridemia With Fibric Acid Derivatives: Impact on Lipid Subfractions and Translation Into a Reduction in Cardiovascular Events

This review investigates how the treatment of hypertriglyceridemia with fibric acid derivatives impacts lipid concentrations, lipid particle size, and the rate of cardiovascular events: expressly, to decide whether the use of fibric acid derivatives is an effective treatment option in the reduction of cardiovascular endpoints for patients with specific lipid parameters at baseline. Fibric acid derivatives reduce fasting triglyceride (TG) values by 15% to 50% (depending on baseline level) and low-density lipoprotein cholesterol (LDL-C) by 8%, and raise high-density lipoprotein cholesterol (HDL-C) by 9%. In conjunction with a statin, the amount of TG lowering is approximately doubled with the addition of the fibrate. When measured, fibrates decrease the TG concentration of very low-density lipoprotein cholesterol particles while increasing the TG content of LDL particles. The mean size of LDL particles increases and there is a substantial reduction in the number and proportion of small, dense LDL. In randomized trials in primary and secondary prevention populations, fibrates were associated with a significant reduction in nonfatal myocardial infarction in most studies. In the subgroup with elevated TG and/or depressed HDL-C at baseline, all trials have found statistically significant relative risk reductions of 27% to 65% in the primary cardiovascular endpoint of myocardial infarction and cardiovascular death.

Intensive statin therapy for Chinese patients with coronary artery disease undergoing percutaneous coronary intervention (ISCAP study)

Myocardial necrosis is related to higher incidence of cardiovascular events and higher mortality rates during follow-up. Statins have been demonstrated to lower the risk of periprocedural myocardial infarction. The aim of this study is to evaluate the safety and efficacy of intensive statin therapy and the long-term outcome of patients in the Asian population. Approximately 1,100 patients with stable angina or non-ST elevation acute coronary syndrome undergoing selective percutaneous coronary intervention (PCI) are enrolled in this study. Patients are randomized either to the experimental group (80 mg atorvastatin 80 mg/day × 2 days before and 40 mg/day × 30 days after PCI) or to the control group (usual care). Creatine kinase-MB (CK-MB), troponin I (cTnI), and serum creatine are measured at 24 hours after the procedure. The total follow-up period is 6 months. The primary objective is to evaluate the efficacy of intensive atorvastatin treatment compared with usual care in reducing 30-day primary cardiovascular endpoints in patients undergoing selective PCI. Secondary endpoints are changes in myocardial biomarkers (cTnI, CK-MB) and hs-CRP, CIN morbidity, 6-month clinical outcomes, and safety. The result of the ISCAP study will provide important evidence on the efficacy and safety of periprocedural serial intensive statin treatment in Asian patients with coronary artery disease undergoing selective PCI.

Blutdruck Zielwerte auf dem Prüfstand

There is little evidence from controlled prospective studies to support the low blood pressure goals stipulated for the treatment of hypertension by present guidelines, especially in high-risk patients with diabetes, renal insufficiency or coronary heart disease. Aim of this review is to scrutinize the potential benefit and risk of low blood pressure on the basis of recent studies and secondary analyses of older studies. In patients with coronary heart disease or equivalent or with diabetes lowering systolic blood pressure to 130 to 135 mmHg reduced primary or secondary cardiovascular endpoints in the majority of studies. Between 120 and 129 mmHg some positive effects could be shown in patients with coronary heart disease but not in patients with diabetes or metabolic syndrome. In patients with diabetic or nondiabetic nephropathy including those with proteinurea no convincing data exist which show a better outcome with systolic blood pressure below 130 versus below 140 mmHg. However, several studies suggest that the risk of stroke may decrease by lowering systolic pressure to 120 mmHg or even lower. Below 120 mmHg an increased risk of cardiac and noncardiac events or death was shown in quite a number of studies. In patients between 70 and 80 years, current evidence suggests lowering systolic blood pressure to 135 to 145 mmHg and in those above 80 years to 145 to 155 mmHg. No evidence was found to justify different diastolic pressure goals for different groups of patients; optimal values fall between 70 and 85 mmHg. Limitations of recent studies are short follow-up, few event rates and small differences in achieved pressure between groups leaving uncertainty about long-term effects. Apart from prevention of stroke there is sparse evidence that lowering systolic blood pressure below 130 mmHg may be beneficial. Current evidence suggests that lowering systolic and diastolic pressure into a range of 130 to 140/70 to 85 may be adequate for all patients with the exception of children, adolescents and patients over 80 years. Further lowering of systolic pressure seems to offer little additional benefit and lowering diastolic pressure below 70 mmHg might increase risk.

EXamination of CArdiovascular OutcoMes with AlogliptIN versus Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE): A cardiovascular safety study of the dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome

Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events.

The prophylactic use of a proton pump inhibitor (PPI) in patients treated with clopidogrel and aspirin for an acute coronary syndrome or placement of a coronary stent reduces the rate of upper gastrointestinal bleeding with no apparent increase in cardiovascular events

Summary In the COGENT trial [5], 3,873 patients with an indication for a dual antiplatelet therapy were randomly assigned to omeprazole or placebo. The primary gastrointestinal (GI) end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization or stroke. Fiftyone patients presented the primary GI end point, with an event rate of 1.1% in the omeprazole group and 2.9% in the placebo group (hazard ratio 0.34, 95% CI 0.18‐0.63; P 0.001). The number of patients who would need to be treated for 6 months to prevent one occurrence of an event

An update on the controversies in anemia management in chronic kidney disease: lessons learned and lost.

Background. Erythropoietin deficiency and anemia occur in Chronic Kidney Disease (CKD) and may be treated with Erythropoietin Stimulating Agents (ESAs). The optimal hemoglobin, in non-End Stage Renal Disease CKD, is controversial. Methods. We review three recent randomized trials in anemia in CKD: CHOIR, CREATE, and TREAT. Results. CHOIR (N = 1432) was terminated early with more frequent death and cardiovascular outcomes in the higher Hb group (HR 1.34: 95% C.I. 1.03–1.74, P = .03). CREATE (N = 603) showed no difference in primary cardiovascular endpoints. Stroke was more common in the higher Hb group (HR 1.92; 95% C.I. 1.38–2.68; P < .001) in TREAT (N = 4038). Conclusions. There is no benefit to an Hb outside the 10–12 g/dL range in this population. To avoid transfusions and improve Quality of Life, ESAs should be used cautiously, especially in patients with Diabetes, CKD, risk factors for stroke, and ESA resistance.

PPI Cut GI Bleeding But Didn't Hike Heart Events

Adding a proton pump inhibitor to dual antiplatelet therapy significantly reduced the risk of gastrointestinal bleeding without raising the risk of cardiovascular events, according to a report published online in the New England Journal of Medicine. The finding is reassuring in view of the results of several previous studies that found a possible adverse drug interaction, said Deepak L. Bhatt, MD, of Harvard Medical School and the Veterans Affairs Boston Healthcare System, and his associates in the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT). “Our trial, in which the study population was at least 10 times as large as those in previous randomized studies and was not selected to represent high-risk patients, showed a significant reduction in clinically manifested gastrointestinal bleeding events, including overt bleeding, with a PPI as compared with placebo,” they noted. COGENT, an international, randomized, double-blind phase III study, assessed the safety and efficacy of omeprazole in 3,761 patients with coronary heart disease who were already taking clopidogrel plus aspirin. The study subjects were enrolled at 393 sites in 15 countries, randomly assigned to add either omeprazole 20 mg (1,876 patients) or placebo (1,885 patients) to their treatment regimen, and followed for a median of 106 days (341 days maximum). The median age was 69 years in both groups. The study was halted prematurely when the sponsor, Cogentus Pharmaceuticals, suddenly lost its financial backing; the company has since become defunct. At 180 days, there were 55 GI-bleeding events, with 47 patients having 1 such event and 4 patients having 2 events. The GI-bleeding event rate was 1.1% with omeprazole, significantly lower than the 2.9% rate with placebo. Similarly, the rates of overt GI bleeding, overt upper GI bleeding of unknown origin, and a composite of all overt and occult GI-bleeding events also were significantly lower with the active drug. “The number of patients who would need to be treated for 6 months to prevent one occurrence of an event that was part of the primary gastrointestinal end point was 55, and the number needed to treat to prevent one occurrence of overt GI bleeding was 98,” Dr. Bhatt and his colleagues said (N. Engl. J. Med. 2010 Oct. 6 [doi 10.1056/NEJMoa1007964]). In addition, at 180 days the percentage of participants with symptoms of gastroesophageal reflux disease was only 0.2% in the omeprazole group, compared with 1.2% in the placebo group. There were 109 cardiovascular adverse events (55 in the omeprazole group and 54 in the placebo group). The two groups were not significantly different in their rates of the primary cardiovascular end point, a composite of death from CV causes, nonfatal myocardial infarction, coronary revascularization, or ischemic stroke. “Although previous observational studies have yielded conflicting results in this regard, [our] study reveals no signal of harm from concomitant clopidogrel and PPI use,” the investigators said. The rates of serious adverse events did not differ significantly between the two study groups (10% with omeprazole and 9% with placebo). Similarly, the rates of overall diverse events did not differ significantly (41% and 43%, respectively). Dr. Bhatt reported receiving grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi Aventis, and the Medicines Company, and his associates reported ties to numerous drug and device manufacturers. Mary Ann Moon is a freelance writer based in Clarksburg, Md.

Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis

ObjectiveTo examine the association of cardiovascular events with tumour necrosis factor (TNF) α antagonist use compared with non-biological disease-modifying antirheumatic drug (DMARD) utilisation in patients with rheumatoid arthritis (RA).MethodsThe study...

Clopidogrel with or without Omeprazole in Coronary Artery Disease

Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Meta-Analysis of Folic Acid Supplementation Trials on Risk of Cardiovascular Disease and Risk Interaction With Baseline Homocysteine Levels

Experimental models and observational studies suggest that homocysteine-lowering therapy with folic acid (FA) may prevent cardiovascular disease (CVD). However, FA also stimulates cell proliferation and might promote progression of atherosclerosis. Our objectives were to perform a meta-analysis of FA supplementation trials on CVD events and to explore a potential interaction between FA supplementation and baseline homocysteine levels on CVD events. We searched MEDLINE for randomized controlled trials of FA supplementation to prevent CVD events (January 1966 to July 2009) and performed meta-analyses using random effects models. For trials that reported responses to FA supplementation stratified by baseline levels of homocysteine, we pooled within-trial estimates of differences in log-relative risks by baseline homocysteine levels using a random effects model. Overall, FA supplementation did not affect primary cardiovascular clinical end points (relative risk 1.02, 95% confidence interval [CI] 0.93 to 1.13, p = 0.66) or stroke (relative risk 0.95, 95% CI 0.84 to 1.08, p = 0.43). However, in trials that reported analyses stratified by baseline homocysteine, effect of FA supplementation differed by strata of baseline homocysteine (p for interaction = 0.030). Specifically, risks of primary clinical CVD events comparing FA supplementation to control were 1.06 (95% CI 1.00 to 1.13) in strata with mean baseline homocysteine levels >12 mumol/L and 0.94 (95% CI 0.86 to 1.03) in strata with baseline homocysteine levels <12 micromol/L. In conclusion, FA had no effect on CVD or stroke. However, analysis of within-trial results stratified by baseline homocysteine suggests potential harm in those with high homocysteine at baseline. This interaction may have important implications for recommendations of FA supplement use. In the meantime, FA supplementation should not be recommended as a means to prevent or treat CVD or stroke.

Relationship between β1‐adrenergic receptor polymorphisms and cardiovascular disease in patients with diabetic nephropathy

Activation of beta1-adrenergic receptor (beta1AR) enhances contractility and heart rate. The polymorphism Arg389Gly in the beta1AR gene was found to be functionally important in determining receptor activity. The relationship between this polymorphism and the risk of cardiovascular disease was investigated in Chinese subjects with overt diabetic nephropathy. A total of 219 type 2 diabetic subjects with nephropathy were recruited. Genotyping of the beta1AR Arg389Gly polymorphism was determined. Patients were followed up to 96 months for the development of cardiovascular events. There were 122, 86 and 11 patients with Arg/Arg, Arg/Gly and Gly/Gly genotype, respectively. At 96 months, the event-free survival of primary composite cardiovascular end-point was 33.0% and 44.3% for Gly(+) and Gly(-) groups, respectively (log-rank test, P = 0.105), while the event-free survival for first ischaemic heart disease was 62.4% and 75.9%, respectively (log-rank test, P = 0.038). However, with multivariate analysis by the Cox proportional hazard model to adjust for confounders, only low-density lipoprotein and baseline glomerular filtration rate were independent predictors of first ischaemic heart event. The beta1AR Arg389Gly polymorphism is not an independent predictor of cardiovascular events in subjects with overt diabetic nephropathy.

Association of interleukin‐18 promoter polymorphism and atherosclerotic diseases in Chinese patients with diabetic nephropathy

Interleukin-18 (IL-18) is a pro-inflammatory cytokine and possibly plays an important role in the pathogenesis of cardiovascular disease. The relationship between two IL-18 gene polymorphisms, namely C-607A and G-137C, and cardiovascular disease in patients with diabetic nephropathy was examined. Two hundred and twenty patients (91 male) with diabetic nephropathy were studied. The IL-18 promoter genotypes were determined. All patients were then prospectively followed for the cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. Mean age was 64.3 +/- 10.6 years; average follow up was 73.9 +/- 33.6 months. The frequencies of CC, CA and AA genotypes of the C-607A polymorphism were 25.5%, 48.2% and 26.8%, respectively; GG, GC and CC genotypes of the G-137C polymorphism were 71.8%, 25.0% and 3.2%, respectively. Neither of the polymorphisms were associated with the development of primary cardiovascular end-point. Cardiovascular survival was 84.8% and 70.6% at 60 months for GG and GC/CC genotypes of the G-137C polymorphism, respectively (P = 0.027); the corresponding actuarial survival was 69.0% and 54.8%, respectively (P = 0.053). However, the G-137C genotype was not an independent predictor of cardiovascular or actuarial survival after adjusting for confounders by multivariate analysis with the Cox model. The C-607A polymorphism had no significant effect on cardiovascular or actuarial survival. The G-137C polymorphism of the IL-18 promoter is associated with the cardiovascular mortality, and a trend of association with all-cause mortality, in patients with diabetic nephropathy. The association, however, becomes insignificant after adjusting for confounding factors. Further studies are needed to test other genetic determinants of the association between systemic inflammation and cardiovascular disease in renal failure patients.

Clinical issues regarding cardiovascular disease and selective estrogen receptor modulators in postmenopausal women

Selective estrogen receptor modulators (SERMs) have offered the promise of reducing the burden of coronary artery disease (CAD) in postmenopausal women, based on the positive effects recorded on intermediate markers (blood lipids and markers of inflammation). The effects of raloxifene, bazedoxifene and lasofoxifene on cardiovascular endpoint markers are presented as reported in recent, randomized, controlled trials. Raloxifene failed to significantly lower the risk of CAD in postmenopausal osteoporotic women, without any effect on stroke or early harm, but doubling the risk of venous thromboembolism. The risk of CAD was lowered in a subgroup of patients at risk of CAD. In a large randomized, controlled trial with CAD as the primary endpoint in patients at risk of CAD, raloxifene failed to significantly reduce CAD, while significantly increasing the incidence of fatal stroke and venous thromboembolism. Bazedoxifene, in an osteoporosis trial, had similar effects on the cardiovascular system when compared to raloxifene. Lasofoxifene has only been studied in postmenopausal osteoporotic women in the PEARL trial. Lasofoxifene reduced the risk of coronary heart disease events as well as the risk of stroke, while the risk of deep vein thrombosis remained in line with other SERMs. These results will need to be confirmed in a study with primary cardiovascular endpoints. Until then, it is unlikely that SERMs will play a major role in strategies aimed at the prevention of coronary heart disease in postmenopausal women.

PPAR‐alpha: therapeutic role in diabetes‐related cardiovascular disease

Among individuals with diabetes mellitus, cardiovascular disease remains the leading cause of death, despite the many treatment modalities that have been developed over time. The PPAR family, including PPAR-alpha, play important roles in glucose and lipid metabolism and atherosclerosis and thus are potential therapeutic targets. Fibrates act upon PPAR-alpha and appear to target the typical dyslipidaemia of diabetes. Several large prospective clinical trials have shown both primary prevention and secondary prevention benefit with fibrates, although they only had small subgroups of patients with diabetes. The first large outcome study to exclusively study those with diabetes was the FIELD study, which showed no reduction in the primary cardiovascular end-point and only some benefit in the secondary end-point. There are many potential explanations for these results; however, it would appear that at present, there is no role for fibrates as monotherapy for the reduction of cardiovascular risk among those with diabetes. However, their potential role in combination with statin therapy remains to be further elucidated with ongoing studies.

The cardiovascular safety of rosiglitazone

Background: Thiazolidinediones (rosiglitazone, pioglitazone) influence insulin sensitivity and are used for the treatment of Type 2 diabetes. Rosiglitazone achieves sustained improvements in glycaemic control, whilst having pleiotropic effects on cardiovascular risk factors. However, analysis of cardiovascular outcomes has been controversial. Objectives: Review the cardiovascular safety of rosiglitazone by conducting a literature search. Methods: We conducted a PubMed search and critically reviewed published work on cardiovascular outcome of rosiglitazone, including clinical studies and meta-analyses. Results/conclusion: The meta-analysis by Nissen and Wolski suggested increased cardiovascular risk in users of rosiglitazone, but this was not supported by an interim analysis of the RECORD trial designed to evaluate this, and several other reports failed to shed conclusive light on this issue. The cardiovascular benefits of pioglitazone have also been in doubt due to the failure of the PROactive trial to reach the primary cardiovascular end points, although this study reported a significant reduction in secondary end points. All of this has left diabetes care in some disarray, with weak evidence for adverse cardiovascular effects driving the reduced use of rosiglitazone, an agent that has important sustained effects on glycaemic control.

Peroxisome Proliferator-Activated Receptor-Gamma Gene Polymorphism and Risk of Cardiovascular Disease in Patients with Diabetic Nephropathy

Background: Peroxisome proliferator-activator receptor-gamma (PPAR-γ) is a nuclear receptor that serves important roles in intermediate metabolism. We examined the relationship between two PPAR-γ gene polymorphisms, namely the P12A and C161T, and cardiovascular disease in patients with diabetic nephropathy. Methods: We studied 170 predialysis and 50 peritoneal dialysis patients with diabetic nephropathy. The PPAR-γ genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assay. The patients were then followed prospectively for the development of cardiovascular events. Cardiovascular mortality and all-cause mortality were also compared. Results: There were 91 male cases. The mean age was 64.3 ± 10.6 years. The frequencies of Pro/Pro and Pro/Ala genotypes of the P12A polymorphism were 95 and 5%, respectively; CC, CT and TT genotypes of the C161T polymorphism were 55.5, 39.5 and 5.0%, respectively. For the P12A polymorphism, the event-free survival was 56.5 and 9.1% at 60 months for Pro/Pro and Pro/Ala genotypes, respectively (p = 0.0005). For the C161T polymorphism, the event-free survival was 61.5 and 44.9% for CC and CT/TT genotypes, respectively (p = 0.0044). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, the independent factors for event-free survival were P12A and C161T polymorphisms, age and diastolic blood pressure. In this model, the Pro/Ala genotype conferred 7.6-fold (95% CI 2.1- to 28.0-fold, p = 0.002) excess hazard of developing primary cardiovascular end point as compared to the Pro/Pro genotype, while each T allele at the 161 position conferred 83.4% (95% CI 15.2–291.9%, p = 0.011) excess hazard. Conclusions: We conclude that P12A and C161T polymorphisms of the PPAR-γ gene are important predictors of cardiovascular event in patients with diabetic nephropathy. Further studies are needed to examine the interaction of PPAR-γ gene polymorphisms and thiazolidinedione treatment on the cardiovascular risk in this group of patients.

Antihypertensive therapy with aliskiren

Aliskiren represents the first member in a new class of antihypertensive drugs. Inhibiting the renin-angiotensin system at its rate-limiting step is an idea that has been pursued for >30 years; however, earlier compounds failed because of problems related to efficacy, bioavailability, and/or side effects. Aliskiren, a 610 Da nonpeptide molecule, has exceptional affinity for the human renin enzymatic site and a half-life of about 40 h, which make its 3% bioavailability clinically unimportant with continued administration. The drug is not metabolized by CYP P450 enzymes and is excreted >90% unchanged by the fecal route. No adjustments are necessary for renal function, liver function, age, ethnicity, or other prescribed drugs. Blood pressure reductions are similar to those provided by other monotherapies. Interestingly, aliskiren combined with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor therapy leads to a further blood pressure reduction as does combination with a diuretic or calcium channel blocker. The fact that plasma renin activity is reduced to low levels with aliskiren could provide a theoretical advantage over other treatments, while increases in total renin (prorenin) after the drug poses additional food for thought. Studies with primary cardiovascular and renal end points to address these possibilities are in progress.

Effects of Candesartan Compared With Amlodipine in Hypertensive Patients With High Cardiovascular Risks

The Candesartan Antihypertensive Survival Evaluation in Japan Trial was designed to compare the long-term effects of the angiotensin II receptor blocker candesartan and the calcium channel blocker amlodipine on the incidence of cardiovascular events, represented as a composite of sudden death and cerebrovascular, cardiac, renal, and vascular events in high-risk Japanese hypertensive patients. We conducted a prospective, randomized, open-label study with blinded assessment of the end point in 4728 Japanese hypertensive patients (mean age: 63.8 years; mean body mass index: 24.6 kg/m(2)). Patients were followed for an average of 3.2 years. Blood pressure was well controlled with both treatment-based regimens (systolic blood pressure/diastolic blood pressure: 136.1/77.3 mm Hg for candesartan-based regimens and 134.4/76.7 mm Hg for amlodipine-based regimens after 3 years). Primary cardiovascular events occurred in 134 patients with both the candesartan- and amlodipine-based regimens. The 2 treatment-based regimens produced no significant differences in cardiovascular morbidity or mortality in the high-risk Japanese hypertensive patients (hazard ratio: 1.01; 95% CI: 0.79 to 1.28; P=0.969). In each primary end point category, there was no significant difference between the 2 treatment-based regimens. New-onset diabetes occurred in fewer patients taking candesartan (8.7/1000 person-years) than in those taking amlodipine (13.6/1000 person-years), which resulted in a 36% relative risk reduction (hazard ratio: 0.64; 95% CI: 0.43 to 0.97; P=0.033). We disclosed that candesartan-based and amlodipine-based regimens produced no statistical differences in terms of the primary cardiovascular end point, whereas candesartan prevented new-onset diabetes more effectively than amlodipine.