The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study.

AIMS: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population. METHODS AND RESULTS: The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM. CONCLUSION: In iron-deficient patients with HF and left ventricular ejection fraction <50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.

Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.

BACKGROUND: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING: Vifor Pharma.

Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis.

AIMS: Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID. METHODS AND RESULTS: Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events. CONCLUSIONS: Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID.

Progression of coronary artery calcification is associated with long-term cardiovascular events in hypertensive adults.

OBJECTIVES: Coronary artery calcification (CAC) is an independent predictor of cardiovascular (CV) events in hypertensive adults. However, the additive value of serial CAC measurements for risk stratification is unclear. The aim of the present study was to find whether CAC progression predicts long-term CV events in hypertensive patients. METHODS: The study group included 210 patients (mean age 64 ± 5.6 years, 54% men), a subgroup of 544 participants in the calcification side arm of the INSIGHT (International Nifedipine Study Intervention as Goal for Hypertension Therapy). All were free of symptoms or known CV disease, had at least two CT scans 1 year apart, and had available long-term follow-up. Progression of CAC was defined as the absolute change in CAC score between maximal score during follow-up and baseline score. The endpoint was the first CV event after the last CT scan. Three categories of CAC progression were defined. Zero progression was defined as 'nonprogressors', and progression below and above the median of maximal progression were defined as 'slow progressors' and 'rapid progressors', respectively. RESULTS: During 15 years of follow-up (mean 11.4 ± 4.4), 83 patients experienced a first CV event. The rate of events was higher in rapid (29/59, 49%), and slow (36/78 46%) than in nonprogressors (18/73 25%); (P=0.005). Compared with nonprogressors, the adjusted hazard ratio for CV events was 1.91 [95% confidence interval (95% CI); 1.05-3.47] in the slow, and 2.13 (95% CI; 1.12-4.03) in the rapid progressors. CONCLUSION: In hypertensive patients, progression of CAC is associated with long-term CV events.

Relation of coronary artery calcium to cardiovascular risk in patients with combined diabetes mellitus and systemic hypertension.

Certain patients with type 2 diabetes mellitus (DM) do not have increased cardiovascular (CV) risk. The aim of the present study was to stratify hypertensive adults with DM into those with low or high CV risk according to the absence or presence of coronary artery calcium (CAC). The study group included 423 patients, a subgroup of the 544 participants in the calcification side arm of the International Nifedipine Study: Intervention as Goal for Hypertension Therapy. All underwent a baseline computed tomography scan with an unenhanced dual-detector spiral computed tomography scan for CAC measurements. All were free of CV disease and completed 3 years (short-term) of follow-up. A total of 268 patients were included in the 15-year (long-term) follow-up period. The study group was divided into 4 subgroups according to the presence or absence of DM and CAC and was analyzed for a first CV event. Of the 423 patients, 164 (39%) had DM. Cardiovascular events occurred in 41 patients during the first 3 years and in 111 of 268 patients during the long-term follow-up. The rate of CV events was greater in the patients with DM with CAC than in those without (15% vs 7% after 3 years and 52% vs 32% after 15 years). Compared to those without DM without CAC, the short-term adjusted hazard ratio for CV event in those with DM with and without CAC was 6.6 (95% confidence interval 1.4 to 30.5) and 3.9 (95% confidence interval 0.7 to 22.6), respectively. A similar trend was seen in the long-term follow-up study. In conclusion, patients with hypertension and DM can be stratified into a lower CV risk in the absence of CAC.

Coronary artery calcification predicts long-term mortality in hypertensive adults.

BACKGROUND: Coronary artery calcification (CAC) predicts mortality in normotensive individuals. We hypothesized that CAC has an impact on long-term mortality in hypertensive patients. METHODS: We followed 423 participants of the INSIGHT (International Nifedipine Study Intervention as Goal for Hypertension Therapy) calcification substudy, for the incidence of mortality as a function of CAC. All patients were hypertensive (mean age 64 ± 6 years, 48% male), without coronary artery or peripheral vascular disease, aged >55 years and with at least one more major cardiovascular (CV) risk factor. All underwent a baseline computed tomography (CT) (Dual slice) to determine the calcification score and were followed for a mean period of 14 ± 0.5 years. Mortality and the cause of death were derived from the registry of the Ministry-of-Interior Affairs. RESULTS: During the follow-up, 94 patients died; 27 from CV causes, 54 from non-CV causes and 13 of undefined causes. The prevalence of calcification at baseline was 59% (195/329) among the survivors compared to 82% (77/94) in participants who died and 96.7% (26/27) among those who died of CV causes. The incidence of CV death was 14 times higher among those with than those without CAC (9.6% (26/272) vs. 0.7% (1/151); P < 0.01). After adjusting for age, gender, left ventricular hypertrophy, proteinuria, duration of hypertension, and renal function the presence of calcification predicted all cause mortality with a hazard ratio (HR) of 1.8 (95% confidence interval (CI) 1.04-3.07). CONCLUSIONS: CAC is associated with long-term mortality in asymptomatic hypertensive adults.

Long-term changes in serum cholesterol level does not influence the progression of coronary calcification.

BACKGROUND: A number of reports controversially describe the influence of cholesterol level and lipid-lowering treatment (LLT) on the progression of coronary calcium (CC). We tested the hypothesis that long-term changes in serum cholesterol (CL) would affect the progression of CC. METHODS: The study population comprised 510 patients with stable angina pectoris, mean age of 63 ± 9 years. At baseline 372 patients received statin and/or fibrate (LLT group) while 138 patients did not (No-LLT at baseline group). Spiral CT every 24 months was used to track the progression of CC over a median 5.6 year follow-up. RESULTS: CL decreased during follow-up in both groups, but more pronouncedly in patients with LLT. The changes in total calcium score (TCS) were similar in both groups (p=0.3). Changes in CL during follow-up were not associated with CC: TCS increased by 501 ± 63 from baseline in the 1st (upper) quartile, and by 350 ± 44, 403 ± 41 and 480 ± 56 in the 2nd, 3rd, and 4th quartiles of CL longitudinal changes (p = 0.2), respectively. Baseline TCS and its changes were not correlated with baseline CL and its changes. New calcified lesions were diagnosed in 132 (28.2%) out of the 467 patients available for this analysis, without significant difference between groups (p=0.4). Multivariate analysis demonstrated that only baseline TCS (p < 0.001), body mass index (p = 0.007) and age (p = 0.006) were independent predictors for the TCS changes. CONCLUSIONS: Longitudinal CL changes do not seem to have a measurable effect on the rate of progression of CC.

Calcification of the thoracic aorta as detected by spiral computed tomography among stable angina pectoris patients: association with cardiovascular events and death.

BACKGROUND: Calcification of the thoracic aorta is associated with atherosclerotic risk factors, yet its pathogenesis and clinical implications are not yet elucidated. The goal of the present study was to assess whether thoracic aorta calcification is associated with an increased risk of cardiovascular events and death in patients with stable angina pectoris. METHODS AND RESULTS: A prospective cohort of 361 stable angina pectoris patients (307 men, 54 women; age range, 37 to 83 years) underwent chest spiral computed tomography and were evaluated for aortic calcification. We recorded the incidence of cardiovascular events and death during a 4.5- to 6-year follow-up. Aortic calcification was documented in 253 patients (70% of patients; 213 men, 40 women). Patients with aortic calcification were older (mean age, 65+/-7 versus 55+/-9 years; P<0.001), and fewer were classified as smokers (13% versus 26%; P=0.014) compared with patients without aortic calcification. Significant correlation was found between patients with and those without aortic calcification for the presence of aortic valve calcification (28% versus 11%; P<0.001), mitral annulus calcification (29% versus 4%; P<0.001), and coronary calcification as expressed by coronary calcium score. (P<0.001). During 4.5 to 6 years of follow-up, 19 patients died, all of whom were in the aortic calcification group. Age-adjusted hazard ratios for total events and cardiovascular events by aortic calcification were 2.84 (95% CI, 1.52 to 5.30; P=0.001) and 2.70 (95% CI, 1.33 to 5.47; P=0.006), respectively. In multivariable analysis, hazard ratios for total events and cardiovascular events were 2.79 (95% CI, 1.46 to 5.20; P=0.002) and 4.65 (95% CI, 1.19 to 18.26; P=0.028), respectively. CONCLUSIONS: Calcification of the thoracic aorta is age related and associated with coronary calcification and valvular calcification. Thoracic aortic calcification is associated with an increased risk of death and cardiovascular disease.

Does the lipid-lowering peroxisome proliferator-activated receptors ligand bezafibrate prevent colon cancer in patients with coronary artery disease?

BACKGROUND: Epidemiologic studies have suggested that hypertriglyceridemia and insulin resistance are related to the development of colon cancer. Nuclear peroxisome proliferator-activated receptors (PPAR), which play a central role in lipid and glucose metabolism, had been hypothesized as being involved in colon cancerogenesis. In animal studies the lipid-lowering PPAR ligand bezafibrate suppressed colonic tumors. However, the effect of bezafibrate on colon cancer development in humans is unknown. Therefore, we proposed to investigate a possible preventive effect of bezafibrate on the development of colon cancer in patients with coronary artery disease during a 6-year follow-up. METHODS: Our population included 3011 patients without any cancer diagnosis who were enrolled in the randomized, double blind Bezafibrate Infarction Prevention (BIP) Study. The patients received either 400 mg of bezafibrate retard (1506 patients) or placebo (1505 patients) once a day. Cancer incidence data were obtained by matching a subject's identification numbers with the National Cancer Registry. Each matched record was checked for correct identification. RESULTS: Development of new cancer (all types) was recorded in 177 patients: in 79 (5.25%) patients from the bezafibrate group vs. 98 (6.51%) from the placebo group. Development of colon cancer was recorded in 25 patients: in 8 (0.53%) patients from the bezafibrate group vs. 17 (1.13%) from the placebo group, (Fisher's exact test: one side p = 0.05; two side p = 0.07). A difference in the incidence of cancer was only detectable after a 4 year lag and progressively increased with continued follow-up. On multivariable analysis the colon cancer risk in patients who received bezafibrate tended to be lower with a hazard ratio of 0.47 and 95% confidence interval 0.2-1.1. CONCLUSION: Our data, derived from patients with coronary artery disease, support the hypothesis regarding a possible preventive effect of bezafibrate on the development of colon cancer.

Optimal management of combined dyslipidemia: what have we behind statins monotherapy?

Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized, prospective trials involving patients with CHD have shown that statins reduce the clinical consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)- cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of statins are more effective mainly for the prevention of the nonfatal cardiovascular events but such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of coronary events still occur and many such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is now being paid to combined atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or 'lipid quartet') - hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and an accumulation of cholesterol-rich remnant particles - emerged as the greatest 'competitor' of LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants, CETP inhibitors and omega-3 fatty acids. Particularly, ezetimibe/statins combinations provide superior lipid-modifying benefits compared Tenenbaum/Fisman/Motro/Adler 128 with any statins monotherapy in patients with atherogenic dyslipidemia. Atherogenic dyslipidemia is associated with increased levels of chylomicrons and their remnants containing 3 main components: apolipoprotein B-48, triglycerides and cholesterol ester of intestinal origin. Reduction in accessibility for one of them (specifically cholesteryl ester lessening due to ezetimibe administration) could lead to a decrease of the entire production of chylomicrons and result in a decrease of the hepatic body triglycerides pool as confirmed in number of clinical studies. However, the ENHANCE study showed no difference in the progression of carotid atherosclerosis between ezetimibe/simvastatin vs. simvastatin alone over a 2-year period. Conclusions regarding ezetimibe/statins combinations should not be made until the three large clinical outcome trials will be completed within the next 2-3 years. In addition, bezafibrate as a pan-PPAR activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism, insulin sensitivity and pancreatic beta cell protection. Because fibrates, niacin, ezetimibe, omega-3 fatty acids and statins each regulate serum lipids by different mechanisms, combination therapy - selected on the basis of their safety and effectiveness, could be more helpful in achieving a comprehensive lipid control as compared with statins monotherapy.

Non-insulin antidiabetic therapy in cardiac patients: current problems and future prospects.

Five types of oral antihyperglycemic drugs are currently approved for the treatment of diabetes: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. We briefly review the cardiovascular effects of the most commonly used antidiabetic drugs in these groups in an attempt to improve knowledge and awareness regarding their influences and potential risks when treating patients with coronary artery disease (CAD). Regarding biguanides, gastrointestinal disturbances such as diarrhea are frequent, and the intestinal absorption of group B vitamins and folate is impaired during chronic therapy. This deficiency may lead to increased plasma homocysteine levels which, in turn, accelerate the progression of vascular disease due to adverse effects on platelets, clotting factors, and endothelium. The existence of a graded association between homocysteine levels and overall mortality in patients with CAD is well established. In addition, metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as heart failure or recent myocardial infarction. Sulfonylureas avoid ischemic preconditioning. During myocardial ischemia, they may prevent opening of the ATP-dependent potassium channels, impeding the necessary hyperpolarization that protects the cell by blocking calcium influx. Meglitinides may exert similar effects due to their analogous mechanism of action. During treatment with glitazones, edema has been reported in 5% of patients, and these drugs are contraindicated in diabetics with NYHA class III or IV cardiac status. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates and on diabetic micro- and macrovascular complications is still unknown. Combined sulfonylurea/metformin therapy reveals additive effects on mortality. Four points should be mentioned: (1) the five oral antidiabetic drug groups present proven or potential cardiac hazards; (2) these hazards are not mere 'side effects' but are deeply rooted in the drugs' mechanisms of action; (3) current data indicate that combined glibenclamide/metformin therapy seems to present a special risk and should be avoided in the long-term management of type 2 diabetics with proven CAD, and (4) Non-Insulin Antidiabetic Therapy in Diabetic Cardiac Patients 155 customized antihyperglycemic pharmacological approaches should be investigated for the optimal treatment of diabetic patients with heart disease. New possibilities are represented by incretin mimetic compounds, dipeptidyl peptidase (DPP)-4 inhibitors, inhaled insulin and eventually oral insulin.

Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial.

BACKGROUND: Evidence suggests that inflammatory mediators contribute to development and progression of chronic heart failure. We therefore tested the hypothesis that immunomodulation might counteract this pathophysiological mechanism in patients. METHODS: We did a double-blind, placebo-controlled study of a device-based non-specific immunomodulation therapy (IMT) in patients with New York Heart Association (NYHA) functional class II-IV chronic heart failure, left ventricular (LV) systolic dysfunction, and hospitalisation for heart failure or intravenous drug therapy in an outpatient setting within the past 12 months. Patients were randomly assigned to receive IMT (n=1213) or placebo (n=1213) by intragluteal injection on days 1, 2, 14, and every 28 days thereafter. Primary endpoint was the composite of time to death from any cause or first hospitalisation for cardiovascular reasons. The study continued until 828 primary endpoint events had accrued and all study patients had been treated for at least 22 weeks. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00111969. FINDINGS: During a mean follow-up of 10.2 months, there were 399 primary events in the IMT group and 429 in the placebo group (hazard ratio 0.92; 95% CI 0.80-1.05; p=0.22). In two prespecified subgroups of patients--those with no history of previous myocardial infarction (n=919) and those with NYHA II heart failure (n=689)--IMT was associated with a 26% (0.74; 0.57-0.95; p=0.02) and a 39% (0.61; 95% CI 0.46-0.80; p=0.0003) reduction in the risk of primary endpoint events, respectively. INTERPRETATION: Non-specific immunomodulation may have a role as a potential treatment for a large segment of the heart failure population, which includes patients without a history of myocardial infarction (irrespective of their functional NYHA class) and patients within NYHA class II.

Coronary and aortic calcifications inter-relationship in stable angina pectoris: A Coronary Disease Trial Investigating Outcome with Nifedipine GITS (ACTION)--Israeli spiral computed tomography substudy.

BACKGROUND: Coronary heart disease and ischemic stroke are among the leading causes of morbidity and mortality in adults, and cerebrovascular disease is associated with the presence of symptomatic and asymptomatic CHD. Several studies noted an association between coronary calcification and thoracic aorta calcification by several imaging techniques, but this association has not yet been examined in stable angina pectoris patients with the use of spiral computed tomography. OBJECTIVES: To examine by spiral CT the association between the presence and severity of CC and thoracic aorta calcification in patients with stable angina pectoris. METHODS: The patients were enrolled in ACTION (A Coronary Disease Trial Investigating Outcome with Nifedipine GITS) in Israel. The 432 patients (371 men and 61 women aged 40-89 years) underwent chest CT and were evaluated for CC and aortic calcification. RESULTS: CC was documented in 90% of the patients (n = 392) and aortic calcification in 70% (n = 303). A significant association (P < 0.05) was found between severity of CC and severity of aortic calcification (as measured by area, volume and slices of calcification). We also found an association between the number of coronary vessels calcified and the presence of aortic calcification: 90% of patients with triple-vessel disease (n = 157) were also positive for aortic calcification (P < 0.05). Age also had an effect: 87% of patients > 65 years (n=219) were positive for both coronary and aortic calcification (P = 0.005) while only 57% < or = 65 (n = 209) were positive for both (P = 0.081). CONCLUSIONS: Our study demonstrates a strong association between the presence and severity of CC and the presence and severity of calcification of thoracic aorta in patients with stable angina pectoris as detected by spiral CT.

Insulin resistance is associated with increased risk of major cardiovascular events in patients with preexisting coronary artery disease.

BACKGROUND: Over the past years it has been recognized that insulin resistance (IR) is an independent risk factor for the development of diabetes, whereas its association with cardiovascular events remains controversial. The aim of our study was to explore the association between IR per se and cardiovascular events among patients with preexisting coronary artery disease. METHODS: The mean follow-up period of this prospective study was 6.2 years. Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained at baseline from 2938 patients aged 45 to 74 years. The homeostatic index of IR (HOMA-IR) was calculated according to the homeostasis model assessment. RESULTS: New major cardiovascular events (fatal and nonfatal myocardial infarction and sudden death) were recorded in 108 (11.1%) patients from the lowest IR tertile, in 147 (14.7%) from the intermediate tertile, and in 166 (17.2%) from the highest tertile (P = .0002). The linear trend for total and cardiac death across the tertiles of HOMA-IR was significant as well (P = .02 and P = .009, respectively). The highest age-adjusted rates for major cardiovascular events and new diabetes were found among patients within the top tertile of HOMA-IR (57% and 130% higher rates, respectively, tertile 3 vs tertile 1, P < .0001 for both). Multivariable analysis identified HOMA-IR (tertile 3 vs tertile 1) as an independent predictor of increased risk of major cardiovascular events and new diabetes with hazard ratios (95% CI) of 1.4 (1.1-1.8) and 1.5 (1.1-2.0), respectively. CONCLUSIONS: Insulin resistance per se is an independent risk factor for cardiovascular events and new diabetes in patients with preexisting coronary artery disease.

Improved exercise tolerance and cardiac function in severe chronic heart failure patients undergoing a supervised exercise program.

BACKGROUND: Exercise intolerance is a widespread and serious problem in chronic heart failure (CHF) patients. However, the impact of a supervised exercise and rehabilitation program on exercise tolerance and cardiac performance in severe CHF patients has not yet been fully investigated. METHODS: Of 56 consecutive patients with severe CHF (New York Heart Association functional class III, Stage D) 44 underwent a hospital-based supervised 18-week, cardiac exercise and rehabilitation program (exercise group), and 12 did not (control group). Cardiac performance was assessed by a 6-minute walk test, peak exercise VO(2), exercise duration time, resting and immediate post peak exercise stroke index (SI), cardiac index (CI) and systemic vascular resistance (SVR), before and after exercise. RESULTS: Both groups were comparable regarding baseline clinical characteristics. Post exercise training, functional and hemodynamic parameters improved significantly in the exercise group compared to controls. A highly significant interaction between the groups and change was found in the 6-minute walk test (p<0.001), exercise test duration (p<0.001), METs during exercise (p<0.001), immediate post peak exercise CI (0.016), delta peak VO(2) (p=0.028), and immediate post peak exercise SVR (p=0.045). CONCLUSIONS: A hospital-based supervised exercise and rehabilitation program significantly improves functional and hemodynamic parameters in severe CHF patients, and may partially contribute to better physical conditioning detected in these patients after exercise training.

Tracking coronary calcification and atherosclerotic lesions in patients with stable angina pectoris undergoing nifedipine therapy.

AIMS: The objective of the Coronary Calcification (CC) study was to determine in patients with chronic symptomatic coronary artery disease, if, in addition to standard therapy, nifedipine GITS, relative to placebo, would arrest or slow down the progression of calcium or the development of new atherosclerotic lesions in the coronary arteries. METHODS AND RESULTS: The CC study was part of the ACTION trial. Multi-slice computerized tomography was used to measure and track the progression of CC. Five hundred and eighteen patients were included in this study. The changes in calcium score from baseline every 24 months, over a period of between 4.5 and 6 years, were similar in the nifedipine and placebo treatment groups (p = 0.8). Compared to placebo, more patients in the nifedipine group (71 vs. 60%) were free of new calcified atherosclerotic lesions during follow-up(p = 0.095). CONCLUSION: Nifedipine GITS was not effective in slowing down the progression of calcium in advanced atherosclerotic plaques in patients with stable angina pectoris. Although statistically not significant, Nifedipine demonstrated a trend in slowing down the development of new atherosclerotic lesions.

Effects of peroxisome proliferator-activated receptor ligands, bezafibrate and fenofibrate, on adiponectin level.

OBJECTIVE: Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. METHODS AND RESULTS: Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARalpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha-RNAi. CONCLUSIONS: Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Long-term effect of bezafibrate on pancreatic beta-cell function and insulin resistance in patients with diabetes.

OBJECTIVE: Development of insulin resistance (IR) and the progressive failure of the pancreatic beta-cell function (BCF) may be important in the pathogenesis of type 2 diabetes. Influence of peroxisome proliferator-activated receptors ligand bezafibrate on BCF and IR in patients with diabetes is unknown. The present study was aimed to investigate the long-term effect of bezafibrate on these parameters in diabetic patients enrolled in the Bezafibrate Infarction Prevention (BIP) Study. METHODS: Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained from 351 diabetic patients (168 treated by bezafibrate and 183 by placebo) who completed a 2-year of randomized, double-blind, placebo-controlled study period. The homeostatic indexes of BCF (HOMA-BCF) and IR (HOMA-IR) were calculated according to the homeostasis model of assessment. RESULTS: Both groups displayed similar baseline characteristics. During follow-up, in the placebo group there was 28% rise of HOMA-IR (p<0.001). In contrast, HOMA-IR in patients in the bezafibrate group did not change (p=0.99). The intergroup differences in HOMA-IR percentage changes were in favor of bezafibrate (p=0.01). HOMA-BCF values have significantly decreased by 13.9% (p=0.04) in patients of placebo group, whereas in patients of bezafibrate group HOMA-BCF was stable during follow-up and its alterations (-2.9%) were non-significant (p=0.59). CONCLUSIONS: Diabetic patients from the placebo group demonstrated a progressive declining of BCF and an increasing of IR over 2 years of follow-up. These longitudinal changes were attenuated when patients used bezafibrate.