Michael Motro

Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial

BACKGROUND Calcium antagonists are widely prescribed for angina pectoris but their effect on clinical outcome is controversial. We aimed to investigate the effect of the calcium antagonist nifedipine on long-term outcome in patients with stable angina pectoris. METHODS We randomly assigned 3825 patients with treated stable symptomatic coronary disease to double-blind addition of nifedipine GITS (gastrointestinal therapeutic system) 60 mg once daily and 3840 to placebo. The primary endpoint was the combination of death, acute myocardial infarction, refractory angina, new overt heart failure, debilitating stroke, and peripheral revascularisation. Mean follow-up was 4.9 years (SD 1.1). Analysis was by intention to treat. FINDINGS 310 patients allocated nifedipine died (1.64 per 100 patient-years) compared with 291 people allocated placebo (1.53 per 100 patient-years; hazard ratio 1.07 [95% CI 0.91-1.25], p=0.41). Primary endpoint rates were 4.60 per 100 patient-years for nifedipine and 4.75 per 100 patient-years for placebo (0.97 [0.88-1.07], p=0.54). With nifedipine, rate of death and any cardiovascular event or procedure was 9.32 per 100 patient-years versus 10.50 per 100 patient-years for placebo (0.89 [0.83-0.95], p=0.0012). The difference was mainly attributable to a reduction in the need for coronary angiography and interventions in patients assigned nifedipine, despite an increase in peripheral revascularisation. Nifedipine had no effect on the rate of myocardial infarction. INTERPRETATION Addition of nifedipine GITS to conventional treatment of angina pectoris has no effect on major cardiovascular event-free survival. Nifedipine GITS is safe and reduces the need for coronary angiography and interventions.

Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: A pilot study

PURPOSE To test the hypothesis that long-term furosemide therapy in patients with congestive heart failure (CHF) is associated with clinically significant thiamine deficiency via urinary loss. DESIGN (1) Biochemical evaluation of thiamine status in hospitalized patients with CHF treated with long-term furosemide and in age-matched control patients. (2) Uncontrolled trial of the effect of intravenous thiamine on cardiac performance in a subset of six patients with CHF. SETTING General medical ward of a teaching community hospital. PATIENTS Twenty-three patients with chronic CHF receiving furosemide, and 16 age-matched control patients without heart failure and not taking diuretics. Daily furosemide doses were 80 to 240 mg, and duration of furosemide therapy was 3 to 14 months. Patients with identifiable causes of inadequate thiamine intake, absorption, or utilization or increased metabolic requirements were excluded. INTERVENTION A 7-day course of intravenous thiamine, 100 mg twice daily, in six consenting patients with CHF. RESULTS A high thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in 21 of 23 furosemide-treated patients and in two of 16 controls (p less than 0.001). The mean (+/- SE) TPPE (normal: 0% to 15%) in furosemide-treated and control patients was 27.7 +/- 2.5% and 7.1 +/- 1.6%, respectively (p less than 0.001). Despite the high TPPE, the mean (+/- SE) urinary thiamine excretion in the furosemide-treated patients (n = 18) was inappropriately high (defined as greater than 130 micrograms/g creatinine), 410 +/- 95 micrograms/g creatinine, even in comparison with that in the controls (n = 14): 236 +/- 69 micrograms/g creatinine. In six patients treated with intravenous thiamine, the elevated TPPE decreased to normal, from a mean (+/- SE) of 27.0 +/- 3.8% to 4.5 +/- 1.3% (p less than 0.001), indicating normal thiamine utilization capacity. Left ventricular ejection fraction increased in four of five of these patients studied by echocardiography. CONCLUSIONS These preliminary findings suggest that long-term furosemide therapy may be associated with clinically significant thiamine deficiency due to urinary loss and contribute to impaired cardiac performance in patients with CHF. This deficit may be prevented or corrected by appropriate thiamine supplements.

Peroxisome Proliferator–Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease

Background—Recent studies have shown that type 2 diabetes is preventable by both lifestyle interventions and medications that influence primary glucose metabolism. Whether pharmacological interventions that influence primary lipid metabolism can also delay development of type 2 diabetes is unknown. The goal of this study was to evaluate the effect of the peroxisome proliferator–activated receptor ligand bezafibrate on the progression of impaired fasting glucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-up period. Methods and Results—The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL (6.1 to 6.9 mmol/L). The patients received either 400 mg bezafibrate retard (156 patients) or placebo (147 patients) once a day. No patients were using statins, and use of ACE inhibitors, which also reduce diabetes incidence, was relatively low. During follow-up, development of new-onset diabetes was recorded in 146 patients: in 80 (54.4%) from the placebo group and 66 (42.3%) from the bezafibrate group (P =0.04). The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo: 4.6±2.3 versus 3.8±2.6 years (P =0.004). Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development (hazard ratio, 0.70; 95% CI, 0.49 to 0.99). Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level (hazard ratio, 1.22; 95% CI 1.0 to 1.51) and body mass index (hazard ratio, 1.10; 95% CI, 1.05 to 1.16). Conclusions—Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose. Whether the combination of bezafibrate with other recommended drugs for secondary prevention (statins and ACE inhibitors) would be as efficacious as suggested by our results remains to be determined.

Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy.

PURPOSE We have previously found thiamine (vitamin B1) deficiency in patients with congestive heart failure (CHF) who had received long-term furosemide therapy. In the present study, we assessed the effect of thiamine repletion on thiamine status, functional capacity, and left ventricular ejection fraction (LVEF) in patients with moderate to severe CHF who had received furosemide in doses of 80 mg/d or more for at least 3 months. PATIENTS AND METHODS Thirty patients were randomized to 1 week of double-blind inpatient therapy with either i.v. thiamine 200 mg/d or placebo (n = 15 each). All previous drugs were continued. Following discharge, all 30 patients received oral thiamine 200 mg/d as outpatients for 6 weeks. Thiamine status was determined by the erythrocyte thiamine-pyrophosphate effect (TPPE). LVEF was determined by echocardiography. RESULTS TPPE, diuresis, and LVEF were unchanged with i.v. placebo. After i.v. thiamine, TPPE decreased (11.7% +/- 6.5% to 5.4% +/- 3.2%; P < 0.01). LVEF increased (0.28 +/- 0.11 to 0.32 +/- 0.09; P < 0.05), as did diuresis (1,731 +/- 800 mL/d to 2,389 +/- 752 mL/d; P < 0.02), and sodium excretion (84 +/- 52 mEq/d to 116 +/- 83 mEq/d, P < 0.05). In the 27 patients completing the full 7-week intervention, LVEF rose by 22% (0.27 +/- 0.10 to 0.33 +/- 0.11, P < 0.01). CONCLUSIONS Thiamine repletion can improve left ventricular function and biochemical evidence of thiamine deficiency in some patients with moderate-to-severe CHF who are receiving longterm furosemide therapy.

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.

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 PPARα 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 PPARα-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 PPARα was knocked down by PPARα-RNAi. Conclusions—Our results suggest that fibrates enhance adiponectin partly through adipose PPARα and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

Calcium Channel Blocker Nifedipine Slows Down Progression of Coronary Calcification in Hypertensive Patients Compared With Diuretics

Calcium controls numerous events within the vessel wall. Permeability of the endothelium is calcium dependent, as are platelet activation and adhesion, vascular smooth muscle proliferation and migration, and synthesis of fibrous connective tissue. Double-helix computerized tomography is a noninvasive technique that can detect, measure, and compare coronary calcification in the coronary arteries. Using this method, our objective was to determine whether administration of nifedipine once daily in lieu of diuretics in high-risk hypertensive patients will arrest or slow down the progression of coronary artery calcification. The study was designed as a side arm of INSIGHT (International Nifedipine Study: Intervention as Goal for Hypertension Therapy), aimed to show the efficacy of nifedipine once daily versus co-amilozide (hydrochlorothiazide 25 mg, amiloride 2.5 mg) in high-risk hypertensive patients. A total of 201 patients with a total calcium score of ≥10 at the onset of study who underwent an annual double-helix computerized tomography for 3 years were analyzed for efficacy. Inhibition of coronary calcium progression was significant in the nifedipine versus the co-amilozide group during the first year (3.18% versus 27%, respectively, P =0.02), not significant during the second year (28.5% versus 47%, respectively, P =0.14), and significant during the third year (40% versus 78%, respectively, P =0.02). The results point to a slower progression of coronary calcification in hypertensive patients on nifedipine once daily versus co-amilozide.

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.

Randomized controlled trial of late in-hospital angiography and angioplasty versus conservative management after treatment with recombinant tissue-type plasminogen activator in acute myocardial infarction

Although both the European Cooperative Study Group and the Thrombolysis in Myocardial Infarction IIB trial indicated that angiography and angioplasty as routine measures after thrombolytic treatment do not improve clinical outcome in patients with acute myocardial infarction, the potential benefit of angioplasty may have been negated by the fact that the procedure was performed too soon (less than 32 hours) after admission. A similar study was designed in which delayed invasive treatment was compared with conservative treatment in 201 patients with acute myocardial infarction given recombinant tissue-type plasminogen activator. The 97 patients randomized to the invasive group underwent routine coronary angiography and angioplasty 5 +/- 2 days after thrombolytic therapy, whereas the 104 patients randomized to the conservative group underwent angiography only for recurrent postinfarction angina or exercise-induced ischemia. Baseline characteristics of both groups were similar. In the invasive group, 92 patients underwent angiography, 49 angioplasty and 11 coronary artery bypass surgery. In the conservative group, 40 patients experienced early ischemia, 39 underwent angiography, 20 angioplasty and 4 coronary artery bypass surgery. Reinfarction rate and preservation of left ventricular function at discharge or 8 weeks after discharge did not differ in the 2 groups. Total mortality after a mean follow-up of 10 months was 8 of 97 in the invasive and 4 of 104 in the conservative groups (p = 0.15). However, if only patients who died after the timing of the scheduled protocol catheterization in the invasive arm were included, mortality was 5 of 94 and 0 of 100 in the invasive and conservative treatment groups, respectively (p = 0.02). (ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR)

The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel (ATP III) guidelines have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without glucose intolerance), prothrombotic and proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated receptors (PPAR) deactivation (mainly obesity-related) is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) with preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2) with massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads to both microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set a basis for a comprehensive approach in their treatment.