International nifedipine trial on anti-atherosclerotic therapy (INTACT) - methodologic implications and results of a coronary angiographic follow-up study using computer-assisted film analysis

Animal experiments demonstrated a significant suppressive effect of various calcium channel blockers on the formation of atherosclerotic lesions. Therefore, a prospective, placebo-controlled, randomized, double blind multicenter study was performed to investigate the inhibitory influence of the calcium channel blocker nifedipine (80 mg/day) on the progression of coronary artery disease in man. Study endpoints were changes of coronary morphology documented by coronary angiography with particular respect to the formation of new coronary stenoses. In 348 out of 425 patients included in the study, coronary angiograms were repeated after three years. The angiograms were standardized by induction of a maximal coronary vasodilation with high doses of nitrates and by using absolutely identical angiographic projections. Quantitative analysis of coronary cineangiograms was performed with the computer-assisted contour detection system CAAS. Parameters were mean and minimal diameter of all segments and minimal stenosis diameter, percent diameter stenosis, length and plaque area of all stenoses. Continuous intake of study medication was registered in 282 patients, 134 on nifedipine and 148 patients on placebo. In these patients, a total of 3808 coronary segments with 893 stenoses (≥ 20% diameter reduction in at least one angiographic projection) were compared on the baseline and follow-up cineangiograms. The changes in all angiographic parameters analyzed averaged over all patients by considering all angiographic projections analyzed, indicated significant progression of the disease (p < 0.006). The average changes in all parameters were even about three times more profound, when in the individual patients only the respective projections indicating the maximal changes were considered for the calculation (p < 0.001). However, with neither of these two analysis modes, the differences in progression between the treatment groups were statistically significant. In the follow-up angiograms, a total of 196 new coronary lesions (185 stenoses, 11 occlusions) were found at previously normal arterial sites. In patients on nifedipine, an average of only 0.58 new lesions per patient were detected versus 0,80 lesions per patient on placebo (-27%; p=0.031). INTACT is the first prospective angiographic trial on the progression of coronary artery disease using computer-assisted quantitative coronary angiography in such a high number of patients. All parameters analyzed indicated significant progression of coronary artery sclerosis. Nifedipine had no influen

Effects of baseline abdominal pain and bloating on response to lubiprostone in patients with irritable bowel syndrome with constipation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134450/1/apt13807.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134450/2/apt13807_am.pd

Effects of baseline abdominal pain and bloating on response to lubiprostone in patients with irritable bowel syndrome with constipation

BACKGROUND: Lubiprostone (8 μg b.d.) received US Food and Drug Administration (FDA) approval in 2008 for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) in women aged ≥18 years. In 2012, the FDA issued new guidance for IBS-C clinical trials, recommending a composite endpoint incorporating both abdominal pain and stool frequency. AIM: In a post hoc analysis, similar criteria were applied to data from two pivotal, phase 3, double-blind, randomised trials of lubiprostone in patients with IBS-C. METHODS: Included patients had a baseline spontaneous bowel movement (SBM) frequency <3/week and abdominal pain or bloating ratings ≥1.36 on a 5-point scale [0 (absent) to 4 (very severe)]. Responders (composite endpoint) had a mean pain reduction ≥30% compared with baseline, and an increase from baseline of ≥1 SBM/week for ≥6 of the 12 treatment weeks. Lubiprostone effects on abdominal pain alone were also evaluated, as were bloating alone and in a composite endpoint with stool frequency. RESULTS: In pooled data, 325 patients received lubiprostone and 180 received placebo. Rates of response were higher with lubiprostone vs. placebo for the composite endpoint of improved pain and stool frequency (26.3% vs. 15.3%, respectively; P = 0.008) and the composite endpoint of improved bloating and stool frequency (23.8% vs. 12.6%, respectively; P = 0.012). Response rates were also higher with lubiprostone vs. placebo for abdominal pain alone (P = 0.005) and bloating alone (P = 0.012). CONCLUSION: Lubiprostone was significantly more effective than placebo in improving abdominal pain or bloating, and also in composite endpoints that included stool frequency

The Cost Effectiveness of Lubiprostone in Chronic Idiopathic Constipation

OBJECTIVE: The objective of this study was to evaluate the cost effectiveness of lubiprostone, prucalopride, placebo and immediate referral to secondary care in chronic idiopathic constipation (CIC) in an economic model that was used by the UK National Institute for Health and Care Excellence (NICE) in developing guidance. METHODS: We developed a cohort state-transition model to reflect the treatment pathway in CIC from the UK NHS and personal social services perspective. Time on treatment was determined by a treatment continuation rule using data from an indirect comparison and survival curves fitted to long-term data. Quality of life was defined by whether CIC was resolved or unresolved, using published values. Costs were determined by drug acquisition costs, invasive procedures and healthcare resource use (associated with resolved or unresolved CIC), using published UK sources. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Over a 10-year time horizon, lubiprostone was more costly and more effective than placebo and immediate referral to secondary care, with incremental cost-effectiveness ratios (ICERs) of £58,979 and £21,152. Lubiprostone dominated prucalopride in the base case and with a time horizon of 1 year. The main sensitivity for the comparison against placebo was the assumptions around placebo cost and efficacy. The main sensitivity for the comparison against prucalopride was the endpoint used in the indirect comparison. CONCLUSION: Lubiprostone may be cost effective compared with prucalopride or immediate referral but not compared with placebo in the base case. The implementation of the guidance issued by NICE should increase quality of life for patients with CIC and provide a further treatment option

Physicians' acquaintance with a new procedure results in higher patient referral: experience of Kosovo in coronary angiography

The first coronary angiography in Kosovo was completed in 2003. We analyzed coronary angiographies performed in our center from October 2003 until October 2009 divided into two 3-year periods. The aims of our study were: to compare the number of coronary angiographies completed in the two periods; to evaluate the prevalence of normal coronary angiographies diagnosed in the first period compared to the second period; and to assess the prevalence of advanced coronary artery disease in the first three years compared to the last three years. This was a prospective angiography study that included 1,139 patients. The first group had 422 patients, who underwent the angiography procedure during the first three years, and the second group had 717 patients that went through the procedure during the last three years. In the first year, 109 coronary angiographies were completed, followed by 137, 176, 213, 218 and 286 (P<0.001) procedures in the subsequent years. In the first period, a normal or near-normal coronary artery profile was found in 27% of patients, while this figure rose to approximately 39% in the second period (P=0.004). Advanced coronary artery disease was found in 45% of the patients who underwent coronary angiography during the first three years, whereas this figure was only 24% of cases during the second period (P<0.001). We believe that the availability of specialized resources and the physicians' familiarity with coronary angiography in our country influenced their decision to refer more patients for this procedure

Five-year follow-up of angiographic disease progression after medicine, angioplasty, or surgery

<p>Abstract</p> <p>Background</p> <p>Progression of atherosclerosis in coronary artery disease is observed through consecutive angiograms. Prognosis of this progression in patients randomized to different treatments has not been established. This study compared progression of coronary artery disease in native coronary arteries in patients undergoing surgery, angioplasty, or medical treatment.</p> <p>Methods</p> <p>Patients (611) with stable multivessel coronary artery disease and preserved ventricular function were randomly assigned to CABG, PCI, or medical treatment alone (MT). After 5-year follow-up, 392 patients (64%) underwent new angiography. Progression was considered a new stenosis of ≥ 50% in an arterial segment previously considered normal or an increased grade of previous stenosis > 20% in nontreated vessels.</p> <p>Results</p> <p>Of the 392 patients, 136 underwent CABG, 146 PCI, and 110 MT. Baseline characteristics were similar among treatment groups, except for more smokers and statin users in the MT group, more hypertensives and lower LDL-cholesterol levels in the CABG group, and more angina in the PCI group at study entry. Analysis showed greater progression in at least one native vessel in PCI patients (84%) compared with CABG (57%) and MT (74%) patients (p < 0.001). LAD coronary territory had higher progression compared with LCX and RCA (P < 0.001). PCI treatment, hypertension, male sex, and previous MI were independent risk factors for progression. No statistical difference existed between coronary events and the development of progression.</p> <p>Conclusion</p> <p>The angioplasty treatment conferred greater progression in native coronary arteries, especially in the left anterior descending territories and treated vessels. The progression was independently associated with hypertension, male sex, and previous myocardial infarction.</p

A randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study†

Aims Endothelial dysfunction and plaque formation are features of atherosclerosis. Inhibition of L-type calcium channels or HMG-CoA pathway improves endothelial function and reduces plaque size. Thus, we investigated in stable coronary artery disease (CAD) the effects of a calcium antagonist on coronary endothelial function and plaque size. Methods and results In 454 patients undergoing PCI, acetylcholine (10−6 to 10−4 M) was infused in a coronary segment without significant CAD. Changes in coronary diameter were measured and an intravascular ultrasound examination (IVUS) was performed. On top of statin therapy, patients were randomized in a double-blind fashion to placebo or nifedipine GITS 30-60 mg/day and followed for 18-24 months. Blood pressure was lower on nifedipine than on placebo by 5.8/2.1 mmHg (P < 0.001) as was total and LDL cholesterol (4.8 mg/dL; P = 0.495), while HDL was higher (3.6 mg/dL; P = 0.026). In the most constricting segment, nifedipine reduced vasoconstriction to acetylcholine (14.0% vs. placebo 7.7%; P < 0.0088). The percentage change in plaque volume with nifedipine and placebo, respectively, was 1.0 and 1.9%, ns. Conclusion The ENCORE II trial demonstrates in a multi-centre setting that calcium channel blockade with nifedipine for up to 2 years improves coronary endothelial function on top of statin treatment, but did not show an effect of nifedipine on plaque volum

Role of calcium channel blocking agents in the prevention of atherosclerosis

Calcium channel blocking agents, although effective and widely used in the symptomatic therapy of hypertension and ischemic heart disease, have an uncertain effect on the development of coronary atherosclerosis, plaque rupture, and postrupture thrombosis. Both nifedipine and nicardipine have been shown to prevent the development of new coronary lesions but not the progression of existing lesions in prospective randomized angiographic studies. Verapamil, in contrast, failed to prevent the development of new coronary lesions and had no significant effect on the progression of existing lesions. Diltiazem, although not studied in patients with coronary atheroscleroses, has been shown to prevent the development of post-transplant coronary vascular disease. Despite the beneficial effects of nifedipine and nicardipine on new coronary lesion development, they have not been shown to reduce the incidence of recurrent ischemic events or mortality in the prospective randomized studies that demonstrated their effect on new coronary lesion development. A relatively new dihydropyridine calcium channel blocking agent, amlodipine, is hypothesized to prevent atherosclerosis due to its calcium channel blocking properties as well as by mechanisms independent of its calcium channel blocking properties. This agent has been selected for evaluation in the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) to explore whether the use of amlodipine over 3 years will reduce the incidence of early atherosclerotic lesions and, possibly, the progression of existing lesions in both the coronary and carotid arterial beds. Amlodipine could play an important future role in the secondary prevention of ischemic heart disease, but further study and a demonstration of a beneficial effect on recurrent ischemic events is required before any final conclusions concerning its effectiveness are reached.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44649/1/10557_2004_Article_BF00878569.pd