Belinda Lees

The effects of different formulations of oral contraceptive agents on lipid and carbohydrate metabolism

BACKGROUND Oral contraceptives can induce changes in lipid and carbohydrate metabolism similar to those associated with an increased risk of coronary heart disease, including increased serum triglyceride, low-density lipoprotein (LDL) cholesterol, and insulin levels and decreased high-density lipoprotein (HDL) cholesterol levels. In this study, we examined whether modification of the type or dose of progestin in oral-contraceptive preparations diminishes these changes. METHODS We measured plasma lipoprotein levels and performed oral glucose-tolerance tests in a cross section of 1060 women who took one of nine types of oral contraceptives for at least three months and 418 women who took none. Seven of the contraceptive formulations contained various doses and types of progestin: levonorgestrel in low (150 micrograms), high (250 micrograms), and triphasic (50 to 125 micrograms) doses; norethindrone in low (500 micrograms), high (1000 micrograms), and triphasic (500 to 1000 micrograms) doses; and a new progestin, desogestrel, in one dose (150 micrograms). All seven contained 30 to 40 micrograms of ethinyl estradiol. Two additional formulations contained progestin alone. RESULTS As compared with controls, women taking combination drugs did not have increased serum total cholesterol levels but did have increases of 13 to 75 percent in fasting triglyceride levels. Levels of LDL cholesterol were reduced by 14 percent in women taking the combination containing desogestrel and by 12 percent in those taking low-dose norethindrone. Levels of HDL cholesterol were lowered by 5 percent and 16 percent by the combinations containing low-dose and high-dose levonorgestrel, respectively; these decreases were due to reductions of 29 percent and 43 percent, respectively, in the levels of HDL subclass 2. The combination pill containing high-dose norethindrone did not affect HDL cholesterol levels, whereas that containing low-dose norethindrone increased HDL cholesterol levels by 10 percent. The desogestrel combination increased HDL cholesterol levels by 12 percent. Levels of apolipoproteins A-I, A-II, and B were generally increased by combination drugs. Depending on the dose and type of progestin, combination drugs were associated with plasma glucose levels on the glucose-tolerance test that were 43 to 61 percent higher than in controls, insulin responses 12 to 40 percent higher, and C-peptide responses 18 to 45 percent higher. Progestin-only formulations had only minor metabolic effects. CONCLUSIONS The appropriate dose and type of progestin may reduce the adverse effects of oral contraceptives on many metabolic markers of risk for coronary heart disease. Progestin-only formulations or combinations containing desogestrel or low-dose norethindrone were associated wtih the most favorable profiles.

Randomized Trial of Bilateral versus Single Internal-Thoracic-Artery Grafts

BACKGROUND The use of bilateral internal thoracic (mammary) arteries for coronary-artery bypass grafting (CABG) may improve long-term outcomes as compared with the use of a single internal-thoracic-artery plus vein grafts. METHODS We randomly assigned patients scheduled for CABG to undergo single or bilateral internal-thoracic-artery grafting in 28 cardiac surgical centers in seven countries. The primary outcome was death from any cause at 10 years. The composite of death from any cause, myocardial infarction, or stroke was a secondary outcome. Interim analyses were prespecified at 5 years of follow-up. RESULTS A total of 3102 patients were enrolled; 1554 were randomly assigned to undergo single internal-thoracic-artery grafting (the single-graft group) and 1548 to undergo bilateral internal-thoracic-artery grafting (the bilateral-graft group). At 5 years of follow-up, the rate of death was 8.7% in the bilateral-graft group and 8.4% in the single-graft group (hazard ratio, 1.04; 95% confidence interval [CI], 0.81 to 1.32; P=0.77), and the rate of the composite of death from any cause, myocardial infarction, or stroke was 12.2% and 12.7%, respectively (hazard ratio, 0.96; 95% CI, 0.79 to 1.17; P=0.69). The rate of sternal wound complication was 3.5% in the bilateral-graft group versus 1.9% in the single-graft group (P=0.005), and the rate of sternal reconstruction was 1.9% versus 0.6% (P=0.002). CONCLUSIONS Among patients undergoing CABG, there was no significant difference between those receiving single internal-thoracic-artery grafts and those receiving bilateral internal-thoracic-artery grafts with regard to mortality or the rates of cardiovascular events at 5 years of follow-up. There were more sternal wound complications with bilateral internal-thoracic-artery grafting than with single internal-thoracic-artery grafting. Ten-year follow-up is ongoing. (Funded by the British Heart Foundation and others; ART Current Controlled Trials number, ISRCTN46552265 .).

Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial

BACKGROUND Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis. METHODS In an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2.5 mg), alternate-day rhDNase (2.5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV(1)). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care. FINDINGS Mean FEV(1) increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0.55). However, daily rhDNase showed a significantly greater increase in FEV(1) than hypertonic saline (8% [2 to 14], p=0.01). The average difference in 12-week cost between daily and alternate-day rhDNase was pound513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was pound1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments. INTERPRETATION Hypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase.

Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss

Transdermal hormone replacement therapy (HRT) is now an accepted form of treatment, but the long-term skeletal effects have not been assessed. Sixty-six early postmenopausal women were randomized to receive either transdermal HRT (continuous 17β-oestradiol 0.05 mg/day, with 0.25 mg/day of norethisterone acetate added for 14 days of each 28-day cycle) or oral HRT (continuous conjugated equine oestrogens 0.625 mg/day, with 0.15 mg/day dl-norgestrel added for 12 days of each 28-day cycle). Treatment was given for 3 years and 30 matched untreated women were studied concurrently as a control group. Bone density was measured in the lumbar spine and proximal femur by dual-photon absorptiometry at 6-monthly intervals. Bone turnover was assessed by measurement of biochemical markers. At 3 years bone density had declined by 4% in the lumbar spine and by more than 5% in the femoral neck in the untreated group. By comparison bone density increased in both treatment groups at both sites (p<0.001 vs. untreated) and biochemical measurements indicated a significant reduction in bone turnover. There were no significant differences between the treatment groups. Twelve per cent of women on transdermal or oral treatments lost a significant amount of bone from the femoral neck by 3 years despite adequate compliance. Women taking therapy primarily for hip fracture prevention may require a follow-up bone density measurement to establish the efficacy of treatment.

Preliminary evaluation of a new ultrasound bone densitometer

SummaryA new ultrasound bone densitometer has been developed that measures ultrasonic properties of the os calcis, namely, the speed of sound (SOS), broadband ultrasound attenuation (BUA), and a proprietary factor derived from SOS and BUA, termed “stiffness.” Short-term precision of ultrasound measurements was 1.4% for BUA, 0.2% for SOS, and 1.5% for stiffness in healthy women, and 1.1% for BUA, 0.1% for SOS, and 1.5% for stiffness in osteopenic women. One hundred seven women underwent measurements by ultrasound, together with dual energy X-ray absorptiometry (DXA) bone mineral density (BMD) measurements of the lumbar spine and proximal femur. Correlations between SOS, BUA, and stiffness measurements and DXA BMD measurements were all highly significant (P < 0.001) with r values varying from 0.54 to 0.67. BUA, SOS, and stiffness measurements were all significantly different between normal and osteopenic women even after adjusting for age, height, and weight (P < 0.05,P < 0.001, andP < 0.01, respectively). These results demonstrate that this ultrasound system measures ultrasonic properties of the os calcis with good precision, the measurements correlate moderately well with DXA BMD measurements and they can differentiate between normals and those with osteopenia.

Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis

In a randomized, double-blind, placebo-controlled trial, we have studied the effects of intranasal salmon calcitonin (SCT) on bone mineral density (BMD) and biochemical markers of bone turnover over a period of 2 years. Our study comprised 117 Caucasian postmenopausal women, otherwise healthy apart from reduced bone density. They received either intranasal synthetic SCT (200 IU either three times weekly or daily) or placebo. Compared with placebo, daily intranasal calcitonin resulted in no significant bone loss in the lumbar spine, as assessed by dual photon absorptiometry, over the 2-year study period(P < 0.02). In this group, women more than 5 years postmenopause, with the lowest baseline bone mass, showed the greatest response to this treatment, with a total increase placebo in lumbar spine BMD of 3.1%. Significant spinal bone loss(P < 0.005) occurred in women receiving either placebo or thrice-weekly calcitonin. Although the rates of bone loss in the proximal femur were not significantly different in the three groups, there were differences over time. Whereas bone loss in the daily calcitonin group was insignificant, women who received placebo or thrice-weekly calcitonin experienced significant bone loss(P < 0.001). No significant changes in biochemical markers were observed in any group. Therapy was well tolerated and there were no significant treatment-related adverse events. We conclude that intranasal SCT 200 IU daily is effective and safe for the prevention of bone loss in postmenopausal women with reduced bone mass.

Randomized Comparison of Stentless Versus Stented Valves for Aortic Stenosis Effects on Left Ventricular Mass

Background— Aortic valve replacement (AVR) is the established treatment for severe aortic stenosis. In response to the long-term results of aortic homografts, stentless porcine valves were introduced as an alternative low-resistance valve. We conducted a randomized trial comparing a stentless with a stented porcine valve in adults with severe aortic stenosis. Methods and Results— The primary outcome was change in left ventricular mass index (LVMI) measured by transthoracic echocardiography and, in a subset, by cardiovascular MR. Measurements were taken before valve replacement and at 6 and 12 months. Patients undergoing AVR with an aortic annulus ≤25 mm in diameter were randomly allocated to a stentless (n=93) or a stented supra-annular (n=97) valve. There were no significant differences in mean LVMI between the stentless versus stented groups at baseline (176±62 and 182±63 g/m2, respectively) or at 6 months (142±49 and 131±45 g/m2, respectively), although within-group changes from baseline to 6 months were highly significant. Changes in LVMI measured by cardiovascular MR (n=38) were consistent with the echo findings. There was a greater reduction in peak aortic velocity (P<0.001) and a greater increase in indexed effective orifice area (P<0.001) in the stentless group than in the stented group. There were no differences in clinical outcomes between the 2 valve groups. Conclusions— Despite significant differences in indexed effective orifice area and peak flow velocity in favor of the stentless valve, there were similar reductions in left ventricular mass at 6 months with both stented and stentless valves, which persisted at 12 months.

Differences in proximal femur bone density over two centuries

The incidence of osteoporotic hip fractures in northern Europe has been increasing over the past few decades faster than the rate adjusted for increased life expectancy. One important factor that determines osteoporotic fracture risk is bone density. The restoration of a London church, during which skeletal material dating from 1729 to 1852 was recovered, gave us the opportunity to compare the rate of bone loss in the femora of these samples with that of present-day women. The rate of bone loss, as judged by dual energy X-ray absorptiometry, was significantly greater in modern-day women than in the women from two centuries ago, both pre-menopausally (p < 0.05) and post-menopausally (p < 0.01). The difference in bone loss in the Wards triangle region between the Spitalfields samples and present-day women remained even when the assumed age at menopause was increased to 48 years or decreased to 42 years. The results suggest that differences in rates of bone loss over two centuries may partly account for the increasing incidence of hip fracture in modern-day women. Reasons for these differences are unclear, but one factor may be a lower degree of physical activity in present-day women.

Protocol for the Arterial Revascularisation Trial (ART). A randomised trial to compare survival following bilateral versus single internal mammary grafting in coronary revascularisation [ISRCTN46552265]

BackgroundStandard coronary artery bypass graft surgery uses a single internal mammary artery and supplemental vein or radial artery grafts. Several observational studies have suggested a survival benefit with two internal mammary artery grafts compared to a single internal mammary artery graft, but this has not been tested in a randomised trial. The Arterial Revascularisation Trial is a Medical Research Council and British Heart Foundation funded, multi-centre international trial comparing single internal mammary artery grafting versus bilateral internal mammary artery grafting.Methods/DesignTwenty centres in the UK, Australia, Poland and Brazil are planning to randomise 3000 coronary artery bypass graft surgery patients to single or bilateral internal mammary artery grafting. Supplemental grafts may be either saphenous vein or radial artery. Coronary artery bypass grafting can be performed as an on-pump or off-pump procedure. The primary outcome is survival at 10 years and secondary end-points include clinical events, quality of life and cost effectiveness. The effect of age, left ventricular function, diabetes, number of grafts, vein grafts and off-pump surgery are pre-specified subgroups.DiscussionThe Arterial Revascularisation Trial is one of the first randomised trials to evaluate the effects on survival and other clinical outcomes of single internal mammary artery grafting versus bilateral internal mammary artery grafting, and will help to establish the best approach for patients requiring coronary artery bypass graft surgery.

Pulmonary metastasectomy in colorectal cancer: the PulMiCC trial

In March 2010, a randomized trial called Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) was launched and is open to recruitment. The evidence for pulmonary metastasectomy reviewed in this supplement includes no randomized trials. Claims for a survival benefit for patients undergoing this surgery rely on case series. Furthermore, there is little documentation of any symptoms attributable to pulmonary metastases that are alleviated or obviated by metastasectomy. The PulMiCC study aims are to examine whether or not surgical resection of pulmonary metastases from colorectal cancer lengthens survival and to record systematically the harms and benefits of such surgery and quality of life.