Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: results from VOYAGER.

BACKGROUND AND AIMS: Diabetes mellitus is a well-known risk factor for cardiovascular disease, and brings an increased risk of vascular events and a higher mortality rate. Treatment guidelines recommend statins in patients with diabetes, with low-density lipoprotein cholesterol (LDL-C) targets of 100 mg dl(-1) (∼2.5 mmol l(-1)), and 80 (∼2.0 mmol l(-1)) or 70 mg dl(-1) (∼1.8 mmol l(-1)) in especially high-risk patients. The current study used the VOYAGER (an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and simvastatin) database to characterise effects of rosuvastatin, atorvastatin and simvastatin in different doses on lipid levels in diabetes patients. METHODS AND RESULTS: The VOYAGER database included individual patient data from 37 studies involving comparisons of rosuvastatin with either atorvastatin or simvastatin. Of the 32 258 patients included, 8859 (27.5%) had diabetes. Rosuvastatin appeared to be the most efficacious of the three statins, both for lowering LDL-C and for reaching a target level of <70 mg dl(-1) for LDL-C. It was also more effective than atorvastatin at raising high-density lipoprotein cholesterol in the diabetes population. These results are consistent with the overall VOYAGER results. CONCLUSIONS: This meta-analysis of 8859 patients with diabetes mellitus shows favourable effects on lipids with the three statins studied, in line with results for the overall VOYAGER population. The importance of using an effective statin at an effective dose to reach treatment goals for such high-risk patients is evident.

Manual or semi-automated edge detection of the maximal far wall common carotid intima-media thickness: a direct comparison.

BACKGROUND: Automated edge detection is thought to be superior to manual edge detection in quantification of the far wall common carotid intima-media thickness (CIMT), yet published evidence making a direct comparison is not available. METHODS: Data were used from the METEOR study, a randomized placebo-controlled trial among 984 individuals showing that rosuvastatin attenuated the rate of change of 2 year change in CIMT among low-risk individuals with subclinical atherosclerosis. For this post hoc analysis, CIMT images of the far wall of the common carotid artery were evaluated using manual and semi-automated edge detection and reproducibility, relation to cardiovascular risk factors, rates of change over time and effects of lipid-lowering therapy were assessed. RESULTS: Reproducibility was high for both reading methods. Direction, magnitude and statistical significance of risk factor relations were similar across methods. Rate of change in CIMT in participants assigned to placebo was 0.0066 mm per year (SE: 0.0027) for manually and 0.0072 mm per year (SE: 0.0029) for semi-automatically read images. The effect of lipid-lowering therapy on CIMT changes was -0.0103 mm per year (SE: 0.0032) for manual reading and -0.0111 mm per year (SE: 0.0034) for semi-automated reading. CONCLUSION: Manual and semi-automated readings of the maximal far wall of the common CIMT images both result in high reproducibility, show similar risk factor relations, rates of change and treatment effects. Hence, choices between semi-automated and manual reading software for CIMT studies likely should be based on logistical and cost considerations rather than differences in expected data quality when the choice is made to use far wall common CIMT measurements.

Increased age, high body mass index and low HDL-C levels are related to an echolucent carotid intima-media: the METEOR study.

INTRODUCTION: Echolucent plaques are related to a higher cardiovascular risk. Studies to investigate the relationship between echolucency and cardiovascular risk in the early stages of atherosclerosis are limited. We studied the relationship between cardiovascular risk factors and echolucency of the carotid intima-media in low-risk individuals. METHODS: Data were analysed from the Measuring Effects on Intima-Media Thickness: an Evaluation of Rosuvastatin (METEOR) study, a randomized placebo-controlled trial including 984 individuals which showed that rosuvastatin attenuated the rate of change of carotid intima-media thickness (CIMT). In this post hoc analysis, duplicate baseline ultrasound images from the far wall of the left and right common carotid arteries were used for the evaluation of the echolucency of the carotid intima-media, measured by grey-scale median (GSM) on a scale of 0-256. Low GSM values reflect echolucent, whereas high values reflect echogenic structures. The relationship between baseline GSM and cardiovascular risk factors was evaluated using linear regression models. RESULTS: Mean baseline GSM (± SD) was 84 ± 29. Lower GSM of the carotid intima-media was associated with older age, high body mass index (BMI) and low levels of high-density lipoprotein cholesterol (HDL-C) [beta -4.49, 95% confidence interval (CI) -6.50 to -2.49; beta -4.51, 95% CI -6.43 to -2.60; beta 2.45, 95% CI 0.47 to 4.42, respectively]. Common CIMT was inversely related to GSM of the carotid intima-media (beta -3.94, 95% CI -1.98 to -5.89). CONCLUSION: Older age, high BMI and low levels of HDL-C are related to echolucency of the carotid intima-media. Hence, echolucency of the carotid intima-media may be used as a marker of cardiovascular risk profile to provide more information than thickness alone.

C-reactive protein lowering with rosuvastatin in the METEOR study.

OBJECTIVES: In addition to its LDL-C-lowering effects, statin treatment reduces the level of C-reactive protein (CRP). Long-term data on this effect in low-risk populations are limited. Furthermore, whether the CRP reduction is a consequence of LDL-C lowering or occurs independently remains unclear. We studied these aspects in the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) study, a randomized placebo-controlled trial amongst 984 low-risk subjects. METHODS: METEOR is a randomized placebo-controlled trial that evaluated the effect of 40 mg of rosuvastatin on 2-year change in carotid intima media thickness (CIMT) amongst 984 low-risk patients (10-year Framingham risk < 10%) with modest CIMT (CIMT > or = 1.2 and < 3.5 mm) and elevated LDL-C. CRP levels were measured at baseline and after 2 years of treatment. RESULTS: Median baseline CRP was 1.4 mg L(-1). Rosuvastatin lowered CRP significantly compared with placebo: -36% in the rosuvastatin group versus no change in the placebo group. There was no relation between change in CRP and change in LDL-C (Spearman correlation: 0.08; SE: 0.04). Stratified analyses showed that the CRP-lowering effect was present amongst all strata of baseline characteristics, including baseline lipids and CRP levels. However, the magnitude of CRP reduction was larger amongst women and participants older than 60 years. CONCLUSIONS: Rosuvastatin (40 mg) lowers CRP independently from its effects on LDL-C in low-risk subjects with normal baseline CRP levels and modest CIMT.

Intensive lipid lowering may reduce progression of carotid atherosclerosis within 12 months of treatment: the METEOR study.

BACKGROUND: In several statin trials, vascular event rates for treatment groups begin to separate 1 year after commencement of treatment. For atherosclerosis progression, the temporal sequence of the effect has not been defined. We used data from the Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) trial to determine the earliest time point at which significant differences in atherosclerosis progression rates could be detected after initiation of statin therapy. METHODS: The METEOR trial was a double-blind, randomized placebo-controlled trial that studied the effect of LDL-C lowering with 40 mg rosuvastatin on the rate of change of carotid intima media thickness (CIMT) measured by B-mode ultrasound amongst 984 low risk subjects. Ultrasound assessments were made at baseline and every 6 months up to 2 years. RESULTS: Rosuvastatin treatment was associated with a 49% reduction in LDL-C-C, a 34% reduction in total cholesterol, an 8.0% increase in HDL-C and a 16% reduction in triglycerides (all P < 0.0001 compared with placebo). The difference in rate of mean maximum CIMT progression between the rosuvastatin and placebo groups (based on near and far wall measurements from both left and right common carotid and internal carotid segments and carotid bifurcation) was not statistically significant after 6 months (0.0023 mm year(-1) and 0.0106 mm year(-1), respectively P = 0.34). After 12 months, CIMT progression rates were significantly different between the groups: 0.0032 mm year(-1) and 0.0133 mm year(-1) in the rosuvastatin-treated and placebo-treated groups, respectively (P = 0.049). This divergence grew with further follow-up: -0.0009 mm year(-1) and 0.0131 mm year(-1) after 18 months (P < 0.001) and -0.0014 mm year(-1) and 0.0131 mm year(-1) after 24 months of treatment (P < 0.001). Results were stronger for the mean common CIMT progression (based on near and far wall measurements from both left and right common carotid segments). CONCLUSION: Aggressive LDL-C lowering seems to exert its beneficial effect on atherosclerosis progression during the first 12 months of treatment. This parallels the timing of event reduction seen in clinical trials and suggests that the efficacy of lipid lowering treatment on CIMT progression can be evaluated in trials with a duration of 1 year, given sufficient sample size, high precision of measurements and a treatment effect comparable to that seen in METEOR.

Costs incurred by patients undergoing advanced colorectal cancer therapy. A comparison of raltitrexed and fluorouracil plus folinic acid.

BACKGROUND: To assess the cost effectiveness of healthcare interventions from a societal perspective, it is necessary to include costs such as patients' travel costs and the opportunity cost of patients' time spent consuming healthcare. OBJECTIVE: To analyse patients' travel and time costs associated with 2 alternative drug therapies for advanced colorectal cancer: raltitrexed and fluorouracil plus folinic acid (leucovorin) [5FU + FA]. DESIGN AND SETTING: The analysis is based on a prospective substudy within a multinational randomised controlled trial of raltitrexed versus 5FU + FA. PATIENTS AND PARTICIPANTS: 495 patients with advanced colorectal cancer were enrolled in the trial, 270 of whom completed the questionnaire on costs. METHODS: Data were collected within the trial to estimate the numbers of journeys made to and from hospital by patients and the time lost from usual activities over the period of therapy. A subset of patients were asked to complete a questionnaire to provide the information necessary to value time and travel costs in monetary terms. These data, together with UK transport costs and forgone time values, were used to value the transport and opportunity costs of time of all patients in the trial. RESULTS: The total travel cost per patient was statistically significantly higher in the 5FU + FA group (p < 0.001; median of 31.50 Pounds with raltitrexed, 96.00 Pounds with 5FU + FA; 1997 prices). Overall time cost per patient was also higher in the 5FU + FA group (p = 0.005; median of 168.80 Pounds with raltitrexed, 224.04 Pounds with 5FU + FA). Adding the two gives a median total cost per patient of 206.08 Pounds [interquartile range (IQR) 108 Pounds to 482 Pounds] among patients randomised to raltitrexed and 342.25 Pounds (IQR 214 Pounds to 555 Pounds) for those in the 5FU + FA group (p < 0.001). The sensitivity analysis showed that, even under extreme assumptions, raltitrexed imposed fewer time and travel costs on patients. These cost differences are likely, in part, to reflect the longer treatment times for 5FU + FA patients (median 16.9 vs 12.7 weeks). CONCLUSIONS: Different chemotherapy regimens for advanced colorectal cancer can impose different travel and time costs on patients. Over the period of treatment in a randomised controlled trial of 495 patients, those randomised to 5FU + FA were found to have a median travel plus time cost 136 Pounds per patient higher than those randomised to raltitrexed.

Measuring quality of life: impact of chemotherapy for advanced colorectal cancer. Experience from two recent large phase III trials.

When assessing the value of a particular treatment, it is important to consider the impact it may have on the quality of life of those being treated. This is particularly so for cancer patients, whose life expectancy may be short. Patients with advanced colorectal cancer who participated in two international comparative studies of raltitrexed ('Tomudex') vs standard 5-fluorouracil (5-FU) plus leucovorin (LV) completed previously validated quality-of-life questionnaires (EORTC questionnaire, EuroQol and Rotterdam Symptom Check List) at various times during the studies. Early statistically significant advantages of raltitrexed vs 5-FU plus LV on quality of life were observed at week 2 in five of eight of the EuroQol and three of four of the Rotterdam Symptom Check List dimensions. Such advantages were not observed using the EORTC questionnaire, which was not completed until week 12. The necessary dose delays and different dose schedules made it difficult in these studies to compare the impact on quality of life of the two treatments. It may be that performance status, effect on disease-related symptoms and the incidence of toxicity are the most important indications of a patient's quality of life.

An evaluation of the effectiveness and safety of razoxane when used as an adjunct to surgery in colo-rectal cancer. Report of a controlled randomised study of 603 patients.

A prospective controlled randomised trial to evaluate the effectiveness and safety of razoxane is reported. Some 603 patients with colo-rectal cancer having curative surgery entered the study, and all have been followed up for a minimum of five years. Statistical analysis showed that razoxane treatment had no effect either beneficial or adverse on the rates of recurrence or on five year survival of patients with colo-rectal cancer. It is possible that a more prolonged course of razoxane might have significantly influenced survival. The incidence of severe adverse reaction was low but it is of concern that one patient developed leukaemia. Should razoxane be considered for future use it is recommended that continuous low dose therapy be given for no longer than 12 months. No renal, hepatic, pulmonary or cardiac toxicity was noted.

Peri-operative heparin: a possible adjuvant to surgery in colo-rectal cancer?

Analysis of data from a randomised trial of adjuvant razoxane involving 603 patients with colo-rectal cancer having curative surgery is reported. The results show that razoxane was ineffective but peri-operative subcutaneous heparin treatment apparently conferred a statistically significant improvement in survival at 5 years, or equivalently a reduction in the risk of death. This beneficial effect is apparent in both razoxane treated and control patients and is not explained by demonstrable differences between heparin and non-heparin treated patients in the distribution of known prognostic factors. Adjustment for these factors slightly increased the apparent magnitude of the beneficial effect.

The relationship between histological grade, oestrogen receptor status, events and survival at 8 years in the NATO ('Nolvadex') trial.

A pathological review was carried out on 600 patients with breast carcinoma entered into the 'Nolvadex' Adjuvant Trial Organisation (NATO) study. The tumours were graded histologically and these results were compared with the oestrogen receptor (ER) status of the tumours, the numbers of recurrences and the length of survival of the patients. It was found that histological grading was predictive both in terms of events and survival, and correlates significantly with oestrogen receptor status; within histological grades I and II, patients receiving 'Nolvadex' had fewer events and deaths compared with patients in the control group. For patients with grade III tumours qualitatively it was in the same direction as the benefit obtained in patients with grade I and II tumours.

Thirty-four year follow up of patients with breast cancer in clinical trial of postoperative radiotherapy.

An extended follow up to a maximum of 34 years was carried out on a series of 1461 patients who had been entered into a randomised clinical trial comparing immediate postoperative radiotherapy (treated group) with an optional delayed radiotherapy policy (watched group) after Halsted radical mastectomy for operable breast cancer. Long term survival was compared separately in patients with negative and positive axillary nodes and in two periods when different techniques of radiotherapy were used. No significant differences were noted in survival overall or in any subgroup. In patients with negative axillary nodes treated in the earlier period when the "quadrate" radiotherapy technique was used, however, the difference in survival was of borderline significance (p = 0.052), to the benefit of the watched group. Because of the large numbers of patients entered and the long follow up any possible harmful or beneficial effect of immediate postoperative radiotherapy would have been apparent in the results of this trial. The absence of any such effect implies that postoperative radiotherapy given to prevent or delay local recurrence of breast cancer is unlikely to be associated with a detectable effect on survival.

The prognostic significance of mediastinal bulk in patients with stage IA-IVB Hodgkin's disease: a report from the Manchester Lymphoma Group.

Three hundred and two previously untreated patients with Stage IA-IVB Hodgkin's disease were reviewed to determine the prognostic significance of mediastinal involvement. Mediastinal bulk disease was defined as either a maximal mediastinal width of 7.5 cm or more, or a ratio of the maximum width of mediastinal disease to the maximum chest diameter of greater than or equal to 0.33, or a ratio of the maximum width of mediastinal disease to the chest diameter at T5-T6 greater than or equal to 0.33, or as an area of mediastinal disease greater than or equal to 100 cm2. Bulk disease outside the chest was defined as a mass of lymph nodes measuring 5 cm or more in any axis. The presence of mediastinal bulk disease was of adverse prognostic significance for remission duration and survival in patients with Stage IA-IIB Hodgkin's disease, but for patients with more advanced disease the effect of mediastinal bulk on remission duration and survival was not statistically significant. The mediastinal bulk variable which most significantly related to prognosis was the ratio of the maximum mediastinal disease to the chest diameter at T5-T6.

Adjuvant low dose radiation in childhood T cell leukaemia/lymphoma (report from the United Kingdom Childrens' Cancer Study Group--UKCCSG).

From November 1977 to July 1983, 82 children with T leukaemia/lymphoma entered a randomised trial of combination chemotherapy and radiotherapy. Twenty-five were designated T lymphoma and 57 T leukaemia, 28 having greater than 100 x 10(9)1(-1) blasts in peripheral blood at diagnosis. Twenty-seven patients with mediastinal primaries who were treated on the companion non-Hodgkin lymphoma (NHL) trial were comparable in all respects to the T lymphoma patients and the results of treatment were therefore combined and analysed together. Overall 4-year survival (48-53%) and failure-free survival (FFS) (37-40%) were similar in all groups except the 28 with T leukaemia and WCC greater than 100 X 10(9)1(-1) (20% and 13%). There was a significant advantage in FFS for patients randomised to receive low dose mediastinal radiation, and this was most marked in patients with T lymphoma (66% vs 18%, P = 0.006).

Adjuvant low dose radiation in childhood non-Hodgkin's lymphoma (report from the United Kingdom Childrens' Cancer Study Group--UKCCSG).

From July 1977 to July 1983, 120 children with non-Hodgkin's Lymphoma entered a randomised trial of combination chemotherapy and radiotherapy. The primary site was abdominal in 42 patients, mediastinal in 27 and in other sites in 51. Failure-free survival (FFS) at 4 years was 74% for the 41 patients with localised disease (Stages I and II) and 51% for the 79 with generalised disease (Stages III and IV). Patients with mediastinal primaries continued to relapse after the completion of 2 years' treatment, but FFS at 4 years for the 93 patients with non-mediastinal primaries was 65% for all stages combined. In the latter group, there was no benefit to patients randomised at the end of induction chemotherapy to receive adjuvant radiation 15 Grays in 10 fractions in 2 weeks to sites of previous bulky disease when compared to those not receiving such radiation (P = 0.6).

Prognostic significance of pretreatment serum beta 2-microglobulin levels in multiple myeloma.

Pretreatment serum beta 2m levels were estimated in 65 patients with multiple myeloma. After correction for changes in renal function, the level of beta 2m attributable to multiple myeloma (beta 2m-m) no longer correlated with the serum creatinine, but showed a strong correlation with the total body myeloma cell mass (P = 0.002). There was an inverse correlation between beta 2m-m and the Karnofsky performance status of patients at presentation (P = 0.001). Patients with a pretreatment beta 2m-m level of less than the median value of 2.94 mg/l survived significantly longer than those with a raised level (P = 0.0008).

Adjuvant tamoxifen for operable carcinoma of the breast: report of clinical trial by the Christie Hospital and Holt Radium Institute.

A large controlled clinical trial with the admission of 1005 patients was carried out using tamoxifen as adjuvant treatment for women with operable carcinoma of the breast. Results were analysed for the first 906 evaluable patients randomised up to December 1981. After mastectomy premenopausal women were randomised to receive either an irradiation menopause or tamoxifen 20 mg daily for one year. Postmenopausal women were randomised to receive either tamoxifen 20 mg daily for one year or no systemic treatment (controls). Analysis at five years suggested that for premenopausal women there was no significant difference between an irradiation menopause and tamoxifen in terms of survival, local recurrence, or distant metastases. Tamoxifen had no appreciable side effects. For postmenopausal women there was a trend in favour of tamoxifen with regard to survival and incidence of distant metastases, and the difference became statistically significant for those patients with four or more positive axillary nodes. If long term results of these studies show only an improved quality of remaining life with tamoxifen, then this drug could be an important contribution to adjuvant treatment.

Manchester regional breast study--5 and 10 year results.

Patients with early breast cancer (n = 1022) were treated between March 1970 and October 1975 in a prospective clinical trial. The results are presented after follow-up of 5-10 years. Clinical stage I cancer cases (n = 714) were randomly allocated to treatment by simple mastectomy and postoperative radiotherapy, or simple mastectomy alone. There was no statistically significant difference in overall survival between the two groups. There was a significant reduction in the frequency of local recurrence in those who received early postoperative radiotherapy compared with those who did not. Clinical stage II cancer cases (n = 308) were randomly allocated to treatment by simple mastectomy and postoperative radiotherapy or radical mastectomy alone. There was no statistically significant difference in survival or in the frequency of local recurrence between the two groups.