Correction to the FIELD study report.
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Letter↗
Biomedical subjects
Anthony Keech
Publications and source records attributed to Anthony Keech.
Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: a clinical perspective.
BACKGROUND: Postmastectomy radiation therapy reduces locoregional recurrence among women with operable breast cancer, but whether it improves survival has been controversial. We reanalyzed the results from 36 unconfounded trials (i.e., addition of radiation therapy was the sole discriminant between treatments being compared) that were identified in previous meta-analyses, which provided 38 comparisons. METHODS: We used three predefined treatment categories for individual patient data: 1) a biologically equivalent dose (BED) of 40-60 Gy in 2-Gy fractions with an appropriate target volume, 2) an inadequate or excessive dose of radiation therapy, and 3) an inappropriate target volume. Effects of radiation therapy on 5-year and 10-year survival in each of the treatment categories were estimated from a cohort of 13 199 patients from the published rates or, if these were unavailable, from the published survival curves. We also used this categorization to reanalyze data from Early Breast Cancer Trialists' Collaborative Group (EBCTCG) postmastectomy studies. At 10 years, 16 (84%) of the 19 comparisons in our study coincided with those reported by the EBCTCG. All statistical tests were two-sided. RESULTS: Twenty-five of the 38 available comparisons had used optimal and complete radiotherapy (i.e., category 1). Of these 25 comparisons, 17 had 5-year data, and these data showed that adjuvant radiation therapy was associated with a 2.9% absolute increase in survival (odds ratio [OR] of death = 0.87, 95% confidence interval [CI] = 0.79 to 0.96; P = .006). Thirteen category 1 trials had data at 10 years, and these data showed that adjuvant radiation therapy was associated with a statistically significant 6.4% absolute increase in survival (OR of death = 0.78, 95% CI = 0.70 to 0.85; P < .001). No statistically significant change in survival was observed among category 2 (OR of death = 0.91, 95% CI = 0.75 to 1.11) or 3 (OR of death = 0.97, 95% CI = 0.61 to 1.55) trials. Among the 33 EBCTCG studies, odds of local recurrence were reduced more among category 1 trials (80% lower) than among category 2 (70% lower) or 3 (64% lower) trials (P(heterogeneity) < .001). Odds of all-cause death were also lower among category 1 trials (13% lower) than among category 2 (3% lower) or 3 (26% higher) trials (P(heterogeneity) = .01). CONCLUSIONS: Adjuvant radiation therapy with an optimal BED and target volume was statistically significantly associated with improved survival for up to 10 years.
Breast Neoplasms↗
Effect of pravastatin in people with diabetes and chronic kidney disease.
Although diabetes is a major cause of chronic kidney disease (CKD), limited data describe the cardiovascular benefit of hydroxymethyl glutaryl CoA reductase inhibitors (statins) in people with both of these conditions. This study sought to determine whether pravastatin reduced the incidence of first or recurrent cardiovascular events in people with non-dialysis-dependent CKD and concomitant diabetes, using data from three randomized trials of pravastatin 40 mg daily versus placebo. CKD was defined by estimated GFR <60 or 60 to 89.9 ml/min per 1.73 m2 with proteinuria. Of 19,737 patients, 4099 (20.8%) had CKD but not diabetes at baseline, 873 (4.4%) had diabetes but not CKD, and 571 (2.9%) had both conditions. The primary composite outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Median follow-up was 64 mo. After adjustment for trial and random treatment assignment, the incidence of the primary outcome was lowest in individuals with neither CKD nor diabetes (15.2%), intermediate in individuals with only CKD (18.6%) or only diabetes (21.3%), and highest in individuals with both characteristics (27.0%). Pravastatin reduced the relative likelihood of the primary outcome to a similar extent in subgroups defined by the presence or absence of CKD and diabetes. For example, pravastatin was associated with a significant reduction in the relative risk of the primary outcome by 25% in patients with CKD and concomitant diabetes and by 24% in individuals with neither characteristic. However, the absolute reduction in the risk of the primary outcome as a result of pravastatin use was highest in patients with both CKD and diabetes (6.4%) and lowest in individuals with neither characteristic (3.5%). In conclusion, stage 2 or early stage 3 CKD and diabetes both are associated with higher cardiovascular risk, and pravastatin reduces cardiovascular event rates in people with neither, one, or both characteristics. Given the high absolute benefit of pravastatin in patient with diabetes and stage 2 or early stage 3 CKD, this population in particular should be targeted for widespread use of statins. Additional studies are needed to determine whether these benefits apply to patients with more severe CKD, and recruitment to such studies should be given high priority.
Adult↗
Effects of pravastatin on coronary events in 2073 patients with low levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol: results from the LIPID study.
AIMS: Fibrates or nicotinic acid are usually recommended for secondary prevention of coronary heart disease in patients with low plasma levels of both low-density lipoprotein cholesterol (LDL-C) < or =140 mg/dL (< or =3.6 mmol/L) and high-density lipoprotein cholesterol (HDL-C) < or =40 mg/dL (< or =1.03 mmol/L). The LIPID trial, a randomised, placebo-controlled trial in 9014 patients at 87 centres in Australia and New Zealand, provided an opportunity to investigate the effects of an HMG-CoA reductase inhibitor in patients with low LDL-C and low HDL-C. METHODS AND RESULTS: Participants in this post hoc substudy were 2073 patients aged 31-75 years with baseline LDL-C < or =140 mg/dL (< or =3.6 mmol/L), HDL-C < or =40 mg/dL (< or =1.03 mmol/L), and triglyceride < or =300 mg/dL (< or =3.4 mmol/L). The relative risk reduction with pravastatin treatment was 27% for major coronary events (95% CI 8-42%), 27% for coronary heart disease mortality (95% CI 0-47%), 21% for all-cause mortality (95% CI 0-38%), and 51% for stroke (95% CI 24-69%). The number needed to treat to prevent a major coronary event over 6 years was 22. CONCLUSIONS: Treatment with pravastatin in patients with both low LDL-C and low HDL-C significantly reduced major coronary events, stroke, and all-cause mortality. The level of HDL-C is crucial to the risk of recurrent CHD events and, consequently, the benefit of lowering LDL-C.
Adult↗
Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial.
OBJECTIVE: Diabetes, a major health problem worldwide, increases the risk of cardiovascular disease and its associated mortality: The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that cholesterol-lowering treatment with pravastatin reduced mortality and coronary heart disease (CHD) events in 9014 patients aged 31-75 years with CHD and total cholesterol 4.0-7.0 mmol/l. We measured the effects of pravastatin therapy, 40 mg/day over 6.0 years, on the risk of CHD death or nonfatal myocardial infarction and other cardiovascular outcomes in 1,077 LIPID patients with diabetes and 940 patients with impaired fasting glucose (IFG). RESULTS: In patients allocated to placebo, the risk of a major CHD event was 61% higher in patients with diabetes and 23% higher in the IFG group than in patients with normal fasting glucose, and the risk of any cardiovascular event was 37% higher in the diabetic group and 19% higher in the IFG group. Pravastatin therapy reduced the risk of a major CHD event overall from 15.9 to 12.3% (relative risk reduction [RRR] 24%, P < 0.001) and from 23.4 to 19.6% in the diabetic group (19%, P = 0.11); in the diabetic group, the reduction was not significantly different from the reductions in the other groups. Pravastatin reduced the risk of any cardiovascular event from 52.7 to 45.2% (21%, P < 0.008) in patients with diabetes and from 45.7 to 37.1% (26%, P = 0.003) in the IFG group. Pravastatin reduced the risk of stroke from 9.9 to 6.3% in the diabetic group (RRR 39%, CI 7-61%, P = 0.02) and from 5.4 to 3.4% in the IFG group (RRR 42%, CI -9 to 69%, P = 0.09). Pravastatin did not reduce the incidence of diabetes. Over 6 years, pravastatin therapy prevented one major CHD event (CHD death or nonfatal myocardial infarction) in 23 patients with IFG and 18 patients with diabetes. A meta-analysis of other major trials confirmed the high absolute risks of diabetes and IFG and the absolute benefits of statin therapy in these patients. CONCLUSIONS: Cholesterol-lowering treatment with pravastatin therapy prevents cardiovascular events, including stroke, in patients with diabetes or IFG and established CHD.
Adult↗
Safety and tolerability of pravastatin in long-term clinical trials: prospective Pravastatin Pooling (PPP) Project.
BACKGROUND: Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety data. METHODS AND RESULTS: The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively accumulated >112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin (40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With >243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline sampling was similar (>3x the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%] patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo. CONCLUSIONS: This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated, with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic decisions regarding this pharmacological agent.
Aged↗
Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors.
BACKGROUND: In two large secondary prevention trials of pravastatin, risk reduction was not significant in participants who had low baseline LDL-C concentrations (that is, <125 mg/dL). We conducted exploratory analyses of participant characteristics, lipid risk factors, and risk reduction in this group. METHODS AND RESULTS: Among 13 173 participants with coronary heart disease (CHD), 2607 had baseline LDL-C <125 mg/dL. Those with LDL-C <125 compared with > or =125 mg/dL were more likely to be diabetic (15% versus 9%), hypertensive (46 versus 41%), and male (89% versus 83%); they had higher triglycerides (169 versus 154 mg/dL), lower HDL-C (36.5 versus 38 mg/dL), and similar body mass index (27 kg/m2); and pravastatin lowered their LDL-C by 36 mg/dL (32%) versus 45 mg/dL (29%). During 5.8-year (mean) follow-up, HDL-C and triglycerides were both significantly stronger predictors of recurrent CHD events in participants with LDL-C <125 than > or =125 mg/dL. In diabetic participants with low LDL-C, pravastatin decreased CHD events from 34% to 22% (relative risk, 0.56; 95% CI, 0.37 to 0.83; P=0.004), significantly different from the effect in nondiabetic participants with low LDL-C (P interaction, 0.005) (event rate, 21%; relative risk, 1.06 [95% CI, 0.89 to 1.27]). There were trends toward risk reduction in smokers and in those with low HDL-C, <40 mg/dL. CONCLUSIONS: Among patients with CHD who have low LDL-C, diabetics have much higher subsequent CHD event rates than do nondiabetics. Pravastatin reduced the event rate in diabetics to that of nondiabetic participants. The results also suggest enhanced therapeutic potential for improving HDL-C and triglycerides in patients with CHD who have low LDL-C concentrations.
Adult↗
Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?
BACKGROUND: The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial showed that pravastatin significantly reduced mortality and coronary heart disease (CHD) events in 9014 patients with known CHD and total cholesterol 4.0 to 7.0 mmol/L at baseline. Secondary objectives included assessment of CHD event reduction according to lipid levels. METHODS AND RESULTS: We investigated the relationships of baseline and on-study lipids with subsequent CHD events in separate Cox models. Treatment effect on CHD event reduction was examined by baseline lipids and after adjustment for on-study lipid levels. Baseline lipids were significant predictors of CHD events. The adjusted relative risk per mmol/L (on placebo) was 1.24 (P=0.004) for total cholesterol, 1.28 (P=0.002) for low-density lipoprotein cholesterol, and 0.52 (P=0.004) for high-density lipoprotein cholesterol. Apolipoproteins A1 and B were strong predictors (each P=0.001). Pravastatin reduced the risk of the composite outcome of fatal CHD or nonfatal myocardial infarction by 24% (95% confidence interval [CI], 15% to 32%) and the expanded end point of fatal CHD, nonfatal myocardial infarction, unstable angina, or coronary revascularization by 17% (95% CI, 10% to 24%). Similar relative effects were observed for different categories of baseline lipids. The proportion of treatment effect explained by on-study lipid levels was 67% (95% CI, 27% to 106%) for the composite and 97% (95% CI, 49% to 145%) for the expanded end point. The most important lipids associated with event reduction were apolipoprotein B, low-density lipoprotein cholesterol, and the combination of total and high-density lipoprotein cholesterol. CONCLUSIONS: Changes in lipid levels can explain all or most of the observed benefit of pravastatin. Some treatment effect may also be mediated through nonlipid changes.
Adult↗
Coronary collateralization: determinants of adequate distal vessel filling after arterial occlusion.
BACKGROUND: The protective effect of collateral vessels in coronary artery disease (CAD) is well established. Little is known, however, about factors that influence collateral formation. METHODS: We studied the coronary angiograms of 200 consecutive patients with single-vessel coronary artery occlusion. Patients were excluded if obstructive stenoses were present in other vessels or if prior revascularization had been undertaken. Collateral circulation to the occluded artery was graded as 'poor' (no or incomplete filling) or 'rich' (complete filling). Patient characteristics, including mode of presentation, medications and CAD risk factors, were assessed. RESULTS: Positive univariate correlates of rich collaterals included increasing age [odds ratio (OR) 1.03, P = 0.016], 'statin' use (OR 2.50, P = 0.005), nitrate use (OR 1.96, P = 0.034), calcium-channel blocker (CCB) use (OR 4.07, P < 0.001), presentation with stable angina (OR 2.34, P = 0.006), longer time since diagnosis of CAD (OR 1.12, P = 0.002) and history of hyperlipidemia (OR 3.55, P < 0.001). Significantly poorer collateralization was observed in the setting of acute myocardial infarction (MI) (OR 0.23, P < 0.001), diabetes mellitus (OR 0.33, P = 0.003), impaired left ventricular function (OR 0.64, P = 0.015) and occlusion of the left anterior descending coronary artery (LAD) (OR 0.28, P < 0.001). On multivariate analysis, rich collateralization was associated with hyperlipidemia (P = 0.003) and CCB use (P = 0.028). Independent predictors of poor collaterals were presence of diabetes (P < 0.001), LAD occlusion (P = 0.001) and presentation with acute MI (P = 0.017). CONCLUSION: Diabetes mellitus, occlusion of the LAD and presentation with acute MI are independently associated with poor distal vessel collateralization, whereas hyperlipidemia and use of CCBs are associated with rich collateralization. Factors determining coronary collateral formation may in turn influence outcomes after coronary artery occlusion.
Australia↗
Risk factors for coronary heart disease in the Japanese--comparison of the background of patients with acute coronary syndrome in the ASPAC study with data obtained from the general population. Asia-Pacific Collaboration on CHD Risk Factor Intervention study.
The relative importance of metabolic risk factors for coronary heart disease (CHD) in the Japanese is assessed by comparing their prevalence in patients with acute coronary syndrome (ACS) enrolled in the Asia-Pacific Collaboration on CHD Risk Factor Intervention (ASPAC) study to that obtained by a serum lipid survey carried out in 1990 and also by comparing them to the ASPAC data from other countries and regions in this area. Hypertension was the most prevalent risk factor among Japanese patients with ACS as in the other countries and regions. The prevalence of obesity with a body mass index (BMI) of 30 or more was several times higher than that in the general population, although the rate was still much lower than in New Zealand and Singapore. In addition to hypercholesterolemia, hypertriglyceridemia and diabetes mellitus were frequently found in Japanese patients with ACS. When the prevalence of metabolic risk factors was compared between people with and without hypertension in the general population, the most remarkable difference was seen in BMI, followed by triglyceride and total cholesterol. These results indicate that hypertriglyceridemia and diabetes mellitus may be more important CHD risk factors in the Japanese population than LDL-cholesterol.
Coronary Disease↗