Stephen MacMahon

Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials

Abstract Objectives: To obtain reliable estimates of the effects of neuraxial blockade with epidural or spinal anaesthesia on postoperative morbidity and mortality. Design: Systematic review of all trials with randomisation to intraoperative neuraxial blockade or not. Studies: 141 trials including 9559 patients for which data were available before 1 January 1997. Trials were eligible irrespective of their primary aims, concomitant use of general anaesthesia, publication status, or language. Trials were identified by extensive search methods, and substantial amounts of data were obtained or confirmed by correspondence with trialists. Main outcome measures: All cause mortality, deep vein thrombosis, pulmonary embolism, myocardial infarction, transfusion requirements, pneumonia, other infections, respiratory depression, and renal failure. Results: Overall mortality was reduced by about a third in patients allocated to neuraxial blockade (103 deaths/4871 patients versus 144/4688 patients, odds ratio=0.70, 95% confidence interval 0.54 to 0.90, P=0.006). Neuraxial blockade reduced the odds of deep vein thrombosis by 44%, pulmonary embolism by 55%, transfusion requirements by 50%, pneumonia by 39%, and respiratory depression by 59% (all P<0.001). There were also reductions in myocardial infarction and renal failure. Although there was limited power to assess subgroup effects, the proportional reductions in mortality did not clearly differ by surgical group, type of blockade (epidural or spinal), or in those trials in which neuraxial blockade was combined with general anaesthesia compared with trials in which neuraxial blockade was used alone. Conclusions: Neuraxial blockade reduces postoperative mortality and other serious complications. The size of some of these benefits remains uncertain, and further research is required to determine whether these effects are due solely to benefits of neuraxial blockade or partly to avoidance of general anaesthesia. Nevertheless, these findings support more widespread use of neuraxial blockade.

Left Ventricular Remodeling With Carvedilol in Patients With Congestive Heart Failure Due to Ischemic Heart Disease

Objectives. The aim of this study, a substudy of the Australia–New Zealand trial of carvedilol in patients with heart failure due to ischemic heart disease, was to determine the effects of this treatment on left ventricular size and function with the use of quantitative two-dimensional (2D) echocardiography. Background. Beta-adrenergic blocking drugs have been shown to improve left ventricular ejection fraction in patients with heart failure due to either ischemic heart disease or idiopathic dilated cardiomyopathy. However, the effects of such treatment on left ventricular size remain uncertain. Methods. One hundred twenty-three patients from 10 centers in New Zealand and Australia participated in the 2D echocardiographic substudy. Echocardiography was performed before randomization and was repeated after 6 and 12 months of treatment. Left ventricular end-diastolic and end-systolic volumes were measured from apical four- and two-chamber views with the use of a modified Simpson’s rule method. Results. After 12 months, heart rate was 8 beats/min lower in the carvedilol than in the placebo group, whereas left ventricular end-diastolic and end-systolic volumes were increased in the placebo group but reduced in the carvedilol group. At 12 months, left ventricular end-diastolic volume index was 14 ml/m2less in the carvedilol than in the placebo group (p = 0.0015); left ventricular end-systolic volume index was 15.3 ml/m2less (p = 0.0001), and left ventricular ejection fraction was 5.8% greater (p = 0.0015). Conclusions. In patients with heart failure due to ischemic heart disease, carvedilol therapy for 12 months reduced left ventricular volumes, increased left ventricular ejection fraction and prevented progressive left ventricular dilation. These changes demonstrate a beneficial effect of carvedilol on left ventricular remodeling in heart failure. The observed changes may explain in part the improved clinical outcomes produced by treatment with carvedilol. (J Am Coll Cardiol 1997;29:1060–6) © 1997 by the American College of Cardiology

Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system.

Objectives To evaluate the blood pressure-dependent and independent effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on major cardiovascular events. Methods Using data from 26 large-scale trials comparing an ACEI or an ARB with placebo or another drug class, meta-regression analyses were conducted in which treatment-specific relative risks for major cause-specific outcomes [stroke, major coronary heart disease (CHD) events and heart failure] were regressed against follow-up blood pressure differences. Results From a total of 146 838 individuals with high blood pressure or an elevated risk of cardiovascular disease, 22 666 major cardiovascular events were documented during follow-up. The analyses showed comparable blood pressure-dependent reductions in risk with ACEI and ARB (P ≥ 0.3 for all three outcomes). The analyses also showed that ACEI produced a blood pressure-independent reduction in the relative risk of CHD of approximately 9% (95% confidence interval 3–14%). No similar effect was detected for ARB, and there was some evidence of a difference between ACEI and ARB in this regard (P = 0.002). For both stroke and heart failure there was no evidence of any blood pressure-independent effects of either ACEI or ARB. Conclusion There are similar blood pressure-dependent effects of ACEI and ARB for the risks of stroke, CHD and heart failure. For ACEI, but not ARB, there is evidence of blood pressure-independent effects on the risk of major coronary disease events.

Blood Pressure and Mortality Among Men With Prior Myocardial Infarction

Background The purpose of the present study was to describe the relation between blood pressure (systolic [SBP] and diastolic [DBP]) and death from coronary heart disease (CHD) and all causes for men with a history of myocardial infarction (MI). Methods and Results The study cohort consisted of men aged 35 to 57 years screened for the Multiple Risk Factor Intervention Trial (MRFIT) in 1973 through 1975 and followed for survival for an average of 16 years through 1990. There were 5362 men who reported prior hospitalization for a heart attack of at least 2 weeks’ duration at the initial screening of MRFIT. There was a J-shaped relation between SBP and DBP with both CHD and all-cause mortality during the first 2 years of follow-up in older (age, 45 to 57 years) men only. Risk nadirs for SBP were 152 and 145 mm Hg, respectively, for CHD death and all-cause mortality; corresponding DBP risk nadirs were 94 and 90 mm Hg. After the first 2 years, there was a positive association between SBP and death from CHD and all causes. By 15 years, cumulative CHD mortality percentages for men with screening SBP .05). However, the relation still appeared J-shaped as cumulative mortality for those with DBP <70, 70 to 79, 80 to 89, 90 to 99, and ≥100 mm Hg was 24.3%, 20.8%, 21.1%, 25.5%, and 29.7%, respectively. When the joint relation of SBP and DBP was considered, there were no survival differences among the four cohorts (SBP ≥140 and DBP <80, SBP ≥140 and DBP ≥80, SBP ≤140 and DBP <80, and SBP ≤140 and DBP ≥80) during the first 2 years. After 2 years, both CHD and all-cause mortality rates were approximately 40% higher for participants with SBP ≥140 mm Hg versus <140 mm Hg regardless of DBP level (<80 or ≥80 mm Hg). Conclusions In this large cohort of men with prior MI, the association of SBP and DBP with CHD and all-cause mortality varied over the 16-year follow-up period. During early follow-up, in older men only, J- or U-shaped relations were evident. However, after 2 years, these same relations had become positive and graded. Given the substantial excess mortality risk in this cohort associated with high blood pressure, particularly SBP, efforts to gradually lower blood pressure should receive high priority among hypertensive men with prior MI.

The Effects of Blood Pressure Reduction in Older Patients: An Overview of Five Randomized Controlled Trials in Elderly Hypertensives

Direct evidence about the effects of antihypertensive treatment on vascular disease in older patients is available from five randomized trials conducted exclusively in patients over the age of 60 years. These trials involved a total of 12,483 individuals with systolic or diastolic hypertension (mean age = 72 years, mean entry blood pressure = 181/88 mmHg). Over an average follow-up period of 4.7 years, a 15/6 mmHg difference in blood pressure between study and control groups was achieved. Among those patients assigned active treatment, stroke incidence was reduced by 34% SD6 and coronary heart disease incidence was reduced by 19% SD7. These proportional reductions were of similar size to those observed in trials in predominantly younger patients. However, the absolute benefits observed in older patients were more than twice as great as those observed in younger patients. The results suggest that over 10 years, treatment would prevent at least one major vascular event among every 10 elderly patients at similar risk to those enrolled in the trials.

Estimation of arterial stiffness, compliance, and distensibility from M-mode ultrasound measurements of the common carotid artery.

Background and Purpose Arterial stiffness may indicate early vascular changes that predispose to the development of major vascular disease. The repeatability of a variety of indices of arterial stiffness calculated from a standard carotid arterial M-mode ultrasound image was investigated. Methods Twenty-six asymptomatic normal subjects were imaged and had blood pressure recordings on each of two separate occasions at least 1 day apart. Using a computer-assisted method, the maximum and minimum internal diameter and average wall thickness of the right common carotid artery were measured over several cardiac cycles, and the following indices of arterial stiffness and distensibility (compliance) were derived: the pressure-strain elastic modulus (Ep), Youngs modulus (E), cross-sectional compliance (CC), and the distensibility coefficient (DC). Results The repeatability of these measures, expressed as coefficients of variation, was as follows: Ep, 18%; E, 24%; CC, 14%; and DC, 13%. In another group of 20 subjects, the coefficient of variation for repeat examination by different sonographers was Ep, 19%; E, 20%; CC, 14%; and DC, 17% and for the one sonographer using two ultrasound machines was Ep, 13%; E, 13%; CC, 11%; and DC, 13%. These values indicate a moderate level of repeatability. In a univariate analysis each of these indices was significantly related to increasing age (Ep=1.0+12.9×AGE, r=.80; E=314.5 +13.9×AGE, r=.48; CC=22.6−0.26×AGE, r=−.63; DC=64.0−0.65×AGE, r=−.78) but not to wall thickness (all P > .47). Using multiple regression techniques to adjust for age, wall thickness is a significant predictor of distensibility (P=.017), cross-sectional compliance (P < .001), and the pressure-strain elastic modulus (P=.019). Because Youngs modulus is calculated from wall thickness, it could not be included in the multivariate analysis. Conclusions We conclude that estimates of carotid artery distensibility and cross-sectional compliance derived from M-mode ultrasound recordings are moderately repeatable and may provide useful additional end points for trials of atherosclerotic progression.

Intensive glucose control improves kidney outcomes in patients with type 2 diabetes

The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes.

Alcohol consumption and the risk of alcohol related cirrhosis in women.

The risks in women of cirrhosis with a likely primary alcohol aetiology were estimated for various levels of alcohol consumption in a case-control study. Data were obtained from 41 women with a first diagnosis of cirrhosis who had no evidence of non-alcohol-related cirrhosis; three matched controls were interviewed for each case. Significant increases in the risk of cirrhosis were detected at levels of consumption between 41 and 60 g daily; above this level a dose-response relation was observed. The risk of cirrhosis did not appear to be influenced by other nutritional factors or history of liver disease or use of hepatotoxic drugs. One per cent of Australian women consume more than 40 g alcohol daily, yet more than 90% of women identified with cirrhosis consumed alcohol at this level. Preventive interventions to reduce alcohol consumption in the small group of women who consume more than 40 g daily have the potential to reduce substantially the incidence of alcohol related cirrhosis.

Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials.

Objective To define the cardiovascular effects of lowering blood pressure in people with chronic kidney disease. Design Collaborative prospective meta-analysis of randomised trials. Data sources and eligibility Participating randomised trials of drugs to lower blood pressure compared with placebo or each other or that compare different blood pressure targets, with at least 1000 patient years of follow-up per arm. Main outcome measures Major cardiovascular events (stroke, myocardial infarction, heart failure, or cardiovascular death) in composite and individually and all cause death. Participants 26 trials (152 290 participants), including 30 295 individuals with reduced estimated glomerular filtration rate (eGFR), which was defined as eGFR <60 mL/min/1.73m2. Data extraction Individual participant data were available for 23 trials, with summary data from another three. Meta-analysis according to baseline kidney function was performed. Pooled hazard ratios per 5 mm Hg lower blood pressure were estimated with a random effects model. Results Compared with placebo, blood pressure lowering regimens reduced the risk of major cardiovascular events by about a sixth per 5 mm Hg reduction in systolic blood pressure in individuals with (hazard ratio 0.83, 95% confidence interval 0.76 to 0.90) and without reduced eGFR (0.83, 0.79 to 0.88), with no evidence for any difference in effect (P=1.00 for homogeneity). The results were similar irrespective of whether blood pressure was reduced by regimens based on angiotensin converting enzyme inhibitors, calcium antagonists, or diuretics/β blockers. There was no evidence that the effects of different drug classes on major cardiovascular events varied between patients with different eGFR (all P>0.60 for homogeneity). Conclusions Blood pressure lowering is an effective strategy for preventing cardiovascular events among people with moderately reduced eGFR. There is little evidence from these overviews to support the preferential choice of particular drug classes for the prevention of cardiovascular events in chronic kidney disease.

Effects of Visit-to-Visit Variability in Systolic Blood Pressure on Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes Mellitus The ADVANCE Trial

Background— Recent evidence suggests that visit-to-visit variability in systolic blood pressure (SBP) and maximum SBP are predictors of cardiovascular disease. However, it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus. Methods and Results— The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) was a factorial randomized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus. The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after randomization. SBP variability (defined as standard deviation) and maximum SBP were determined during the first 24 months after randomization. During a median 2.4 years of follow-up from the 24-month visit, 407 major macrovascular (myocardial infarction, stroke, or cardiovascular death) and 476 microvascular (new or worsening nephropathy or retinopathy) events were observed. The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors (both P<0.05 for trend). Hazard ratios (95% confidence intervals) for the highest tenth of SBP variability were 1.54 (0.99–2.39) for macrovascular events and 1.84 (1.19–2.84) for microvascular events in comparison with the lowest tenth. For maximum SBP, hazard ratios (95% confidence intervals) for the highest tenth were 3.64 (1.73–7.66) and 2.18 (1.04–4.58), respectively. Conclusion— Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00145925.