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Biomedical subjects

Andrew Tonkin

Publications and source records attributed to Andrew Tonkin.

At least 19 recordsLinked to original sources
PubMed2007

Clozapine-associated myocarditis: a review of 116 cases of suspected myocarditis associated with the use of clozapine in Australia during 1993-2003.

BACKGROUND: Clozapine is an antipsychotic medication associated with a lower suicide rate compared with other antipsychotic agents. Clozapine is used specifically in patients for whom previous therapy was inadequate or not tolerated, and is the only antipsychotic agent associated with the development of myocarditis. OBJECTIVE: To retrospectively review all adverse drug reaction reports voluntarily submitted to the Australian Adverse Drug Reactions Unit mentioning suspected myocarditis in clozapine-treated patients. PATIENTS AND METHODS: We accessed all electronic database entries and case reports citing suspected myocarditis associated with clozapine therapy from January 1993 through to December 2003, inclusive. RESULTS: 116 case reports of suspected myocarditis amongst clozapine-treated patients were identified during the specified time frame (incidence between 0.7% and 1.2% of treated patients). Median patient age for these cases was 30 years (SD 11.1 years) compared with 37 years from the Clopine registry. The condition developed within a median 16 days (mean 19.8 days; SD 17.3 days) of commencing clozapine for the bulk of patients developing myocarditis within 6 months (n=93, 80.2%). For all cases with known treatment commencement and cessation dates (n=106), the condition developed within a median 17 days (mean 171.7 days, SD 530.9 days). Over nine-tenths of cases were prescribed clozapine within the dose range of 100 mg/day to 450 mg/day. Sixty patients (51.8%) recovered from their episode when reported or during follow-up reports, whereas 17 patients (14.7%) had not yet recovered: 27 patients (23.3%) had unknown outcome when reported and the remaining 12 patients (10.3%) died. CONCLUSION: Clozapine is uncommonly but importantly related to myocarditis, often fatal or near fatal and sometimes in relatively young patients with early onset after treatment initiation. The most striking feature about this condition is the wide diversity of nonspecific symptoms that occur in afflicted patients. Additional pharmacovigilance, improved reporting systems and further investigation of mechanisms of drug-induced myocarditis and related cardiovascular conditions (such as heart failure) are clearly warranted. A case-control study would be suitable for investigation of baseline predictors.

Adult↗
PubMed2006

Primary health care research--essential but disadvantaged.

Primary health care is the foundation of effective, sustainable population health and is associated with higher patient satisfaction and reduced aggregate health spending. Although improving patient care requires a sound evidence base, rigorously designed studies remain under-represented in primary care research. The pace of research activity in general practice and the rate and quality of publications do not match the pace of structural change or the level of funding provided. Recruitment difficulties are a major impediment, fuelled by general practitioners' time constraints, lack of remuneration, non-recognition, and workforce shortages. Radical reform is required to redress imbalances in funding allocation, including: funding of GP Research Network infrastructure costs; formalising relationships between primary care researchers and academic departments of general practice and rural health; and mandating that research funding bodies consider only proposals that include in the budget nominal payments for GP participation and salaries for dedicated research nurses.

Australia↗
PubMed2006

Association between impaired glucose metabolism and quality of life: results from the Australian diabetes obesity and lifestyle study.

AIMS: We examined the association of quality of life with glucose tolerance status in an Australian population to determine the stage in the development of diabetes that quality of life is impaired. METHODS: The Australian Diabetes, Obesity and Lifestyle study (AusDiab) was a population-based study of 11,247 people from randomly selected areas of Australia. As part of the study, participants underwent an oral glucose tolerance test and completed the SF-36 quality of life questionnaire. RESULTS: Previously diagnosed diabetes was associated with a significantly greater risk of being in the lowest quartile of each dimension of the SF-36 scale (except for mental health) and this association was only partially attenuated by adjustment for age, sex, body mass index (BMI), physical activity and treatment for hypertension and lipid abnormalities (adjusted odds ratios [95% CI]: bodily pain, 1.51 [1.18-1.94]; general health, 2.20 [1.64-2.95]; physical functioning, 1.50 [1.10-2.05]; role limitation (emotional), 1.43 [1.07-1.91]; role limitation (physical), 1.57 [1.13-2.18]; social functioning, 1.93 [1.46-2.54] and vitality, 2.24 [1.56-3.22]. Among those with newly diagnosed diabetes (NDM) and impaired glucose tolerance (IGT), there was also evidence of reduced quality of life on some dimensions of the SF-36 scale (NDM, general health, physical functioning and role limitation (physical); IGT, physical functioning and social functioning) after adjustment for confounders. CONCLUSION: These findings show that diabetes is associated with a reduced quality of life and that this is evident in the early stage of the disease, particularly in relation to the ability to perform physical activities.

Australia↗
PubMed2005

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↗
PubMed2005

Neither plasma coenzyme Q10 concentration, nor its decline during pravastatin therapy, is linked to recurrent cardiovascular disease events: a prospective case-control study from the LIPID study.

Statins decrease LDL cholesterol and the risk of atherosclerotic cardiovascular disease (CVD). They also decrease coenzyme Q10 (CoQ10), an effect that may negate some of the statin benefit on CVD. We examined the relationship between plasma CoQ10 concentration and CVD in a prospective case-control study of the effect of pravastatin. Plasma samples from 250 LIPID trial patients who over 6 years suffered a recurrent CVD event (CVD death, nonfatal MI or stroke) and 250 matched controls who remained event-free for the same duration of follow-up were assayed for CoQ10 and lipids (cholesterol and cholesterylesters). Mean plasma CoQ10 concentrations were significantly lower in pravastatin-treated patients than in those assigned placebo (0.51 versus 0.60 micromol/L, P = 0.006), and there was a moderate correlation between CoQ10 and common cholesterylesters (Pearson correlation coefficients in patients randomised to placebo, range r = 0.42-0.63). Univariate conditional logistic regression did not suggest any relationship between plasma CoQ10 and the risk of future CVD events (odds ratio 1.18; 95% CI 0.74-1.87; P = 0.49). Instead, we observed a reduction in the rate of recurrent CVD events with increasing ratio of plasma cholesterylarachidonate to cholesteryllinoleate. This study confirms that pravastatin lowers plasma CoQ10 concentrations, but this does not appear to predict the risk of recurrent CVD events.

Cardiovascular Diseases↗
PubMed2005

Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease.

BACKGROUND: Limited data suggest that HMG-CoA reductase inhibitors (statins) reduce rates of kidney function loss. We performed this analysis to determine whether pravastatin reduced the rate of kidney function loss over approximately 5 years in people with or at high risk for coronary disease. METHODS AND RESULTS: This was a post hoc subgroup analysis of data from 3 randomized double-blind controlled trials comparing pravastatin 40 mg/d and placebo in subjects with a previous acute coronary syndrome or who were at high cardiovascular risk. The primary outcome was the rate of change in estimated glomerular filtration rate (GFR; in mL/min per 1.73 m2/y). The Modified Diet and Renal Disease Study (MDRD) and Cockcroft-Gault equations were used to estimate GFR. We studied 18,569 participants, 3402 (18.3%) of whom had moderate chronic kidney disease as defined by an estimated GFR of 30 to 59.9 mL/min per 1.73 m2 body surface area. In subjects with moderate chronic kidney disease at baseline, pravastatin reduced the adjusted rate of kidney function loss by approximately 34%, although the absolute reduction in the rate of loss was small (0.22 mL/min per 1.73 m2/y by MDRD-GFR; 95% CI, 0.07 to 0.37). Pravastatin did not reduce the frequency of > or =25% decreases in kidney function in this group when MDRD-GFR was used to estimate GFR (relative risk [RR], 0.84; 95% CI, 0.66 to 1.06). When all 18,569 subjects were considered, pravastatin reduced the adjusted rate of kidney function loss by 8% (0.08 mL/min per 1.73 m2/y by MDRD-GFR; 95% CI, 0.01 to 0.15) and the risk of acute renal failure (RR, 0.60; 95% CI, 0.41 to 0.86) but did not significantly reduce the frequency of a > or =25% decline in kidney function by MDRD-GFR (RR, 0.94; 95% CI, 0.88 to 1.01). CONCLUSIONS: Pravastatin modestly reduced the rate of kidney function loss in people with or at risk for cardiovascular disease. However, the primary indication for the use of statins in people with or at risk for coronary events remains the reduction in mortality that results from their use.

Aged↗
PubMed2005

Comparison of the effects of pravastatin and atorvastatin on fracture incidence in the PROVE IT-TIMI 22 trial--secondary analysis of a randomized controlled trial.

Recent observational studies suggest that patients using statins have higher bone densities and lower fracture rates. However, this finding has not been supported by a secondary analysis of a large randomized controlled trial, assessing pravastatin. It has been suggested that the latter finding might be attributable to the failure of pravastatin, which is hydrophilic, to gain access to bone. The recently published TIMI 22 study, which compared pravastatin with more intensive therapy with the bone-active statin, atorvastatin, offers the possibility of re-assessing the effects of these agents, on fractures. This study assessed 4162 patients over a mean period of 24 months, and compared 40 mg of pravastatin daily with 80 mg of atorvastatin daily. There were 30 fractures in the pravastatin group and 31 in the atorvastatin group, producing a relative risk for any fracture of 1.02 (95% CI, 0.62-1.68) in the atorvastatin group. This study has sufficient fractures for a relative risk of fracture of 0.52 to be significant, which is of the order that has been observed in some of the observational studies. These data do not provide any support for the hypothesis that pravastatin and atorvastatin have different effects on fracture, and are consistent with the conclusions from the other controlled trials-that currently available statins do not impact on fracture risk.

Atorvastatin↗
PubMed2005

Secondary prevention of CHD.

BACKGROUND: Coronary heart disease (CHD) is still the single largest health problem for Australia. It is considered essentially preventable. Risk of future events is highest in those who already have manifest disease (secondary prevention) and hence are likely to benefit from aggressive therapy. OBJECTIVE: This article explores issues of management of risk factors postacute myocardial infarction using a case vignette of a woman who consults her general practitioner after discharge from hospital. DISCUSSION: The consultation allows the GP to reassess the patient's CHD risk factor management including lifestyle factors, and reinforce the need for lifelong use of proven secondary prevention drug therapies and participation in a rehabilitation program. Reflective learning from this case should assist the treating GP and her or his colleagues to help other patients avoid a similar fate.

Adrenergic beta-Antagonists↗
PubMed2005

Chronic heart failure--optimising care in general practice.

BACKGROUND: Chronic heart failure (CHF) is a significant cause of mortality and morbidity in developed countries where it predominantly affects elderly persons with a range of other comorbid conditions requiring polypharmacy. In Australia, over 300 000 people are affected by CHF. Quality general practice forms the cornerstone for early diagnosis and evidence based integrated care. OBJECTIVE: This article examines the epidemiology of CHF, its clinical diagnosis, contemporary management and future treatment possibilities, as well as current barriers to optimal care. DISCUSSION: The global prevalence of CHF is rising. Optimal treatment requires a coordinated interdisciplinary approach using a biopsychosocial model of care in order to maximise compliance with therapy. Pharmacological treatment is essential and should include an angiotensin converting enzyme inhibitor and beta blocker where possible. Device based treatment and cardiac surgery may benefit selected cases.

Adrenergic beta-Antagonists↗
PubMed2004

Effect of pravastatin on cardiovascular events in people with chronic kidney disease.

BACKGROUND: Limited data describe the cardiovascular benefit of HMG-CoA reductase inhibitors (statins) in people with moderate chronic kidney disease (CKD). The objective of this analysis was to determine whether pravastatin reduced the incidence of cardiovascular events in people with or at high risk for coronary disease and with concomitant moderate CKD. METHODS AND RESULTS: We analyzed data from the Pravastatin Pooling Project (PPP), a subject-level database combining results from 3 randomized trials of pravastatin (40 mg daily) versus placebo. Of 19 700 subjects, 4491 (22.8%) had moderate CKD, defined by an estimated glomerular filtration rate of 30 to 59.99 mL/min per 1.73 m2 body surface area. The primary outcome was time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization. Moderate CKD was independently associated with an increased risk of the primary outcome (adjusted HR 1.26, 95% CI 1.07 to 1.49) compared with those with normal renal function. Among the 4491 subjects with moderate CKD, pravastatin significantly reduced the incidence of the primary outcome (HR 0.77, 95% CI 0.68 to 0.86), similar to the effect of pravastatin on the primary outcome in subjects with normal kidney function (HR 0.78, 95% CI 0.65 to 0.94). Pravastatin also appeared to reduce the total mortality rate in those with moderate CKD (adjusted HR 0.86, 95% CI 0.74 to 1.00, P=0.045). CONCLUSIONS: Pravastatin reduces cardiovascular event rates in people with or at risk for coronary disease and concomitant moderate CKD, many of whom have serum creatinine levels within the normal range. Given the high risk associated with CKD, the absolute benefit that resulted from use of pravastatin was greater than in those with normal renal function.

Adult↗
PubMed2004

Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their meta-analyses.

BACKGROUND: In randomized trials of secondary prevention, pravastatin sodium and aspirin reduce risks of cardiovascular disease. Pravastatin has a predominantly delayed antiatherogenic effect, and aspirin has an immediate antiplatelet effect, raising the possibility of additive clinical benefits. METHODS: In 5 randomized trials of secondary prevention with pravastatin (40 mg/d), comprising 73 900 patient-years of observation, aspirin use was also prescribed in varying frequencies, and data were available on a large number of confounding variables. We tested whether pravastatin and aspirin have additive benefits in the 2 large trials (Long-term Intervention With Pravastatin in Ischaemic Disease trial and the Cholesterol and Recurrent Events trial) that were designed to test clinical benefits. We also performed meta-analyses of these 2 trials and 3 smaller angiographic trials that collected clinical end points. In all analyses, multivariate models were used to adjust for a large number of cardiovascular disease risk factors. RESULTS: Individual trials and all meta-analyses demonstrated similar additive benefits of pravastatin and aspirin on cardiovascular disease. In meta-analysis, the relative risk reductions for fatal or nonfatal myocardial infarction were 31% for pravastatin plus aspirin vs aspirin alone and 26% for pravastatin plus aspirin vs pravastatin alone. For ischemic stroke, the corresponding relative risk reductions were 29% and 31%. For the composite end point of coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or ischemic stroke, the relative risk reductions were 24% and 13%. All relative risk reductions were statistically significant. CONCLUSION: More widespread and appropriate combined use of statins and aspirin in secondary prevention of cardiovascular disease will avoid large numbers of premature deaths.

Aged↗
PubMed2004

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↗
PubMed2003

Why do phase III trials of promising heart failure drugs often fail? The contribution of "regression to the truth".

There has been considerable recent disappointment with the failure of a number of major new pharmacological strategies for the treatment of chronic heart failure. In turn, there has been much speculation as to why trials of these therapies have not shown benefit. Among a number of plausible and scientifically valid reasons, consideration should be afforded to the potential contribution of "regression to the truth." Regression to the truth derives from the biological concept of regression to the mean, whereby random fluctuations in a biological variable occur over time, such that the true value of the variable is approached with repeated measurements. This same concept can be applied to clinical trial programs for new drugs for heart failure. Because only strongly positive trials generally go on to phase III testing, and some of these early phase studies are positive by chance alone, on retesting in phase III the results are very likely not be as strongly positive. Numerous examples of regression to the truth apply for trials of heart failure therapies, as well as in other areas. A major concern is how to minimize negative outcomes in phase III trials. One approach is to perform major rigorous phase II testing. Alternatively, avoidance of phase II testing will minimize "regression to the truth" because there are no data in phase II from which regression might occur. However, this approach does not obviate the need for an evaluation process in the selection of candidate agents (and their appropriate dose) in order to proceed to definitive testing.

Cardiotonic Agents↗
PubMed2003

Effect of pravastatin on cardiovascular events and mortality in 1516 women with coronary heart disease: results from the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study.

BACKGROUND: The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study showed that cholesterol-lowering therapy prevented further events in patients with coronary heart disease and average cholesterol levels. The aim of this subgroup analysis was to assess the effects of pravastatin in women. METHODS: A total of 1516 women (756 assigned to take pravastatin) in a cohort of 9014 patients with previous myocardial infarction or unstable angina and a baseline plasma cholesterol level of 4.0 to 7.0 mmol/L (155-271 mg/dL) were assigned to receive pravastatin (40 mg/d) or placebo. Major cardiovascular disease events in 6 years were measured. RESULTS: Women were at a lesser risk than men for death from any cause (10.3% vs 14.8%, P <.01), death from coronary heart disease (6.6% vs 8.6%, P =.04), and coronary revascularization (13.6% vs 16.2%, P =.05) and at a similar risk of myocardial infarction (9.2% vs 10.5%, P =.26), stroke (3.6% vs 4.7%, P =.11), and hospitalization for unstable angina (25.1% vs 24.5%, P = 0.90). Pravastatin significantly reduced the risk of all prespecified cardiovascular events in all LIPID patients. Relative treatment effects in women did not differ significantly from those in men (P >.05) for any events except hospitalization for unstable angina. There were too few events to demonstrate separately significant effects in women; the estimated relative risk reduction with pravastatin was 11% (95% CI -18%-33%) for coronary heart disease death or nonfatal myocardial infarction, 18% (95% CI -25%-46%) for coronary heart disease death, 16% (95% CI -19%-41%) for myocardial infarction, and 17% (95% CI -2%-33%) for coronary heart disease death, myocardial infarction, or coronary revascularization. CONCLUSIONS: The study had the largest secondary-prevention female cohort studied thus far, but was not adequately powered to show separate effects in women. Nevertheless, the results were consistent with the main results of this and other trials in showing reduced risks with cholesterol-lowering treatment.

Adult↗