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Biomedical subjects

Andrew M Tonkin

Publications and source records attributed to Andrew M Tonkin.

At least 19 recordsLinked to original sources
PubMed2026

Polygenic Risk Identifies Older Adults Who May Benefit From Aspirin for the Primary Prevention of Ischemic Stroke.

BACKGROUND: Low-dose aspirin is no longer recommended for routine primary prevention in older adults due to bleeding risks outweighing vascular benefits. We hypothesized that an integrative polygenic score (iPGS) could identify a subgroup of older individuals who derive net benefit from aspirin for the primary prevention of ischemic stroke. METHODS: We performed post hoc analysis of the ASPREE randomized, placebo-controlled trial (Aspirin in Reducing Events in the Elderly) of daily 100-mg aspirin, in 12 031 genotyped participants of European ancestry aged >70 years without prior cardiovascular disease. The iPGS was derived from >1.2 million variants and evaluated both continuously and by quintiles. Cox models assessed associations between polygenic risk, ischemic stroke, and major bleeding events, and tested the interaction between the iPGS and treatment allocation, with adjustment for baseline lifestyle and clinical covariates. RESULTS: The mean age of participants was 75.1 years, and 54.9% were women. Over a median of 4.6 years, 187 ischemic strokes and 373 major bleeds occurred, including 101 intracranial bleeds (46 hemorrhagic strokes). Each 1-SD increase in the iPGS was associated with higher incident ischemic stroke risk (hazard ratio, 1.39 [95% CI, 1.20-1.62]). An interaction between the continuous iPGS and aspirin allocation was observed for ischemic stroke (P=0.04) but not major bleeding. In the highest iPGS quintile, aspirin reduced ischemic stroke by 51% (hazard ratio, 0.49 [95% CI, 0.28-0.85]) without significantly increasing major bleeding (hazard ratio, 1.15 [95% CI, 0.71-1.88]). No benefit was observed in the overall cohort or in lower-risk quintiles. CONCLUSIONS: Among older adults, high polygenic risk identifies individuals who may experience substantial stroke reduction with aspirin, with no excess bleeding. These findings raise the possibility that genomic risk stratification may enable targeted aspirin use for the primary prevention of ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Humans↗
PubMed2006

Six year incidence and progression of diabetic retinopathy: results from the Mauritius diabetes complication study.

AIMS: To determine the incidence, progression and risk factors for diabetic retinopathy in the multiethnic population of Mauritius. METHOD: A longitudinal, population-based study was conducted in Mauritius, during 1987, 1992 and 1998. Participants identified through the study as having diabetes (both known and newly diagnosed, by self-report and oral glucose tolerance test) and one in four participants with impaired glucose tolerance (IGT) underwent complications screening in 1992 and 1998. Retinal photographs were taken using a TRC-50VT retinal camera in three fields of the right eye (centred on the optic disc; macula (temporal to the optic disc); and nasal to disc). Photographs were graded according to a simplified version of the Wisconsin grading system. RESULTS: The 6-year incidence of diabetic retinopathy was 23.8% (sight-threatening in 0.4%). Among those with known diabetes mellitus (KDM) and free of retinopathy at baseline the incidence of non-proliferative diabetic retinopathy (NPDR) was 29.2% and proliferative diabetic retinopathy (PDR) was 1.0%. Among those with newly diagnosed diabetes mellitus (NDM) at baseline the incidence of NPDR was 19.1% (no incident cases of PDR were found). Independent risk factors for retinopathy using the baseline population characteristics were duration of diabetes and fasting plasma glucose. CONCLUSIONS: This is one of the few recent population-based studies of diabetic retinopathy undertaken in a developing nation. The incidence of retinopathy in Mauritius was high among those with NDM at baseline, with one in five developing retinopathy over 6 years. These results support the concept that screening for diabetes is important.

Adult↗
PubMed2006

Cost-effectiveness of cholesterol-lowering therapy with pravastatin in patients with previous acute coronary syndromes aged 65 to 74 years compared with younger patients: results from the LIPID study.

BACKGROUND: We compared cost-effectiveness of pravastatin in a placebo-controlled trial in 5500 younger (31-64 years) and 3514 older patients (65-74 years) with previous acute coronary syndromes. METHODS: Hospitalizations and long-term medication within the 6 years of the trial were estimated in all patients . Drug dosage, nursing home, and ambulatory care costs were estimated from substudies. Incremental costs per life saved of pravastatin relative to placebo were estimated from treatment effects and resource use. RESULTS: Over 6 years, pravastatin reduced all-cause mortality by 4.3% in the older patients and by 2.3% in the younger patients. Older patients assigned pravastatin had marginally lower cost of pravastatin and other medication over 6 years (A dollar 4442 vs A dollar 4637), but greater cost offsets (A dollar 2061 vs A dollar 897) from lower rates of hospitalizations. The incremental cost per life saved with pravastatin was A dollar 55500 in the old and A dollar 167200 in the young. Assuming no treatment effect beyond the study period, the life expectancy to age 82 years of additional survivors was 9.1 years in the older and 17.3 years in the younger. Estimated additional life-years saved from pravastatin therapy were 0.39 years for older and 0.40 years for younger patients. Incremental costs per life-year saved were A dollar 7581 in the older and A dollar 14944 in the younger, if discounted at 5% per annum. CONCLUSIONS: Pravastatin therapy was more cost-effective among older than younger patients, because of their higher baseline risk and greater cost offsets, despite their shorter life expectancy.

Acute Disease↗
PubMed2006

Hormone therapy and cardiovascular disease: a systematic review and meta-analysis.

BACKGROUND: Despite decades of evidence from observational studies, the use of hormone therapy for the prevention of cardiovascular disease (CVD) among postmenopausal women is controversial. The recent completion of several randomised clinical trials examining the effects of hormone therapy on CVD presents an opportunity to provide a more precise estimate of the cardiovascular risks of hormone therapy. OBJECTIVE: To summarise the effects of hormone therapy on CVD in postmenopausal women. SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Library, DARE and CENTRAL were searched for clinical trials reporting mortality and/or CVD outcomes in association with hormone therapy. Bibliographies and editorials were also reviewed. All studies were reviewed and rated for quality independently by two reviewers. SELECTION CRITERIA: High quality, randomised placebo-controlled clinical trials of hormone therapy (duration greater than one year) in non-hospitalised postmenopausal women were included. DATA COLLECTION AND ANALYSIS: Summary relative risks were estimated for all-cause mortality, coronary heart disease (CHD) mortality, non-fatal acute myocardial infarction (AMI) and all stroke. MAIN RESULTS: Seven randomised clinical trials met the inclusion criteria. The use of hormone therapy had no significant effect on all-cause mortality, non-fatal AMI or CHD mortality, with relative risks of 1.02 [95% confidence interval (CI) 0.93-1.13], 1.00 (0.88-1.14) and 0.99 (0.82-1.21), respectively. For all stroke, the summary relative risk was 1.29 (1.13-1.48). AUTHOR'S CONCLUSIONS: This systematic review, incorporating the latest available trial data, shows that hormone therapy does not significantly change the risk of all-cause morality, CHD death or non-fatal AMI but increases the risk of stroke in postmenopausal women.

Coronary Disease↗
PubMed2006

Safety of drug therapies used for weight loss and treatment of obesity.

Some of the medications used for weight loss in the management of obesity have been associated with unacceptable morbidity and mortality. Safety concerns have led to the withdrawal of aminorex, followed by the fenfluramines in 1997, and phenylpropanolamine (norephedrine) in 2000. Aminorex was associated with an increased prevalence of primary pulmonary hypertension (PPH), fenfluramines with an increased prevalence of PPH and valvulopathy, and phenylpropanolamine with an increased risk of haemorrhagic stroke. Several studies have investigated the safety of the fenfluramines, yet the benefit-risk profile has not been conclusively quantified. This is due to several deficiencies in the published studies, including a lack of data on the baseline prevalences of comorbid conditions in obese subjects, and potential confounders and biases in the study designs. Although several studies and systematic reviews support an increased risk of PPH and valvulopathy in patients who have taken fenfluramines, without knowledge of the background prevalence it is not possible to determine if the exposure preceded the outcome. The population at higher risk of these adverse effects includes those taking higher doses or with a longer duration of exposure to fenfluramines and those with pre-existing cardiac disease or a genetic predisposition. Patients exposed to fenfluramines continue to be monitored, with some follow-up studies indicating no overall worsening in valvulopathy over time. There are limited efficacy and safety data for amfepramone (diethylpropion) and phentermine and their approval for the management of obesity is limited to short-term use. Orlistat and sibutramine are the only currently approved medications for long-term management of obesity. Although the benefit-risk profiles of sibutramine and orlistat appear positive, sibutramine continues to be monitored because of long-term safety concerns. The safety and efficacy of currently approved drug therapies have not been evaluated in children and elderly patient populations and there is limited information in adolescents, whilst the long-term safety of current and potential new drug therapies in adults will require several years of postmarketing surveillance to fully elucidate their adverse effect profiles.

Anti-Obesity Agents↗
PubMed2005

Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial.

OBJECTIVES: Our objective was to determine the timing of benefit with intensive statin therapy after an acute coronary syndrome (ACS) in two time windows: an early window soon after an ACS and a late window in more stable patients. BACKGROUND: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial showed that the use of intensive statin therapy improved clinical outcomes over two years in ACS patients versus standard therapy. The relative contributions of early or late effects to the overall clinical efficacy of intensive therapy are presently unclear. METHODS: A total of 4,162 patients with ACS were recruited in the PROVE IT-TIMI 22 trial. Patients were randomized to intensive statin therapy (atorvastatin, 80 mg) or standard therapy (pravastatin, 40 mg). The composite triple end point of death, MI, or rehospitalization for recurrent ACS was determined in each group at 30 days. The composite triple and primary end points were assessed in stable patients from six months to the end of study, after censoring for clinical events before six months. RESULTS: The composite end point at 30 days occurred in 3.0% of patients receiving atorvastatin 80 mg versus 4.2% of patients receiving pravastatin 40 mg (hazard ratio [HR] = 0.72; 95% confidence interval [CI], 0.52 to 0.99; p = 0.046). In stable patients, atorvastatin 80 mg was associated with a composite event rate of 9.6% versus 13.1% in the pravastatin 40 mg group (HR = 0.72; 95% CI, 0.58 to 0.89; p = 0.003). CONCLUSIONS: Intensive statin therapy early after ACS leads to a reduction in clinical events at 30 days, consistent with greater early pleiotropic effects. In stable patients, intensive statin therapy provides long-term reduction in clinical events when compared with standard therapy. Thus, ACS patients should be started in-hospital and continued long-term on intensive statin therapy.

Acute Disease↗
PubMed2005

White blood cell count predicts reduction in coronary heart disease mortality with pravastatin.

BACKGROUND: Elevated serum inflammatory marker levels are associated with a greater long-term risk of cardiovascular events. Because 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) may have an antiinflammatory action, it has been suggested that patients with elevated inflammatory marker levels may have a greater reduction in cardiovascular risk with statin treatment. METHODS AND RESULTS: We evaluated the association between the white blood cell count (WBC) and coronary heart disease mortality during a mean follow-up of 6.0 years in the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) Study, a clinical trial comparing pravastatin (40 mg/d) with a placebo in 9014 stable patients with previous myocardial infarction or unstable angina. An increase in baseline WBC was associated with greater coronary heart disease mortality in patients randomized to placebo (hazard ratio for 1x10(9)/L increase in WBC, 1.18; 95% CI, 1.12 to 1.25; P<0.001) but not pravastatin (hazard ratio, 1.02; 95% CI, 0.96 to 1.09; P=0.56; P for interaction=0.004). The numbers of coronary heart disease deaths prevented per 1000 patients treated with pravastatin were 0, 9, 30, and 38 for baseline WBC quartiles of <5.9, 6.0 to 6.9, 7.0 to 8.1, and >8.2x10(9)/L, respectively. WBC was a stronger predictor of this treatment benefit than the ratio of total to high-density lipoprotein cholesterol and a global measure of cardiac risk. There was also a greater reduction (P=0.052) in the combined incidence of cardiovascular mortality, nonfatal myocardial infarction, and stroke with pravastatin as baseline WBC increased (by quartile: 3, 41, 61, and 60 events prevented per 1000 patients treated, respectively). CONCLUSIONS: These data support the hypothesis that individuals with evidence of inflammation may obtain a greater benefit from statin therapy.

Aged↗
PubMed2005

Relation of diet to cardiovascular disease risk factors in subjects with cardiovascular disease in Australia and New Zealand: analysis of the Long-Term Intervention with Pravastatin in Ischaemic Disease trial.

BACKGROUND: Comparisons of the relation of diet with coronary heart disease (CHD) between countries with similar socioeconomic environments have been few. Patients in Australia and New Zealand (n = 9014) who participated in a large secondary prevention trial had significantly different CHD mortality rates. OBJECTIVE: The objective of this study was to ascertain the effects of nutrient consumption on cardiovascular disease risk in patients from the 2 countries. DESIGN: Nutrient consumption patterns were surveyed in a subgroup of 1077 patients on 3 occasions over 4 y during an intervention trial with a statin. RESULTS: Within the entire cohort of 9014 patients, the New Zealanders had significantly (40%) more cardiovascular deaths than did the Australians. In the subgroup of 1077 patients, the New Zealanders were found at entry to have eaten significantly more total (69.34 +/- 12.35 compared with 66.45 +/- 12.9 g/d) and saturated (26.23 +/- 8.41 compared with 24.37 +/- 7.36 g/d) fat (P < 0.001 for each) and to have significantly (4%) higher concentrations of LDL cholesterol (3.96 +/- 0.74 compared with 3.8 +/- 0.76 mmol/L; P < 0.001) than did the Australians. At baseline, patients with previous coronary artery bypass grafting had diets that were significantly different from those of patients without previous coronary artery bypass grafting. Relations between nutrients and plasma lipids confirmed the direct effects of saturated fatty acids on LDL cholesterol and of alcohol on plasma triacylglycerol and HDL cholesterol. Dietary counseling throughout the trial led to significant improvements in compliance with guidelines. However, neither the baseline nor the improved 1-y nutrient intakes predicted future changes in cardiovascular events. CONCLUSION: Differences in CHD mortality and in LDL-cholesterol concentrations between 2 populations with similar socioeconomic and cultural backgrounds were consistent with the amounts and types of fats eaten.

Aged↗
PubMed2004

Statins for stroke prevention: disappointment and hope.

The occurrence of stroke increases with age, particularly affecting the older elderly, a population also at higher risk for coronary heart disease (CHD). Epidemiological and observational studies have not shown a clear association between cholesterol levels and all causes of stroke. Nonetheless, large, long-term statin trials in patients with established CHD or at high risk for CHD have shown that statins decrease stroke incidence in these populations. Combined data from 9 trials including 70,070 patients indicated relative and absolute risk reductions for stroke of 21% and 0.9%, respectively, with statins. The number of strokes prevented per 1000 patients treated for 5 years in patients with CHD is 9 for statins, compared with 17.3 for antiplatelet agents. Statins have not yet been shown to reduce stroke risk in the typical general population without known CHD, nor have they been shown to prevent recurrent stroke in patients with prior stroke. Potential reasons for the effects of statins on stroke and the non-cholesterol-lowering mechanisms that may be involved are discussed. Treatment strategies based on global cardiovascular risk may be most effective. Additional studies in patients representative of the typical stroke population are needed.

Adult↗
PubMed2004

Albuminuria is evident in the early stages of diabetes onset: results from the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).

BACKGROUND: Albuminuria is a common complication of diabetes and a leading cause of end-stage renal disease. We determined the prevalence of and factors associated with albuminuria in an Australian population and examined the association of albuminuria with glucose tolerance. METHODS: The Australian Diabetes, Obesity, and Lifestyle Study included 11,247 adults aged 25 years and older from 42 randomly selected areas of Australia. Microalbuminuria is defined as an albumin-creatinine ratio of 22 to 220 mg/g (2.5 to 25 mg/mmol) in men and 31 to 220 mg/g (3.5 to 25 mg/mmol) in women, and macroalbuminuria is defined as an albumin-creatinine ratio of 220 mg/g or greater (> or =25.0 mg/mmol). RESULTS: Overall, 25.3% of patients with diabetes mellitus (known [KDM] and newly diagnosed [NDM], type 1 and type 2) had evidence of albuminuria (21.0%, microalbuminuria; 4.3%, macroalbuminuria). Prevalence increased with increasing glycemia (normal glucose tolerance [NGT], 5.1%; impaired fasting glucose [IFG], 9.3%; impaired glucose tolerance, 11.0%; NDM, 17.8%; and KDM, 32.6% [type 2 only]). Patients with diabetes (KDM and NDM) and IFG had an increased risk for albuminuria compared with those with NGT independent of age, sex, and other known risk factors for albuminuria. Logistic regression modeling identified age, duration of diabetes, systolic blood pressure, current smoking, body mass index, and glycated hemoglobin level as independent risk factors for albuminuria. CONCLUSION: This Australian population-based study shows that albuminuria is common among patients with established diabetes, is present before the onset of diabetes, and becomes more prevalent with worsening glucose tolerance.

Aged↗