Prevention progression arterial disease diabetes trial

A large proportion of the participants were taking statins and antihypertensive drugs, and only a small proportion were current smokers. The trial has shown that aspirin is beneficial in reducing cardiovascular events, but it also adversely increases the risk of major bleeding. Based on the results of ASCEND, it has been estimated that the numbers needed to treat to avoid a serious cardiovascular event and to induce a major bleeding episode are 91 and , respectively.

The absolute benefits from avoiding major cardiovascular events are therefore mostly negated by the increased risk of hemorrhage. Even when participants were stratified according to their baseline cardiovascular risk, there was no group in which the benefits of aspirin clearly outweighed the hazards in ASCEND. In light of the new evidence from the recent contemporary aspirin trials, how should physicians approach the use of aspirin for primary prevention in people with diabetes?

It is clear that although people with diabetes have increased cardiovascular risk, the mere presence of diabetes is insufficient to bestow a distinct advantage for cardiovascular protection using aspirin with respect to bleeding. There is a fine balance between the risks and benefits of aspirin, and the overall magnitude of the net benefit of aspirin in primary prevention is likely to be small.

National Center for Biotechnology Information , U. Journal List J Diabetes Investig v. J Diabetes Investig. Published online Feb 8. Author information Article notes Copyright and License information Disclaimer. Kathryn CB Tan, Email: kh. Unique Identifier: NCT Abstract Background: Rosiglitazone has several properties that may affect progression of atherosclerosis. Patients events, and interventions. The results of electrocardio- with an ankle brachial pressure index of less than 1.

The electrocardiograms were reviewed manually for evidence of silent myocardial infarction After providing written informed consent, patients on the basis of criteria from the Minnesota code.

When were randomly assigned to one of four treatment relevant, a copy of data from hospital admissions was groups: aspirin plus antioxidant, aspirin plus placebo, obtained for use by the committee deciding on the antioxidant plus placebo, or double placebo.

The presence or absence of a specific end point using allocation sequence used randomised permuted blocks predefined criteria. For example, any electrocardio- of eight and was computer generated by the trial grams obtained from a hospital admission in the case of statisticians. To ensure allocation concealment an a suspected myocardial infarction were also coded independent pharmacist packaged the drugs into using the criteria of the Minnesota code so that the numbered containers.

Recruiting nurses dispensed appearances of the electrocardiograms were consid- the trial drugs on the day of randomisation, under the ered in a uniform manner along with clinical and authority of the consultant or primary care doctor.

We emphasised to the investigators the use of appropriate Outcome measures background cardiovascular risk reduction therapy We used two hierarchical composite primary end according to current international guidelines. This equates ankle amputation for critical limb ischaemia; and death to events occurring during the trial. With this from coronary heart disease or stroke. Definitions for sample size but both treatments equally effective, so these events were according to the World Health slightly lower overall event rates, events would be Organization criteria for the diagnosis of coronary expected in the four years of follow-up.

This would still events and strokes fatal and non-fatal. Eventually patients were recruited and the final power calculations, undertaken in , projected Power calculations that if follow-up continued until June then The event rate for similar end points in patients with events would be expected to occur during the trial.

We assessed the interventions by fitting terms Composite end point corresponding to aspirin, antioxidants, and the inter- Death from coronary heart disease or stroke action between these treatments. We 20 assessed the assumption of proportionality of hazards and we used Kaplan-Meier plots for the survival 15 experience by treatment group. Specific adverse events 10 were assessed using logistic regression with terms corresponding to aspirin, antioxidants, and the inter- 5 action between these treatments.

All disease death analyses were done on an intention to treat basis, with Stroke death 12 1. Non-fatal myocardial 49 7. The trial was done in amputation for critical accordance with good clinical practice regulations. The progress of the Coronary artery 12 1.

This committee met at six angioplasty monthly or yearly intervals depending on the stage of Development of 69 No formal stopping rules were used. The angina principle employed was that early termination for Peripheral arterial 4 0.

Peripheral arterial 12 1. A total of claudication patients were potentially eligible and had an ankle Adverse events: brachial pressure index of 0. Of these, Malignancy 65 The treatment groups were Allergy including 68 The median length of follow-up for 20 Expected randomised participants was 6. A total of patient years of follow- 10 up were completed. Seventy No antioxidant 56 eight participants died from coronary heart disease or Fig 5 Kaplan-Meier estimates for antioxidant and no stroke, an event rate of 1.

The interaction between the aspirin and antioxidant between these two groups were not statistically treatments was not statistically significant either for the significant for either of the primary end points. No significant differences were found between the aspirin evidence was found of an interaction for the specific and no aspirin groups for any of the secondary end adverse events. Because there was no evidence of an points.

Specific adverse event rates were not statisti- interaction between aspirin and antioxidant, patients in cally significantly different between the aspirin and no the two groups randomised to receive aspirin were aspirin groups table 3.

Aspirin versus no aspirin Figure 4 shows the cumulative percentages of patients Table 3 shows the proportion of participants with each over time who experienced each of the primary end of the primary and secondary end points in the aspirin points. No statistically significant differences were and no aspirin groups. Figure 2 shows the cumulative found between these two groups for either of the percentages of patients over time who experienced primary end points.

Fig 4 Kaplan-Meier estimates for antioxidant and no antioxidant groups of proportion of patients who experienced the composite end point of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or above ankle amputation for critical limb ischaemia; and death from coronary heart disease or stroke. Comparison between antioxidant and no antioxidant groups in number percentage of patients with diabetes who experienced primary end points, secondary end points, and specific adverse events.

This difference in all cause mortality seems to be partly due to a relative deficiency of deaths in the no antioxidant group compared with an age and sex matched Scottish population and partly due to a relative excess of deaths in the antioxidant group. No statistically significant differences were found between the antioxidant and no antioxidant groups for any of the other secondary end points.

Fig 5 Kaplan-Meier estimates for antioxidant and no antioxidant groups of proportion of patients who died from any cause, compared with proportion expected based on age and sex specific population rates for Scotland, The end points committee classified the deaths as coronary heart disease, stroke, other cardiac, other vascular, cancer, trauma, or other.

The deaths from coronary heart disease were further classified as being due to myocardial infarction or other coronary heart disease, whereas the deaths from stroke were classified as ischaemic, haemorrhagic, or of unknown cause.

Cause of death in patients with diabetes according to treatment group. Although subgroup analyses were planned, the trial steering committee asked that analyses of the primary end points compared aspirin and no aspirin groups by subgroups of age, sex, or ankle brachial pressure index.

This was because of concern that particular patients with an ankle brachial pressure index of less than 0. Comparison of aspirin and no aspirin groups in subgroups of specified baseline characteristics for primary end points.

We evaluated the effect of aspirin or antioxidant on cardiovascular events and mortality in a large cohort of people with diabetes mellitus with asymptomatic peripheral arterial disease. These two clinical criteria were selected for study as guidelines 15 16 17 18 were being published, without evidential support, recommending aspirin use as primary prevention of cardiovascular disease in patients with diabetes mellitus and with asymptomatic peripheral arterial disease.

We found no evidence of benefit from either aspirin or antioxidant treatment on the composite hierarchical primary end points of cardiovascular events and cardiovascular mortality. Clinically important benefits are unlikely from the results of this study, although it is possible that small effects may be shown with larger trials continued for a longer time. Secondly, using such a design provided an opportunity for testing the interaction between the two interventions, although the power to detect an interaction was low.

This design yields double the information of single factorial designs. In examining why aspirin may have been ineffective the question was asked as to whether these patients were at sufficient risk, in terms of peripheral arterial disease, as the cut-off point of an ankle brachial pressure index of 0. Furthermore, one of the current major interventions in the specialty of diabetes mellitus is statin therapy.

Calculations by two of the centres DM and CK in over 10 people with diabetes showed a mean total cholesterol level of 6. As aspirin was the first drug to have an evidence base for secondary prevention of cardiovascular disease it is always given to patients in subsequent trials and it might be asked if aspirin does indeed provide additional benefit when statins are used to good effect. The importance of the neutral effect of aspirin on cardiovascular events is that this drug is not without side effects.

The number of prescriptions is increasing. Aspirin is one of the top 10 causes of adverse drug events reported to the Commission on Human Medicines. In a meta-analysis the number needed to treat to cause an adverse event has been calculated as , 36 and this is relevant to the large and increasing population with diabetes.

Of concern was the fact that there was a tendency to harm in the antioxidant group. It should be noted that the increase in number of deaths in the antioxidant groups seems to partly reflect better survival than expected of the groups who did not receive antioxidants, rather than just an obvious negative effect of the antioxidants. Thus this may at least in part be a difference achieved by chance.

This agrees with recently published work, 37 and these data should be added to future systematic reviews and meta-analyses.

Anecdotally, many people with diabetes supplement with antioxidants after major publicity in the lay press of a deficiency in antioxidants in such people. We found no evidence for this perceived benefit from our study. We found no evidence to support the use of either aspirin or antioxidants in the primary prevention of cardiovascular events and mortality in people with diabetes.

Aspirin should, however, still be given for secondary prevention of cardiovascular disease in people with diabetes mellitus, when the evidence base is convincing, and the results of this study must not detract from this important standard of care. Aspirin is effective in the secondary prevention of cardiovascular events in patients with symptomatic peripheral arterial disease and with or without diabetes.

No large intervention trial has shown any reduction of events with antioxidant intervention. Aspirin was not effective in the primary prevention of cardiovascular events in patients with asymptomatic peripheral arterial disease and diabetes. We thank Bayer for donating the aspirin and placebo tablets, Scotia Pharmaceuticals formerly Cardinal for the anitioxidant capsules and matching placebo, and the study nurse team of the prevention of progression of arterial disease and diabetes trial. Nursing staff: JBan senior research nurse.

Contributors: All authors were members of the Royal College of Physicians Edinburgh and as such helped in the development and completion of the protocol and the project. All researchers were independent of the funder. Ethical approval: This work was approved by the local research ethics committees of all participating centres and by a multiresearch ethics committee.

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