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Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus [75% were on statin]..,.also is study looking at n-3 fatty acids in sub study, also in diabetics with 75% using a statin, adherence was 77%
 
 
  Download the PDF here
 
Download the PDF here
 

statin

Aug 26 2018 NEJM
• The ASCEND Study Collaborative Group
 
Abstract
 
Background

 
Diabetes mellitus is associated with an increased risk of cardiovascular events. Aspirin use reduces the risk of occlusive vascular events but increases the risk of bleeding; the balance of benefits and hazards for the prevention of first cardiovascular events in patients with diabetes is unclear.
 
Methods
 
We randomly assigned adults who had diabetes but no evident cardiovascular disease to receive aspirin at a dose of 100 mg daily or matching placebo. The primary efficacy outcome was the first serious vascular event (i.e., myocardial infarction, stroke or transient ischemic attack, or death from any vascular cause, excluding any confirmed intracranial hemorrhage). The primary safety outcome was the first major bleeding event (i.e., intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding). Secondary outcomes included gastrointestinal tract cancer.
 
Using minimized randomization, we then assigned eligible participants to receive 100 mg of aspirin once daily or a matching placebo tablet16; participants were also assigned to receive 1-g capsules containing n-3 fatty acid once daily or a matching placebo capsule. The participants were then mailed a 6-month supply of aspirin or placebo tablets and n-3 fatty acids or placebo capsules, as appropriate.
 
Results
 
A total of 15,480 participants underwent randomization. During a mean follow-up of 7.4 years, serious vascular events occurred in a significantly lower percentage of participants in the aspirin group than in the placebo group (658 participants [8.5%] vs. 743 [9.6%]; rate ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.97; P=0.01). In contrast, major bleeding events occurred in 314 participants (4.1%) in the aspirin group, as compared with 245 (3.2%) in the placebo group (rate ratio, 1.29; 95% CI, 1.09 to 1.52; P=0.003), with most of the excess being gastrointestinal bleeding and other extracranial bleeding. There was no significant difference between the aspirin group and the placebo group in the incidence of gastrointestinal tract cancer (157 participants [2.0%] and 158 [2.0%], respectively) or all cancers (897 [11.6%] and 887 [11.5%]); long-term follow-up for these outcomes is planned.
 
Conclusions
 
Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease at trial entry, but it also caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. (Funded by the British Heart Foundation and others; ASCEND Current Controlled Trials number, ISRCTN60635500; ClinicalTrials.gov number, NCT00135226.)
 
Outcomes
 
While recruitment was still ongoing, we modified the original primary outcome to include transient ischemic attack in the definition of serious vascular event, a change that was made to increase the statistical power of the trial. Thus, the prespecified primary efficacy outcome was the first serious vascular event, which was defined as a composite of nonfatal myocardial infarction, nonfatal stroke (excluding confirmed intracranial hemorrhage) or transient ischemic attack, or death from any vascular cause (excluding confirmed intracranial hemorrhage). The primary safety outcome was the first occurrence of any major bleeding event, which was defined as a composite of any confirmed intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or any other serious bleeding (i.e., a bleeding event that resulted in hospitalization or transfusion or that was fatal). Secondary outcomes were gastrointestinal tract cancer (overall and excluding those occurring during the first 3 years of follow-up) and the composite of any serious vascular event or any arterial revascularization procedure. All the reports of possible primary or secondary outcomes were adjudicated centrally by clinicians who were unaware of the trial-group assignments in accordance with prespecified definitions. The data analysis plan prespecified that analyses would be based on all the confirmed events plus unrefuted events (see the Methods section in Supplementary Appendix 1).
 
It is well established that aspirin use is beneficial for patients with cardiovascular disease, but it is less clear that there is overall benefit in persons who have not yet had a cardiovascular event.1,2 Patients with diabetes mellitus have a risk of vascular events that is two to three times as high as the risk among those without diabetes,3 but most of the estimated 400 million persons with diabetes worldwide do not have manifest vascular disease.4
 
The 2009 Antithrombotic Trialists' Collaboration meta-analysis involving 95,000 patients in six primary prevention trials showed that assignment to aspirin use led to a 12% (95% confidence interval [CI], 6 to 18) lower risk of serious vascular events than control.1 On average, however, the approximate 50% higher risk of bleeding with aspirin use than with control counterbalanced much of the benefit in these low-risk patients. Only approximately 4% of participants in those trials had diabetes, and the lower relative risk among them was similar to that observed among participants without diabetes (as was also observed in the context of secondary prevention). Likewise, the higher relative risk of bleeding with aspirin use than with control was similar among persons with diabetes and those without diabetes.
 
Since the analyses of the Antithrombotic Trialists' Collaboration, four trials of aspirin use for primary prevention (two specifically involving patients with diabetes5,6 and two in broader populations7,8) have been reported; none showed a clear benefit or reported detailed information regarding bleeding events, so the balance of benefits and risks associated with aspirin use for primary prevention among persons with diabetes remains uncertain. Partly as a result of these studies, there has been speculation that diabetes may be associated with reduced efficacy of the antiplatelet effects of aspirin.9 Retrospective meta-analyses of selected randomized trials of mainly low-dose aspirin have suggested that aspirin use may result in an incidence of cancer or death from cancer that is 15 to 20% lower than that with control.10-13 In particular, reductions of 30 to 40% in the incidence of gastrointestinal cancers (particularly colorectal cancer) were observed, with the effects appearing to increase with more prolonged exposure and with longer follow-up up to 20 years. Data from randomized trials of sufficient size and duration will be useful in assessing any effects of aspirin use on cancer more reliably. We performed the ASCEND (A Study of Cardiovascular Events in Diabetes) randomized trial to assess the efficacy and safety of enteric-coated aspirin at a dose of 100 mg daily, as compared with placebo, in persons who had diabetes without manifest cardiovascular disease at trial entry. Using a factorial design in the same trial, we also randomly assigned the patients to receive a daily regimen of either n-3 fatty acids, administered as 1-g capsules, or placebo, findings that are now reported elsewhere in the Journal.14
 
Discussion
 
In this trial involving persons who had diabetes without manifest cardiovascular disease, assignment to the use of aspirin at a dose of 100 mg daily for 7.4 years resulted in a risk of serious vascular events that was 12% lower than that with placebo but also in a risk of major bleeding that was 29% higher. The lower risk of serious vascular events is similar to the risk that was reported previously in the Antithrombotic Trialists' Collaboration meta-analysis of primary prevention trials of similar doses of aspirin (which used slightly different outcome definitions; see the Methods section in Supplementary Appendix 1).1 In contrast to those previous trials, there were high rates of the use of cardioprotective treatments among the participants in ASCEND, with the majority of participants taking statins and blood pressure–lowering therapy. Hence, the present trial provides a direct assessment of the balance of the benefits and hazards of aspirin use in a contemporary context.
 
In our trial, factors such as the large number of participants and clinical outcomes, long duration of follow-up, the randomized, blinded design of the trial, and the almost complete follow-up of the participants who underwent randomization have allowed reliable detection of these moderate but important effects on the incidence of vascular events and on both the severity and incidence of bleeding. Our findings do not support the hypothesis that persons with diabetes have a resistance to aspirin.9Although the proportional effects of aspirin use are likely to be generalizable to the wider population of persons with diabetes, the absolute event rates and adherence rates reflect this population of persons with well-treated diabetes. Overall, on the basis of the absolute percentage differences between the groups in the incidence of serious vascular events (1.1 percentage points lower in the aspirin group than in the placebo group) and in bleeding events (0.9 percentage points higher in the aspirin group), 91 patients would need to be treated to avoid a serious vascular event over a period of 7.4 years, and 112 to cause a major bleeding event.
 
These results of intention-to-treat analyses tend to underestimate the effect of actual aspirin use, both with respect to events avoided and bleeding events caused owing to a lack of full adherence to the regimen during the trial. Exploratory analyses comparing participants at different levels of vascular risk extrapolated the rate ratios in the intention-to-treat analysis to full adherence and assumed that the proportional effects on the incidence of serious vascular events and bleeding were the same across different levels of vascular risk. The results of these analyses provide a more reliable estimate of the absolute differences in the event rates resulting from aspirin use by applying the extrapolated overall rate ratios to the event rates with placebo in each risk group. On the basis of these assumptions, the predicted number of serious vascular events that would be avoided by participants actually taking aspirin was closely balanced by the predicted number of major bleeding events caused, even among persons who had a 5-year vascular risk of 10% or more (Fig. S6 in Supplementary Appendix 1). A recent analysis suggesting a greater benefit of low-dose aspirin use on the incidence of vascular events among persons with a body weight of less than 70 kg was not confirmed in exploratory subgroup analyses (and, indeed, a trend in the opposite direction was observed).19
 
The assessment of the balance between the benefit and harm of aspirin use in the context of primary prevention is complicated by the difficulty of comparing the severity of the vascular events avoided and the bleeding events caused. For example, although transient ischemic attacks are minor in themselves, they are associated with increased risks of subsequent stroke and cognitive impairment.20 Approximately half the excess of bleeding was in the gastrointestinal tract, with approximately one third in the upper gastrointestinal tract. However, even near the end of the trial in 2016, only approximately one quarter of participants were receiving proton-pump inhibitors (PPIs). It is possible that bleeding rates among aspirin users might be lower if PPIs were routinely used in these persons, provided that longer-term trials of PPIs21,22 confirm the substantial reductions in the incidence of bleeding in the upper gastrointestinal tract that has been seen in short-term studies,23 as well as confirming long-term safety. Several meta-analyses of selected randomized trials of generally low-dose aspirin have suggested that aspirin use might reduce the risk of cancer - in particular, gastrointestinal tract cancer - by up to one third during long-term follow-up, with effects becoming apparent approximately 3 years after randomization.10,12,13,24 However, despite more than 7 years of aspirin treatment and follow-up in ASCEND, we found no evidence of a reduction in the incidence of gastrointestinal tract cancer or of cancer at any other site, even during the later years of follow-up. These analyses had limited statistical power to detect the hypothesized effects, so follow-up is being continued through central registries.
 
In conclusion, the use of low-dose aspirin led to a lower risk of serious vascular events than placebo among persons with diabetes who did not have evident cardiovascular disease at trial entry. However, the absolute lower rates of serious vascular events were of similar magnitude to the absolute higher rates of major bleeding, even among participants who had a high vascular risk. The use of low-dose aspirin did not result in a lower risk of gastrointestinal tract cancer or other cancer over the mean follow-up of 7.4 years, but further follow-up is needed to assess any longer-term effects on cancer reliably.

 
 
 
 
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