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OBJECTIVE —We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes. The primary end point was a composite end point of cardiovascular death, stroke, or myocardial infarction.
In nondiabetic subjects, RRs for the main end point, total cardiovascular events, and cardiovascular deaths were 0. No ificant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects. If confirmed, these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation, thus making the balance between benefits and harms of aspirin treatment unfavorable.
Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed. Diabetic macroangiopathy is the leading cause of mortality and morbidity in people with diabetes 1. In type 2 diabetic patients, mortality and morbidity for cardiac and cerebrovascular causes is two- to fourfold greater than in the general population 2.
The alterations of hemostatic and thrombotic parameters are among the principal causes for the cardiovascular risk increase in diabetic patients 3. It has also been suggested that oxidative stress can contribute to diabetic vascular complications 4and lower antioxidant defenses in diabetes have been described 5. Despite the high cardiovascular risk, clear evidence of benefit of antiplatelet therapy in diabetic people without CVD is still lacking. As for vitamin E, several randomized trials have recently failed to show a benefit deriving from its use in preventing cardiovascular events in different high-risk groups, including diabetic patients 1013 — The Primary Prevention Project PPP is a randomized, open-label trial with a factorial de testing whether chronic treatment with aspirin and vitamin E reduces the frequency of major cardiovascular events in patients without CVD and with one or more cardiovascular risk factors We present the relative to diabetic patients and compare the of diabetic patients with those of nondiabetic patients who have other cardiovascular risk factors.
After the study was planned, we decided to specifically explore the effects of antiplatelet and antioxidant therapy in type 2 diabetic patients. For this purpose, in parallel with the main trial, which was conducted in general practice, we also involved 14 diabetes clinics with the aim of recruiting an additional sample of diabetic patients. After a median follow-up of 3. For this reason, even the enrollment of diabetic patients by diabetes clinics was stopped.
Details on study de and main of the trial have been reported elsewhere Briefly, patients were randomly allocated to receive aspirin or no aspirin and vitamin E or no vitamin E, following a two-by-two factorial de. Treatments were centrally ased on telephone verification of the correctness of inclusion criteria with a separate computer-generated randomization table produced for each physician or center in random permuted blocks of 12, allowing stratification by physician or center.
At the beginning, and repeatedly during the trial, all patients received advice on compliance with background treatments and control of cardiovascular risk. Exclusion criteria were severe pathology, treatment with antiplatelet drugs history of vascular events or diseasechronic use of anti-inflammatory agents or anticoagulants, chronic use of aspirin or vitamin E, contra-indications to aspirin, disease with predictable poor short-term prognosis, and predictable psychological or logistical difficulties affecting compliance with the trial requirements.
The trial procedures were planned to respect the conditions of routine care in patients with diabetes.
Visits to renew drug supplies and to check tolerance and compliance to the trial treatments were arranged every 4 months. Follow-up clinical visits were scheduled yearly and included reassessment of the presence and level of cardiovascular risk factors and recording of outcome events. A compliance form was completed at 3 months after randomization. The primary study efficacy end point was the reduction of the incidence of major cardiovascular and cerebrovascular events cardiovascular deaths, nonfatal myocardial infarction, and nonfatal stroke.
Predefined analyses included cardiovascular deaths, total deaths, total cardiovascular events cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, angina pectoris, transient ischemic attacks [TIAs], peripheral artery disease, and revascularization procedures. Details for the definition of the different end points are reported elsewhere The study was deed to recruit up to 4, participants with diabetes.
The study was ended prematurely on the recommendation of the independent data safety and monitoring board. Therefore, we report for a median follow-up period of 3. Analyses were done according to the intention-to-treat principle. Kaplan-Meier survival curves were estimated for the main end point, and comparisons were made using the log-rank test.
Between and4, patients were recruited, of whom 1, had diabetes. Among the latter, Baseline patient characteristics according to the presence of diabetes are reported in Table 1. Of the 1, diabetic patients enrolled, were randomly ased to receive mg aspirin per day and ased to receive mg vitamin E per day. Table 2 shows baseline characteristics of the population by treatment group. Patient characteristics were well balanced across the groups, with the only exception of a higher percentage of subjects with hypertension and hypercholesterolemia in the aspirin group compared with the no aspirin group.
Kaplan-Meier curves for the main combined end point according to the presence of diabetes are reported in Fig. The use of vitamin E was not associated with a better outcome in both groups. The efficacy profiles for aspirin and vitamin E in patients with and without diabetes are summarized in Fig.
No ificant reduction in any of the end points considered could be found with aspirin in diabetic patients, whereas in nondiabetic individuals, a ificant reduction in the main combined end point, total cardiovascular events, cardiovascular deaths, and peripheral artery disease was documented. As for vitamin E, no ificant reduction in any of the end points considered could be found among diabetic patients, whereas a marginal reduction in the risk of peripheral artery disease was documented in nondiabetic individuals Fig. The rate of noncardiovascular deaths was similar in the treatment groups Table 2.
An excess of nonfatal events was reported for aspirin due to bleeding complications 1. Overall, 10 episodes of bleeding were reported in the aspirin group 8 gastrointestinal and 1 gastrointestinal in the control group. No intracranial hemorrhages were documented.
The 38 new cancer diagnoses were evenly distributed in the treatment groups 20 cases in the aspirin group and 18 in the control group. Diabetes is associated with a substantial increase in the risk of CVD, and the use of low-dose aspirin is thus recommended by existing guidelines 16 Despite the general consensus, the evidence supporting the use of aspirin for the prevention of CVD in diabetic patients is surprisingly scant.
Within the meta-analysis, relative to aspirin mainly derived from the Early Treatment of Diabetic Retinopathy Study ETDRSthe only trial specifically conducted in diabetic patients Due to the low statistical power, our data cannot be considered conclusive. Nevertheless, they are coherent with the existing literature in suggesting the hypothesis that low-dose aspirin might be less effective in diabetic patients as compared with the general population.
Several mechanisms have been suggested that can act in combination and be responsible for these findings. First of all, diabetes might represent a particular case of aspirin resistance. In fact, in diabetic patients, platelets could be activated through different mechanisms that can lead to thrombosis despite aspirin therapy.
The involvement of aspirin-insensitive Cox-2, an inducible enzyme mainly expressed in monocyte-macrophages under inflammatory stimuli, as an additional source of TxA2 is one of these possible mechanisms Interestingly, circulating levels of different endothelial-derived adhesive molecules, which indicate the inflammatory phenotype of endothelial cells, are increased in diabetes 20 The upregulated inflammatory response present in diabetic patients could therefore be responsible for aspirin resistance. It has also been suggested that hyperglycemia can lead to the generation of a relevant quantity of thromboxane and endoperoxides bypassing the cyclooxygenase step 22thus contributing to aspirin resistance.
Diabetes is also often associated with other cardiovascular risk factors, such as hypertension and hypercholesterolemia. In the PPP trial, As for hypercholesterolemia, it has been shown 24 to be associated with reduced responsiveness of platelets to aspirin. Another explanation for the lower-than-expected effect of aspirin can be represented by the low dose used. In fact, in diabetic patients, platelets have an increased turnover, and higher doses of aspirin may be necessary to achieve the same levels of thromboxane inhibition as in nondiabetic subjects Finally, recent studies have suggested that the benefits of aspirin and ACE inhibitors may be attenuated when both agents are used together 26but a recent meta-analysis 27 showed no such interaction.
In our study, we did not find any differential effect of aspirin in patients treated or not with ACE inhibitors. relative to vitamin E are highly consistent with those of the main trial as well as with the existing literature, showing a substantial lack of effect of antioxidant vitamin supplementation in preventing major cardiovascular events in patients at risk. On this ground, the recommendation of antioxidant vitamin supplementation in diabetic patients is hardly justified.
Finally, some of the potential limitations of our study need to be discussed. Therefore, the efficacy of aspirin in the primary prevention of CVD in patients with diabetes cannot be ruled out. Second, the study was open label. The choice not to use a blinded de is related to the pragmatic nature of the trial, which was mainly conducted in general practice; in other words, we wanted to test the efficacy and safety of preventive strategies while respecting the conditions of routine care in patients with cardiovascular risk factors.
The open de did not lead to overtreatment in one group at the expense of the other. In fact, study arms did not differ for the entire study period in terms of antihypertensive and lipid-lowering treatments, and the two groups showed superimposable values in terms of HbA 1clipid profile, and blood pressure levels.
Furthermore, only a few patients in the control group were treated with aspirin, thus confirming that the open de did not affect the interpretation of the. In conclusion, our data seem to show a lower effect of primary prevention of CVD with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors.
If confirmed, these findings may suggest that in diabetic patients the antiplatelet effects of aspirin are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation, thus making the balance between benefits and harms of aspirin treatment unfavorable. Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed, together with studies aimed at identifying the mechanisms by which diabetic patients may fail aspirin therapy.Looking for texting friend 2 Preganziol
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