Acta Diabetol DOI 10.1007/s00592-014-0623-x
ORIGINAL ARTICLE
Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy: results from 8 years follow-up of NID-2 study Ferdinando Carlo Sasso • Raffaele Marfella • Antonio Pagano • Giovanni Porta • Giuseppe Signoriello • Nadia Lascar • Roberto Minutolo • Ornella Carbonara • Marcello Persico • Federico Piscione • Luca De Nicola • Roberto Torella • Giuseppe Paolisso
Received: 25 March 2014 / Accepted: 28 June 2014 Ó Springer-Verlag Italia 2014
Abstract The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics. A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22
Managed by Massimo Federici. For the NID-2 Study Group. NID-2 Study Group members are provided in the ‘‘Appendix’’ section.
patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan–Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91–1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy. Keywords
Aspirin CV prevention Nephropathy
Introduction Cardiovascular (CV) disease is a major complication of diabetes and is responsible for 50–80 % of early deaths. A large Danish population-based study [1] showed that diabetic patients without a previous myocardial infarction have a risk of cardiac mortality of 20 % over 7 years, which is equal to the risk of nondiabetic patients after myocardial
F. C. Sasso (&) A. Pagano G. Porta O. Carbonara R. Torella Department of Internal and Experimental Medicine ‘‘Magrassi-Lanzara’’, Second University of Naples, Via F. Petrarca, 64, 80122 Naples, Italy e-mail: [email protected]
N. Lascar School of Life and Health Sciences, Aston University, Birmingham, UK
R. Marfella G. Paolisso Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy
M. Persico F. Piscione Department of Medicine and Surgery, University of Salerno, Salerno, Italy
R. Minutolo L. De Nicola Unit of Nephrology, Second University of Naples, Naples, Italy
G. Signoriello Unit of Medical Statistic, Department of Medicine and Public Health, Second University of Naples, Naples, Italy
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infarction. When compared to nondiabetic patients, those with type 2 diabetes mellitus are 2–4 times at increased CV risk including coronary, cerebrovascular and peripheral arterial ischemia [2, 3]. Despite advances in clinical management, cardiovascular disease (CVD) is the main cause of death, and atherothrombosis is the underlying cause of most CV events [4, 5]. In diabetic patients, the development of the platelet-rich thrombus is promoted by a prothrombotic state, due to insulin resistance and hyperglycemia, characterized by endothelial dysfunction, hypercoagulability and reduced response to fibrinolysis [6]. The dysfunctional endothelial cells fail to produce platelet antagonists such as prostacyclin and nitric oxide, leading to an accelerated atherosclerosis, which clinically results in an increased risk of CV events [7]. For several years, the inhibition of platelet function based on aspirin therapy has been a cornerstone in the prevention and treatment of CVD. Unfortunately, findings from clinical trials are not homogeneous. Therefore, the risk-to-benefit ratio for the use of low dose of aspirin in primary CV prevention in patients with diabetes mellitus remains to be clarified. Remarkably, Position Statement of American Diabetes Association (ADA) suggests the treatment with ACE inhibitors or ARBs (level of evidence A) and a reduction of protein intake in presence of chronic kidney disease (level of evidence C) in patients with diabetic nephropathy. However, there are no recommendations regarding the use of aspirin [8]. Therefore, we evaluated the effect of aspirin on risk of CV events in a cohort of type 2 diabetic patients with nephropathy attending diabetes clinics, in order to verify the usefulness of guidelines in clinical practice. Our prospective study may provide useful insights for future RCT by providing information in high-risk patients, such as those with diabetic nephropathy.
Briefly, inclusion criteria were as follows: type 2 diabetes mellitus, age C 40 years, therapy with diet and/or oral hypoglycemic agents during the first year of the diagnosis of diabetes, persistent albuminuria C30 mg/24 h in at least two urine collections over the previous 6 months, a severe diabetic retinopathy (DR) as judged by means of fundus oculi, and fluoroangiography when necessary. Severe DR was defined as a proliferative diabetic retinopathy or a severe nonproliferative diabetic retinopathy with vascular closure. The presence of severe DR has been used as the clinical hallmark of DN [11], thus excluding other possible causes for increased albuminuria, since renal biopsies are not indicated for diagnostic purposes in microalbuminuric diabetic patients. Exclusion criteria were as follows: dialysis or renal transplant, diagnosis of diabetes at \30 years of age, insulin therapy during the first year of diagnosis of the disease (in order to exclude unknown autoimmune diabetes of adults), severe liver or heart failure and known neoplastic or psychiatric disease, low compliance to any medication suggested by the physicians. All the physicians involved in the study declared that they adhered to recommendations of the clinical practice guidelines issued by the ADA [8]. Ethical committee of Second University of Naples, Italy, approved the study, and all the patients signed informed consent. We selected 564 patients free of CVD from this cohort, 242 of them were receiving ASA (100 mg orally once a day, group A) and 322 were not treated with antiplatelet drugs (group B) based on physician clinical judgment. In all patients, the lack of CVD at baseline was proven by both negative clinical history (included any chest pain or a suspected TIA) and absence of abnormalities at resting ECG, and stress-ECG performed according to Bruce protocol suggestive for CVD. Stress-ECGs performed in all patients had to be conclusive for absence of CAD. Patients without diagnostic tests underwent a stress-ECG. Only patients with stress-ECG negative for CAD were enrolled in the study.
Materials and methods Outcomes and follow-up Study design We carried out a prospective study on a group of type 2 diabetic patients from the NID-2 study cohort [9, 10], selecting for the specific purpose of the current study only patients free of CVD at baseline. Setting and participants As previously described [9, 10], the NID-2 study recruited 847 type 2 diabetic patients at high CV risk with diabetic nephropathy (diagnosed by clinical criteria, i.e., micro/ macro-albuminuria and diabetic retinopathy) from 21 centers of secondary diabetes care in Italy.
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Active follow-up, with control visits planned every 6 months, performed during an average follow-up of 8.0 years, was completed on June 2012. Baseline information included past medical history (myocardial infarction and stroke), blood pressure (BP) measurement (calculated as a mean of three measurements taken at right harm in a sitting position after 10 min of rest), height and body weight as well as laboratory and therapeutic features. Laboratory tests were performed locally and included glycemic, lipidic and renal function assessment. GFR was calculated by the four-variable Modification of Diet in Renal Disease (MDRD) equation, and albuminuria was measured on 24-h urine collection;
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microalbuminuria and macroalbuminuria were defined by values of 30–300 and [300 mg/day, respectively. Throughout the follow-up, the patients of group A received a daily oral H? pump inhibitor treatment (omeprazole 20 mg, or equivalent), in order to minimize the risk of gastro-intestinal bleeding. In both groups, during follow-up the physicians verified and motivated the adherence of each patient to all drug prescriptions. Self-reported adherence to therapy was assessed at each follow-up by asking for the name, the dose and the percentage of pills that should have been taken. None of patients resulted nonadherent (i.e., medication assumption B80 %). Mean medication adherence between the two groups was compared by using a t test for independent groups. Primary outcome was the total major adverse cardio-vascular events (MACE), defined as CV death, nonfatal myocardial infarction, nonfatal stroke, revascularization or major amputation, whichever occurred first. Secondary outcomes were, separately, (1) fatal and (2) nonfatal CV events. When a CV event was suspected, hospital records were collected to make the diagnosis according to European Society of Cardiology and American College of Cardiology criteria [12, 13]. Death certificates and autopsy reports were used to establish the underlying cause of death and to adjudicate CV deaths, through the ninth revision of the International Classification of Diseases.
Statistic analysis Kaplan–Meier survival curves were used tocompare cumulative probability of time free from MACE, from fatal MACE and from nonfatal MACE. The comparison between the two groups was performed using the log-rank test. To assess the independent effect of ASA therapy on primary end point, hazard ratio, with 95 % confidence intervals (HR, 95 % CIs), was estimated by a Cox regression model with demographics (age and gender) and several potentially treatable risk factors (smoking habit, GFR, Albumin Excretion Rate, HbA1c, systolic blood pressure, BMI and cholesterol) variables as covariates. Given the descriptive nature of this observational study and the small number of observed events, traditional power calculations based on hypothesis-testing were not applicable. Statistical significance was fixed at 0.05. Statistical analyses were performed using SPSS version 12.0 (SPSS Inc, Chicago, IL) software package.
at target according to current guidelines [8] for glycemic control (HbA1c: 7.4 ± 1.3 %), and diastolic blood pressure (78.2 ± 7.3 mmHg). The systolic blood pressure was 135.9 ± 13.2 mmHg, total cholesterol was 196 ± 41.2 mg/dl, albumin excretion rate was 143.1 ± 136.3 mg/24 h, and GFR was 66.4 ± 24.3 ml/min/1.73 m2. More than a quarter of the population were smoker (25.7 %). Clinic characteristics of overall subjects at baseline are showed in Table 1. At baseline, no difference was found for demographic, clinical, laboratory and therapeutic parameters between group A and B (Table 1). Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. In particular, in the group A occurred 22 cardiovascular deaths (9.1 %), 17 nonfatal myocardial infarctions and/or revascularizations (7 %), 10 nonfatal strokes (4.1 %). In the group B occurred 20 cardiovascular deaths (6.2 %), 21 nonfatal myocardial infarctions and/or revascularizations (6.4 %) and 11 nonfatal strokes (3.4 %). No major amputation occurred in both groups (Fig. 1). Remarkably, the distribution of MACE (fatal and not) was homogeneous among the centers and not clustered in just some of them. Table 2 describes the MACE divided for each canter. The analysis of the Kaplan–Meier survival curves showed a not statistically significant difference in the incidence of total MACE in the two groups (p = 0.201) (Fig. 2, panel A). No differences were observed between the two groups in the analysis of the secondary end points: The analysis of the Kaplan–Meier showed a not statistically significant difference in the incidence of both fatal and nonfatal MACE between the two groups (respectively p = 0.225 and p = 0.573) (Fig. 2, panel B and C). These data were confirmed also after adjustments (Table 3). Similarly at baseline, no significant difference in GFR at the end of the follow-up period between the two groups was showed (60.5 ± 26.5 vs. 63.8 ± 25.3 ml/min/ 1.73 m2, p = 0.22). Notably, during the clinical follow-up, no difference was found in major bleeding between ASA- and non-ASAtreated groups (6.2 vs. 4.9 %, respectively, p = 0.32).
Discussion Results At baseline, patients (44.9 % men, aged 64.7 ± 8.8 years) were meanly overweight (BMI: 29.3 ± 4.6 kg/m2) and not
This prospective multicentric long-term study originally shows the lack of CV protective effect of low dose of ASA in type 2 diabetics in primary prevention at very high CV risk.
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Acta Diabetol Table 1 Clinic characteristics at baseline of overall subjects, group A and B
Overall (n = 564)
Group A (n = 242)
Group B (n = 322)
p*
Sex [M/F (%)]
44.9/55.1
45.2/54.8
44.4/55.6
0.21
Age (years)
64.7 ± 8.8
65.2 ± 9.0
64.4 ± 8.5
0.25
BMI (kg/m2)
29.3 ± 4.6
29.1 ± 4.5
29.2 ± 4.6
0.18 0.13
Duration of diabetes (years)
9.0 ± 4.1
8.7 ± 3.6
9.1 ± 4.2
Smoking habit (%)
25.7
24.3
26.4
0.11
HbA1c (%)
7.4 ± 1.3
7.5 ± 1.2
7.3 ± 1.1
0.23
SBP (mmHg)
135.9 ± 13.2
136.4 ± 13.8
135.3 ± 12.8
0.26
DBP (mmHg)
78.2 ± 7.3
77.7 ± 6.9
78.8 ± 6.6
0.23 0.22
Tot. chol. (mg/dl)
196 ± 41.2
199.6 ± 39.4
195.9 ± 37.2
HDL (mg/dl)
48.8 ± 11.9
47.8 ± 11.2
49.1 ± 12.2
0.11
Triglycerides (mg/dl) AER (mg/24 h)
149.3 ± 80.8 143.1 ± 136.3
154.6 ± 75.7 135.7 ± 132.5
147.5 ± 85.7 148.6 ± 140.3
0.14 0.10
GFR (ml/min/1.73 m2)
66.4 ± 24.3
64.1 ± 27.2
67.5 ± 22.9
0.27
Statins
46
45
47
0.12
Aspirin
42.8
100
0
* Group A versus group B
Beta-blockers
20
21
19
0.14
ACE-I angiotensin-converting enzyme inhibitors, ARB angiotensin II receptor blockers
Calcium-antagonists
23
24
22
0.14
ACE-I/ARB
65
67
64
0.17
At baseline, the two groups A and B were matched for age, duration of diabetes, body mass index (BMI), HbA1c, systolic and diastolic blood pressure, lipid profile, albumin excretion rate (AER), glomerular filtration rate (GFR) and CV therapy, except for aspirin treatment
Therapy (%)
847 recruited patients (NID 2 cohort)
564 CV primary prevention
22 fatal MACE
Group A (n242)
Group B (n322)
ASA treated
Non-ASA treated
27 nonfatal MACE
20 fatal MACE
4 not CV death
3 not CV death
17 AMI/RV
21 AMI/RV
10 Stroke
11 Stroke
Fig. 1 Design of the study. AMI acute myocardial infarction. RV, revascularization procedure
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32 nonfatal MACE
Acta Diabetol Table 2 Distribution of total MACE, fatal MACE and nonfatal MACE in the two groups of treatment for each center
Center
Group A (ASA treated)
Group B (non-ASA treated)
Patients
Total MACE
Fatal MACE
Nonfatal MACE
Patients
Total MACE
Fatal MACE
Nonfatal MACE
1
16
3
2
1
29
7
5
2
2
13
1
1
0
16
3
1
2
3
13
1
0
1
27
5
2
3
4
16
3
3
0
18
3
2
1
5
6
2
0
2
6
3
0
3
6
12
4
3
1
16
4
1
3
7 8
8 11
1 1
0 0
1 1
19 21
4 2
1 1
3 1
9
15
3
0
3
27
4
1
3
10
3
0
0
0
3
0
0
0
11
5
1
0
1
8
2
0
2
12
6
1
1
0
28
3
1
2
13
27
6
3
3
8
0
0
0
14
17
4
4
0
8
0
0
0
15
15
5
1
4
14
4
1
3
16
11
2
0
2
11
0
0
0
17
24
6
3
3
22
4
1
3
18
4
0
0
0
14
1
1
0
19
11
4
0
4
10
2
1
1
20
7
1
1
0
15
1
1
0
21
2
0
0
0
2
0
0
0
We studied the nephropathy cohort enrolled in the NID2 study that showed a 10-year risk of CV events definitely exceeding 10 % [10]. In particular, we want to underline that previous CV events were reasonably excluded according to the above-mentioned inclusion criteria, and thus, the population studied was actually in primary CV prevention as well as at high CV risk. Latest ADA guidelines recommend in all diabetic patients therapy with low-dose aspirin (75–162 mg/die) for secondary prevention of CV events (level of evidence A). Conversely, aspirin use for primary prevention is exclusively limited to high-risk individuals, i.e., subjects with a 10-year risk of CV events exceeding 10 % and who do not have an increased risk for bleeding (i.e., men of [50 years of age or women of[60 years of age, with a family history of CVD or with at least one of the following risk factors: hypertension, hypercholesterolemia, albuminuria or smoking habit). ASA is not recommended in patients with a 10-year CV risk \5 %, while patients with a 10-year CV risk between 5 and 10 %, the choice must be personalized [8]. However, recommendations on primary prevention are weak (level of evidence C) based on controversial results. ETDRS [14] is the main study supporting the use of ASA in primary prevention of diabetic patients. This multicenter, randomized clinical trial of aspirin versus placebo investigated the effects of ASA (325 mg, once per
day) in primary prevention on 3,711 diabetics (type 1 and 2), between 18 and 70 years old, with various degrees of retinopathy. Results showed that ASA did not affect retinopathy progression, but was associated with a reduction of the incidence of fatal and nonfatal AMI. In particular, the estimate of relative risk for the occurrence of fatal and nonfatal myocardial infarction for aspirin-treated patients compared with placebo-treated patients was 0.83 for the entire follow-up period. Therefore, the ETDRS results support the use of aspirin in people with diabetes at increased risk of cardiovascular disease. The Physicians’ Health Study, a randomized, doubleblind, placebo-controlled trial, designed to determine whether aspirin (325 mg every other day) decreased CV events in primary prevention, demonstrated a significant reduction in the risk of myocardial infarction, without conclusive evidence concerning stroke and total CV deaths [15]. Therefore, the guidelines recommending aspirin for primary cardiovascular prevention in diabetes were, surprisingly, based on limited and inconclusive data, conducted before the era of statins and other established cardiovascular preventative strategies, with some studies employing unconventional doses of aspirin. A recent meta-analysis [16] performed on nine randomized trials showed that primary prevention with aspirin decreased
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Acta Diabetol Kaplan–Meier estimates of the composite end point of total major adverse CV events (Panel a), fatal CV events (Panel b) and nonfatal CV events (Panel c) in ASA-treated group (discontinuous line) and non-ASA-treated group (solid line), during the average follow-up of 8 years. The p value was calculated with the use of the log-rank test
b Fig. 2
Total MACE
A
Antiplatelet therapy No Yes
Table 3 To assess the independent effect of the CV risk factors on primary end point, hazard ratio, with 95 % CIs, was estimated by a Cox regression model with demographics (gender) and several potentially treatable risk factors (smoking habit, ASA therapy, HbA1c, systolic blood pressure, BMI, cholesterol, GFR and AER) variables as covariates HR Log-Rank test p = 0.202
Fatal CV events
B
Antiplatelet therapy No Yes
Log-Rank test p = 0.225
Non-Fatal CV events
C
Antiplatelet therapy No Yes
Log-Rank test p = 0.573
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CI 95 % Lower limit
CI 95 % Upper limit
p
Antiplatelet agents (yes/no)
1.107
0.905
1.35
0.32
Male gender
0.884
0.696
1.12
0.31
BMI (kg/m2)
1.03
0.987
1.08
0.17
Smoking habit (yes/no)
1.37
1.067
1.76
0.013
Systolic blood pressure (mmHg)
1.013
0.997
1.03
0.11
HbA1c (%)
1.204
1.035
1.40
0.016
Total cholesterol (mg/dl)
0.998
0.992
1.00
0.36
GFR \ 60 ml/min (yes/no)
1.521
1.331
1.761
0.003
AER (mg/24 h)
1.31
1.024
1.598
0.011
the risk of total CV events and nonfatal MI, but there were no significant differences in the incidences of stroke, CV mortality, all-cause mortality and total coronary heart disease. Our study was performed in high-risk patients as testified by 18 % MACE rate and related at least in part to the associated nephropathy. Under these conditions, the use of ASA failed to show a positive effect of primary CV prevention in diabetic patients at high CV risk. These findings agree with other recent studies, such as JPAD [17], in which 2,539 diabetic patients were divided in two groups, the intervention group, who used antiplatelet therapy (ASA 81–100 mg/die), and the control group. In this RCT, there was no statistical reduction of primary end point (sudden death and fatal and nonfatal MACE) in patients treated with aspirin versus controls, except for a subgroup older than 65 years. Similar results were reached by POPADAD trial [18] that included 1,276 patients, with fatal and nonfatal MACE as primary end points. Primary Prevention Project Trial [19], which included 4,000 patients (1,000 with diabetes) in primary cardiovascular prevention to analyze the efficacy of low dose of ASA plus vitamin E in preventing CV death, nonfatal stroke and AMI, did not show a reduction of composite end point in diabetic patients.
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All these findings underline the need to design trials to investigate the clinical efficacy of the different dosing regimens of aspirin. Besides, ASA is associated with gastrointestinal and intracranial hemorrhagic complications: This bleeding risk sharply increased in individuals older than 70 years [20]. A meta-analysis by the Antithrombotic Trialists’ Collaboration suggested that diabetes, in addition to being an independent risk factor for CV disease, also increased the risk of extracranial hemorrhage or bleeding [21]. An increment of relative risk equal to 55 % in major bleeding was recently found during ASA treatment with exception of diabetic patients [22]. A possible explanation may be an accelerated platelet turnover in this population, which could justify the limited efficacy of aspirin in preventing major CV events. A very recent observational study on a large cohort from the Swedish National Diabetes Register showed no association between low-dose aspirin use and beneficial effects either on risks of CVD or mortality for patients with diabetes and not previously affected by CVD [23]. This result supports the trend toward a more restrictive use of aspirin in primary CV prevention, also because of the increased risk of bleeding associated with aspirin. Unlike our study, this investigation indicated originally more unfavorable benefit– risk ratios associated with aspirin treatment in women, suggesting a gender effect. Therefore, the advice about ASA utilization in primary prevention needs a careful assessment of benefits–risks, especially when facing the patient with nephropathy. ASA treatment seems to represent a paradigmatic example of the tailored therapy needed in diabetic patients. Notably, in our study, a significant difference in major bleeding between ASA- and non-ASA-treated groups was not observed. On this regard, however, it is relevant to underline that ASA group received a daily oral gastro-protection. Recently, major scientific Societies in USA [24] and Europe [25] issued guidelines on diabetes and CV disease. Conclusions of the two panels of experts regarding the use of aspirin for the primary prevention of CV disease in individuals with diabetes were totally divergent [26]. In fact, US statement recommends the use of aspirin for primary prevention in all individuals aged [40 and with additional risk factors [24]. In contrast, in the European guidelines there is no mention of aspirin for the primary prevention of myocardial infarction or CV death, while it is recommended for the prevention of stroke [25].
Nonetheless, Guidelines rise from the results of several RCT that often are far from ‘‘real life’’ of the patients. In fact, in this study we observed a dichotomy between the level evidence of guidelines and the lack of effect of aspirin on CV primary prevention in type 2 diabetic patients at high CV risk. Not significant difference at baseline was observed between two groups in the treatment as well as the levels of principal CV risk factors. Moreover, a regular control by physicians on the compliance to the therapy of each patient was performed during the follow-up, and the interference on MACEs by other CV risk factors was statistically corrected. Despite this, for the observational nature of the study, a bias due to other CV risk factor and any drugs cannot be excluded. Although the two groups were treated with the same medications at baseline, the personal therapeutic ‘‘style’’ of each physician could influence the outcomes of the study. However, the absence of clusters of events within the participating centers indicates a good similarity of the clinical management. Moreover, a confounding by indication effect cannot be excluded. Finally, although data analysis showed a not statistically significant difference, confirmed also after adjustments, in the incidence of both fatal and nonfatal MACE between the two groups, the Kaplan–Meier curves of MACE in the two groups appear to separate against aspirin therapy after 40 months. Therefore, longer-term studies may be needed, preferably in properly designed randomized trials.
Limitations
Acknowledgments This work was partially supported by an Italian Government grant from M.I.U.R. (Ministero della Istruzione, Universita‘ e Ricerca) Rome, Italy. The study sponsor had no role in the collection, analysis and interpretation of data in the writing of the report and in the decision to submit the paper for publication. Sasso
The main limitation of this study is that the observational nature precludes a proper cause-effect analysis.
Conclusion Our study originally supports the hypothesis of the inefficacy of antiplatelet therapy with 100 mg of ASA in primary prevention also in type 2 diabetic patients with clinically detected diabetic nephropathy and so at high CV risk. Although this observational study presents some limitations, it has several strengths: the setting of a large sample of type 2 diabetes subjects with nephropathy enrolled in 21 centers, a reasonably large follow-up period of 8 years and the strict criteria of inclusion that allowed us to investigate the usefulness of aspirin in primary CV prevention in real life of our patients. Finally, these findings further support the need of randomized clinical trials aimed to test efficacy of low-dose aspirin for primary prevention in type 2 diabetic patients with nephropathy.
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Acta Diabetol FC had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interest Ferdinando Carlo Sasso, Raffaele Marfella, Antonio Pagano, Giovanni Porta, Giuseppe Signoriello, Nadia Lascar, Roberto Minutolo, Ornella Carbonara, Marcello Persico, Federico Piscione, Luca De Nicola, Roberto Torella, and Giuseppe Paolisso declare that they have no conflict of interest. Human and animal rights All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent Informed consent was obtained from all patients for being included in the study.
Appendix: NID-2 (Nephropathy In Diabetes-type 2) Study Group F.C. Sasso, O. Carbonara, R. Torella, R. D’Urso, A. Lampitella Jr, N. Lascar, R. Nasti, A. Pagano, E. Pisa, L. Zirpoli, F. Zibella, M. Corigliano, G. Conte, L. De Nicola, R. Minutolo, P. Trucillo, V. Armentano, P. Calatola, G. Corigliano, E. Del Vecchio, N. De Rosa, G. Di Giovanni, A. De Matteo, O. Egione, A. Gatti, S. Gentile, L. Gesue`, L. Improta, A. Lampitella, A. Lanzilli, S. Masi, P. Mattei, V. Mastrilli, P. Memoli, E. Rossi, S. Sorrentino, R. Troise, A.A. Turco, S. Turco.
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7. Ware JA, Heistad DD (1993) Seminars in medicine of the Beth Israel Hospital, Boston. Platelet–endothelium interactions. N Engl J Med 328:628–635 8. Clinical Practice Recommendation (2014) Standards of medical care in diabetes. Diabetes Care 37:S14–S80 9. Sasso FC, De Nicola L, Carbonara O, Nasti R, Minutolo R, Salvatore T, Conte G, Torella R (2006) Cardiovascular risk factors and disease management in type 2 diabetic nephropathy. Diabetes Care 29:498–503 10. Sasso FC, Chiodini P, Carbonara O, De Nicola L, Conte G, Salvatore T, Nasti R, Marfella R, Gallo C, Signoriello S, Torella R, Minutolo R, Nephropathy In Type 2 Diabetes Study Group (2012) High cardiovascular risk in patients with Type 2 diabetic nephropathy: the predictive role of albuminuria and glomerular filtration rate. The NID-2 Prospective Cohort Study. Nephrol Dial Transpl 27:2269–2274 11. Fioretto P, Mauer M, Brocco E, Velussi M, Frigato F, Muollo B, Sambataro M, Abaterusso C, Baggio B, Crepaldi G, Nosadini R (1996) Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia 39:1569–1576 12. American College of Cardiology Committee (2000) Myocardial infarction redefined-a consensus document of The Joint European Society of Cardiology/American College of Cardiology for the redefinition of myocardial infarction. J Am Coll Cardiol 36:959–969 13. Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D, Goldberg RJ, Hand MM, Jaffe AS, Julian DG, Levy D, Manolio T, Mendis S, Mensah G, Pajak A, Prineas RJ, Reddy KS, Roger VL, Rosamond WD, Shahar E, Sharrett AR, Sorlie P, Tunstall-Pedoe H, AHA Council on Epidemiology and Prevention, AHA Statistics Committee, World Heart Federation Council on Epidemiology and Prevention, European Society of Cardiology Working Group on Epidemiology and Prevention, Centers for Disease Control and Prevention, National Heart, Lung, and Blood Institute (2003) Case definitions for acute coronary heart disease in epidemiology and clinical research studies. A statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation 108:2543–2549 14. ETDRS Investigators (1992) Aspirin effects on mortality and morbidity in patients with diabetes mellitus: early treatment diabetic retinopathy study report 14. JAMA 268(10):1292–1300 15. Steering Committee of the Physicians’ Health Study Research Group (1989) Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 321:129–135 16. Bartolucci AA, Tendera M, Howard G (2011) Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 107(12):1796–1801 17. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Saito Y, Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators (2008) Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 300(18):2134–2141 18. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, Bancroft J, MacEwan S, Shepherd J, Macfarlane P, Morris A, Jung R, Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, O’Brien I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh (2008) The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of
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aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 337. doi:10.1136/bmj. a1840. de Gaetano G, Collaborative Group of the Primary Prevention Project (2001) Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet 357(9250):89–95 Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353(22):2373–2383 Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A, Antithrombotic Trialists’ (ATT) Collaboration (2009) Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 373(9678):1849–1860 De Berardis G, Lucisano G, D’Ettorre A, Pellegrini F, Lepore V, Tognoni G, Nicolucci A (2012) Association of aspirin use with major bleeding in patients with and without diabetes. JAMA 307(21):2286–2294 Ekstro¨m N, Cederholm J, Zethelius B, Eliasson B, Fha¨rm E, Rolandsson O, Miftaraj M, Svensson AM, Gudbjo¨rnsdottir S (2013) Aspirin treatment and risk of first incident cardiovascular diseases in patients with type 2 diabetes: an observational study from the Swedish National Diabetes Register. BMJ Open 3(4). doi:10.1136/bmjopen-2013-002688 Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL, American Heart Association, American Stroke Association
Stroke Council (2006) Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 113:e873–e923 25. Ryden L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, Cosentino F, Jonsson B, Laakso M, Malmberg K, Priori S, Ostergren J, Tuomilehto J, Thrainsdottir I, Vanhorebeek I, Stramba-Badiale M, Lindgren P, Qiao Q, Priori SG, Blanc JJ, Budaj A, Camm J, Dean V, Deckers J, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo J, Zamorano JL, Deckers JW, Bertrand M, Charbonnel B, Erdmann E, Ferrannini E, Flyvbjerg A, Gohlke H, Juanatey JR, Graham I, Monteiro PF, Parhofer K, Pyorala K, Raz I, Schernthaner G, Volpe M, Wood D, Task Force on Diabetes, Cardiovascular Diseases of the European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD) (2007) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007(28):88–136 26. Nicolucci A, De Berardis G, Sacco M, Tognoni G (2007) AHA/ ADA vs. ESC/EASD recommendations on aspirin as a primary prevention strategy in people with diabetes: how the same data generate divergent conclusions. Eur Heart J 28(16):1925–1927
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ORIGINAL ARTICLE
Lack of effect of aspirin in primary CV prevention in type 2 diabetic patients with nephropathy: results from 8 years follow-up of NID-2 study Ferdinando Carlo Sasso • Raffaele Marfella • Antonio Pagano • Giovanni Porta • Giuseppe Signoriello • Nadia Lascar • Roberto Minutolo • Ornella Carbonara • Marcello Persico • Federico Piscione • Luca De Nicola • Roberto Torella • Giuseppe Paolisso
Received: 25 March 2014 / Accepted: 28 June 2014 Ó Springer-Verlag Italia 2014
Abstract The risk-to-benefit ratio for the use of low dose of aspirin in primary cardiovascular (CV) prevention in patients with diabetes mellitus remains to be clarified. We assessed the effect of aspirin on risk of CV events in type 2 diabetic patients with nephropathy, in order to verify the usefulness of Guidelines in clinical practice. We carried out a prospective multicentric study in 564 patients with type 2 diabetic nephropathy free of CV disease attending outpatient diabetes clinics. A total of 242 patients received antiplatelet treatment with aspirin 100 mg/day (group A), and 322 were not treated with antiplatelet drugs (group B). Primary end point was the occurrence of total major adverse cardio-vascular events (MACE). Secondary end points were the relative occurrence of fatal MACE. The average follow-up was 8 years. Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22
Managed by Massimo Federici. For the NID-2 Study Group. NID-2 Study Group members are provided in the ‘‘Appendix’’ section.
patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. Kaplan–Meier analysis did not show a statistically significant difference of cumulative MACE between the two groups. A not statistically significant difference in the incidence of both fatal (p = 0.225) and nonfatal CV events (p = 0.573) between the two groups was observed. These results were confirmed after adjustment for confounders (HR for MACE 1.11, 95 % CI 0.91–1.35). These findings suggest that low dose of aspirin is ineffective in primary prevention for patients with nephropathy. Keywords
Aspirin CV prevention Nephropathy
Introduction Cardiovascular (CV) disease is a major complication of diabetes and is responsible for 50–80 % of early deaths. A large Danish population-based study [1] showed that diabetic patients without a previous myocardial infarction have a risk of cardiac mortality of 20 % over 7 years, which is equal to the risk of nondiabetic patients after myocardial
F. C. Sasso (&) A. Pagano G. Porta O. Carbonara R. Torella Department of Internal and Experimental Medicine ‘‘Magrassi-Lanzara’’, Second University of Naples, Via F. Petrarca, 64, 80122 Naples, Italy e-mail: [email protected]
N. Lascar School of Life and Health Sciences, Aston University, Birmingham, UK
R. Marfella G. Paolisso Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy
M. Persico F. Piscione Department of Medicine and Surgery, University of Salerno, Salerno, Italy
R. Minutolo L. De Nicola Unit of Nephrology, Second University of Naples, Naples, Italy
G. Signoriello Unit of Medical Statistic, Department of Medicine and Public Health, Second University of Naples, Naples, Italy
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infarction. When compared to nondiabetic patients, those with type 2 diabetes mellitus are 2–4 times at increased CV risk including coronary, cerebrovascular and peripheral arterial ischemia [2, 3]. Despite advances in clinical management, cardiovascular disease (CVD) is the main cause of death, and atherothrombosis is the underlying cause of most CV events [4, 5]. In diabetic patients, the development of the platelet-rich thrombus is promoted by a prothrombotic state, due to insulin resistance and hyperglycemia, characterized by endothelial dysfunction, hypercoagulability and reduced response to fibrinolysis [6]. The dysfunctional endothelial cells fail to produce platelet antagonists such as prostacyclin and nitric oxide, leading to an accelerated atherosclerosis, which clinically results in an increased risk of CV events [7]. For several years, the inhibition of platelet function based on aspirin therapy has been a cornerstone in the prevention and treatment of CVD. Unfortunately, findings from clinical trials are not homogeneous. Therefore, the risk-to-benefit ratio for the use of low dose of aspirin in primary CV prevention in patients with diabetes mellitus remains to be clarified. Remarkably, Position Statement of American Diabetes Association (ADA) suggests the treatment with ACE inhibitors or ARBs (level of evidence A) and a reduction of protein intake in presence of chronic kidney disease (level of evidence C) in patients with diabetic nephropathy. However, there are no recommendations regarding the use of aspirin [8]. Therefore, we evaluated the effect of aspirin on risk of CV events in a cohort of type 2 diabetic patients with nephropathy attending diabetes clinics, in order to verify the usefulness of guidelines in clinical practice. Our prospective study may provide useful insights for future RCT by providing information in high-risk patients, such as those with diabetic nephropathy.
Briefly, inclusion criteria were as follows: type 2 diabetes mellitus, age C 40 years, therapy with diet and/or oral hypoglycemic agents during the first year of the diagnosis of diabetes, persistent albuminuria C30 mg/24 h in at least two urine collections over the previous 6 months, a severe diabetic retinopathy (DR) as judged by means of fundus oculi, and fluoroangiography when necessary. Severe DR was defined as a proliferative diabetic retinopathy or a severe nonproliferative diabetic retinopathy with vascular closure. The presence of severe DR has been used as the clinical hallmark of DN [11], thus excluding other possible causes for increased albuminuria, since renal biopsies are not indicated for diagnostic purposes in microalbuminuric diabetic patients. Exclusion criteria were as follows: dialysis or renal transplant, diagnosis of diabetes at \30 years of age, insulin therapy during the first year of diagnosis of the disease (in order to exclude unknown autoimmune diabetes of adults), severe liver or heart failure and known neoplastic or psychiatric disease, low compliance to any medication suggested by the physicians. All the physicians involved in the study declared that they adhered to recommendations of the clinical practice guidelines issued by the ADA [8]. Ethical committee of Second University of Naples, Italy, approved the study, and all the patients signed informed consent. We selected 564 patients free of CVD from this cohort, 242 of them were receiving ASA (100 mg orally once a day, group A) and 322 were not treated with antiplatelet drugs (group B) based on physician clinical judgment. In all patients, the lack of CVD at baseline was proven by both negative clinical history (included any chest pain or a suspected TIA) and absence of abnormalities at resting ECG, and stress-ECG performed according to Bruce protocol suggestive for CVD. Stress-ECGs performed in all patients had to be conclusive for absence of CAD. Patients without diagnostic tests underwent a stress-ECG. Only patients with stress-ECG negative for CAD were enrolled in the study.
Materials and methods Outcomes and follow-up Study design We carried out a prospective study on a group of type 2 diabetic patients from the NID-2 study cohort [9, 10], selecting for the specific purpose of the current study only patients free of CVD at baseline. Setting and participants As previously described [9, 10], the NID-2 study recruited 847 type 2 diabetic patients at high CV risk with diabetic nephropathy (diagnosed by clinical criteria, i.e., micro/ macro-albuminuria and diabetic retinopathy) from 21 centers of secondary diabetes care in Italy.
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Active follow-up, with control visits planned every 6 months, performed during an average follow-up of 8.0 years, was completed on June 2012. Baseline information included past medical history (myocardial infarction and stroke), blood pressure (BP) measurement (calculated as a mean of three measurements taken at right harm in a sitting position after 10 min of rest), height and body weight as well as laboratory and therapeutic features. Laboratory tests were performed locally and included glycemic, lipidic and renal function assessment. GFR was calculated by the four-variable Modification of Diet in Renal Disease (MDRD) equation, and albuminuria was measured on 24-h urine collection;
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microalbuminuria and macroalbuminuria were defined by values of 30–300 and [300 mg/day, respectively. Throughout the follow-up, the patients of group A received a daily oral H? pump inhibitor treatment (omeprazole 20 mg, or equivalent), in order to minimize the risk of gastro-intestinal bleeding. In both groups, during follow-up the physicians verified and motivated the adherence of each patient to all drug prescriptions. Self-reported adherence to therapy was assessed at each follow-up by asking for the name, the dose and the percentage of pills that should have been taken. None of patients resulted nonadherent (i.e., medication assumption B80 %). Mean medication adherence between the two groups was compared by using a t test for independent groups. Primary outcome was the total major adverse cardio-vascular events (MACE), defined as CV death, nonfatal myocardial infarction, nonfatal stroke, revascularization or major amputation, whichever occurred first. Secondary outcomes were, separately, (1) fatal and (2) nonfatal CV events. When a CV event was suspected, hospital records were collected to make the diagnosis according to European Society of Cardiology and American College of Cardiology criteria [12, 13]. Death certificates and autopsy reports were used to establish the underlying cause of death and to adjudicate CV deaths, through the ninth revision of the International Classification of Diseases.
Statistic analysis Kaplan–Meier survival curves were used tocompare cumulative probability of time free from MACE, from fatal MACE and from nonfatal MACE. The comparison between the two groups was performed using the log-rank test. To assess the independent effect of ASA therapy on primary end point, hazard ratio, with 95 % confidence intervals (HR, 95 % CIs), was estimated by a Cox regression model with demographics (age and gender) and several potentially treatable risk factors (smoking habit, GFR, Albumin Excretion Rate, HbA1c, systolic blood pressure, BMI and cholesterol) variables as covariates. Given the descriptive nature of this observational study and the small number of observed events, traditional power calculations based on hypothesis-testing were not applicable. Statistical significance was fixed at 0.05. Statistical analyses were performed using SPSS version 12.0 (SPSS Inc, Chicago, IL) software package.
at target according to current guidelines [8] for glycemic control (HbA1c: 7.4 ± 1.3 %), and diastolic blood pressure (78.2 ± 7.3 mmHg). The systolic blood pressure was 135.9 ± 13.2 mmHg, total cholesterol was 196 ± 41.2 mg/dl, albumin excretion rate was 143.1 ± 136.3 mg/24 h, and GFR was 66.4 ± 24.3 ml/min/1.73 m2. More than a quarter of the population were smoker (25.7 %). Clinic characteristics of overall subjects at baseline are showed in Table 1. At baseline, no difference was found for demographic, clinical, laboratory and therapeutic parameters between group A and B (Table 1). Total MACE occurred in 49 patients from group A and in 52 patients from group B. Fatal MACE occurred in 22 patients from group A and in 20 from group B; nonfatal MACE occurred in 27 patients from group A and in 32 patients from group B. In particular, in the group A occurred 22 cardiovascular deaths (9.1 %), 17 nonfatal myocardial infarctions and/or revascularizations (7 %), 10 nonfatal strokes (4.1 %). In the group B occurred 20 cardiovascular deaths (6.2 %), 21 nonfatal myocardial infarctions and/or revascularizations (6.4 %) and 11 nonfatal strokes (3.4 %). No major amputation occurred in both groups (Fig. 1). Remarkably, the distribution of MACE (fatal and not) was homogeneous among the centers and not clustered in just some of them. Table 2 describes the MACE divided for each canter. The analysis of the Kaplan–Meier survival curves showed a not statistically significant difference in the incidence of total MACE in the two groups (p = 0.201) (Fig. 2, panel A). No differences were observed between the two groups in the analysis of the secondary end points: The analysis of the Kaplan–Meier showed a not statistically significant difference in the incidence of both fatal and nonfatal MACE between the two groups (respectively p = 0.225 and p = 0.573) (Fig. 2, panel B and C). These data were confirmed also after adjustments (Table 3). Similarly at baseline, no significant difference in GFR at the end of the follow-up period between the two groups was showed (60.5 ± 26.5 vs. 63.8 ± 25.3 ml/min/ 1.73 m2, p = 0.22). Notably, during the clinical follow-up, no difference was found in major bleeding between ASA- and non-ASAtreated groups (6.2 vs. 4.9 %, respectively, p = 0.32).
Discussion Results At baseline, patients (44.9 % men, aged 64.7 ± 8.8 years) were meanly overweight (BMI: 29.3 ± 4.6 kg/m2) and not
This prospective multicentric long-term study originally shows the lack of CV protective effect of low dose of ASA in type 2 diabetics in primary prevention at very high CV risk.
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Acta Diabetol Table 1 Clinic characteristics at baseline of overall subjects, group A and B
Overall (n = 564)
Group A (n = 242)
Group B (n = 322)
p*
Sex [M/F (%)]
44.9/55.1
45.2/54.8
44.4/55.6
0.21
Age (years)
64.7 ± 8.8
65.2 ± 9.0
64.4 ± 8.5
0.25
BMI (kg/m2)
29.3 ± 4.6
29.1 ± 4.5
29.2 ± 4.6
0.18 0.13
Duration of diabetes (years)
9.0 ± 4.1
8.7 ± 3.6
9.1 ± 4.2
Smoking habit (%)
25.7
24.3
26.4
0.11
HbA1c (%)
7.4 ± 1.3
7.5 ± 1.2
7.3 ± 1.1
0.23
SBP (mmHg)
135.9 ± 13.2
136.4 ± 13.8
135.3 ± 12.8
0.26
DBP (mmHg)
78.2 ± 7.3
77.7 ± 6.9
78.8 ± 6.6
0.23 0.22
Tot. chol. (mg/dl)
196 ± 41.2
199.6 ± 39.4
195.9 ± 37.2
HDL (mg/dl)
48.8 ± 11.9
47.8 ± 11.2
49.1 ± 12.2
0.11
Triglycerides (mg/dl) AER (mg/24 h)
149.3 ± 80.8 143.1 ± 136.3
154.6 ± 75.7 135.7 ± 132.5
147.5 ± 85.7 148.6 ± 140.3
0.14 0.10
GFR (ml/min/1.73 m2)
66.4 ± 24.3
64.1 ± 27.2
67.5 ± 22.9
0.27
Statins
46
45
47
0.12
Aspirin
42.8
100
0
* Group A versus group B
Beta-blockers
20
21
19
0.14
ACE-I angiotensin-converting enzyme inhibitors, ARB angiotensin II receptor blockers
Calcium-antagonists
23
24
22
0.14
ACE-I/ARB
65
67
64
0.17
At baseline, the two groups A and B were matched for age, duration of diabetes, body mass index (BMI), HbA1c, systolic and diastolic blood pressure, lipid profile, albumin excretion rate (AER), glomerular filtration rate (GFR) and CV therapy, except for aspirin treatment
Therapy (%)
847 recruited patients (NID 2 cohort)
564 CV primary prevention
22 fatal MACE
Group A (n242)
Group B (n322)
ASA treated
Non-ASA treated
27 nonfatal MACE
20 fatal MACE
4 not CV death
3 not CV death
17 AMI/RV
21 AMI/RV
10 Stroke
11 Stroke
Fig. 1 Design of the study. AMI acute myocardial infarction. RV, revascularization procedure
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32 nonfatal MACE
Acta Diabetol Table 2 Distribution of total MACE, fatal MACE and nonfatal MACE in the two groups of treatment for each center
Center
Group A (ASA treated)
Group B (non-ASA treated)
Patients
Total MACE
Fatal MACE
Nonfatal MACE
Patients
Total MACE
Fatal MACE
Nonfatal MACE
1
16
3
2
1
29
7
5
2
2
13
1
1
0
16
3
1
2
3
13
1
0
1
27
5
2
3
4
16
3
3
0
18
3
2
1
5
6
2
0
2
6
3
0
3
6
12
4
3
1
16
4
1
3
7 8
8 11
1 1
0 0
1 1
19 21
4 2
1 1
3 1
9
15
3
0
3
27
4
1
3
10
3
0
0
0
3
0
0
0
11
5
1
0
1
8
2
0
2
12
6
1
1
0
28
3
1
2
13
27
6
3
3
8
0
0
0
14
17
4
4
0
8
0
0
0
15
15
5
1
4
14
4
1
3
16
11
2
0
2
11
0
0
0
17
24
6
3
3
22
4
1
3
18
4
0
0
0
14
1
1
0
19
11
4
0
4
10
2
1
1
20
7
1
1
0
15
1
1
0
21
2
0
0
0
2
0
0
0
We studied the nephropathy cohort enrolled in the NID2 study that showed a 10-year risk of CV events definitely exceeding 10 % [10]. In particular, we want to underline that previous CV events were reasonably excluded according to the above-mentioned inclusion criteria, and thus, the population studied was actually in primary CV prevention as well as at high CV risk. Latest ADA guidelines recommend in all diabetic patients therapy with low-dose aspirin (75–162 mg/die) for secondary prevention of CV events (level of evidence A). Conversely, aspirin use for primary prevention is exclusively limited to high-risk individuals, i.e., subjects with a 10-year risk of CV events exceeding 10 % and who do not have an increased risk for bleeding (i.e., men of [50 years of age or women of[60 years of age, with a family history of CVD or with at least one of the following risk factors: hypertension, hypercholesterolemia, albuminuria or smoking habit). ASA is not recommended in patients with a 10-year CV risk \5 %, while patients with a 10-year CV risk between 5 and 10 %, the choice must be personalized [8]. However, recommendations on primary prevention are weak (level of evidence C) based on controversial results. ETDRS [14] is the main study supporting the use of ASA in primary prevention of diabetic patients. This multicenter, randomized clinical trial of aspirin versus placebo investigated the effects of ASA (325 mg, once per
day) in primary prevention on 3,711 diabetics (type 1 and 2), between 18 and 70 years old, with various degrees of retinopathy. Results showed that ASA did not affect retinopathy progression, but was associated with a reduction of the incidence of fatal and nonfatal AMI. In particular, the estimate of relative risk for the occurrence of fatal and nonfatal myocardial infarction for aspirin-treated patients compared with placebo-treated patients was 0.83 for the entire follow-up period. Therefore, the ETDRS results support the use of aspirin in people with diabetes at increased risk of cardiovascular disease. The Physicians’ Health Study, a randomized, doubleblind, placebo-controlled trial, designed to determine whether aspirin (325 mg every other day) decreased CV events in primary prevention, demonstrated a significant reduction in the risk of myocardial infarction, without conclusive evidence concerning stroke and total CV deaths [15]. Therefore, the guidelines recommending aspirin for primary cardiovascular prevention in diabetes were, surprisingly, based on limited and inconclusive data, conducted before the era of statins and other established cardiovascular preventative strategies, with some studies employing unconventional doses of aspirin. A recent meta-analysis [16] performed on nine randomized trials showed that primary prevention with aspirin decreased
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Acta Diabetol Kaplan–Meier estimates of the composite end point of total major adverse CV events (Panel a), fatal CV events (Panel b) and nonfatal CV events (Panel c) in ASA-treated group (discontinuous line) and non-ASA-treated group (solid line), during the average follow-up of 8 years. The p value was calculated with the use of the log-rank test
b Fig. 2
Total MACE
A
Antiplatelet therapy No Yes
Table 3 To assess the independent effect of the CV risk factors on primary end point, hazard ratio, with 95 % CIs, was estimated by a Cox regression model with demographics (gender) and several potentially treatable risk factors (smoking habit, ASA therapy, HbA1c, systolic blood pressure, BMI, cholesterol, GFR and AER) variables as covariates HR Log-Rank test p = 0.202
Fatal CV events
B
Antiplatelet therapy No Yes
Log-Rank test p = 0.225
Non-Fatal CV events
C
Antiplatelet therapy No Yes
Log-Rank test p = 0.573
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CI 95 % Lower limit
CI 95 % Upper limit
p
Antiplatelet agents (yes/no)
1.107
0.905
1.35
0.32
Male gender
0.884
0.696
1.12
0.31
BMI (kg/m2)
1.03
0.987
1.08
0.17
Smoking habit (yes/no)
1.37
1.067
1.76
0.013
Systolic blood pressure (mmHg)
1.013
0.997
1.03
0.11
HbA1c (%)
1.204
1.035
1.40
0.016
Total cholesterol (mg/dl)
0.998
0.992
1.00
0.36
GFR \ 60 ml/min (yes/no)
1.521
1.331
1.761
0.003
AER (mg/24 h)
1.31
1.024
1.598
0.011
the risk of total CV events and nonfatal MI, but there were no significant differences in the incidences of stroke, CV mortality, all-cause mortality and total coronary heart disease. Our study was performed in high-risk patients as testified by 18 % MACE rate and related at least in part to the associated nephropathy. Under these conditions, the use of ASA failed to show a positive effect of primary CV prevention in diabetic patients at high CV risk. These findings agree with other recent studies, such as JPAD [17], in which 2,539 diabetic patients were divided in two groups, the intervention group, who used antiplatelet therapy (ASA 81–100 mg/die), and the control group. In this RCT, there was no statistical reduction of primary end point (sudden death and fatal and nonfatal MACE) in patients treated with aspirin versus controls, except for a subgroup older than 65 years. Similar results were reached by POPADAD trial [18] that included 1,276 patients, with fatal and nonfatal MACE as primary end points. Primary Prevention Project Trial [19], which included 4,000 patients (1,000 with diabetes) in primary cardiovascular prevention to analyze the efficacy of low dose of ASA plus vitamin E in preventing CV death, nonfatal stroke and AMI, did not show a reduction of composite end point in diabetic patients.
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All these findings underline the need to design trials to investigate the clinical efficacy of the different dosing regimens of aspirin. Besides, ASA is associated with gastrointestinal and intracranial hemorrhagic complications: This bleeding risk sharply increased in individuals older than 70 years [20]. A meta-analysis by the Antithrombotic Trialists’ Collaboration suggested that diabetes, in addition to being an independent risk factor for CV disease, also increased the risk of extracranial hemorrhage or bleeding [21]. An increment of relative risk equal to 55 % in major bleeding was recently found during ASA treatment with exception of diabetic patients [22]. A possible explanation may be an accelerated platelet turnover in this population, which could justify the limited efficacy of aspirin in preventing major CV events. A very recent observational study on a large cohort from the Swedish National Diabetes Register showed no association between low-dose aspirin use and beneficial effects either on risks of CVD or mortality for patients with diabetes and not previously affected by CVD [23]. This result supports the trend toward a more restrictive use of aspirin in primary CV prevention, also because of the increased risk of bleeding associated with aspirin. Unlike our study, this investigation indicated originally more unfavorable benefit– risk ratios associated with aspirin treatment in women, suggesting a gender effect. Therefore, the advice about ASA utilization in primary prevention needs a careful assessment of benefits–risks, especially when facing the patient with nephropathy. ASA treatment seems to represent a paradigmatic example of the tailored therapy needed in diabetic patients. Notably, in our study, a significant difference in major bleeding between ASA- and non-ASA-treated groups was not observed. On this regard, however, it is relevant to underline that ASA group received a daily oral gastro-protection. Recently, major scientific Societies in USA [24] and Europe [25] issued guidelines on diabetes and CV disease. Conclusions of the two panels of experts regarding the use of aspirin for the primary prevention of CV disease in individuals with diabetes were totally divergent [26]. In fact, US statement recommends the use of aspirin for primary prevention in all individuals aged [40 and with additional risk factors [24]. In contrast, in the European guidelines there is no mention of aspirin for the primary prevention of myocardial infarction or CV death, while it is recommended for the prevention of stroke [25].
Nonetheless, Guidelines rise from the results of several RCT that often are far from ‘‘real life’’ of the patients. In fact, in this study we observed a dichotomy between the level evidence of guidelines and the lack of effect of aspirin on CV primary prevention in type 2 diabetic patients at high CV risk. Not significant difference at baseline was observed between two groups in the treatment as well as the levels of principal CV risk factors. Moreover, a regular control by physicians on the compliance to the therapy of each patient was performed during the follow-up, and the interference on MACEs by other CV risk factors was statistically corrected. Despite this, for the observational nature of the study, a bias due to other CV risk factor and any drugs cannot be excluded. Although the two groups were treated with the same medications at baseline, the personal therapeutic ‘‘style’’ of each physician could influence the outcomes of the study. However, the absence of clusters of events within the participating centers indicates a good similarity of the clinical management. Moreover, a confounding by indication effect cannot be excluded. Finally, although data analysis showed a not statistically significant difference, confirmed also after adjustments, in the incidence of both fatal and nonfatal MACE between the two groups, the Kaplan–Meier curves of MACE in the two groups appear to separate against aspirin therapy after 40 months. Therefore, longer-term studies may be needed, preferably in properly designed randomized trials.
Limitations
Acknowledgments This work was partially supported by an Italian Government grant from M.I.U.R. (Ministero della Istruzione, Universita‘ e Ricerca) Rome, Italy. The study sponsor had no role in the collection, analysis and interpretation of data in the writing of the report and in the decision to submit the paper for publication. Sasso
The main limitation of this study is that the observational nature precludes a proper cause-effect analysis.
Conclusion Our study originally supports the hypothesis of the inefficacy of antiplatelet therapy with 100 mg of ASA in primary prevention also in type 2 diabetic patients with clinically detected diabetic nephropathy and so at high CV risk. Although this observational study presents some limitations, it has several strengths: the setting of a large sample of type 2 diabetes subjects with nephropathy enrolled in 21 centers, a reasonably large follow-up period of 8 years and the strict criteria of inclusion that allowed us to investigate the usefulness of aspirin in primary CV prevention in real life of our patients. Finally, these findings further support the need of randomized clinical trials aimed to test efficacy of low-dose aspirin for primary prevention in type 2 diabetic patients with nephropathy.
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Acta Diabetol FC had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of interest Ferdinando Carlo Sasso, Raffaele Marfella, Antonio Pagano, Giovanni Porta, Giuseppe Signoriello, Nadia Lascar, Roberto Minutolo, Ornella Carbonara, Marcello Persico, Federico Piscione, Luca De Nicola, Roberto Torella, and Giuseppe Paolisso declare that they have no conflict of interest. Human and animal rights All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent Informed consent was obtained from all patients for being included in the study.
Appendix: NID-2 (Nephropathy In Diabetes-type 2) Study Group F.C. Sasso, O. Carbonara, R. Torella, R. D’Urso, A. Lampitella Jr, N. Lascar, R. Nasti, A. Pagano, E. Pisa, L. Zirpoli, F. Zibella, M. Corigliano, G. Conte, L. De Nicola, R. Minutolo, P. Trucillo, V. Armentano, P. Calatola, G. Corigliano, E. Del Vecchio, N. De Rosa, G. Di Giovanni, A. De Matteo, O. Egione, A. Gatti, S. Gentile, L. Gesue`, L. Improta, A. Lampitella, A. Lanzilli, S. Masi, P. Mattei, V. Mastrilli, P. Memoli, E. Rossi, S. Sorrentino, R. Troise, A.A. Turco, S. Turco.
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