Aspirin for primary prevention in cad in type II DM
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Recent studies have questioned the use of low-dose aspirin for primary prevention of cardiovascular disease in patients with type 2 diabetes. The JPAD trial found that aspirin did not reduce cardiovascular events and increased risk of gastrointestinal bleeding. Similarly, the ASCEND trial found aspirin reduced vascular events but increased major bleeding. A meta-analysis found aspirin was not associated with lower mortality and increased risk of major bleeding and intracranial hemorrhage. The ARRIVE and ASPREE trials also found aspirin increased bleeding risk without reduction in cardiovascular outcomes or mortality. Current recommendations are that aspirin may not be beneficial for those under 50 or at low risk, and risks vs benefits should be considered individually for other patients.
![Results
• Mean FU – 7.4 years
• Serious vascular events occurred in a significantly
lower percentage of participants in the aspirin
group
8.5% (Aspirin gp) vs. 9. 6% (Placebo) [P=0.01]
• Major bleeding events occurred in the aspirin
group
4.1% (Aspirin gp) vs. 3.2% (Placebo) [P=0.003]
Are benefits outweighing the risks?](https://image.slidesharecdn.com/aspirinforprimarypreventionincadint2dm-190528194235/85/Aspirin-for-primary-prevention-in-cad-in-type-II-DM-14-320.jpg)
![Results
• Mean FU – 6.6 years
• Aspirin was not associated with a lower incidence
of all-cause mortality
[risk ratio (RR) 0.98, 95% confidence interval (CI) 0.93–
1.02; P = 0.30]
• Aspirin was associated with an increased incidence
of major bleeding
[RR 1.47, 95% CI 1.31–1.65; P < 0.0001]
• Aspirin was associated with an increased incidence
of intracranial hemorrhage
[RR 1.33, 95% CI 1.13–1.58; P = 0.001]](https://image.slidesharecdn.com/aspirinforprimarypreventionincadint2dm-190528194235/85/Aspirin-for-primary-prevention-in-cad-in-type-II-DM-16-320.jpg)
Aspirin for primary prevention in cad in type II DM
- 1. Aspirin in Primary Prevention in CAD in T2DM---really needed? Dr. Pijush Kanti Mandal Assistant Professor Department of Medicine Malda Medical College ,Malda
- 2. Introduction • 382 million people worldwide have diabetes mellitus, and is expected to reach 592 million by the year 2035. •Atherosclerotic Cardiovascular Disease (ASCVD) remains the principal cause of death and disability among patients with Diabetes Mellitus (DM). Guariguata L et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103:137–149
- 3. • ASCVD in DM manifests as – Coronary heart disease Ischemic stroke Peripheral artery disease Heart failure
- 4. Age-standardized rates of selected vascular diseases in individuals with or without diabetes mellitus in the years 1990, 2000, and 2010 – 20 years surveillance data Rates of vascular diseases are decreasing in persons with diabetes mellitus but are still higher than in persons without diabetes mellitus Low Wang CC et al. Circulation. 2016 Jun 14;133(24):2459-502.
- 5. Development & Progression of atherosclerosis in DM Adapted from Low Wang CC et al. Circulation. 2016 Jun 14;133(24):2459-502.
- 6. CVD in DM • Individuals with diabetes have a 2–4 fold increased risk for serious cardiovascular events as a result of Increased coronary thrombus formation, Increased platelet reactivity, and Worsened endothelial dysfunction • Controversies regarding the use of low dose aspirin in DM is a hot topic of debate Pignone M et al. Circulation. 2010 Jun 22; 121(24):2694-701
- 7. Aspirin in DM • Guidelines from early 2000s recommended the use of low-dose aspirin for primary prevention in patients with diabetes mellitus over a certain age or in the presence of concomitant cardiovascular risk factors Recommendation was based largely on results from randomized clinical trials that showed a positive effect of low-dose aspirin in healthy volunteers In patients with hypertension for secondary prevention in patients after myocardial infarction Saito Y et al. Circulation. 2017;135:659–670
- 8. ADA position statement • Aspirin therapy (75–162 mg/day) May be considered as a primary prevention strategy in those with type 1 or type 2 diabetes who are at increased cardiovascular risk This includes most men and women with diabetes aged ≥50 years who have at least one additional major risk factor (family history of premature atherosclerotic cardiovascular disease, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk of bleeding. Saito Y et al. Circulation. 2017;135:659–670
- 9. Pros & Cons Adapted from Pignone M et al. Nat Rev Endocrinol. 2010 November ; 6(11): 619–628
- 10. What does recent evidences suggest ?
- 11. Design Patients Inclusion criteria Dosage Primary outcome Open label, RCT 2539 T2DM without pre- existing CVD Aspirin group (81- 100 mg) Vs No Aspirin group CV events including sudden deaths, fatal & non fatal CADs, stroke, PVDs Saito Y et al. Circulation. 2017;135:659–670 JPAD (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes) Trial
- 12. Results • Median FU: 10.3 years; 1621 patients (64%) • Low-dose aspirin did not reduce cardiovascular events in the per-protocol cohort (hazard ratio, 1.14; 95% confidence interval, 0.91–1.42). • Incidence of hemorrhagic stroke was not different between groups. • GI bleeding risk 2% (Aspirin gp) vs. 0.9% (non Aspirin gp) Concluding Remark: Low-dose aspirin did not affect the risk for cardiovascular events but increased risk for gastrointestinal bleeding in patients with type 2 diabetes mellitus in a primary prevention setting
- 13. Design Patients Inclusion criteria Dosage Primary outcome RCT 15480 T2DM without evidence of CVD Aspirin group (100 mg) Vs Placebo 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 ASCEND Study Collaborative Group. N Engl J Med 2018;379:1529-39. ASCEND (A Study of Cardiovascular Events in Diabetes)
- 14. Results • Mean FU – 7.4 years • Serious vascular events occurred in a significantly lower percentage of participants in the aspirin group 8.5% (Aspirin gp) vs. 9. 6% (Placebo) [P=0.01] • Major bleeding events occurred in the aspirin group 4.1% (Aspirin gp) vs. 3.2% (Placebo) [P=0.003] Are benefits outweighing the risks?
- 15. Design Patients Inclusion criteria Primary outcome Meta- analysis 11 trials with 1,57,248 subjects were included Subjects without established atherosclerotic disease All cause mortality Mahmoud AN et al. Eur Heart J. 2019 Feb 14;40(7):607-617. ASPREE (Aspirin in Reducing Events in the Elderly)
- 16. Results • Mean FU – 6.6 years • Aspirin was not associated with a lower incidence of all-cause mortality [risk ratio (RR) 0.98, 95% confidence interval (CI) 0.93– 1.02; P = 0.30] • Aspirin was associated with an increased incidence of major bleeding [RR 1.47, 95% CI 1.31–1.65; P < 0.0001] • Aspirin was associated with an increased incidence of intracranial hemorrhage [RR 1.33, 95% CI 1.13–1.58; P = 0.001]
- 17. Design Patients Inclusion criteria Dosage Primary outcome DB, PC, Multic entred RCT 12546 enrolled Men ≥ 55 years & Women ≥ 60 years Aspirin 100 mg Vs Placebo Composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack Gaziano MJ et al. Lancet. 2018 Sep 22;392(10152):1036-1046. ARRIVE (Aspirin to reduce risk of initial vascular events)
- 18. Results • Mean FU – 60 months • Primary endpoint occurred in 4·29% patients in the aspirin group versus 4·48% patients in the placebo group (P=0·6038) • GI bleeding events 0.97% in Aspirin group vs. 0.46% in the placebo group (P=0.0007)
- 19. Design Patients Inclusion criteria Dosage Primary outcome RCT 19114 ≥70 years without CVD Aspirin 100 mg Vs Placebo Mortality comparison between the groups ASPREE (Aspirin in Reducing Events in the Elderly) McNeil JJ et al. N Engl J Med. 2018 Oct 18;379(16):1519-1528
- 20. Results • FU – 4.7 years • Total deaths occurred – 1052 • Risk of deaths from any cause 12.7 (aspirin groups) vs. 11.1 (placebo group) events every 1000 person-years • Cancer was the major contributor to the deaths in Aspirin group Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo
- 21. 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.
- 22. RECOMMENDATIONS <50 Years of Age aspirin is not recommended for those at low risk of ASCVD (such as men and women aged ,50 years with diabetes with no other major ASCVD risk factors) as the low benefit is likely to be outweighed by the risks of bleeding. Clinical judgment should be used for those at intermediate risk (younger patients with one or more risk factors or older patients with no risk factors) until further research is available. Patients’ willingness to undergo long-term aspirin therapy should also be considered. Aspirin use in patients aged ,21 years is generally contraindicated due to the associated risk of Reye syndrome.
- 23. THANKS…..
Editor's Notes
- #6: Insulin resistance is present before the onset of prediabetes or diabetes mellitus, and increases progressively over time, whereas hyperglycemia develops in prediabetes and worsens with development of diabetes mellitus. Insulin resistance with impairment of insulin signaling, hyperinsulinemia, and hyperglycemia contribute to multiple processes including elevated free fatty acids (FFA), advanced glycation end-product (AGE) production, protein kinase C (PKC) activation, oxidative stress, mitochondrial dysfunction, and epigenetic modifications, which together contribute to endothelial dysfunction and inflammation resulting in activation of vascular smooth muscle cells (VSMC), endothelial cells (EC), and monocytes. Concentrations of modified (oxidized) low-density lipoproteins (LDL) are higher in diabetes mellitus, and are retained in the subendothelial layer of vulnerable sections of the vasculature. Circulating leukocytes attach and migrate through the endothelial wall into the VSMC layer of the intimal media. These monocytes engulf retained lipoproteins and transform into lipid-laden foam cells/macrophages producing proteinases and inflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukins. Stress responses including inflammasome complex formation and endoplasmic reticulum (ER) stress result in macrophage proliferation and inflammatory activation with resultant macrophage and VSMC phenotypic switch (proliferation, migration, and dedifferentiation). In response to vascular injury, VSMC secrete collagen to form a fibrous cap, which promotes atherosclerotic plaque stability. However, when stable lesions remodel inward, progressive stenosis of arteries occurs. Plaques can become vulnerable with thinning of the fibrous cap and apoptosis of macrophages in advanced atherosclerotic lesions, where impaired efferocytosis (phagocytic clearance) of lipid laden macrophages results in formation of a necrotic core accelerating vascular inflammation, necrosis, thrombosis. The resulting unstable atherosclerotic lesion complex is prone to sudden expansion from acute thrombus formation, forming a nidus for platelet thrombosis, hemorrhage of atherosclerotic plaque microvessels, and rupture of the fibrous cap. Akt indicates protein kinase B; ERK, extracellular signal-regulated kinase; GlcNAc, N-Acetylglucosamine; IL, interleukin; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; NF-κβ, nuclear factor–kappa beta; NOS, nitric oxide synthase; PI3K, phosphoinositide 3-kinase; RNS, reactive nitrogen species; and ROS, reactive oxygen species.