Aspirin in primary and secondary prevention of cardiovascular diseases: Recommendations based on trials

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1 Aspirin in primary and secondary prevention of cardiovascular diseases: based on trials Avinash Verma, MD; Upendra Kaul, MD Fortis Escorts Heart Institute & Research Centre, New Delhi, India Abstract Aspirin has been recommended by various authorities for primary and secondary prevention of cardiovascular disease (CVD). This review aims to analyse the evidence base of these recommendations to gain insight into their merits and limitations. Use of aspirin for secondary prevention has a more convincing case however in light of recent guidelines; aspirin s role in primary prevention is also being constantly evaluated and revised. Initial assessment of risk of CVD and bleeding risk is imperative for effectiveness of its role in primary prevention. Evidence also suggests that gender difference exist and females derive more benefit in terms of stroke prevention whereas males get benefit from decreased risk of myocardial infarction. Other high risk populations such as diabetics, stable angina, and asymptomatic coronary artery disease patients also have an evidence base for aspirin recommendation as stated respective guidelines. Key Words Aspirin Primary prevention Secondary prevention Stroke prevention Diabetes mellitus Introduction 1 Aspirin is a widely used drug in clinical cardiology. With an availability of new evidence for its role in primary and secondary prevention of vascular events various academic 2 bodies have updated their recommendations for it. This review aims at bringing the whole range of recommendations for use of aspirin in primary and secondary prevention of cardiovascular disease (CVD) in a perspective. Aspirin in primary prevention Evidence Since discovery of its inhibitory role in Thromboxane platelet activation pathway in 1980s, aspirin has been extensively used for treatment and secondary prevention of cardiovascular (CV) events. It was the aspirin s role in primary prevention of CV events that has been controversial; to a certain extent because the absolute risk of these events is much lower than in secondary 3 prevention. In contrast to a large number of trials for secondary prevention, we have very few good quality trials for primary prevention. In fact, to date the sex specific Meta-analysis of six good 4 quality RCTs by Berger and Colleagues is the only reference data available in this regard. Aspirin use in women was associated with statistically significant reductions in CV events (OR: 0.88 [CI: 0.79 to 0.99]) and ischemic strokes (OR: 0.76 [CI: 0.63 to 0.93]); no statistically significant benefit was found in the reduction of myocardial infarctions or CV mortality. In men, aspirin use was associated with a statistically significant reduction Received: ; Revised: ; Accepted: Disclosures: This article has not received any funding and has no vested commercial interest Acknowledgements: None 299

2 Verma A, et al in CV events (OR: 0.86 [CI: 0.78 to 0.94]) and myocardial infarctions (OR: 0.68 [CI: 0.54 to 0.86]); no statistically significant benefit was found in the reduction of ischemic strokes or CV mortality. Total mortality was not significantly reduced by aspirin use in men or women. Several international major preventive health bodies have given considerable importance to these trials and these meta-analyses. Recently, United State Preventive Services Task Force has given its recommendation for use of aspirin for the 5 prevention of CVD. Their evidence included the 4 aforementioned meta-analysis by Berger and Colleagues, 6 and subgroup analysis of: Women Health Study (WHS), 7 Primary Prevention Project (PPP) trial, and Hypertension 8 Optimal Treatment (HOT) randomized trial. These recommendations apply to adult men and women without a history of coronary heart disease (CAD) or stroke. Risk Assessment Initial risk assessment of an individual for CAD and bleeding events forms the bedrock of USPSTF recommendations. The initial 10 year coronary heart disease (CHD)/stroke risk is assessed by using Framingham Heart Study data. This tool uses sex, age, smoking, diabetes, blood pressure, total cholesterol and 9 HDL cholesterol levels as risk factors for CHD. Risk for stroke can also be calculated on the basis of 10 Framingham data. For calculating the risk of bleed the USPSTF considered age and sex to be the most important risk factors for gastrointestinal bleeding. Other risk factors for bleeding include upper gastrointestinal tract pain, gastrointestinal ulcers, and NSAID use. NSAID drug therapy combined with aspirin approximately quadruples the risk for serious gastrointestinal bleeding compared with the risk with aspirin alone. The rate of serious bleeding in aspirin users is approximately 2 to 3 times greater in patients with a history of a gastrointestinal ulcer. Men have twice the risk for serious gastrointestinal bleeding than women. Aspirin is indicated for primary prevention of CV events for men and women > 45 years and > 55 years, respectively if they are likely to have a net benefit from the intervention. The 10-year CHD/stroke risk at which the risk reduction of CV events outweighs the risk of bleeding was calculated using various trial and registry data by USPSTF (Table 1). The Table 1 applies to adults who are not taking NSAIDs and who do not have upper GI pain or a history of GI ulcers. 300 Table 1: The 10-year event risk above which the net benefit of aspirin becomes apparent Age (years) > > > > > > 11 NSAID use, combined with aspirin use, approximately quadruples the risk of serious GI bleeding. The rate of serious bleeding in aspirin users is approximately 2 3 times higher in patients with a history of GI ulcers. USPSTF recommends use of aspirin for primary prevention of CV events under following heading with 5 respective grade levels. Dosage: mg, although dose 75 mg is shown to be as effective as higher doses with less bleeding. 1. Men (age years): Encourage aspirin use when potential CVD benefit (MIs prevented) outweighs potential harm of GI hemorrhage (Grade A). 2. Women (age years): Encourage aspirin use when potential CVD benefit (strokes prevented) outweighs potential harm of GI hemorrhage (Grade A). 3. Men (age < 45 years): Do not encourage aspirin use for MI prevention (Grade D). 4. Women (age < 55 years): Do not encourage aspirin use for stroke prevention (Grade D). 5. Men & Women (age 80 years): No Recommendation (Grade I) insufficient evidence. Primary prevention in diabetics Evidence Men 10-year CHD risk (%) Age (years) Women 10-year CHD stroke risk (%) (Adapted from Aspirin for the Prevention of Cardiovascular Disease: 5 USPSTF Recommendation Statement) Majority of the evidence of aspirin s role in primary prevention of CVD in diabetics comes from six 11 trials British Male Doctor s Trial (BMDT), Physicians 12 Health Study (PHS), Thrombosis Prevention Trial (TPT), Hypertension Optimal Treatment (HOT) trial, 15 Primary Prevention Project (PPP), Women s Health 6 Study (WHS), which were population based and did not focus specifically on patients with diabetes. The percentage of patients with diabetes in these studies ranged from 1% to 2% in TPT, BMDT, and PHS to 22% in PPP. Two recent trials, the Japanese Prevention of 16 Atherosclerosis with aspirin for Diabetes (JPAD) and the Prevention of Progression of Arterial Disease and Diabetes

3 Aspirin in primary and secondary prevention of CVDs 17 (POPADAD), and one older trial, the Early Treatment of 18 Diabetic Retinopathy Study (ETDRS) enrolled only patients with diabetes. Based on the above evidences American Heart Association (AHA) and American College of Cardiology (ACC) in collaboration with American Diabetic Association (ADA) has come up with specific recommendations for use of aspirin for primary prevention 19 of CVD in diabetic population. 1. Low-dose ( mg/day) aspirin use for prevention is reasonable for adults with diabetes and no previous history of vascular disease who are at increased CVD risk (10-year risk of CVD events over 10%) and who are not at increased risk for bleeding (based on a history of previous gastrointestinal bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk, such as NSAIDS or warfarin). Those adults with diabetes at increased CVD risk include most men over age 50-years and women over age 60-years who with one or more of the following additional major risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria (ACCF/AHA Class IIa, Level of Evidence: B). 2. Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (men under age 50 years and women under 60 years with no major additional CVD risk factors; 10-year CVD risk under 5%) as the potential adverse effects from bleeding offset the potential benefits (ACCF/AHA Class III, Level of Evidence: C). 3. Low-dose (75 to 162 mg/day) aspirin use for prevention might be considered for those with diabetes at intermediate CVD risk (younger patients with one or more risk factors, or older patients with no risk factors, or patients with 10 year CVD risk of 5% to 10%) until further research is available (ACCF/AHA Class IIb, Level of Evidence: C). Aspirin in secondary prevention Evidence The Antithrombotic Trialists Collaboration conducted a meta-analysis that reviewed 287 studies involving 135,000 patients in comparisons of aspirin versus control and 77,000 patients in comparisons of different antiplatelet regimens in patients with myocardial infarction (MI), stroke, transient ischemic attack (TIA), CAD, peripheral vascular disease (PVD), at-risk of pulmonary embolism, or with other high-risk conditions such as diabetes mellitus, hemodialysis, and carotid disease. The main outcome measures included nonfatal MI, nonfatal stroke, and vascular death, collectively termed as serious vascular event. Overall, antiplatelet treatment produced a 34% proportional reduction in nonfatal myocardial infarction (P < ); and a 26% reduction in nonfatal myocardial infarction or death from coronary heart disease (P < ). Due to availability of evidence for secondary prevention of CVD in various subgroups, the recommendations for each are dealt with separately according to respective subgroups. Dosage Among the trials of higher daily doses of aspirin vs.no aspirin, no particular range of aspirin dose was preferable for the prevention of serious vascular events. The proportional reduction in vascular events was 19% with mg daily, 26% with mg daily, and 32% with mg daily. However, daily doses < 75 mg seemed to have a somewhat smaller effect (proportional 2 reduction 13%; (X = 7.7, df = 3; P = 0.05). However, among 3570 patients in three trials directly comparing aspirin >75 mg daily vs. aspirin < 75 mg daily there was no significant difference between the different aspirin regimens. 1. Secondary prevention for acute MI: Among 18,788 patients with a history of MI in 12 trials, a mean duration of 27 months of antiplatelet therapy resulted in 36 fewer serious vascular events per 1000 patients. This benefit reflects large and highly significant reductions in nonfatal re-infarction (RR reduction of 28%; P < ) and vascular death (RR reduction of 15%; P = ); as well as a smaller, but still significant, reduction in all cause mortality (RR,21 reduction of 11%; P = 0.002). ACC/AHA has following recommendation for patients with 21 STEMI. For STEMI: A daily dose of aspirin mg orally should be given indefinitely to patients recovering from STEMI (Class I, Level of Evidence: A). 2. Secondary prevention for NSTEMI/UA: The following recommendations are based on above stated evidence for AMI which also had patients of NSTEMI, along with evidence for UA in 12 trials involving 5031 patients with 535 events showing relative risk reduction of 40% in the subgroup. ACC/AHA has following sets of recommendations for patients with 22 NSTEMI/UA. 301

4 Verma A, et al For UA/NSTEMI patients treated medically without stenting: Aspirin ( mg/day) should be prescribed indefinitely (Class I, Level of Evidence: A). For UA/NSTEMI patients treated with bare-metal stents: Aspirin mg/day should be prescribed for at least 1 month (Class I, Level of Evidence: B), then continued indefinitely at a dose of mg/day (Class I, Level of Evidence: A). For UA/NSTEMI patients treated with DES: Aspirin mg/day should be prescribed for at least 3 months after sirolimus-eluting stent implantation and 6 months after paclitaxel-eluting stent implantation then continued indefinitely at dose of mg/day (Class I, Level of Evidence: B). 3. Secondary prevention for patients undergoing PCI: In the meta-analysis by Antithrombotic Trialists Collaboration, nine trials comprising of 3212 patients undergoing PCI with 132 events demonstrated relative risk reduction of 51% in occurrence of serious vascular 23,24 events. Based on the above and other evidences ACC/AHA has following sets of 25 recommendations for patients who underwent PCI. After PCI: Use of aspirin should be continued indefinitely (Class I, Level of Evidence: A). After PCI: It is reasonable to use aspirin 81 mg per day in preference to higher maintenance doses (Class IIa, Level of Evidence: B). 4. Secondary prevention for patients undergoing coronary artery bypass graft (CABG): Aspirin significantly improves saphenous venous graft patency rates, particularly during the first postoperative year. Administered in the immediate postoperative period following bypass surgery it decreases the rate of graft occlusion by approximately 50%, and continued 26,27 therapy leads to further decreases because arterial graft patency rates are high even in the absence of antiplatelet therapy, the administration of such therapy has not shown an improvement. Trials have demonstrated a graft patency benefit when aspirin was 28,29 started at 1, 7, or 24 hours after operation ; in contrast, the benefit of postoperative aspirin on SVG patency was lost when it was initiated >48 hours after 30 surgery. ACC/AHA has following recommendations 31 for patients undergoing CABG. For CABG: Aspirin ( mg/day) should be administered to CABG patients preoperatively (Class I, Level of Evidence: B). 302 For CABG: If aspirin ( mg/day) was not initiated preoperatively, it should be initiated within 6 hours postoperatively and then continued indefinitely to reduce the occurrence of SVG closure and adverse cardiovascular events (Class I, Level of Evidence: A). 5. Secondary prevention for CAD (asymptomatic or symptomatic, i.e., stable angina): In the Physicians 12 Health Study, aspirin (325 mg), given on alternate days to asymptomatic persons, was associated with a decreased incidence of MI. In the Swedish Angina 32 Pectoris Aspirin Trial in patients with stable angina, the addition of 75 mg of aspirin to sotalol resulted in a 34% reduction in primary outcome events of MI and sudden death and a 32% decrease in secondary vascular events. In the meta-analysis by Antithrombotic Trialists Collaboration, 7 trials comprising of 29 patients having stable angina or asymptomatic CAD with total of 352 events, demonstrated a relative risk reduction of 30% in occurrence of serious vascular events. In the light of the above mentioned evidences ACC/AHA has given its recommendations for use of aspirin for prevention of cardiovascular events in symptomatic (stable 33 angina) and asymptomatic coronary artery 34 disease in 02 and 11, respectively. For CAD: The Aspirin mg daily is recommended in all patients with CAD unless contraindicated (Class I, Level of Evidence: A). Hazards of aspirin discontinuation García Rodríguez and colleagues assess the effect of withdrawal of low dose ( mg/day) aspirin when it has originally been prescribed for the secondary prevention 35 of cardiovascular disease. They used a dataset of 39,513 patients followed for more than three years;1222 people who died as a result of CAD were analyzed with 5000 random controls. They found that aspirin had been withdrawn in 12.2% of cases and 11.0% of controls. Compared with current use, recent discontinuation was associated with a clinically and statistically significant increase in the risk of non-fatal myocardial infarction (rate ratio 1.63, 95% confidence interval 1.23 to 2.14), and in the combined outcome of death from coronary heart disease and non-fatal myocardial infarction (1.43, 1.12 to 1.84). 36 Zoccai et al. had reported a similar outcome in their systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for CAD. They included six studies, one study with 31,750 patients on adherence to aspirin therapy in the secondary prevention of CAD, two studies (2594

5 Aspirin in primary and secondary prevention of CVDs patients) on aspirin discontinuation in acute CAD, two studies (13,706 patients) on adherence to aspirin therapy before or shortly after CABG, and another (2229 patients) on aspirin discontinuation among patients undergoing drug-eluting stenting. Overall, aspirin non-adherence/ withdrawal was associated with three-fold higher risk of major adverse cardiac events (OR=3.14 [ ], P=0.0001). This risk was greatly increased in patients with intracoronary stents, as discontinuation of antiplatelet treatment was associated with an even higher risk of adverse events (OR=89.78 [ ]). Primary and secondary prevention in women: A special consideration The epidemiology of CVD events differs for men and women. After 40 years of age men have 49% lifetime risk for a coronary heart disease event, whereas women older 37 than 40 years have a 32% risk. More women die of stroke than men because of their longer life expectancy. The lifetime risk for ischemic stroke is greater in women than in men from age 55 to 75 years (approximately 17% to 18% in 10,37 women and 13% to 14% in men). With this difference in Table 2: Classification of CVD Risk in Women Risk Status High risk (>1 high-risk states) At risk (>1 major risk factor[s]) Ideal cardiovascular health (all of these) Criteria Clinically manifest CHD Clinically manifest cerebrovascular disease Clinically manifest peripheral arterial disease Abdominal aortic aneurysm End-stage or chronic kidney disease Diabetes mellitus 10-years predicted CVD risk > 10% Cigarette smoking SBP > 1 mm Hg, DBP > 80 mm Hg, or treated hypertension Total cholesterol > 0 mg/dl, HDL-C <50 mg/dl, or treated for dyslipidemia Obesity, particularly central adiposity Poor diet Physical inactivity Family history of premature CVD occurring in first-degree relatives in men <55 years of age or in women <65 years of age Metabolic syndrome Evidence of advanced subclinical atherosclerosis (e.g., coronary calcification, carotid plaque, or thickened IMT) Poor exercise capacity on treadmill test and/or abnormal heart rate recovery after stopping exercise Systemic autoimmune collagen-vascular disease (e.g., lupus or rheumatoid arthritis) History of preeclampsia, gestational diabetes, or pregnancy-induced hypertension Total cholesterol <0 mg/dl (untreated) BP <1/<80 mm Hg (untreated) Fasting blood glucose <100 mg/dl (untreated) 2 Body mass index <25 kg/m Abstinence from smoking Physical activity at goal for adults > years of age: > 150 min/wk moderate intensity, > 75 min/wk vigorous intensity, or combination Healthy (DASH-like) diet (see Appendix) CVD indicates cardiovascular disease; CHD, coronary heart disease; SBP, systolic blood pressure; DBP, diastolic blood pressure; HDL-C; high-density lipoprotein cholesterol; IMT, intima-media thickness; BP, blood pressure; and DASH, Dietary Approaches to Stop Hypertension. 38 (Adapted from ACC/AHA Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women 11 Update). 303

6 Verma A, et al risk profile and real world perspective ACC/AHA has recently come up with women specific primary prevention 38 recommendations. Risk assessment ACC/AHA uses a different scheme for risk assessment and stratification for women. It s based on the fact that Framingham 10-year predicted risk for CHD > % could be used to identify a woman at high risk but that a lower score was not sufficient to ensure that an individual woman 38,39 was at low risk. Limitations of stratification schemes, 38,40 such as the Framingham risk score is growing. ACC/AHA risk stratification algorithm includes consideration of factors beyond the 10-year predicted risk for CHD used in current National Cholesterol Education 41 Panel guidelines of lipid management. The panel emphasized that healthcare professionals should take several factors into consideration beyond just the Framingham risk score, including medical and lifestyle history, family history of CVD, markers of preclinical disease, and other conditions, as they make decisions about the intensity of preventive therapy 38 (Table 2). 1. High-risk women: Aspirin therapy ( mg/d) should be used in women with CHD unless contraindicated (Class I; Level of Evidence A). Aspirin therapy ( mg/day) is reasonable in women with diabetes mellitus unless contraindicated (Class IIa; Level of Evidence B). If a high-risk woman has an indication but is intolerant of aspirin therapy, clopidogrel should be substituted (Class I; Level of Evidence B). 2. Other at-risk or healthy women: Aspirin therapy can be useful in women 65 years of age (81 mg/ day or 100 mg every other day), if blood pressure is controlled and benefit for ischemic stroke and MI prevention is likely to outweigh risk of gastrointestinal bleeding and hemorrhagic stroke (Class IIa; Level of Evidence B) and may be reasonable for women <65 years of age for ischemic stroke prevention (Class IIb; Level of Evidence B). Conclusion Aspirin is an important drug for prevention of CV events in high risk population. Its effectiveness in primary prevention depends upon age, sex and initial risk stratification of the patient. It is recommended by the authorities for primary prevention in males >45 years and females >55 years, if they have appropriate risk profiles. It 304 is recommended in high risk populations like diabetics with one more risk factor beyond the age of 50-years in males and more than 60-years in females after ruling out high risk of bleeding. 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