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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 1  |  Page : 3-7

Aspirin for primary prevention: The changing paradigms!


Department of Cardiology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication29-Mar-2019

Correspondence Address:
Dr. Akshyaya Kumar Pradhan
Department of Cardiology, King George's Medical University, Lucknow - 226 007, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/heartindia.heartindia_5_19

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  Abstract 


Aspirin has been a widely used antiplatelet drug for management of cardiovascular disease for last five decades. Multiple studies have established its role in secondary prevention of cardiovascular diseases. For primary prevention, the situation is not so simple. Initial studies (though large and with long follow up) performed two decades ago suggested an impressive positive risk -benefit profile. But such benefits could not be replicated in subsequent studies performed in the new millennium. Recently, three back to back studies of aspirin in primary prevention in contemporary era failed to demonstrate any benefits or the benefits were counterbalanced by bleeding events. Hence, the role of aspirin for primary prevention of cardiovascular disease is under intense scrutiny.

Keywords: Anti-platelet, Cardiovascular disease, gastrointestinal bleeding


How to cite this article:
Pradhan AK, Gupta V, Vishwakarma P. Aspirin for primary prevention: The changing paradigms!. Heart India 2019;7:3-7

How to cite this URL:
Pradhan AK, Gupta V, Vishwakarma P. Aspirin for primary prevention: The changing paradigms!. Heart India [serial online] 2019 [cited 2019 Sep 19];7:3-7. Available from: http://www.heartindia.net/text.asp?2019/7/1/3/255293



“Everything we hear is an opinion, not a fact.

Everything we see is a perspective, not the truth.”

-Marcus Aurelius (121 AD-180 AD)


  Introduction Top


The fascinating story of “the wonder drug” aspirin dates back >3500 years when willow bark was used as a painkiller and antipyretics by Hippocrates and other people. Bayer marketed it in the 19th century. Its use as antiplatelet drug started in the late 1960s and early 1970s.[1] Since then, role of low-dose aspirin in cardiovascular (CV) protection has been supported by >200 studies involving >200,000 patients.[2] Aspirin has been well established in the secondary prevention of Cardiovascular diseases (CVDs). However, despite multiple studies, the role of aspirin for the primary prevention remains controversial.


  Aspirin for Primary Prevention: the Golden Phase Top


Six large randomized studies have tested the role of aspirin for the primary prevention of CVDs since the late 1980s [Table 1]. The largest two among them are worth mentioning. In 1989, The Physicians' Health Study randomized 22,071 male participants to aspirin, with an average follow-up of 60 months. Aspirin use was associated with a 44% reduction in the risk of myocardial infarction (MI); however, this effect was mainly present in men >50 years of age and no reduction in total CV mortality (risk ratio: 0.96; 95% confidence interval: 0.60–1.54) was observed. A slightly increased risk of stroke was observed among those taking aspirin.[3] The Women's Health Study randomized 39,876 healthy women aged >45 years of age to low-dose aspirin (100 mg every other day) versus placebo for a mean follow-up of 10 years. They found no reduction in the primary composite end-point of nonfatal MI, nonfatal stroke, or death from a CV cause. Aspirin use, however, was associated with a 17% reduction in the risk of stroke.[4]
Table 1: Pivotal studies establishing the role of aspirin in primary prevention

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The pivotal Antithrombotic Trialists Collaboration meta-analysis pooled individual patient data of 95,000 patients from these six primary prevention studies.[2] The collaborative meta-analysis demonstrated 12% reduction in serious vascular events with the use of aspirin which was driven principally by 23% reduction in nonfatal MI [Figure 1].[2] There was also a 14% reduction in ischemic strokes which was counterbalanced by increase in hemorrhagic strokes by 32%. The net effect on strokes was not significant, while the effect on vascular mortality was not different from placebo. These benefits were accrued at the cost of almost 50% increase in bleeding which were chiefly gastrointestinal (GI) and extracranial in location.
Figure 1: Effects of aspirin use in the primary prevention in a collaborative meta-analysis of six large randomized trials – modified from the Antithrombotic Trialists Collaboration.[2] There was a 14% reduction in ischemic strokes too, but the net effect on stroke was nonsignificant. Vascular mortality also did not differ between the groups. (MI: Myocardial infarction)

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  Differential Effect of Aspirin Based on Gender – men are from Venus and Women are from Mars! Top


Interestingly, despite the varied sex-specific inclusion criteria in majority of these studies, the benefits of aspirin in the above-mentioned meta-analysis were independent of gender and baseline 5-year CV risk. One sex-specific meta-analysis of six large studies studied 51,342 women and 44,114 men randomized to aspirin (doses ranging between 100 mg every other day and 500 mg daily) versus placebo for 3.7 years–10 years. Aspirin therapy was associated with a significant 12% reduction in CV events and a 17% reduction in stroke, predominantly resulting from reduced rates of ischemic stroke in females, but there was no significant effect on MI or CV mortality. While in males, aspirin therapy was associated with a significant 14% reduction in CV events and a 32% reduction in MI. There was no significant effect on stroke or CV mortality.[5]

Hence, these initial trials and meta-analyses demonstrated clear efficacy of aspirin. Based on these studies, low-dose aspirin was given Class IIa recommendation for females >65 years of age at risk for primary prevention and Class IIb recommendation for females <65 years of age for ischemic stroke prevention.[6] Aspirin (75–162 mg daily) in men at intermediate risk (10-year risk of coronary heart disease >10%) was advised for primary prevention.[7] The American College of Cardiology along with the American Heart Association also gave Class IIa recommendation to low-dose aspirin in 2010 in adults with diabetes mellitus (DM) and no previous history of vascular disease who are at increased CVD risk (10-year risk >10%) and who are not at increased risk for bleeding. Those adults with DM at increased CVD risk include most men >50 years of age or women >60 years of age who have at least one additional major risk factor.[8]


  Fallout of Aspirin in the New Millenium Top


After 2008, many negative studies came into the picture. Two studies (POPADAD and JPAD studies) assessed effects of aspirin in diabetes. Aspirin was not found to reduce the risk of adverse CV events in diabetic patients in these studies.[9],[10] Subsequently, aspirin was not found to reduce the risk of CV events in those with an Ankle–Brachial Index <0.95 in The Aspirin for Asymptomatic Atherosclerosis trial.[11]

However, the updated systematic review of 11 randomized controlled trials (incorporating the above trials), published by the US Preventive Services Task Force in 2016, still revealed an impressive 22% relative risk reduction in nonfatal MI with aspirin but only minor reduction in nonfatal stroke, CV death, and total mortality [Figure 2].[12] Interestingly, elderly patients demonstrated more robust reduction in MI. At lower doses of aspirin (<100 mg), 14% reduction in nonfatal strokes were seen, while reduction on MI was sustained. However, aspirin use increased major GI bleeding risk by 58% and hemorrhagic stroke risk by 27%.[13],[14]
Figure 2: Benefits of aspirin for the primary prevention of cardiovascular events in adults aged >40 years in the updated systematic review of 11 trials for US Preventive Services Task Force – adapted from Guirguis et al.[12] (Elderly patients had greater relative reduction in myocardial infarction; lower aspirin doses (<100 mg/d) produced greater reduction (14%) in nonfatal stroke; MI: Myocardial infarction)

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Such conflicting results with aspirin studies have led to inconsistent guidelines for aspirin use in primary prevention. Some societies were in favor of aspirin use, while others were against its use. The US. Preventive Services Task Force recommends low-dose aspirin use for the primary prevention of CVD in adults aged 50–59 years who have a 10% or greater 10-year CVD risk [Figure 3]. While in adults aged 60–69 years who have a 10% or greater 10-year CVD risk, aspirin initiation was advised on individual basis.[15] Use of aspirin for the primary prevention of CVD was not endorsed by European Guidelines due to lack of clear evidence in support of its efficacy and increase in bleeding events.[16]
Figure 3: Summary of guideline recommendations on the use of aspirin for primary prevention of atherosclerotic cardiovascular diseases[19]

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  2018: Waterloo for Aspirin Top


In the background of emerging equivocal data about the role of aspirin primary prevention, three large randomized trials involving close to 47,000 patients were published recently. These three trials tried to address the unresolved issues of aspirin in primary prevention to some extent [Table 2]. In the ASCEND trial, aspirin use was tested in 15,840 persons with diabetes but without overt CVD.[17] At a median follow-up of 7.4 years, aspirin prevented serious CV events by 12%, but it also caused a 29% rise in major bleeding events. Hence, bleeding events counterbalanced the absolute benefits seen with aspirin use for primary prevention. The ARRIVE trial enrolled 12,546 patients (age >55 years for men and >60 for women) with moderate CV risk across seven countries. The use of aspirin did not decrease the risk of major CV events in the patients vis-a-vis placebo (hazard ratio –0.96; P = 0.6).[18] Again, as in ASCEND study, the GI bleeds were up by two times with the use of drug. ASPREE trial specifically tested aspirin use in 19,114 elderly patients for primary prevention.[19] Treatment with 100 mg/day of aspirin did not decrease major adverse CV events at median follow-up of 4.7 years. In this trial, use of enteric-coated aspirin led to increased major bleeding by 38%. Interestingly, there was increase in death from any cause with aspirin use, especially cancer-related deaths. This is surprising given the established role of aspirin in cancer prevention.[20]
Table 2: Comparison of three large contemporary randomized controlled trials of aspirin in primary prevention

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These three studies used contemporary pharmacotherapy in the management of CVD. With large sample size and close to half-decade follow-up in these studies, the results would be hard to neglect. One can only speculate about the various possible reasons for contrasting results seen in the pristine trials. The initial aspirin trials occurred in an era when other risk factors of vascular diseases were not well controlled such as blood pressure and lipid profile. With development of statins, renin–angiotensin–aldosterone system blockers, and better management of CV risk factors, event rates are already on decline. Not surprisingly, the statin use was high in these three studies with maximum use in ASCEND study (75%). Variation in sample size, patient population, drug dosage, compliance, event rates, and study design are other possible explanations. Theoretical addition of other preventive strategies such as statin and angiotensin-converting enzyme inhibitors coupled with better control of CV risk factors has the potential to negate the beneficial effects of aspirin in older trials.[21]


  Conclusion Top


The use of aspirin for primary prevention of CVD is now under scrutiny in view of recent trials. Even in diabetic patients, the use of aspirin is controversial in the light of increased bleeding events seen in recent trials. Pending a clear-cut advice from guidelines, routine use of aspirin for primary prevention in all is not advisable at present. Physicians need to take an individualized decision on a case-to-case base. The eternal dilemma still remains the same – balancing the bleeding risk with ischemic benefits.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots – A concise summary. Vascul Pharmacol 2018. pii: S1537-1891(18)30354-9.  Back to cited text no. 1
    
2.
Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849-60.  Back to cited text no. 2
    
3.
Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing physicians' health study. N Engl J Med 1989;321:129-35.  Back to cited text no. 3
    
4.
Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-304.  Back to cited text no. 4
    
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Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL, et al. Aspirin for the primary prevention of cardiovascular events in women and men: A sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295:306-13.  Back to cited text no. 5
    
6.
Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation 2007;115:1481-501.  Back to cited text no. 6
    
7.
Pearson TA, Blair SN, Daniels SR, Eckel RH, Fair JM, Fortmann SP, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. American Heart Association Science Advisory and Coordinating Committee. Circulation 2002;106:388-91.  Back to cited text no. 7
    
8.
Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee D, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: A position statement of the American Diabetes Association, a Scientific Statement of the American Heart Association, and an expert consensus document of the American College of Cardiology foundation. Circulation 2010;121:2694-701.  Back to cited text no. 8
    
9.
Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: Factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.  Back to cited text no. 9
    
10.
Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: A randomized controlled trial. JAMA 2008;300:2134-41.  Back to cited text no. 10
    
11.
Fowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: A randomized controlled trial. JAMA 2010;303:841-8.  Back to cited text no. 11
    
12.
Guirguis-Blake JM, Evans CV, Senger CA, O'Connor EA, Whitlock EP. Aspirin for the primary prevention of cardiovascular events: A systematic evidence review for the U.S. Preventive services task force. Ann Intern Med 2016;164:804-13.  Back to cited text no. 12
    
13.
Whitlock EP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks with aspirin use for primary prevention in adults: A systematic review for the U.S. preventive services task force. Ann Intern Med 2016;164:826-35.  Back to cited text no. 13
    
14.
Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive services task force recommendation statement. Ann Intern Med 2016;164:836-45.  Back to cited text no. 14
    
15.
Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice: The Sixth Joint Task Force of the European Society of Cardiology and other Societies on Cardiovascular Disease Prevention in Clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.  Back to cited text no. 15
    
16.
ASCEND Study Collaborative Group, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med 2018;379:1529-39.  Back to cited text no. 16
    
17.
Gaziano JM, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick PB, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): A randomised, double-blind, placebo-controlled trial. Lancet 2018;392:1036-46.  Back to cited text no. 17
    
18.
McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med 2018;379:1509-18.  Back to cited text no. 18
    
19.
Ridker PM, Libby P, Buring JE. Risk markers and primary prevention of cardiovascular disease. In: Zipes DP, Libby P, Bonow RO, Mann DL, Tomaselli GF, editors. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 11th ed. Philadelphia, PA: Elsevier; 2019. p. 876-909.  Back to cited text no. 19
    
20.
Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol 2012;9:259-67.  Back to cited text no. 20
    
21.
Verheugt FW. The role of the cardiologist in the primary prevention of cardiovascular disease with aspirin. J Am Coll Cardiol 2015;65:122-4.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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Introduction
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