Academiejaar 2011 - 2012
Aspirin in primary prevention
Promotor: Dr. T. De Backer
Scriptie voorgedragen in de 2de Master in het kader van de opleiding
MASTER IN DE GENEESKUNDE
Academiejaar 2011 - 2012
Aspirin in primary prevention
Promotor: Dr. T. De Backer
Scriptie voorgedragen in de 2de Master in het kader van de opleiding
MASTER IN DE GENEESKUNDE
“De auteur(s) en de promotor geven de toelating deze scriptie voor consultatie beschikbaar te stellen en delen ervan te kopiëren voor persoonlijk gebruik. Elk ander gebruik valt onder de beperkingen van het auteursrecht, in het bijzonder met betrekking tot de verplichting uitdrukkelijk de bron te vermelden bij het aanhalen van resultaten uit deze scriptie.”
(handtekening student (en))
Voorwoord De keuze voor het onderwerp was voor mij snel gemaakt. Allereerst was ik al geprikkeld door de cardiovasculaire thematiek, daarnaast konden we via de lessen inschatten dat dit onderwerp zeer relevant is. Het verbaasde mij dat wat doorgaat als een van de oudste en meest gebruikte medicijnen toch nog ter discussie staat en dat vandaag nog verschillende studies lopen om aan te tonen voor welke indicatie aspirine wel of niet een toepassing zou kunnen hebben. Dit werk was voor mij een grote uitdaging maar dankzij de goede opvolging, het gegeven vertrouwen en de expertise van verschillende mensen heb ik dit tot een goed einde kunnen brengen. Ik zou deze gelegenheid willen nemen om toch enkele mensen te bedanken voor de inspanning en interesse die zij de laatste twee jaar getoond hebben in mijn thesis. In eerste instantie wil ik mijn promotor dr. Tine De Backer bedanken voor de constructieve feedback, voor de toegankelijkheid, en voor het vertrouwen om mij als student geneeskunde te laten werken aan een Engelstalige publicatie. Ik kreeg meestal de dag zelf nog antwoord op mijn mails en haar deur stond altijd open om mij te ontvangen. Ik kon bouwen op haar expertise over het onderwerp om zelf mijn werk te kunnen laten slagen. Ten tweede wil ik prof. Robert Vander Stichele bedanken: dankzij zijn kritische geest, zijn innovatieve blik, zijn ervaring met guidelines en zijn goede kennis van academisch Engels is het artikel stelselmatig leesbaarder en beter geworden. Ook wil ik prof. Guy De Backer bedanken. Als internationaal expert in de cardiovasculaire preventie en zijn levenslange academische ervaring werd het artikel beter. Ik besef dat het een hele eer is als student te mogen samenwerken met iemand met zulk een indrukwekkend palmares. Verder dank ik Mark de Buyzere voor het nalezen van het manuscript. Prof. Vander Stichele omschreef Mark de Buyzere als een wandelende encyclopedie, hetgeen toch iets wil zeggen. Ik wil ook mijn ouders bedanken voor de jarenlange steun tijdens de studies en de vrijheid die ik heb gekregen om een eigen keuze te kunnen maken. Mijn vader verdient hier zeker een belangrijke plaats, want het is op het artikel over vergelijking van internationale richtlijenen dat hij samen schreef met prof.em. Marc De Meyere, dat ik me gebaseerd heb om te studie te schrijven. Ook kon ik met vragen altijd bij hem terecht.
Voorwoord.......................................................................................................... I Inhoudstafel....................................................................................................... II Abstract............................................................................................................... 1 Samenvatting: Nederlands…………………………………………………….………….. 2 1. Introduction….………………….......................................................................................... 4 2. Methods……………………………..................................................................................... 5 3.Results……………………………........................................................................................ 7 3.A.Guidelines…………………………........................................................………....….. 7 4.B.Recent evidence (meta-analyses and pivotal trials)…………………………………... 14 4. Discussion………………………………………………………………………………... 19 formulation of specific practice recommendations……………………………………….. 21 5. Conclusion…………………………….…………….…………….…………….……….. 21 6.References…………………………...….………………………………………………... 22
Aims Many countries have national guidelines for the treatment with aspirin in the primary prevention of cardiovascular events. Given the uncertainties about aspirin in primary prevention, our aim was to compare the recommendations and the reported evidence in guidelines for the treatment with aspirin of subjects free of cardiovascular disease with or without diabetes.
Methods and Results Guidelines were retrieved via Medline and other electronic databases and through a web-based search for guideline development organisations. The content of the recommendations and the underlying evidence were analysed with qualitative and bibliometric methods. We also performed a search for recent studies to assess whether they underscore the current recommendations. We included 12 guidelines: six European, three North American, and one from respectively New Zealand, Australia and the World Health Organization. Recommendations differ with regard to outcome (morbidity, mortality), time-span (years of risk), cut-off percentage between high and low risk, the dose of aspirin. Most guidelines are not in line with recent evidence showing that aspirin is of uncertain net value as the reduction in absolute risk for occlusive CV events needs to be weighed against an increase in the risk of major bleeds. Conclusion The uncertainties about the use of aspirin for the primary prevention of cardiovascular events are reflected in conflicting recommendations formulated in various guidelines: most of these are not upto-date and not in accordance with recent evidence. The available evidence indicates that the preventive use of aspirin is not justifiable in patients with a low cardiovascular risk, nor in patients with diabetes.
Veel landen hebben nationale richtlijnen voor de plaats van aspirine in de primaire preventie van cardiovasculaire aandoeningen. Aangezien er onzekerheden bestaan over aspirine in de primaire preventie was ons doel enerzijds de bestaande aanbevelingen te vergelijken en andezijds de beschikbare evidence in richtlijnen na te gaan voor de behandeling met aspirine bij mensen zonder cardiovasculaire aandoeningen met of zonder diabetes.
Methode en Resultaten
De richtlijnen werden bekomen via Medline en andere electronische databanken en via een zoektocht op het internet naar organisaties die zich bezighouden met richtlijnen. De inhoud van de aanbevelingen en de onderliggende evidentie werden geanalyseerd door middel van kwantitieve en bibliometrische methodes. We hebben ook een zoektocht ondernomen naar recente evidentie om na te gaan of zij deze recente aanbevelingen onderschrijven. We weerhielden 12 richtlijnen: Zes Europese, drie NoordAmerikaanse, en één uit respectievelijk New Zealand, Australië en de Wereld Gezondheids Organisatie. Aanbevelingen waren verschillend op het vlak van uitkomst (morbiditeit, mortaliteit), looptijd (aantal risicojaren), cut-off percentage tussen hoog en laag risico en de dosis aspirine. De meeste richtlijnen blijken niet in overeenstemming te zijn met de recente evidentie die aantoont dat aspirine een onzekere netto-waarde heeft aangezien de reductie in absoluut risico voor occlusieve CV aandoeningen moet worden afgewogen tegenover een verhoogd risico op majeure bloedingen.
De onzekerheden over het gebruik van aspirine in het kader van de primaire preventie van cardiovasculaire aandoeningen worden weerspiegeld in tegenstrijdige aanbevelingen geformuleerd in de verschillende richtlijnen: de meeste aanbevelingen zijn niet up-to-date en niet in overeenstemming met de recente literatuur. De recente literatuur toont aan dat het preventief gebruik van aspirine niet te rechtvaardigen valt bij patiënten met een laag cardiovasculair risico, noch bij patiënten met diabetes.
Review of guidelines on primary prevention of cardiovascular disease with aspirin: how much evidence is needed to turn a tanker?
Submitted to: Eur. Heart J.
Matthys Frederik1 De Backer Tine1, PhD De Backer Guy², PhD Vander Stichele Robert³ , PhD 1
Department of Cardiovascular Disease, University Hospital Ghent, Belgium
² Unit Nutrition and Food Safety, Department of Public Health, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium ³
Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
Tine De Backer [email protected]
; Frederik Matthys [email protected]
; Guy De Backer: [email protected]
; Robert vander Stichele: [email protected]
Correspondence to: Matthys Frederik, Department of Cardiovascular Disease, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium ; Email: [email protected]
, Tel: 0032 9 332 34 76 Fax: 0032 9 332 62 96
Given the burden caused by cardiovascular disease (CVD) in the world, the prevention of vascular events and their disabling and life-threatening complications is of major importance.
Low dose aspirin has been proposed for prevention of cardiovascular events, based on its inhibition of cyclo-oxygenase, which blocks production of thromboxane A2 and disrupts platelet aggregation and prevents vasoconstriction.
For secondary prevention of CVD, there is sufficient evidence regarding the use of aspirin. Long-term antiplatelet therapy reduces the risk of major cardiovascular events by about 25% (non-fatal myocardial infarction, non-fatal stroke, vascular death)1. This decrease is most distinct for non-fatal events, and to a lesser extent for vascular death. The downside of using antiplatelet therapy is that it increases the risk of bleeding, mainly gastrointestinal bleeding, but at a magnitude lower than its protective effect on CVD.
In primary prevention of CVD, however, in adults without known cardiovascular disease, the value of aspirin is less clear, and this uncertainty is reflected in conflicting recommendations in various guidelines. In primary prevention, the balance between benefit and risk is less favourable than in secondary prevention, especially in the light of widespread nonadherence.2,3
A different outcome of aspirin in primary prevention was found between men and women. Aspirin leads to a reduction in the number of myocardial infarctions (MI) in men but not in women. However, aspirin reduces the number of strokes in women but not in men.4
Diabetes is a matter of particular interest in this issue, as the incidence of CVD is three to five times higher in patients with type 2 diabetes than in the general population without diabetes5. The paradigm that diabetes is in itself a strong risk factor for cardiovascular disease results in guidelines recommending daily aspirin in patients with diabetes. The recommendations remain largely based on extrapolation of data from other high risk groups, and assume that the cardiovascular risk of a patient with diabetes is equivalent to that of a patient with coronary heart disease.
To our knowledge, no systematic attempt has been made to compare recommendations from existing guidelines on aspirin in primary prevention, and to compare the recommendations with the recent evidence from pivotal trials and meta-analyses.
The aim of this review is
To compare (inter)national guidelines on aspirin prophylaxis in primary cardiovascular prevention, and in patients with diabetes without cardiovascular disease.
To summarize recent evidence (meta-analyses and pivotal trials) and to compare it with recommendations in the guidelines.
To formulate specific practice recommendations for aspirin prophylaxis in primary prevention without grading these.
We performed a systematic search for clinical practice guidelines and for recent evidence on aspirin in the primary prevention, published between 2000 and 15 th of January 2012 in electronic databases. For our first aim, we performed a search for guidelines in MEDLINE, TRIP Database, SUMsearch, Scopus, Guidelines International Network (GIN), and Dare. The following keywords were used for our search for guidelines: cardiovascular disease and prevention. The limits for our search for guidelines were: practice guideline as publication type, published in the last 10 years. Via the Internet we also sought for well-known national organizations involved in guidelines on cardiovascular disease and prevention such as Clinical Knowledge Summaries(CKS/NICE), Joint British Societies, Scottish Intercollegiate Guidelines Network, European Society of Cardiology, U.S. Preventive Services Task Force, American Heart Association, Canadian Guidelines and Protocols Advisory Committee, New Zealand Guidelines Group, National Heart Foundation of Australia, the World Health Organization, the Dutch College of General Practitioners, and Domus Medica (the organization of general practitioners in Flanders, Belgium). We selected guidelines with a national or international status, formally published or readily accessible on the Internet. In the selected guidelines the following parameters were examined: organisation, website, title, year of publication, grade of recommendation, level of evidence, location per continent, type of risk tables, outcome (morbidity, mortality), timespan (years of risk), cut-off percentage between high and low risk, the dose of aspirin in primary prevention and in patients with diabetes. We extracted the main findings and the conclusions and identified the grading system used to scale the evidence. We analysed the reference list to identify the evidence base of the guideline, as to year of publication and geographical origin of the meta-analyses and RCTs cited. We did not perform a quality appraisal of the retrieved guidelines.
To fulfill our second aim, we searched for recent evidence (meta-analyses and pivotal trials) in MEDLINE, The Cochrane Library, DARE, Clinical Evidence, TRIP Database, SUMsearch, Scopus, Prescrire International and MINERVA, a Belgian evidence based journal. Keywords used were: aspirin, primary prevention, myocardial infarction, stroke, cardiovascular disease, bleeding and a combination of these. The limits were: meta-analysis, review and randomised controlled trial as publication type, published in the last 5 years. A manual search for additional references was conducted in the selected publications (snowballing). Meta-analyses, which duplicated previous synthesis efforts and which did not expand the pool of trials on which they were based, were not selected. For the evidence, we extracted the main findings and the conclusions. We described the concordance between the conclusions in recent meta-analyses and pivotal trials on the one hand, and the recommendations of the guidelines on the other hand. We plotted the guidelines, the meta-analyses and recent pivotal trials on a timeline and visualized the citing links. To fulfill our third aim, we formulated our interpretation of the available evidence in specific practice recommendations in an algorithmic form (IF… THEN …), as described by Georg et al.6
Results A. Guidelines. Twelve guidelines were selected (six European, three North American, and one from respectively New Zealand, Australia and the World Health Organization): five were retrieved through Medline and seven via well-known national organizations involved in guidelines. In Table 1 we give an overview of the characteristics of the selected guidelines and in Fig. 1a we give the flowchart of the systematic search for guidelines.
TABLE 1: Characteristics of selected guidelines Country
Clinical Knowledge Summaries Joint British Societies SIGN
European Society http://www.escardio.org of Cardiology
The Netherlands Dutch College of http://nhg.artsennet.nl/home.htm General Practitioners
Year of publication 2009
Level of evidence / grade of recommendation Not indicated
Prevention of cardiovascular disease in clinical practise Risk estimation and the prevention of cardiovascular disease
management of diabetes
Diabetes 1++ A
European guidelines on 2007 cardiovascular disease prevention in clinical practise Cardiovasculair 2006 risicomanagement
Globaal Cardiovasculair risicobeheer
≥10% = level 1 5-10% = level 3
US Preventive Services Task Force American Heart Association
Aspirin for the Prevention of Cardiovascular Disease
men 45 to 79 y A women 55 to 79 y A
Guidelines for the primary prevention of stroke
Class I, Level of Evidence A
ADA/AHA/ACCF Aspirin for 2010 Primary Prevention of Cardiovascular Events in People With Diabetes Cardiovascular disease - Primary 2008 Prevention
Diabetes Class lla, Level of Evidence B
New Zealand Cardiovascular guidelines handbook
Aspirin for cardiovascular disease prevention
Prevention of Cardiovascular Disease
Guidelines and http://www.bcguidelines.ca Protocols Advisory Committee New Zealand http://www.nzgg.org.nz Guidelines Group National Heart Foundation of Australia World Health Organization
see box 2
Box 1 gives a summary of the recommendations of the different guidelines.
Box 1. Recommendations for aspirin in the 12 guidelines (annex to Table 2)
The guidelines of the National Institute of Clinical Evidence (CKS/NICE) recommend aspirin (75 mg/day) in asymptomatic patients with a 10-year risk of 20% or more. CKS/NICE uses Framingham calculators, QRISK®2 based on UK GP population, and ASSIGN developed in Scotland including an index of deprivation and also family history. In patients with type 2 diabetes, the use of aspirin in primary prevention is recommended for all patients over 50 years, or for those with hypertension or other significant risk factors.7
The Joint British Societies recommend aspirin (75 mg/day) for patients older than 50 years, with a 10-year cardiovascular risk of ≥20% (Joint British Societies’ CVD risk prediction chart) and for patients with type 2 diabetes over 50 years, or diagnosed with diabetes for over 10 years or those being treated for hypertension. In patients with diabetes aspirin is started when the blood pressure is controlled (150/90 mmHg max).8
The Scottish Intercollegiate Guidelines Network (SIGN) concludes that in 1000 patients with a 10% risk (based on Framingham calculators, Joint British Societies’ CVD risk prediction chart or ASSIGN) at 10 years, aspirin prevents 12 to 40 myocardial infarctions but leads to 0 to 4 haemorrhagic strokes and 4 to 8 major gastrointestinal bleedings. It therefore proposes that in the primary prevention 75 mg of aspirin daily is useful with a 10-year cardiovascular risk of 20% or more9. Until 2007, SIGN recommended aspirin in all patients with type 2 diabetes older than 50 years. More recent guidelines10 state that low-dose aspirin is not recommended for primary prevention of vascular disease in patients with type 2 diabetes.
The European Society of Cardiology (ESC) recommends aspirin (75-150mg/day) in primary prevention for patients with a SCORE-based 10-year risk of 10% or more when the blood pressure is under control.5
The Dutch College of General Practitioners does not recommend the use of aspirin in primary prevention. Aspirin is also not recommended for patients with type 2 diabetes.11
The Belgian guidelines for general practitioners recommend aspirin (75-150 mg/day) for the primary prevention of cardiovascular events in individuals with a 10-year risk of 10% or more, based on the SCORE model, and for individuals with a 10-year SCORE risk of 5% or more if other risk factors, e.g. obesity or sedentary lifestyle, are present. Patients with type 2 diabetes are automatically considered in the high-risk group and are recommended to take aspirin.12
In the U.S. Preventive Services Task Force (USPSTF) which is Framingham based, the use of aspirin (75mg/day) has an A recommendation for men aged 45 to 79 years, when the potential benefit due to a reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal haemorrhage. In women, this recommendation is justified from the age of 55 years onwards for the prevention of stroke.13
The American Heart Association states that the use of aspirin (81mg/day or 100mg/2days) for cardiovascular prophylaxis is recommended for persons with a Framingham 10-year risk score of cardiovascular events of 6 to 10%14. Low-dose (75–162 mg/d) aspirin use for prevention is also 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. Those adults with diabetes at increased CVD risk include most men older than 50 years and women older than 60 years who have one or more of the following additional major risk factors: smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria.15
The Canadian guideline recommends low-dose aspirin (e.g. 81 mg) to prevent platelet aggregation for people under age 70 who are not aspirin intolerant and who have a ten-year CHD risk ≥ 20% (Framingham calculators). Blood pressure must be well controlled. Low-dose aspirin therapy for patients (men and women) over age 70 is not recommended at this time due to insufficient evidence16. The Canadian guideline does not give a recommendation for patients with diabetes. According to the Canadian Diabetes Association, aspirin (75–325 mg/day) should be considered in all people with diabetes at high risk of a CV event17.
The New Zealand guideline recommends low-dose aspirin (75-150mg/day) in patients with a 5-year risk of more than 20% (New Zealand Cardiovascular Risk Calculator). In patients with an estimated total CV risk of 15% or more, intensive lifestyle advice is recommended for three to six months before considering aspirin. Hereby, specific 5-year risk tables are provided for patients with diabetes.18
The National Heart Foundation of Australia19 recommends that people with an annual risk of >1% (Framingham calculators) may reduce the risk by taking low-dose aspirin (75-150mg/day). No recommendation is given for patients with diabetes. According to Diabetes Australia, low dose aspirin (75– 325 mg/day) should be considered for cardiovascular protection for all people with diabetes 20.
The World Health Organization recommends aspirin (75mg/day) for individuals with a 10-year risk of a cardiovascular event of more than 30% (Framingham calculators). In individuals with a risk between 20 and 30%, aspirin should be considered in areas where coronary heart disease rates exceed stroke rates.21 Hereby, specific 10-year risk tables are provided for patients with diabetes.
Table 2 and Box 1 show the recommendations for aspirin in the 12 guidelines, and the references according to the type of study.
TABLE 2: Comparison of the recommendations in the selected guidelines and references according to type of study A. EUROPE U.K. CKS-NICE
≥ 50 y
> 50 y
Risk of morbidity +/- mortality in number of years
The Netherlands NHG
Belgium Domus Medica
men 45-79 y women 55-79 y
≥ 10% / ≥ 5% if risk factors are present
morbidity + mortality
B. OUTSIDE EUROPE USA USA US-PSTF AHA
C. INTERNATIONAL WHO
≥ 30% ***
morbidity + mortality
morbidity + mortality
morbidity + morbidity mortality + mortality
morbidity + mortality
consider in high risk patients / 75–325 mg/day ****
diabetics have consider in specific 5-year all diabetic risk tables patients/ 75–325 mg/day ****
diabetics have specific 10year risk tables
< 70 y
Morbidity / mortality
morbidity + mortality
morbidity + mortality
morbidity + mortality
≥ 50 y or < 50 y with other additional risk factors
≥ 50 y, or diagnosed with diabetes for over 10 y or those being treated for hypertension
aspirin is usually recommended
75-150 mg/ day
Patients with diabetes
diabetes is a men ≥ 50 y risk factor in women ≥ 60 y the used with other cardiovascular additional risk risk models factors / 75–162 mg/day 75mg/day
81mg/day or 100mg/2days
81 mg/day 75-150mg/ day
* men : 45-59y ≥4% 60-69y ≥9% 70-79y ≥12% women : 45-59y ≥3% 60-69y ≥8% 70-79y ≥11%
Meta-analysis Used references according to type of study in subjects without diabetes
1, 35, 36
35, 42, 51
4, 39, 42, 54, 55
(systematic) review RCT
52, 66, 67
59, 70, 75
34, 41, 44
26, 27, 34 ,38, 40, 41, 44, 45, 46, 47, 73, 80
25, 30, 32
26, 27, 38
others** = research support, comment, education and debate, overview
4, 35, 36, 39, 42, 88 61
38, 44, 45, 46, 86, 87 50
62, 63, 64, 65 1, 4, 25, 32, 33, 35, 72, 83, 84
*** in 20 to < 30%, aspirin should be considered in areas where coronary heart disease rates exceed stroke rates
Meta-analysis Used references according to type of study in patients with diabetes
39, 48, 51
13, 66, 82 56, 57, 60, 68, 69, 71, 74, 76, 77, 78, 79, 81, 85
**** according to diabetes guidelines of Canada and Australia http://www.diabetes.ca/ http://www.diabetesaustralia.com.au/
38, 40, 44, 45, 46, 47
Points of Agreement. Points of agreement in the different guidelines are the use of a model to assess the total cardiovascular risk, the determination of an arbitrary threshold to discriminate low and high risk profiles with a percentage of total cardiovascular risk, and the administration of a low dose of aspirin (75 mg/day in most guidelines). In subjects without diabetes patients, aspirin is recommended in all the guidelines (except the Dutch NHG guidelines).
Differences among Guidelines. Recommendations differ with regard to age, outcome (morbidity and/or mortality referring to different risk tables), time-span (years of risk), cut-off percentage between high and low risk, the dose of aspirin and co-morbidities such as diabetes. Differences were also observed in patient definition (age, being treated for hypertension, additional risk factors) (Table 2) and in grading system. (See Box 2)
Further, we found a selective use of the evidence in the different guidelines, as different meta-analyses and different studies were cited, with rather little overlap. Fig 2a + Fig 2b and Table 2.
The 12 guidelines included a total of 63 references, of which 19 in non-diabetes, 31 in diabetes and 13 in both groups. Five guidelines out of 12 show no references on diabetes and one guideline (New Zealand) did not mention any references. None of the available meta-analyses or landmark studies was used in all the guidelines. Six guidelines share the same meta-analysis35 and five guidelines share the same RCT40 for subjects without diabetes.
North American guidelines cited proportionally more American publications than European guidelines (15/18 versus 7/19 (83.3% vs 37.0%) for subjects without diabetes and 26/38 versus 6/15 (68.4% vs 40.0%) for patients with diabetes). Table 2. Guidelines use specific models to estimate total CV risk: most used are the model based on results from the Framingham study and the SCORE model. In the Framingham study, the endpoints are both morbidity and mortality of coronary heart disease. For models based on the ‘Framingham Heart Study’, a 10-year risk of 20% is a cut-off between low and high risk. The endpoint in SCORE is the 10-year risk of fatal cardiovascular events (mortality). In SCORE a 10 year risk >5% is considered high risk. Other specific tables are QRISK®2 based on UK GP population, ASSIGN developed in Scotland including an index of deprivation and family history; the Joint British Societies’ CVD risk prediction chart; and the New Zealand Cardiovascular Risk Calculator.
B. Recent evidence (meta-analyses and pivotal trials)
We selected five recent meta-analyses (ATT, De Berardis, Pignone, Stavrakis, Younis)1,25,28,29,30 and three recent pivotal trials (AAA, POPADAD, JPAD)23,26,27. Fig 1b shows the flowchart of the systematic search for recent evidence and BOX 3 with recent evidence of aspirin in the primary prevention in the general population without established CVD and in people with diabetes mellitus.
For the general population without established CVD, we focused on the meta-analysis (ATT), which states that aspirin reduces the risk of serious vascular events by 12%. No significant difference in stroke or vascular mortality was observed, but aspirin increased major gastrointestinal and other extracranial bleeds by about half in the primary prevention trials (0.10% vs 0.07% per year). The results of the ‘Aspirin for Asymptomatic Atheroslerosis’ (AAA) trial confirm that in patients without established cardiovascular events and with documented occlusive peripheral arterial disease (ABI ≤ 0.95), aspirin does not reduce cardiovascular events. For people with diabetes mellitus, an increasing amount of data suggests that factors specific to diabetes may have a role in atherothrombosis24 and that diabetes has to be considered an entity in itself.25 We focused on the two recent trials, POPADAD26 and JPAD27, which confirm the results of previous trials, that aspirin in primary prevention in patients with diabetes yields no significant decline towards the end points of cardiovascular events. Since the publication of these two recent trials (JPAD and POPADAD) several large meta-analyses25,28,29,30 were performed in which these two new trials were combined with already existing RCTs. The results of these meta-analyses do not support the routine use of aspirin in primary prevention of cardiovascular disease in diabetes mellitus. The benefit was too modest or could not be observed.
Box 3 Recent evidence of aspirin in primary prevention of cardiovascular events Meta-analyses 1. In the general population without established CVD Severe vascular complications occur more frequently at an earlier age in men than in women. However, in the large meta-analysis of primary prevention trials (the Antithrombotic Trialists’ (ATT) Collaboration), the proportional reduction in the occurrence of vascular events was equal for men and women. Therefore, in this and some other studies, no distinction by sex is upheld.1 In the ATT with six primary prevention trials on aspirin prophylaxis with 95,000 individuals at low average risk, the chance of serious vascular events was 0.51% per year in people allocated aspirin compared with 0.57% per year in those allocated control. This small absolute reduction (only 0.06% per year) represented a 12% proportional reduction in serious vascular events (p=0.0001), mainly due to a reduction of about a fifth in non-fatal myocardial infarction (0.18% versus 0.23% per year, p15%.22 % (fatal and non-fatal myocardial infarction, ischaemic stroke, or haemorrhagic stroke) Also, the current guidelines state that the risk of bleeding remains approximately constant for all subgroups. The ATT trial1 shows that different risk factors for cardiovascular disease are responsible for a higher risk of bleeding. With increasing age, male gender, diabetes mellitus, smoking, high blood pressure, the relative risk of severe coronary disease and ischemic stroke increases as well as the risk of severe extracranial bleeding and haemorrhagic stroke. According to the ATT trial, a high BMI does also leads to more extra-cranial bleeding.
2. In people with diabetes mellitus The meta-analysis of De Berardis (2009) included six trials, of which three in patients with diabetes only, in which aspirin (50 mg to 650 mg daily) versus placebo was randomised in 10,117 patients without cardiovascular history25. Data on major cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, nonfatal stroke, and all cause mortality) were extracted and pooled with a random effect model. In this meta-analysis with a follow-up ranging from 3.6 to 10.1 years, no clear benefit could be demonstrated from aspirin in primary prevention of major cardiovascular events (five studies, 9584 participants, 1258 events; relative risk 0.90, 0.81 to 1.00; P=0.06), cardiovascular mortality (four studies, n=8557, 0.94; 0.72 to 1.23), or all cause mortality (four studies, n=8557; 0.93, 0.82 to 1.05). Significant heterogeneity was found in the analysis for myocardial infarction (I²=62.2%; P=0.02) and stroke (I²=52.5%; P=0.08). Subgroup analysis by sex confirmed that aspirin significantly reduced the risk of myocardial infarction in men by 43% (three studies, 3126 participants, 265 events; 0.57, 0.34 to 0.94; P=0.03) whereas no benefit was found in women. No significant reduction in the risk of stroke with aspirin compared with placebo or no treatment was found in men (1.11, 0.75 to 1.64; P=0.61) or in women (0.75, 0.37 to 1.53; P=0.43). There was no statistically significant increase in the risk of any bleeding (RR 2.50 0.76 to 8.21) and cancer (RR 0.84 0.62 to 1.14). A clear benefit of aspirin in the primary prevention of major cardiovascular events or mortality in people with diabetes could not be identified in this meta-analysis. This meta-analysis suggests that the benefit may be lower in patients with diabetes than in other high risk populations. The expected benefits of aspirin in people with diabetes might not exceed the risk of major bleedings, particularly among those at low cardiovascular risk (70 years) at high risk of bleeding A second meta-analysis (Pignone)28 comes to the conclusion that the effect of aspirin for primary prevention of CVD events in adults with diabetes is currently unclear. Trials to date have reached mixed results, but overall suggest that aspirin modestly reduces risk of cardiovascular events. More research is needed to better define the specific effects of aspirin in diabetes, including any sex-specific differences A third meta-analysis (Stavrakis)29 concludes that, in patients with diabetes but without apparent cardiovascular disease, the use of low-dose aspirin does not lead to protection against the predetermined end points of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. There was no significant reduction in the individual endpoints of myocardial infarction, cardiovascular death, stroke and other causes of mortality during the aspirin use. It is assumed that the pro-inflammatory and prothrombotic state associated with diabetes mellitus can create an environment where full blockade of cyclooxygenase-1 by aspirin does not influence the platelet response and has little effect on thrombus formation.
A fourth meta-analysis (Younis)30 does not support the routine use of aspirin in primary prevention of cardiovascular disease in diabetes mellitus. There was no significant benefit in reducing cardiovascular events, myocardial infarction and cardiovascular death. The fact that no advantage could be demonstrated may be due to insufficient power of the individual trials. Overall, given the results of this analysis, a small benefit could not be excluded. It may be that aspirin is less useful in patients with diabetes by so-called 'aspirin resistance'. It was suggested that due to higher platelet turnover and thromboxane A2 synthesis in diabetes mellitus, an increased or two times per day administration of aspirin may be needed to reduce thromboxane A2 concentrations adequately. RCT’s 1. In the general population without established CVD The ‘Aspirin for Asymptomatic Atheroslerosis’(AAA) trial23, a recent double-blind randomised controlled trial, compared the efficacy of 100 mg enteric-coated aspirin with placebo in 3350 Scottish patients between 50 and 75 years with no history of vascular events and with an ankle brachial index (ABI) of ≤ 0.95. Over an average follow-up period of 8.2 years, no difference was detected between both groups in the composite primary end point (initial fatal or nonfatal coronary event or stroke or revascularization: HR 1.03, 95% CI 0.84 to 1.27) and also no difference for all reported cardiovascular events combined (primary outcome or angina, intermittent claudication or transient ischemic attack: HR 1.00, 95% CI 0.85 to 1.17) or all-cause mortality (HR 0.95; 95% CI 0.77 to 1.16). The authors identified an increased number of bleeding requiring hospitalization (HR 1.71, 95% CI 0.99 to 2.97). The results of this study confirm that in patients without established cardiovascular events and with documented occlusive peripheral arterial disease (ABI ≤ 0.95), a preventive dose of aspirin does not reduce cardiovascular events. 2. In people with diabetes mellitus The POPADAD trial26 studied whether treatment with aspirin and antioxidant therapy, combined or alone, are more effective than placebo in reducing cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease. A total of 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease, were randomly assigned to one of four treatment groups: aspirin 100 mg plus antioxidant (n=320), aspirin 100 mg plus placebo (n=318), antioxidant plus placebo (n=320), or double placebo (n= 318). Two composite primary end points were death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or above ankle amputation for critical limb ischaemia and death from coronary heart disease or stroke. No statistically significant differences were observed between the two groups for any endpoint. Overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% versus 18.3%) hazard ratio 0.98 (95% confidence interval 0.76 to 1.26).
In the aspirin groups 43 deaths occurred from coronary heart disease or stroke compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). According to the results of the study, clinically important benefits appear to be unlikely, although it is possible that small effects can be discovered with larger trials followed over a longer period of time. Furthermore, one of the current major interventions in diabetes mellitus is statin therapy. Calculations in over 10 000 people with diabetes showed a mean total cholesterol level of 6.0 mmol/l in 1996 decreasing to 4.3 mmol/l in 2007. Therefore it might be doubtful if aspirin does provide additional benefit when statins are used . In the JPAD study ,the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in 27
patients with type 2 diabetes was examined in a multicentre, prospective, randomised, open-label, blinded, end-point trial which enrolled 2539 Japanese patients with type 2 diabetes without a history of atherosclerotic disease. Patients were assigned to the low-dose aspirin group (81 or 100 mg per day) or the nonaspirin group and had a median follow-up of 4.37 years. Primary end points were atherosclerotic events, including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. Secondary end points included each primary end point and combinations of primary end points as well as death from any cause. A total of 154 atherosclerotic events occurred: 68 in the aspirin group (13.6 per 1000 person-years) and 86 in the nonaspirin group (17.0 per 1000 person-years) (HR, 0.80; 95% CI, 0.58-1.10; log-rank test, P = .16). The combined end point of fatal coronary events and fatal cerebrovascular events occurred in one patient (stroke) in the aspirin group and 10 patients (five fatal myocardial infarctions and five fatal strokes) in the nonaspirin group (HR, 0.10; 95% CI, 0.01-0.79; P = .0037). A total of 34 patients in the aspirin group and 38 patients in the nonaspirin group died from any cause (HR, 0.90; 95% CI, 0.57-1.14; log-rank test, P = .67). The composite of haemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and nonaspirin groups. The number of bleeding (gastrointestinal or other) and the incidence of anaemia and non-haemorrhagic gastrointestinal events were higher with aspirin (gastrointestinal bleeding: 12 patients in the aspirin group and 4 in the nonaspirin group and retinal haemorrhage: 8 patients in the aspirin group and four in the nonaspirin group). This study in Japan confirms that the benefits of aspirin for primary prevention in patients with type 2 diabetes without peripheral arterial disease is not proven but it increases morbidity due to side effects. Current treatment of cardiovascular risk factors in patients with type 2 diabetes has improved since the 1990s and may have accounted for the lower event rates: there is better control of glucose, blood pressure, and lipid levels in clinical practice.
Discussion To our knowledge, this study is the first that compared national guidelines on the use of aspirin in primary prevention and in patients with diabetes. We also simultaneously compared the clinical content of the guideline recommendations with recent evidence. We found important differences in recommendations for the use of aspirin in primary prevention and in patients with diabetes. Recommendations differ with regard to age, outcome (morbidity and/or mortality referring to different risk tables), years of risk, the percentages of total cardiovascular risk, the dose of aspirin, comorbidities such as diabetes and in grading system. Although aspirin is recommended in most current guidelines on primary prevention, often with the highest level of evidence, recent meta-analyses and RCTs conclude that low dose aspirin in primary prevention is of an uncertain net effect.1 A high NNT (1667 in the ATT study among asymptomatic patients), combined with a significant increase in bleeding risk, seem to make a widespread use of aspirin unjustifiable. There are several limitations to this study. We may not have found all existing guidelines through the indexed literature or the internet, and we omitted regional guidelines. Furthermore, we did not perform a quality assessment of the selected guidelines with a validated tool such as AGREE. We did not indulge in the careful analysis of subtle differences in consecutive meta-analyses31,89 which repeated a pooled analysis of similar collections of trials. The lack of effect of aspirin in diabetic patients may be due to underpowered trials, bad compliance, or wrong dosage regimens. Several large trials are ongoing with over 10.000 patients : ASCEND trial (A Study of Cardiovascular Events in Diabetes), the ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes) and the ASPREE trial (ASPirin in Reducing Events in the Elderly). Their results might bring additional information to this discussion. The guidelines use different cardiovascular risk models, and these models might have some shortcomings. For instance, in most models, not all risk factors were taken into account. Modifying factors en qualifiers, such as family history, diabetes, social class, sedentary lifestyle, were mostly not taken into account. Moreover, we still know little about the interactions between these various factors. Some risk models are gender specific and use 1 -, 5 - or 10-year cardiovascular risk assessment. However, the evidence in support of that might be weak.
According to existing guidelines, the use of aspirin in primary prevention of cardiovascular events is recommended. However, there is little consensus on the practicalities. Guidelines advice aspirin at different percentages of risk (>1%/year, ≥6%/5 years to 30%/10 years). The recommendations and the reporting of them vary as well as their references used by the various organisations. Compared to the European guidelines, the Norwegian guideline (as does the US-PSTF guideline) gives three different thresholds for patients aged up to 49, 59, and 69 years. This shifts the emphasis of treatment from older to younger people and the total sum of life gained is about the same, but the number of patients treated is considerably lower. In this guideline, aspirin is not mentioned for primary prevention.90 The question arises whether by using aspirin in primary prevention of CVD important medicalization of the healthy population occurs. Prior to the consideration of drug therapy it is desirable achieving changes in life style, such as smoking cessation, healthy eating and regular physical activity. Another aspect is the increasing use of statins. Since the efficacy and relative safety of statins, they could be preferred to aspirin in monotherapy. It is also questionable whether in the future, there is a place preserved for aspirin with a statin: when the risk of occlusive vascular disease is sufficiently reduced by statins or other preventive measures it could be argued that the additional benefit of aspirin is rather limited. The first studies of aspirin use in primary prevention often predate the widespread use of statin. Differences among guidelines are not merely academic 91; they have important consequences for daily practice. A patient consulting a physician in the context of cardiovascular prevention will be managed differently according to the country. The differences seem to be related to selection and interpretation of the available studies. We conclude that there is a need for more systematic reviews (e.g. Cochrane..) on this subject and ensuing specific practice recommendations, explicitly stating that the use of aspirin is not recommended for primary prevention, should be graded using GRADE. Further, the definition of primary versus secondary prevention, or more appropriately, low versus high cardiovascular risk should be refined and harmonized.
Formulation of specific practice recommendations Finally, we attempted to transform the selected evidence from pivotal trials and meta-analyses in a proposal for 3 specific practice recommendations, to be subjected to a systematic review and grading with the GRADE system:
If patients are free of cardiovascular disease and have a low total cardiovascular risk, administration of low-dose aspirin is not recommended.
If patients are free of cardiovascular disease and have diabetes, low-dose aspirin is not recommended.
If patients are free of cardiovascular disease and have a high cardiovascular risk, aspirin use is justifiable, but, the chance for protection should be individually weighed against the risk of bleeding.
The uncertainties about the use of aspirin for the primary prevention of cardiovascular events are reflected in conflicting recommendations formulated in various guidelines. Although the evidence for the primary prevention is easily available, national guidelines are different with regard to the choice of the evidence and the interpretation for clinical practice. The available evidence indicates that the preventive use of aspirin is not justifiable in patients with a low cardiovascular risk, nor in patients with diabetes. It is time to critically review most of the existing guidelines and to bring them in line with recent evidence.
Aknowledgement We thank prof.em. Marc De Meyere (University Ghent) and dr. Jan Matthys (University Ghent) for the concept of this study. Conflict of interest: none
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