Review of guidelines on primary prevention of cardiovascular disease with aspirin: how much evidence is needed to turn a tanker?

EURO PEAN SO CIETY O F CARDIOLOGY ® Review Review of guidelines on primary prevention of cardiovascular disease with aspirin: how much evidence is n...
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EURO PEAN SO CIETY O F CARDIOLOGY ®

Review

Review of guidelines on primary prevention of cardiovascular disease with aspirin: how much evidence is needed to turn a tanker?

European Journal of Preventive Cardiology 2014, Vol. 21(3) 354–365 ! The European Society of Cardiology 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/2047487312472077 ejpc.sagepub.com

Frederik Matthys1, Tine De Backer1, Guy De Backer2 and Robert Vander Stichele3

Abstract Aims: There are numerous national and international guidelines on the use of aspirin for the primary prevention of cardiovascular disease. 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 through Medline and other electronic databases and through a webbased search for guideline development organizations. The content of the recommendations and the underlying evidence were analysed with qualitative and bibliometric methods. In addition, we searched for recent studies to assess whether they underscore the current recommendations. We included 12 guidelines: six European, three North American, and one each from 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, and the dose of aspirin. Most guidelines are not in line with recent evidence, which show 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: We found conflicting recommendations in various guidelines about the use of aspirin for the primary prevention of cardiovascular events, which reflect differences in selection of the evidence and in the timing of publication. According to recent evidence, in general, the use of aspirin seems no longer justifiable in primary prevention in patients with or without diabetes.

Keywords Aspirin, cardiovascular prevention, evidence, guideline, primary prevention, review Received 5 July 2012; accepted 30 November 2012

Introduction 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, 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

1 Department of Cardiovascular Disease, University Hospital Ghent, Belgium 2 Department of Public Health, Ghent University, Ghent, Belgium 3 Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium

Corresponding author: Frederik Matthys, Department of Cardiovascular Disease, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium. Email: [email protected]

Matthys et al. bleeding, mainly gastrointestinal bleeding, but at a magnitude lower than its protective effect on CVD. In adults without established 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 of regular medication intake.2,3 A gender difference in outcome of aspirin in primary prevention was suggested, leading to a reduction in the number of myocardial infarctions in men but not in women. However, aspirin might reduce 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 3–5-times higher in patients with type 2 diabetes than in the general population without diabetes.5 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 . summarize recent evidence (meta-analyses and pivotal trials) and compare it with recommendations in the guidelines . formulate specific practice recommendations for aspirin prophylaxis in primary prevention in a way that evaluation of the level of evidence and strength of recommendation is facilitated.

Methods We performed a systematic search for clinical practice guidelines and for recent evidence on aspirin in the primary prevention, published between 2000 and 15 June 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

355 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 Internet the we also sought for wellknown national organizations involved in guidelines on cardiovascular disease and prevention such as Clinical Knowledge Summaries (NICE), Joint British Societies, Scottish Intercollegiate Guidelines Network, European Society of Cardiology, US 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: organization, website, title, year of publication, grade of recommendation, level of evidence, location per continent, type of risk tables, outcome (morbidity, mortality), time span (years of risk), cutoff percentage between high and low risk, and the dose of aspirin in primary prevention in the general population and in patients with diabetes. We extracted the main findings and the conclusions and identified the grading system used to scale the level of evidence and the strength of recommendation. 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 randomized controlled trials (RCTs) cited. We did not perform an official quality appraisal of the retrieved guidelines. To fulfil our second aim, we searched for recent evidence (meta-analyses and pivotal trials) in MEDLINE, Cochrane Library, DARE, Clinical Evidence, TRIP Database, SUMsearch, Scopus, and Prescrire International. Keywords used were: ‘aspirin’, ‘primary prevention’, ‘myocardial infarction’, ‘stroke’, ‘cardiovascular disease’, ‘bleeding’ and a combination of these. The limits were: meta-analysis, review, and RCT 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.

356 To fulfil 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 Guidelines Twelve guidelines were selected (six European, three North American, and one each from New Zealand, Australia, and the World Health Organization): five were retrieved through Medline5,8,13,14,19 and seven via well-known national organizations involved in guidelines.7,9,11,12,16,18,21 Table 1 gives an overview of the characteristics of the selected guidelines and Figure 1a gives the flowchart of the systematic search for guidelines. Supplementary Box S1 (available online) gives a summary of the recommendations5,7–21 for aspirin in the 12 different guidelines. Table 2 shows the recommendations5,7–21 for aspirin in the 12 guidelines and the references1,4,13,25–27,30,32–86 according to the type of study. 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 low-dose aspirin (75 mg/day in most guidelines). In subjects without diabetes and a high cardiovascular risk, aspirin is recommended in 10 out of 12 guidelines (except for the ESC and 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 comorbidities such as diabetes. Differences were also observed in patient definition (age, being treated for hypertension, additional risk factors). (Table 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 (Figure 2 and Table 2). The 12 guidelines included a total of 62 references, of which 19 in non-diabetes, 30 in diabetes, and 13 in both groups. Four guidelines out of 12 show no references on diabetes and one guideline (New Zealand) did not mention any references.

European Journal of Preventive Cardiology 21(3) None of the available meta-analyses or landmark studies were used in all the guidelines. For subjects without diabetes, one meta-analysis35 was shared by six guidelines and one RCT40 was shared by four guidelines. North American guidelines cited more North American references than did European guidelines (41/56 (73.2%) vs. 11/35 (31.4%), and vice versa 24/ 35 (68.6%) vs. 15/56 (26.8%) (Table 2). Guidelines use specific models to estimate total CV risk: most used are the models 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 10year risk 5% is considered high risk. Other specific tables are: QRISK2, 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.

Recent evidence (meta-analyses and pivotal trials) We selected five recent meta-analyses (ATT, De Berardis, Pignone, Seshasai, Younis)1,25,28,29,30 and three recent pivotal trials (AAA, POPADAD, JPAD).23,26,27 Figure 1b shows the flowchart of the systematic search for recent evidence and Supplementary Box S2 (available online) shows the recent evidence of aspirin in the primary prevention in the general population without established CVD and in people with diabetes mellitus without established CVD. For the general population without established CVD, we focused on the meta-analysis ATT (95,000 subjects), which states that aspirin reduces the risk of serious vascular events by 12%. No significant difference in stroke or vascular mortality was observed. However, 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. A more recent meta-analysis (102,621 subjects)29 including AAA, similarly concludes that, despite important reduction in non-fatal myocardial infarction, aspirin prophylaxis in people without prior cardiovascular disease does not lead to reductions in either cardiovascular death or cancer mortality.

Clinical Knowledge Summaries Joint British Societies SIGN

European Society of Cardiology

Dutch College of General Practitioners Domus Medica US Preventive Services Task Force

American Heart Association

Guidelines and Protocols Advisory Committee New Zealand Guidelines Group National Heart Foundation of Australia World Health Organization

UK UK Scotland

ESC

The Netherlands

USA

Canada

New Zealand Australia International

Belgium USA

Organization

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Table 1. Characteristics of selected guidelines5,7–21

http://www.nzgg.org.nz http://www.mja.com.au http://www.who.int/en/

http://www.bcguidelines.ca

http://www.domusmedica.be http://www.uspreventiveservic estaskforce.org http://www.heart.org

http://nhg.artsennet.nl/home.htm

http://www.escardio.org

http://www.cks.nhs.uk/home http://www.bcs.com http://www.sign.ac.uk

Website

New Zealand Cardiovascular guidelines handbook Aspirin for cardiovascular disease prevention Prevention of Cardiovascular Disease

Guidelines for the primary prevention of stroke ADA/AHA/ACCF Aspirin for Primary Prevention of Cardiovascular Events in People With Diabetes Cardiovascular disease – Primary Prevention

Globaal Cardiovasculair risicobeheer Aspirin for the Prevention of Cardiovascular Disease

Antiplatelet treatment Prevention of cardiovascular disease in clinical practice Risk estimation and the prevention of cardiovascular disease Management of diabetes European Guidelines on cardiovascular disease prevention in clinical practice Cardiovasculair Risicomanagement

Title

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(a) GUIDELINES

(b) RECENT EVIDENCE MEDLINE: Cardiovascular disease and prevention 185,504 citations

184,734 excluded based on predefined filter Practice Guideline, published in the last 10 years

Search for: - organisations - guideline societies - countries with guidelines - websites for guidelines (hand search) on cardiovascular disease prevention

MEDLINE: aspirin and primary prevention and cardiovascular disease: 1823 citations 768 excluded based on predefined filter Meta-Analysis, Randomized Controlled Trial, Review (as publication type) 1055 citations

770 citations

729 excluded based on predefined filter published in the last five years (date)

765 guidelines excluded because not addressing the use of aspirin in primary prevention 5 guidelines retrieved

7 guidelines retrieved

326 citations 318 excluded because not addressing the use of aspirin in primary prevention

12 guidelines included for comparison 8 citations

Figure 1. Flowcharts of the systematic searches for guidelines (a) and recent evidence (b).

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 JPAD,27 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, several large meta-analyses25,28,30,87 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.

Formulation of specific practice recommendations Finally, we attempted to transform the selected evidence from pivotal trials and meta-analyses in a proposal for a specific practice recommendation, to be subjected to a systematic review and grading with the GRADE system. If patients are free of cardiovascular disease (no history of events and no objective signs of organ damage), then administration of low-dose aspirin seems no longer recommended, neither in subjects without diabetes nor in patients with diabetes.

Discussion To our knowledge, this study is the first that compared national guidelines on the use of aspirin in primary prevention in the general population and in patients with diabetes. We also simultaneously compared the clinical content of the guideline recommendations with recent evidence. We found that various guidelines are not up-to-date and not in accordance with recent evidence. We found important differences in recommendations for the use of aspirin in primary prevention as well in the general population as specifically 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, and comorbidities such as diabetes and in grading system. Although aspirin is recommended in most current guidelines on primary prevention, often with a high strength of recommendation, recent meta-analyses and RCTs conclude that low-dose aspirin in primary prevention is of an uncertain net effect.1 A high number-needed-to-treat (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. The results of a follow-up of 6.0 years involving over 100,000 participants showed that aspirin treatment

20%

Risk

75 mg/day

Aspirin regimen

75 mg/day

10y

20%



Scotland SIGN

52

Patients with diabetes 50y or 50

UK JBS

Subjects without diabetes Age (years) 50

UK CKS-NICE

A. Europe

Not

1



recommended

Aspirin not justified



Europe ESC

Not recommended

35, 39



Aspirin not justified



The Netherlands NHG

Aspirin is usually recommended

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35

75–150 mg/ day

10y (only risk of mortality)

10%, 5% if risk factors are present



Belgium Domus Medica



USA AHA

Diabetes is a risk factor in the used cardiovascular risk models

60, 61, 62, 63

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75 mg/day

10y

10y

20%

1%

1y



WHO



Australia

(continued)

Diabetics have spe- Consider in all dia- Diabetics have cific 5-year risk betic patients specific tables 75–325 mg/daya 10-year risk tables

75–150 mg/ day

5y

15%



New Zealand

C. International

Matthys et al. 359

38

Othersa

(practice) Guidelines

55, 56

26, 27, 38

According to diabetes guidelines of Canada and Australia. bResearch support, comment, education and debate, overview.

41 34, 41, 43

42 25, 35, 50 Used references according to type of study in patients with diabetes Meta-analysis 25, 30, 32 25

a

64

55, 56, 58, 66, 67, 69, 72, 74, 75, 76, 77, 79, 83

26, 27, 34,38, 40, 41, 43, 44, 45, 46, 71, 78 RCT

13, 64, 80

57, 68, 73 (systematic) Review

1, 4, 25, 32, 33, 35, 70, 81, 82

USA US-PSTF UK CKS-NICE

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Table 2. Continued

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Scotland SIGN

Europe ESC

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Belgium Domus Medica

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USA AHA

Canada

New Zealand

Australia

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reduced total CVD events by 10% (number-needed-totreat 120), driven primarily by reduction in nonfatal myocardial infarction; but there was a 30% increased risk of nontrivial bleeding events (number-needed-toharm ¼ 73).29 According to more recent evidence, the number of major bleeding events is underestimated in the clinical trials compared to a real-world setting. De Berardis et al.88 found a 5-times higher incidence of major bleeding leading to hospitalization among aspirin users as well as among those not using aspirin. This study also shows that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes. These results can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in patients with diabetes. 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 focus on the careful analysis of subtle differences in consecutive meta-analyses31,87 which repeated a pooled analysis of similar collections of trials. The lack of effect of aspirin in diabetic patients may be real or may be due to underpowered trials, bad compliance, or wrong dosage regimens. Several large trials are ongoing with over 10,000 patients: ASCEND (A Study of Cardiovascular Events in Diabetes), ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes), and ASPREE (ASPirin in Reducing Events in the Elderly). Their results might add new information to this discussion. Although almost all guidelines on the primary prevention of CVD recommend adapting the intensity of preventive strategies in accordance with the total CVD risk of the individual, large differences exist in the models that are used to estimate total CVD risk. A majority of these models estimate the risk of developing a fatal or non-fatal CV event in the coming 5 or 10 years; but the definition of non-fatal events vary between models. In SCORE only fatal CVD events are considered. The risk factors included in the models vary also; most models are gender specific and include age, blood pressure, and total or LDL cholesterol. The use of HDL cholesterol, diabetes, family history, social class, and high-sensitivity C-reactive protein varies mostly on the basis of the availability of the information and on the incremental predictive value of the variables. The definition of high risk on the basis of the models may also be different between guidelines; in the most recent European guidelines on CVD prevention four

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Figure 2. Guidelines on aspirin in primary prevention: selective use of meta-analyses and recent RCTs in subjects without diabetes (a) and with diabetes (b). DM, Domus Medica; NZ, New Zealand.

categories of total CVD risk are considered in contrast to two groups in previous issues. Not all models of total CVD risk estimation have been externally validated. Several risk prediction models for cardiovascular disease are available and their head to head comparisons would benefit from standardized reporting and formal, consistent statistical comparisons.89 According to most existing guidelines, the use of aspirin in primary prevention of cardiovascular events is still recommended. However, there is little consensus on the practicalities. Guidelines advise 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 organizations. This might confuse the distinction between low and high risk. The Norwegian guideline (as does the US-PSTF guideline) gives three different thresholds in their risk prediction models for patients aged up to 49, 59, and 69 years. This shifts the emphasis of treatment from older to younger people and life years 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

362 The question arises whether, by using aspirin in primary prevention of CVD, important medicalization of the healthy population occurs. Before considering medication, 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, aspirin can be associated 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. The finding that various guidelines are not up-todate and not in accordance with recent evidence is a plea for more regular but careful updates of guidelines, especially when new evidence is available. In setting up guidelines one should consider to focus the guidelines by addressing a single clinical decision and by this also make them more accessible and more feasible to updating. We found that nine guidelines out of 12 still recommend low-dose aspirin in patients with diabetes. 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 maybe more appropriately, low versus high cardiovascular risk should be refined and harmonized.

Conclusion We found conflicting recommendations in various guidelines about the use of aspirin for the primary prevention of cardiovascular events, which reflect differences in selection of the evidence and in the timing of publication. 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. According to recent evidence, in general, the use of aspirin seems no longer

European Journal of Preventive Cardiology 21(3) justifiable in primary prevention in patients with or without diabetes. Acknowledgement We thank Prof Emeritus Marc De Meyere and Dr Jan Matthys (University of Ghent) for the concept of this study.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest None.

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