Effectiveness and patient safety of platelet aggregation inhibitors in the prevention of cardiovascular disease and ischemic stroke in older adults – a systematic review

As described in the publication of our methodology [19], we employed a step-wise approach that consisted of four searches, of which the consecutive one was only conducted when the prior one did not lead to recent and high quality results. Search 1 was targeted at SR and meta-analyses (MA) in the Cochrane Database of Systematic Reviews (OVID interface, 2005 onwards) and Database of Abstracts or Reviews of Effects (DARE, OVID interface, 1991 onwards). Search 2 was also directed at SR and MA, but extended to MEDLINE (OVID interface, 1946 onwards), EMBASE (OVID interface, 1974 onwards), Health Technology Assessment (HTA, OVID interface 2001 onwards), and International Pharmaceutical Abstracts (IPA, OVID interface 1970 onwards). Search 3a was performed to find single studies (randomized controlled trials (RCT) and observational studies (OS) from SR and MA not included in searches 1 and 2 due to not meeting our inclusion criteria but containing eligible studies. Search 3b looked for RCT and OS in MEDLINE, EMBASE, HTA and IPA.

For this SR, searches 1 and 2 were performed in December 8th, 2015. The search string (see additional file 1) was developed with the help of a PICOS (population, intervention, comparison, outcomes and study design) framework. In search 3a, we identified eligible randomised controlled trials and OS from SR and MA, which themselves were not eligible for inclusion in our review (mainly because they were not focussed at older people). In parallel to the study selection of searches 1 and 2, we prepared a list of references to be checked in search 3a. Search 3b was considered as not being necessary because the SR and MA retrieved covered all eligible studies (see results) and we did not expect to find any additional eligible studies. In addition to database searches, all the references of the included studies were checked to obtain a comprehensive list of studies. Study protocols were collected to consider future updates of the SR. We also obtained articles from other sources (e.g. hand search).

Two reviewers (AR, MM) independently screened titles and abstracts. When the abstracts seemed to meet the inclusion criteria, full texts were retrieved and assessed for inclusion. When needed, a third reviewer (ARG) was consulted to solve any disagreements. At the end of each search stage, the quality and completeness of the obtained studies were assessed and it was decided whether or not to proceed to the next stage of the search.

Articles were assessed for inclusion regarding the type of study, age of participants, type of intervention, and clinical relevance of the outcomes.

The following articles were excluded: editorials, opinion papers, case reports, case series, narrative reviews, letters, qualitative studies, and OS which do not provide information regarding our outcomes. Articles not focussing on patient relevant outcomes were also excluded.

Table 1 displays details of the inclusion and exclusion criteria.

Data extraction and quality appraisal were performed using piloted forms. One reviewer did data extraction and quality appraisal and a second reviewer checked the forms for completeness and accuracy. A third reviewer was used in cases of disagreement. Four reviewers (AR, CS, MM, MK) participated at this stage of the SR. Data extracted included the specific drugs and dosages, study methods, time to follow-up, characteristics of the participants, outcomes and results. The quality of the included studies was assessed using specifically validated assessment tools for each type of study design: for SR and MA the AMSTAR appraisal tool [20, 21] and for clinical trials the Cochrane Collaboration’s tool for assessing risk of bias [22]. For observational studies a selection of questions from the critical appraisal skills programme (CASP) was used [23, 24].

A document containing a summary of all included studies, emphasising the risks and benefits of PAI was developed. This document and the quality of the study provided the basis for the development of recommendations on the discontinuation of PAI in older adults with cerebrovascular disease, peripheral artery occlusive disease, and coronary disease. Recommendations were judged regarding strength and quality of the evidence using the Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology [25‐27]. The final recommendations were worded following a standardised scheme clarifying strength and quality. Four reviewers (ARG, AS, IK, MM) were involved in the development and approval of the recommendations.

Figure 1 displays the identification process of studies for inclusion in the SR in a PRISMA flow-chart. Searches 1, 2 and 3a were performed. The research team decided not to perform search 3b for the reasons described above.

There were 964 references identified in the electronic databases during search 1 and 2. After the exclusion of all duplicates, a total of 853 references remained. Through other sources 1532 additional records were identified leading to a total number of 2385 screened records.

Out of those, 403 were identified and selected for full text evaluation, which led to the exclusion of 368 studies. Only 35 articles published between 1987 and 2016 met all inclusion criteria. A list of excluded studies along with the reason for exclusion is available from the authors upon request. The most frequent reason for exclusion was not meeting our age group target.

Among the included studies, there were 22 SR and MA, 11 RCT, and 2 OS. An overview of the main characteristics and quality of the included studies is presented in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11. PAI were tested for the following indications: ASA in primary [28‐35] and secondary prevention of cardiovascular disease (CVD) [36], ASA in the primary and secondary prevention of stroke in patients with and without AF [30, 34, 37‐50]ADP-receptor inhibitors in secondary prevention of cardiovascular events [51, 52] and stroke/TIA [52‐54], and dipyridamol in secondary prevention of stroke [55, 56]. Regarding the demographics of the sample, the mean age of participants in the included studies ranges between 57 to 84.6 years. This wide range is due to ten [28, 29, 31, 33, 36, 51, 52, 56, 57] studies that were included because of a subgroup analysis of people aged above 65 years despite a mean age below the threshold. Polypharmacy was not assessed in any of our included studies. None of the included papers reported on the outcomes quality of life, hospitalisation and life expectancy. Information on the presence of comorbidities was reported by 26 of the included studies, mostly consisting of the presence of cardiovascular risk factors or cardiovascular diseases such as stroke and TIA. Coincident medications were declared in 7 of 40 included references. Frailty was only reported by one study [58] and cognitive status by none (see Tables 9, 10 and 11).

Three SR/MA [28‐30] and five RCT [31‐35] were included, which examined the primary prevention of CVD. Tha MA of Baigent et al. [28] detected an insignificant reduction in the occurrence of a composite endpoint of serious vascular events including myocardial infarction, stroke, or death from a vascular cause (including sudden death, pulmonary embolism, haemorrhage) in the subgroup of participants older than 65 years (RR 0.88; 95% CI: 0.77–1.01). Even in the complete study group, the benefit of ASA with an absolute risk reduction (ARR) of 0.06% per year for serious vascular events was very low (number needed to treat (NNT) = 1666 per year). Moreover, there was no difference in vascular or all cause mortality between the ASA group and the placebo group (0.19% vs. 0.19% per year; p = 0.7), whereas the risk of major gastrointestinal and extracranial bleeds increased under a treatment with ASA (0.10% vs. 0.07% per year, p ≤ 0.0001) (secondary endpoints and adverse effects not calculated for older subgroup).

The study of Kjeldsen et al. (2000) with 18,790 participants [31] revealed a significant relative risk reduction in the occurrence of myocardial infarction in the subgroup of participants ≥65 years (RR 0.62; 95% CI: 0.38–0.98; p = 0.04), but the relative risk of major cardiovascular events was not significantly reduced in the age group ≥65 years (RR 0.92; 95% CI: 0.74–1.15; p = 0.47).

The clinical trial of Ikeda et al. (2014) [35] including 14,464 adults with a mean age of 70 years analysed the impact of ASA on the risk of cardiovascular events in older Japanese patients with multiple atherosclerotic risk factors in comparison to placebo. The primary endpoint of this study was a composite of death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or haemorrhagic), and nonfatal myocardial infarction. Overall, no significant difference in the occurrence of the composite endpoint was observed between the two groups (hazard ratio (HR): 0.94; 95% CI: 0.77–1.15; p = 0.54). Moreover, in comparison to the placebo group, the treatment with ASA was associated with a significant increased risk of extracranial haemorrhage requiring transfusion or hospitalization (HR for ASA: 1.85 (95% CI: 1.22–2.81); p = 0.004), absolute risk increase 0.35, number needed to harm 286).

Concerning the risk of bleeding in the primary prevention with ASA in older people, the RCT of Silagy et al. [32] with the oldest participants in this subject area (participants n = 400, mean age of participants 73 years) identified more gastrointestinal bleeding events in the ASA group in comparison to the placebo group (3% vs. 0%) with a significant decrease in mean hemoglobin levels (0.33 g/dl vs. 0.11 g/dl; p < 0.05). He et al. (1998) [29] conducted in a MA a subgroup-analysis of participants above and below 64 years with regard to the risk of haemorrhagic stroke with ASA in comparison to placebo. In the subgroup of participants ≥64 years, the absolute risk difference between the ASA and placebo group was 34 per 10,000 persons (95% CI: 1–66).

The only benefit for ASA was suggested in the RCT of Ogawa et al. (2008) with 2539 participants [33], (which included only people with diabetes mellitus), where in the subgroup of people older than 65 years the benefit in reducing atherosclerotic events (including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease) was significant (HR 0.68; 95% CI: 0.46–0.99; p = 0.047).

The trial of Huyhn et al. (2001) with 135 participants [36], analysed the effectiveness of ASA, warfarin, and the combination therapy of ASA and warfarin in participants with prior bypass surgery for the secondary prevention of coronary events. The primary endpoint of this study was a composite of any-cause death, myocardial infarction, or unstable angina requiring a new hospitalization. Monotherapy with ASA as well as ASA plus warfarin were associated with the lowest event rate of the composite endpoint (14.6% warfarin, 11.5% ASA, 11.4% ASA warfarin, p = 0.76). For patients aged >65 years, an overall higher event rate was detected, but ASA monotherapy revealed the lowest event rate (41.7, 34.8% and 36.8 events respectively). HR were not reported in this publication.

Patients with AF: Six SR/MA [38‐40, 42, 44, 49] showed conflicting evidence regarding the benefit of ASA compared to placebo in the primary prevention of stroke and all cause mortality. While four of the SR demonstrated no benefit for ASA [38, 40, 44, 49] (OR for stroke 0.70 (95% CI:0.47–1.07) [49], 0.56 (95% CI:0.19–1.65) [38] and RR 0.81 (95% CI:0.65–1.01) [40] and 1.30 (95% CI:0.96–1.72) [44] respectively, and for mortality 0.75 (95% CI:0.54–1.04) [49], 0.87 (95% CI: 0.68–1.12) [38] and RR 0.86 (95% CI:0.69–1.07) [40] and 1.28 (95% CI:0.98–1.65) [44], respectively), two SR [39, 42] found a significant benefit for stroke, but not for mortality (RR of 0.64 (95% CI: 0.44–0.88) for stroke, no data for mortality [42], RR 0.78 (95% CI: 0.62–0.98) for stroke and 0.84 (95% CI:0.67–1.05) for mortality [39]).

In all included trials with ASA [38, 40, 42, 44, 49, 59] except for one MA [39], ASA increased the risk of bleeding, especially for gastrointestinal bleeding in comparison to placebo. In the SR of Coleman et al. (2012) [60], the risk of major gastrointestinal bleeding was three times greater under a treatment with ASA compared with placebo. However, these results did not reach statistical significance (odds ratio (OR) 3.23; 95% CI: 0.56–18.66). Connolly et al. (2013) [61] also showed an increased risk of a subdural haematoma under a treatment with ASA in comparison to placebo (OR 2.2; 95% CI: 0.6–7.8; p = 0.6), but this was not significant.

Eleven SR/MA [30, 37‐46], one RCT [47] and one OS [48] reported that ASA was less effective in preventing stroke in patients with AF than warfarin. The risk of nonfatal ischemic stroke and systemic embolism was significantly higher with a treatment with ASA compared to warfarin [30, 37, 39, 41, 43, 45, 47, 62]. Apart from the results of the MA of Dogliotti et al. [41], there was no significant difference in mortality between the two groups [38‐40, 44, 45, 47]. With the exception of six trials [30, 42, 45‐47, 57], bleeding events were significantly less frequent in all included studies [37‐41, 43, 44, 48, 60] when patients were treated with ASA compared to warfarin. Concerning the use of new oral anticoagulants (NOAC) in older people, ASA were associated with a higher risk of stroke or systemic embolism than NOACs in all included studies [41, 44, 46, 63]. The MA of Lin et al. (2015) [63] showed that in ≥75 years old people ASA was less beneficial concerning the prevention of stroke and systemic embolism compared to the dabigatran treated group (dabigatran 110 mg vs. ASA rate ratio: 1.31 (95% CI: 0.84–2.07). Concerning the risk of bleeding inconsistent results were detected. ASA was associated with a decreased risk of bleeding events in comparison to NOACs (apixaban vs. ASA: OR 0.88; 95% CI: 0.31–2.18 [41]; ASA vs. edoxaban: RR 2.41; 95% CI: 1.02–6.80) [44]. However, in the SR of Cameron et al. (2014) [46], ASA increased the risk of major bleeding events (ASA <100 mg/d vs. edoxaban 30 mg/d: OR 2.27; 95% CI: 1.26–4.1).

The clinical trial of Uchiyama et al. [50] with 14,464 participants (mean age 70 years) analysed the impact of ASA on the risk of stroke and intracranial haemorrhage in older Japanese patients without AF in comparison to placebo. Overall, no significant difference in the occurrence of the cumulative rate of fatal or nonfatal stroke was observed between the two groups (HR: 0.92; 95% CI: 0.74–1.16; p = 0.51). Five years after randomization, the cumulative rate of fatal or nonfatal stroke in the ASA group was 2.068% (95% CI: 1.75–2.44) as opposed to 2.29% (95% CI: 1.96–2.69) in the placebo group (HR 0.927; 95% CI: 0.741–1.160; p = 0.509). Moreover, in comparison to the placebo group, a non-significant reduction of the risk of ischemic stroke or transient ischemic attack was observed in the ASA group (HR 0.783; 95% CI: 0.606–1.012; p = 0.061). A treatment with ASA, was associated with a non-significant increase in risk of intracranial haemorrhage in comparison to the placebo group (HR 1.46; 95% CI: 0.956–2.237; p = 0.078).

In these patients, ASA in comparison to placebo showed a higher reduction in secondary than in primary prevention [39, 40]. The ARR of stroke was between 1.5% (NNT = 67) [39] and 0.8% per year (NNT= 125) [40] in the primary prevention trials, and 2.5% per year (NNT = 40) in the secondary prevention trials [39, 40]. In the EAFT trial with 1007 participants [34] no significant reduction in the risk of a recurrent stroke by ASA in comparison to placebo was observed (HR 0.86; 95% CI: 0.64–1.15), while the risk of bleeding non-significantly increased under the treatment with ASA (HR 1.3; 95% CI: 0.8–2.15). Warfarin was much more effective than ASA in the secondary prevention of stroke leading to a significant relative risk reduction of 40% in the occurrence of a recurrent stroke (HR 0.60; 95% CI: 0.41–0.87; p = 0.008) [34]. On the other hand, the risk of bleeding was 2.8 fold higher in the warfarin group than in the ASA group (HR 2.8; 95% CI: 1.7–4.8; p < 0.001) [34].

One study [58] including 505 patients with cerebral infarction, minor or major stroke and a mean age of 68 years analysed the secondary prevention of stroke with ASA in comparison to placebo. The primary endpoints of this study were the recurrence of stroke and death. The incidence of stroke recurrence was 6.3% in the ASA treated group and 6.4% in those randomised to placebo. The OR for stroke recurrence and death comparing ASA to placebo was 1.04 (95% CI: 0.68–1.58), reflecting no significant difference between both groups.

One RCT including 13,608 adults with a mean age of 61 years and a subgroup analysis with people older than 75 years, compared prasugrel and clopidogrel for the management of acute coronary syndromes with scheduled percutaneous coronary intervention [51]. The primary endpoint of this study was a composite of cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke. In all included patients, the composite primary endpoint (as mentioned above) was reached in 12.1% of patients randomised to clopidogrel and 9.9% of those randomised to prasugrel (HR 0.81; 95% CI: 0.73–0.90; p ≤ 0.001). Moreover, prasugrel was more effective in reducing the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; p ≤ 0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; p ≤ 0.001), and stent thrombosis (2.4% vs. 1.1%; p ≤ 0.001). Several subgroup-analyses were carried out. One subgroup-analysis of participants aged ≥75 years considered the composite endpoint of death from any cause, nonfatal myocardial infarction, nonfatal stroke, or non-CABG-related nonfatal major bleeding. It showed that in the subgroup of patients older than 75 years, there was no benefit of prasugrel in comparison to clopidogrel regarding this composite endpoint (HR 0.99; 95% CI: 0.81–1.21; p = 0.92). Another subgroup-analysis examined the combined endpoint of death from any cause, nonfatal myocardial infarction, and nonfatal stroke under a treatment with prasugrel or clopidogrel in three different age groups (<65 years, 65–74 years, and ≥75 years). In the age group of patients <65 the combined endpoint (as mentioned above) was reached in 8.1% in the prasugrel group compared to 10.6% in the clopidogrel group (risk reduction 25%, HR not reported). In the age group between 65 years and 74 years the occurrence of the combined endpoint was 10.7% in the prasugrel group and 12.3% in the clopidogrel group (risk reduction 14%, no HR reported). In the age group of participants ≥75 years, the risk reduction attributed to prasugrel in comparison to clopidogrel was the lowest of the considered three age groups (17.2% prasugrel group, 18.3% clopidogrel group, risk reduction of 6%, HR or OR not reported). The MA of Zhou et al. [52] with 7 trials including 48,248 participants, investigated the risks and benefits of a dual therapy with ASA and clopidogrel vs. monotherapy for the secondary prevention of cardiovascular and cerebrovascular events (see below). The population, included in this MA, were a mixed population. The participants had for example atrial fibrillation, multiple atherothrombotic risk factors, previous coronary artery bypass grafting/PCI or acute coronary syndromes without ST-segment elevation. The combination therapy was non-significantly more effective than the single drug therapy alone in reducing the rate of major cardiovascular events (9% RR reduction; 95% CI: 2–17) when all participants were included. The relative risk of MI was decreased by 14% (RRR 14%; 95% CI: 3–24). Overall, the ARR of major cardiovascular events due to the combination therapy was 1.06 with a NNT of 83. On the other hand, the combination therapy resulted in a significant 62% RR increase of major bleeding events (95% CI: 26–108) when compared to single drug therapy. For the subgroup analysis of participants older than 65 years, a comparison between the combination therapy and a monotherapy with ASA was performed. In the older participants (≥65 years), the reduction of major cardiovascular events was marginally significant (≥65 years RR: 0.90; 95% CI: 0.83–0.98), whereas the risk of major bleeding events under a treatment with ASA plus clopidogrel vs. ASA monotherapy was significantly higher (≥65 years: RR: 1.56; 95% CI: 1.29–1.89).

The MA of Zhou et al. [52] described above also investigated, the secondary prevention of cardiovascular events, and the secondary prevention of stroke. With regard to this outcome, the greatest reduction was detected in the occurrence of stroke (RR 16%; 95% CI: 1–28).

In the RCT of Diener et al. (2004) with 7599 participants [53] the benefit to risk ratio did not show the additional clinical value of adding ASA to clopidogrel in high-risk patients with transient ischaemic attack or ischaemic stroke. A subgroup analysis (n = 4537) by age (≥65 years) showed that the event rate for clopridogrel plus ASA was 17.4% and for clopidogrel plus placebo 17.7%.

The dual antiplatelet therapy (DAPT) with ASA and clopidogrel was associated with an increased risk of 30-day major stroke, spontaneous MI, all-cause mortality, and combined lethal and major bleeding in the DAPT group compared to monotherapy even in patients who underwent Transcatheter Aortic Valve Implantation (TAVI) (OR 1.88; 95% CI: 1.00–3.56). The biggest increase was detected in the occurrence of lethal and major bleeding events (OR 2.62; 95% CI: 1.29–5.33) [54].

The MA of Leonardi-Bee et al. [55] with 11,459 participants including a subgroup-analysis of participants older than 65 years identified a non-significant decrease in the reoccurrence of stroke under treatment with DP in comparison to placebo (OR 0.82; 95% CI: 0.68–1.00). In the subgroup of participants ≥65 years the reduction of stroke was non-significant (DP vs. placebo subgroup ≥65 years: OR 0.81; 95% CI: 0.65–1.02). The combination therapy of ASA + DP in comparison to an ASA monotherapy revealed a significant reduction of stroke [55, 56] (ASA + DP vs. ASA monotherapy: Age ≥ 65 years: OR 0.78; 95% CI: 0.63–0.97) [55]. There was no difference in mortality between the two treatment groups (ASA + DP vs. ASA: HR 1.01, 95% CI 0.87–1.17) [56].

Table 5 displays the results of quality appraisal of the SR and MA. One MA [52] fulfilled all requirements of the AMSTAR appraisal tool. Several quality deficits were detected when evaluating the other studies using the AMSTAR appraisal tool. In all included MA/SR an a priori design was provided. A duplicate study selection and data extraction were missing in the MA/SR of Baigent et al. [28], Lip et al. [45] and Cooper et al. [42]. In the SR/MA of Leonardi-Bee et al. [55], Taylor et al. [37], and Assiri et al. [44] this information was not available. A comprehensive literature search was not performed in the MA/SR of Connolly et al. [61] and He et al. [29]. Eleven MA [28, 29, 38, 40‐45, 56, 60] did not search for grey literature. Quality appraisal of the included studies was not performed in 10 MA/SR [28, 29, 39, 41‐43, 45, 46, 56, 61]. Possible conflicts of interest were not declared in four MA [39, 42, 60, 61]. All included SR/MA described the characteristics of the included studies. The likelihood of publication bias was presented in seven MA/SR [37, 43, 45, 52, 54, 60, 63].

Table 6 displays the results of quality appraisal of the RCTs. An appropriate random sequence generation was used in seven [31, 33‐35, 50, 53, 58] of 11 RCTs. In four RCTs [32, 36, 47, 51], the random sequence was unclear. Allocation concealment was fulfilled in six studies [33‐35, 50, 53, 58] and unclear in five studies [31, 32, 36, 47, 51]. Serious limitations were found in blinding of personnel and participants in five RCTs [33‐35, 47, 50], whereas Huynh et al. [36] and Britton et al. [58] performed appropriate blinding of personnel and participants. In four RCTs [31, 32, 51, 53] this remained unclear. The outcomes were unlikely to be influenced by a lack of blinding in five studies [33‐35, 50, 58]. The blinding of trials was appropriate in five studies [33‐35, 50, 58]. In the remaining studies the blinding outcome was unclear. In the study of Ogawa et al. [33], a high risk for selective reporting was detected due to a missing representation of adverse events in the subgroup analysis of adults ≥65 years of age. Inclusion and exclusion criteria for participants and the primary outcomes were clearly defined and stated in all studies. In two trials [31, 36] differences between the treatment groups after randomisation were identified. The loss to follow-up was less than 5% in six trials [31, 32, 36, 51, 53, 58] whereas the RCT of Ogawa et al. [33], the EAFT trial [34] and the clinical trial of Ikeda et al. [35] had a higher loss to follow-up. In the two other trials [47, 50] it remained unclear. Conflicts of interests were stated in all RCTs except in two trials [31, 34]. In the EAFT [34] trial a high risk for biased selection of participants was detected because all participants who were not eligible for a treatment with warfarin (e.g. due to previous bleeding events) were assigned to the ASA group.

Table 7 displays the results of quality appraisal of the OS. In the two included OS [48, 59] we could not identify important confounding factors due to a lack of information and an undersized database. The results could be influenced by a lack of blinding of personnel and participants in all included studies.

We developed three recommendations which are presented in Table 8. One recommendation was rated as strong with moderate quality of evidence. The two other recommendations were assessed as weak with low quality of evidence. Table 8 reports on the main articles, which constitute the evidence base for each recommendation, although all included studies were taken into account for the risk/benefit balance during the review process. The quality appraisal of each RCT included in the SR and MA provided the evidence base for the recommendations. All quality appraisals were considered in assessing the quality of the evidence of the recommendations and are available from the authors upon request. Based on the evaluated evidence we formulated three recommendations. The first recommendation deals with the use of ASA in the primary prevention of CVD and stroke in older people without diabetes. The strength of the recommendation is weak and the quality of the evidence was judged as low. Concerning the primary prevention of CVD and stroke in the elderly with ASA, no benefit could be shown in patients without AF compared to placebo. Moreover, the risk of haemorrhagic stroke [28, 29], major gastrointestinal [28, 32] and other extracranial non-fatal bleeds [28, 31, 35] were significantly increased. In contrast, for people with diabetes mellitus the trial of Ogawa et al. [33] showed that the greatest benefit of a treatment with ASA in comparison to placebo was detected in the subgroup of participants older than 65 years. Due to this effect, adults with diabetes mellitus were not included in our recommendation. However, a high risk for selective reporting was detected in this study due to a lack of reporting adverse events in the subgroup analysis of adults ≥65 years of age.

Overall, we reached similar conclusions to the Beers criteria for potentially inappropriate medications in older people, which recommend using ASA with caution in adults older than 80 years for primary prevention of CVD [64, 65].

The second recommendation was developed based on the evidence of MA of Zhou et al. [52] and the RCT of Diener et al. [53]. We recommend avoiding the combination of a dual therapy in the secondary prevention of TIA and stroke with clopidogrel and ASA and to consider monotherapy instead. The evidence shows that a dual therapy increases the risks of bleeding complications and is not beneficial in the secondary prevention of vascular events, especially in the subgroup of adults aged 65 years or older. Adults with another indication for dual therapy (see Table 8) must be excluded from this recommendation. Due to the high quality of the evidence base the strength of the recommendation was rated as strong whereas the quality of evidence was downgraded to moderate quality caused by the indirectness of results. This recommendation was similar to the recommendation of the STOPP/START criteria for potentially inappropriate prescribing in older people, which recommends to stop a dual therapy with ASA and clopidogrel for secondary prevention of stroke (expections are: the patient underwent coronary stenting in the previous 12 months or has a high grade symptomatic carotid arterial stenosis) [66].

The third recommendation is to discontinue the use of ASA for the primary prevention of stroke in older adults with AF (including adults older than 75 years), because current evidence points at an unfavourable risk/benefit ratio for ASA compared to placebo. None of the identified SR demonstrated a benefit regarding mortality, and only two older SR [39, 42] appear to show a benefit regarding stroke. The most recent and reliable SR including a comprehensive network meta-analysis does not show this benefit [44]. Instead, the use of a Vitamin K Antagonist should be considered. This recommendation is based on the evidence of eleven SR/MA [30, 37‐41, 46, 57, 63] and one clinical trial [47]. The recommendation was rated as weak and the quality of the evidence as low. The evidence showed a superiority of warfarin in the prevention of cerebrovascular diseases. In regard to the risk of bleeding, contrasting results were found. With the exception of three trials [46, 47, 57], bleeding events were significantly more frequent when compared to ASA. However, the trial [47] with the oldest participants suggested a benefit of warfarin over ASA in octogenarians. There were significantly more ischemic strokes and systemic embolism with ASA than with warfarin but there were significantly fewer adverse events (including bleeding) with warfarin than ASA, assuming a safe handling even in adults older than 80 years. The dose of ASA and the target-INR in the included studies were roughly comparable. A major limitation of this recommendation is that the dose of ASA of 300 mg per day (as it was used in several studies) was higher than the usual applied dose.

We were limited to providing three recommendations to stop treatments because of a lack of reliable studies in our age group. In relation to secondary prevention, the recommendations for the use of PAI are mainly based on studies of younger patients, and it is currently unknown whether these recommendations are transferable to older people. Nonetheless, taking current best evidence regarding younger patients into account, it does not seem justified to formulate a stop recommendation for older people.