Primary and Secondary Prevention of Cardiovascular DiseasePrevention of Cardiovascular Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines FREE TO VIEW

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommendations sections to indicate recommendations that are newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.1. For persons aged 50 years or older without symptomatic cardiovascular disease, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B).

Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profile if taken over 10 years. In people at moderate to high risk of cardiovascular events, the reduction in myocardial infarction (MI) is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time period for very small benefits will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin.

3.1.1-3.1.5. For patients with established coronary artery disease (CAD), defined as patients 1-year post-acute coronary syndrome (ACS), with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, (including patients after the first year post-ACS and/or with prior coronary artery bypass graft [CABG] surgery):

3.2.1-3.2.5. For patients in the first year after an ACS who have not undergone percutaneous coronary intervention (PCI):

For patients in the first year after an ACS who have undergone PCI with stent placement:

Remarks: Evidence suggests that prasugrel results in no benefit or net harm in patients with a body weight of < 60 kg, age > 75 years, or with a previous stroke/transient ischemic attack.

For patients with ACS who undergo PCI with stent placement, we refer to sections 4.3.1 to 4.3.5 for recommendations concerning minimum and prolonged duration of treatment.

3.2.6-3.2.7. For patients with anterior MI and left ventricular (LV) thrombus, or at high risk for LV thrombus (ejection fraction < 40%, anteroapical wall motion abnormality), who do not undergo stenting:

For patients with anterior MI and LV thrombus, or at high risk for LV thrombus (ejection fraction < 40%, anteroapical wall motion abnormality), who undergo bare-metal stent (BMS) placement:

For patients with anterior MI and LV thrombus, or at high risk for LV thrombus (ejection fraction < 40%, anteroapical wall motion abnormality) who undergo drug-eluting stent (DES) placement:

4.1.1-4.3.5. For patients who have undergone elective PCI with placement of BMS:

For patients who have undergone elective PCI with placement of DES:

Remarks: Absolute minimum duration will vary based on stent type (in general, 3 months for -limus stents and 6 months for -taxel stents).

For patients who have undergone elective BMS or DES stent placement:

For patients with CAD undergoing elective PCI but no stent placement:

5.1-5.3. For patients with systolic LV dysfunction without established CAD and no LV thrombus, we suggest not to use antiplatelet therapy or warfarin (Grade 2C).

Remarks: Patients who place a high value on an uncertain reduction in stroke and a low value on avoiding an increased risk of GI bleeding are likely to choose to use warfarin.

For patients with systolic LV dysfunction without established CAD with identified acute LV thrombus (eg, Takotsubo cardiomyopathy), we suggest moderate-intensity warfarin (INR 2.0-3.0) for at least 3 months (Grade 2C).

For patients with systolic LV dysfunction and established CAD, recommendations are as per the established CAD recommendations (see recommendations 3.1.1-3.1.5).

This article is devoted to long-term administration of antithrombotic drugs designed for primary and secondary prevention of cardiovascular disease. It does not address initial management of acute coronary syndromes (ACS) or periprocedural use of antithrombotic therapies.

We consider the desirable and undesirable consequences of antithrombotic treatment in the following populations and patient groups: (1) persons without established coronary artery disease (CAD); (2) patients with established CAD (established CAD is defined throughout as patients 1-year post ACS, with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing); including those post-ACS and post-coronary artery bypass graft (CABG) surgery; (3) patients with recent or remote percutaneous coronary intervention (PCI) with or without stents (bare-metal stents [BMS] or drug-eluting stents [DES]); and (4) patients with systolic left ventricular (LV) dysfunction (ischemic and nonischemic).

Table 1 describes the clinical questions (ie, population, intervention, comparator, and outcome) for each of the recommendations that follow. We define only patient characteristics relevant to our questions. For example, because whether ACS occurs with or without ST-segment elevation is not relevant to long-term secondary prevention, we provide a single set of recommendations for all patients following ACS. We have selected the same patient-important outcomes across all recommendations (eg, total mortality, nonfatal myocardial infarction [MI], nonfatal stroke, major extracranial bleed). We consider burden of treatment an important outcome for patients taking warfarin.

Stent thrombosis frequently is reported in trials evaluating antiplatelet agents in patients undergoing PCI with stent placement. We have not included stent thrombosis as an important outcome because stent thrombosis derives its patient importance from consequent MI and deaths. Additional reporting of stent thrombosis along with MI and deaths would result in double counting of events and a distorted balance of benefits and harms.

Nonfatal hemorrhagic strokes and ischemic strokes are included together as nonfatal strokes. Although the former is a complication and prevention of the latter is a beneficial effect of antithrombotic therapy, their impact on patient morbidity is similar.

In order to estimate absolute benefits and harms associated with a given therapy, we performed the several steps. We first generated relative effect estimates (relative risks) from the highest-quality published meta-analysis of randomized controlled trials (RCTs) comparing therapies for a specific indication. If no such meta-analyses were available, we conducted our own meta-analyses of relevant RCTs or used relative risk estimates from single RCTs in the absence of other relevant RCTs.

Ideally, in order to approximate the benefit of a given therapy in the real world, population-based observational studies would inform estimates of baseline risk. Unfortunately, for most of our clinical questions, we were unable to identify observational studies of sufficient quality that reported all relevant outcomes. In such cases, we estimated control group risk from the control arm of either a relevant meta-analysis or a relevant RCT and adjusted them to our specified time frame. Individual sections present detailed explanations of our choices.

There are limited data to guide us with respect to the relative impact of outcomes on patient quality of life (see MacLean et al¹ in this supplement). As described in the methodology article by Guyatt et al² in these guidelines, we have used ratings from guideline panelists striving to infer a patient’s valuation of the outcomes of interest. The ratings suggest that major extracranial bleeding (which is usually readily treated and with few long-lasting consequences) carries only slightly less weight than a nonfatal MI (which also often has minimal long-term consequences) but substantially less weight than a stroke (which is often associated with long-term disability). Our decisions are based on a disutility of stroke of three times the disutility, or negative weight, of a major extracranial bleed.

Trade-offs between desirable and undesirable consequences of alternative management strategies sometimes represent close-call situations. For example, in the comparison of clopidogrel and aspirin vs aspirin alone in established CAD, available evidence from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial cannot rule out a benefit of dual antiplatelet therapy over aspirin alone, with a nonsignificant trend for benefit in cardiovascular outcomes such as vascular mortality, MI, and stroke.³ There is, however, suggested harm in terms of increased major bleeding events, with imprecise estimates of borderline statistical significance. In making recommendations in such situations, we have taken a primum non nocere approach, placing the burden of proof with those who would claim a benefit of treatment. In other words, when there is uncertain benefit and an appreciable probability of important harm (such as the aforementioned situation), we recommend against such treatments.

We identified the relevant evidence for our clinical questions with the assistance of a team of methodologists and medical librarians as outlined in the methodology article in this supplement.² Systematic literature searches for systematic reviews and original studies were performed until the date of January 15, 2010. After that date, we scanned the literature regularly, although this was not performed as systematic literature searches.

In this section, we address the effects of aspirin in primary prevention of cardiovascular disease. In addition, we consider recent meta-analyses demonstrating a reduction in cancer mortality and total mortality with long-term use of aspirin.^4‐6 We do not include other antiplatelet therapies (eg, clopidogrel alone or in combination with aspirin) or oral anticoagulation (eg, warfarin) because they are not likely used in primary prevention. Whether aspirin should be prescribed in patients already receiving warfarin for atrial fibrillation (or other conditions) to enhance primary and secondary prevention of cardiovascular disease remains controversial. This topic is addressed in You et al.⁷

Users of this guideline require a tool to estimate risk of a cardiovascular event in the individual patient. Figure 1 shows the Framingham risk score that predicts the 10-year risk of developing a cardiovascular event (composite end point of MI and coronary death) as low (< 10%), moderate (10%-20%), and high (> 20%) risk.⁸

We present absolute risk estimates for people at low, moderate, and high cardiovascular risk in a 10-year time frame based on the widely used Framingham risk score (Table 2). In order to derive our baseline control group risk estimates, we assumed patients with low, moderate, and high risk to have a 5%, 15%, and 25% risk of experiencing combined nonfatal and fatal MI, respectively.

We believe that it is important to provide estimates separately for outcomes that patients value differently, as is the case for nonfatal MI, fatal MI, and stroke. The Framingham risk score does not allow separate calculation of nonfatal and fatal MI, and it does not include stroke or major extracranial bleeding. Therefore, to estimate the probability of each of these critical outcomes, we used the observed ratio of nonfatal MI to fatal MI to nonfatal stroke to major extracranial bleeding events in an individual participant data meta-analysis assessing benefits and harms of aspirin in primary prevention of cardiovascular disease.⁹ For example, a patient with a 5% (low) risk of fatal and nonfatal MI over 10 years based on the Framingham score would have a 3.3% risk of nonfatal MI, a 1.7% risk of a fatal MI, a 2.6% risk of nonfatal stroke, and a 1% risk of a major nonfatal extracranial bleed. Similar calculations were made to derive control group risk estimates for moderate- and high-risk strata.⁹

We made one additional modification to estimates from the Framingham risk score. The Framingham risk score overestimates 10-year coronary heart disease risk by 32% in men and 10% in women and is of little value in people aged > 85 years.^10,11 We have adjusted our control group risk estimates accordingly, assuming 20% overestimation across sexes. For example, whereas Framingham estimates that 33 of 1,000 people at low cardiovascular risk will have a nonfatal MI without aspirin, our best estimate is that 27 of 1,000 people will have a nonfatal MI. Similar adjustments have been performed for vascular and bleeding outcomes because the Framingham risk estimate for nonfatal MI serves as the basis for the other risk estimates through our use of ratios from the individual participant data meta-analysis described later in this article.⁹

Table 2 (Table S1) summarizes results from an individual participant data meta-analysis that provides the best evidence regarding the benefits and harms of aspirin in primary prevention of cardiovascular disease.⁹ The meta-analysis includes 95,000 individuals (660,000 person-years, 3,554 vascular events) from six large trials (British Doctor Study, US Physicians’ Health Study, Thrombosis Prevention Trial, Hypertension Optimal Treatment Trial, Primary Prevention Project, and Women’s Health Study) that compared long-term aspirin use vs control.^12‐17 Doses of aspirin varied between 75 mg and 300 mg without an apparent difference in benefit or harm. For total mortality, we used the relative-effect estimate derived from a high-quality systematic review and meta-analysis that included the most recent trials omitted from the individual participant data meta-analysis.⁴

Based on these analyses, aspirin use in patients at low risk would be associated with six fewer MIs and four more major bleeding events per 1,000 treated, with little or no effect on nonfatal stroke over a 10-year period (Table 2, Table S1). Aspirin would be associated with six fewer total deaths, but the 95% CI includes zero fewer deaths. For moderate- to high-risk patients, aspirin again would reduce nonfatal MI (19 fewer/1,000 treated and 31 fewer/1,000 treated, respectively) and increase major bleeding (16 more/1,000 treated and 22 more/1,000 treated, respectively), with a similar impact on total mortality (six fewer total deaths) as in the low-risk group. Our baseline risk estimate of 10-year mortality is derived from population-based data in Norway (www.ssb.no) and applies to a 60-year-old man. The overall quality of evidence is rated as moderate given the imprecision in the relative effect estimates for total mortality.

Patients averse to taking therapy for an extended duration for the potential of a very small decrease in total mortality may be disinclined to use long-term aspirin therapy for primary cardiovascular prevention. Patients (and physicians) may be interested in the effects on cause-specific mortality when considering aspirin prophylaxis. The individual participant data meta-analysis by Baigent et al⁹ reported a relative risk estimate for vascular mortality of 0.97 (95% CI, 0.87-1.09) associated with aspirin over a 10-year period. In another individual patient data meta-analysis, aspirin was associated with a reduction in cancer mortality (risk ratio [RR], 0.66; 95% CI, 0.50-0.87), which translated to ∼20 fewer cancer deaths (30 fewer to eight fewer) per 1,000 treated for 10 years.⁵ The impressive relative and anticipated absolute effect of aspirin therapy on cancer mortality contrast with the more-modest relative and absolute effect of aspirin on total mortality (three fewer deaths per 1,000). The difference in absolute effect is likely partly explained by the high 10-year risk of cancer mortality derived from the trials included in the individual participant data meta-analysis (60 per 1,000) compared with the low 10-year risk of total mortality derived from population-based data in a 50-year-old man (10 per 1,000). Apparently, patients enrolled in trials of aspirin aimed at reducing vascular risk were a population at high risk for cancer deaths.

We do not make specific recommendations for the use of aspirin based on patient characteristics, such as older age, sex, and diabetes mellitus. Other guidelines that do modify recommendations according to the presence or absence of such characteristics largely ignore any differences in bleeding risks and base their recommendations on evidence from what we believe are subgroup analyses of questionable validity.^18‐22 Sophisticated risk calculators used in decision aids for specific populations may enhance individual decision-making, and when well done, we encourage their use.

Concerning diabetes, we (in contrast to some others) interpret current evidence as suggesting that the relative benefit of aspirin is similar in patients with and without diabetes. In two systematic reviews that include recent trials of patients with diabetes, CIs for the diabetes subgroup overlap with our estimates of relative effects from the combined population.^23,24 Furthermore, analyses from the individual participant data meta-analysis provide no support for a difference in relative effect of aspirin in those with or without diabetes.⁹

Recommendation

2.1. For persons aged 50 years or older without symptomatic cardiovascular disease, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B).

Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profile if taken over 10 years. In people at moderate to high risk of cardiovascular events, the reduction in MI is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time period for very small benefits will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin.

The evidence supporting the use of specific antithrombotic therapies sometimes differs between patients who have recently experienced an ACS and those with stable CAD. For purposes of these guidelines, and based on available data, recommendations for therapy following ACS will apply to the postdischarge period and extend to 1 year. Thereafter, patients will be considered to have established CAD. This definition is by necessity somewhat arbitrary, and we acknowledge that the higher-risk period following ACS may end before 1 year.

Most studies evaluating antithrombotic therapy immediately following CABG surgery have focused on a surrogate outcome, bypass graft patency, as the primary outcome. However, in making our recommendations, we focus exclusively on the relevant patient-important outcomes: nonfatal MI, nonfatal stroke, major extracranial bleeding, and death. Although substudies of large RCTs of antiplatelet therapy in patients with either CAD or recent ACS have examined clinical end points in patients with a history of remote CABG, these analyses do not suggest any significant differences in the associated relative benefit or harm compared with the overall study population.^3,25‐27 In addition, loss of bypass graft patency derives its patient importance from consequent MI and deaths. Additional reporting of graft patency along with MI and death would result in double counting of events and a distorted balance of benefits and harms.

Accordingly, our recommendations for antithrombotic therapy in patients following elective CABG or CABG following ACS mirror those for patients with chronic CAD or recent ACS, respectively. For recommendations regarding continuation and discontinuation of antithrombotic therapy and timing of reinitiation relative to CABG, see Douketis et al²⁸ in this supplement.

Control group risk estimates for nonfatal MI and stroke in patients not taking aspirin and in patients taking aspirin come from a meta-analysis of 16 RCTs adjusted to a 5-year time frame.⁹ Because this meta-analysis does not provide data on total mortality or nonfatal major extracranial bleeds, we derived baseline risk estimates from the aspirin arm in the CHARISMA trial (total mortality) and Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (major extracranial bleeds).^3,29 To estimate control group risks for total mortality and major bleeds in patients not taking aspirin, we used estimates from the aspirin arm in these trials as the starting point and then applied the relative risks for total mortality and major bleeds to get to the control group risk estimate without aspirin.^3,29 We used data regarding relative effects from the clopidogrel arm of the CAPRIE study, applied to baseline risks as previously mentioned, to generate control group risk estimates of vascular events and bleeding in patients taking clopidogrel alone.²⁹

Table 3 (Table S2) summarizes the quality of evidence and main findings from a meta-analysis of individual participant data from 16 randomized trials with 17,000 patients with established vascular disease (six trials of previous MI and 10 trials of previous transient ischemic attack [TIA] or stroke).⁹ In this population at high risk for a serious vascular event (8.2% yearly risk), aspirin significantly reduced total mortality, nonfatal MI, and nonfatal stroke at the cost of increased nonfatal extracranial bleeding events. The number of vascular events and total deaths prevented is far greater than the number of bleeding events that result from aspirin.

The beneficial effects of aspirin are likely to also apply to patients with stable angina pectoris without prior MI. A well-performed systematic review and meta-analysis of antiplatelet therapy for prevention of vascular events in high-risk patients found that antiplatelet agents exerted similar effects on vascular events in patients with a history of MI (12 trials) and in patients with a history of stable angina and CAD (seven trials).³⁰

The CAPRIE trial is the only randomized trial directly comparing clopidogrel and aspirin in the secondary prevention of cardiovascular events, and we consider this trial to be the most credible source of evidence.²⁹ More than 19,000 patients with atherosclerotic vascular disease manifested as a recent stroke, recent MI, or symptomatic peripheral arterial disease received clopidogrel or aspirin. After a mean follow-up of 1.9 years, clopidogrel was associated with a possible reduction in nonfatal MI and nonfatal extracranial bleeding and little or no effect on total mortality. Table 4 (Table S3) summarizes the quality of evidence and main findings of the CAPRIE trial with anticipated absolute effects in a 5-year time frame for patients with established CAD. The results indicate no effect of clopidogrel on total mortality compared with aspirin. These results are consistent with a meta-analysis of 10 studies examining the effects of thienopyridine derivatives (eg, clopidogrel, ticlopidine) vs aspirin in patients at high vascular risk.³¹

Four studies that met criteria for review examined the cost-effectiveness of clopidogrel vs aspirin for secondary prevention of cardiovascular disease (Table S4). These studies considered multiple patient populations. Three studies^32‐34 were based on the CAPRIE trial²⁹ (patients with ischemic stroke in the prior 6 months, MI in the prior 35 days, or peripheral arterial disease). The fourth study was based on patients with prior TIA or nondisabling ischemic stroke.³⁵ The latter study was included because patients with prior TIA or stroke are at higher risk for coronary heart disease. Coronary heart disease was considered as an outcome in all these studies. All these studies demonstrated that clopidogrel was cost-effective compared with aspirin, with incremental cost-effectiveness ratios similar after adjustment for the cost year. These results are limited in that they neglect any possible incremental benefit of aspirin over clopidogrel after > 5 years of use on cancer incidence (see section 2.1).

A Cochrane systematic review evaluated short- and long-term dual antiplatelet therapy in patients with established CAD.³⁶ Only one large-scale RCT, the CHARISMA trial, has evaluated the long-term efficacy of clopidogrel and aspirin vs aspirin alone.³ This trial followed 15,603 patients with established vascular disease or multiple risk factors for a mean period of 28 months. Table 5 (Table S5) summarizes the quality of the evidence and findings from this trial. Results of the study failed to demonstrate or exclude an effect of dual antiplatelet therapy relative to aspirin on total mortality or nonfatal MI. Dual antiplatelet therapy was associated with a possible reduction in nonfatal stroke and a possible increase in nonfatal extracranial bleeding. The quality of evidence is rated moderate because of imprecise effect estimates for all outcomes. Although this study included patients with other vascular diseases, we considered its findings directly applicable to patients with established CAD. We did not deem subgroup analyses suggesting different effects of dual antiplatelet therapy in symptomatic vs asymptomatic patients to be credible based on criteria by Sun et al.³⁷

There are no studies comparing aspirin and clopidogrel to clopidogrel for secondary prevention in patients with CAD. The Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent TIA or Ischemic Stroke (MATCH) study evaluated the efficacy and safety of clopidogrel plus aspirin compared with clopidogrel alone for 18 months in 7,599 patients with recent stroke or TIA and one other risk factor.³⁸ Dual antiplatelet therapy was associated with a possible reduction in nonfatal stroke and a significant increase in major extracranial bleeding. Results failed to demonstrate or exclude an effect of dual antiplatelet therapy on vascular mortality or nonfatal MI (Table S6). We rated the overall quality of evidence from this trial as moderate given imprecision of point estimates for outcomes of MI, stroke, and total mortality. We did not rate down for indirectness because we considered the relative effects generated from this trial of patients with cerebrovascular disease to be directly applicable to patients with established CAD.

Prior studies evaluating low-dose warfarin (international normalized ratio [INR] < 2.0) plus aspirin have not shown it to be more effective than aspirin alone in patients with CAD.^39‐41 High-intensity warfarin (INR 2.8-4.2) without aspirin has proven to be more effective than aspirin alone in two prior randomized controlled clinical trials but was associated with increased bleeding risk.^42,43 As a result, low-intensity warfarin plus aspirin or high-intensity warfarin are seldom used and will not be discussed further.

Rothberg et al⁴⁴ performed a systematic review and meta-analysis of 10 randomized trials involving 5,938 patients with recent ACS who were randomized to moderate-to-high-intensity warfarin plus low-dose aspirin vs aspirin alone. We have performed our own meta-analysis of these studies (Table S7). In brief, the meta-analysis provides evidence of a substantial reduction in MI and nonfatal stroke with moderate-intensity warfarin plus aspirin at the costs of increased major extracranial bleeds.

These studies were completed in the pre-stent era, the majority started therapy immediately after ACS and had < 1-year follow-up, and we identified heterogeneity for the prevention of vascular events among patients with CAD, peripheral arterial disease, and nonembolic stroke. It is difficult to apply this evidence to patients with chronic CAD or ACS in the current era; therefore, we do not make recommendations for warfarin in these patient populations.

The best evidence of the effects of different aspirin doses on vascular and bleeding events comes from subgroup analyses in the Antithrombotic Trialists’ Collaboration³⁰ meta-analysis of antiplatelet therapy, which included direct and indirect comparisons of different daily doses of aspirin (500-1,500 mg vs 160-325 mg vs 75-150 mg vs < 75 mg) on vascular events. In the direct comparisons of high- vs low-dose aspirin, there were no significant differences (ie, lower doses of aspirin were just as effective as higher doses). However, the small number of studies with aspirin < 75 mg left uncertainty about whether such low doses are as effective as daily doses of ≥ 75 mg. The indirect comparisons of higher daily doses of aspirin vs no aspirin provide no evidence to support that high doses of aspirin (eg, > 160 mg/d) are more effective than 75 to 160 mg. A subsequent systematic review of aspirin doses for the prevention of cardiovascular events in 2007 identified eight prospective trials that included nearly 10,000 patients taking aspirin 30 to 1,300 mg/d.⁴⁵ A significant benefit of higher doses of aspirin was not identified in any of these studies, and in most, the lowest event rates were seen among patients randomized to the lower-dose group.

With respect to bleeding, a number of studies have suggested a potential relationship between increased aspirin doses and bleeding. A systematic review assessing bleeding rates associated with different doses of aspirin included > 190,000 patients enrolled in 31 RCTs.⁴⁶ Aspirin > 200 mg was associated with an ∼30% increase in major bleeding compared with doses < 200 mg (P = .05). There was an increase in nonmajor bleeding in patients receiving 100 to 200 mg of aspirin per day compared with patients taking < 100 mg/d. The Antiplatelet Trialists’ Collaboration³⁰ found no difference in the proportional increase in the risk of a major extracranial bleed between differing aspirin doses (< 75, 75-150, and 160-325 mg) compared with placebo but did not comment on doses > 325 mg. Taken together, the findings provide moderate-quality evidence (rated down for risk of bias because of indirect comparisons of different aspirin doses) to support the use of aspirin 75 to 100 mg/d for patients with established CAD.

Recommendations

3.1.1-3.1.5. For patients with established CAD (including patients after the first year post-ACS and/or with prior CABG surgery):

For the purposes of these guidelines, we include patients with ST-segment elevation MI, non-ST-segment elevation MI, and unstable angina in the ACS population. This reflects our judgment that the relative efficacy and safety of specific therapies in the year following presentation does not differ substantially between these diagnostic entities. In addition, many studies evaluating antithrombotic therapy following ACS have included patients undergoing early PCI, stent placement, or both. Therefore, we use evidence from the total study cohorts, and for the most part, our recommendations apply to patients with ACS regardless of whether they undergo PCI. One exception is prasugrel, which has been studied primarily in patients with ACS with planned PCI; recommendations for this agent are restricted to this specific population. Recommendations for patients undergoing elective PCI/stenting (without ACS) are presented in a subsequent section.

There have been numerous studies of antithrombotic therapy following ACS. Depending on study population, date, and use of concomitant interventions, baseline risks vary widely. Ideally, we would identify a single population receiving different antithrombotic strategies in order to derive baseline risks. Because this is not possible, we use control group risks from Clopidogrel in Unstable Angina To Prevent Recurrent Events (CURE) for comparisons where aspirin constitutes the control group (as it did in CURE) and the Platelet Inhibition and Patient Outcomes (PLATO) study for comparisons where aspirin and clopidogrel constitute the control group.^47,48 We selected CURE and PLATO because they were designed as large, simple trials; use accepted definitions for both vascular and bleeding events; and include a large proportion of patients who underwent cardiac catheterization/PCI, which reflects current practice in high-income countries.

Table 3 summarizes the evidence from a meta-analysis with individual participant data from 16 RCTs with 17,000 patients with established vascular disease treated with aspirin vs placebo (including six trials of patients with previous MI).⁹ We deem this meta-analysis directly applicable to patients with recent ACS.

We again base our recommendation on evidence from the CAPRIE study, a randomized comparison of clopidogrel vs aspirin in the secondary prevention of cardiovascular events.²⁹Table 6 (Table S8) summarizes the evidence from the CAPRIE trial as it applies to an ACS population.

During the past decade, the use of clopidogrel in addition to aspirin during the first 9 to 12 months after an ACS has become standard clinical practice. As recognized in a Cochrane systematic review,³⁶ the CURE trial is the only study that has addressed the effects of clopidogrel in addition to aspirin in patients with ACS without ST-segment elevation.⁴⁷Table 7 (Table S9) presents the quality of the evidence and main findings of this trial that randomized 12,562 patients with a recent ACS to clopidogrel and aspirin or aspirin alone for 3 to 12 months, included 2,658 patients who underwent PCI following ACS, and provided moderate-quality evidence that dual antiplatelet therapy reduces MI and increases major bleeding events. Results failed to demonstrate or exclude an effect of dual antiplatelet therapy vs aspirin alone on vascular mortality or nonfatal stroke.

Six studies^33,49‐53 examined the cost-effectiveness of combined antiplatelet therapy with clopidogrel plus aspirin vs aspirin alone in patients after a recent ACS. These studies are consistent in demonstrating the cost-effectiveness of combined antiplatelet therapy with clopidogrel plus aspirin compared with aspirin alone after ACS. Schleinitz et al⁵³ examined the effect of varying treatment duration and found that longer treatment duration was increasingly expensive, with incremental cost-effectiveness ratios (in 2010 US dollars) of $38,252/quality-adjusted life year (QALY) for 2 years, $74,204/QALY for 3 years, and $883,665/QALY for 5 years of treatment. Not only does cost-effectiveness decrease after 1 year but also the estimates represent extrapolation from the available data (patients were followed for only 1 year). Furthermore, evidence from a comparison of aspirin and clopidogrel vs aspirin raise serious questions about the extrapolation.³ Overall, the benefits of combined antiplatelet therapy with clopidogrel plus aspirin come at acceptable cost for the first year after ACS.

Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has more-rapid onset and more-pronounced platelet inhibition than clopidogrel.^54,55Table 8 (Table S10) summarizes the quality of evidence and key findings from the PLATO trial that evaluated the effects of ticagrelor vs clopidogrel in patients with a recent ACS.⁵⁶ In this study, 18,624 patients were randomized to receive, in addition to aspirin 75 mg/d, ticagrelor (180-mg loading dose, 90 mg bid thereafter) or clopidogrel (300-to 600-mg loading dose, 75 mg thereafter) for 6 to 12 months. At 12-month follow-up, ticagrelor significantly reduced vascular mortality and MI. Results failed to demonstrate or exclude an effect on nonfatal stroke. The rate of death from any cause was also reduced with ticagrelor (4.5% vs 5.9% with clopidogrel, P < .001). However, ticagrelor was associated with a higher rate of major bleeding not related to CABG (2.8% vs 2.2%, P = .03). The quality of evidence from this study was deemed moderate because of imprecision in nonfatal stroke and major extracranial bleeding.

A separate publication reports results from the subset of patients who underwent PCI.⁴⁸ PCI was performed during the index hospitalization in 61% of patients, of whom 60% received intracoronary stents. The effects of ticagrelor compared with clopidogrel on vascular mortality, MI, stroke, and major bleeds appear to be similar in this subset of patients compared with the overall population.

Although the original study design was not intended to stratify observed outcomes by geographical region, patients enrolled in North America reportedly had a higher incidence of adverse cardiovascular outcomes (whereas net benefit was observed in other areas), which initially delayed US approval of ticagrelor pending further data review. After further post hoc analysis, the only baseline covariate identified as possibly contributing to geographic variation was use of higher doses of aspirin in the United States. To date, these data have not been published. The US Food and Drug Administration approved ticagrelor for patients with ACS in July 2010 but recommend against this agent in patients taking > 100 mg of aspirin per day.

Prasugrel is a novel thienopyridine that achieves more-rapid and more-consistent platelet inhibition than standard-dose clopidogrel. Table 9 (Table S11) summarizes the quality of evidence and key findings from the TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction) 38, the only published randomized trial to evaluate prasugrel vs clopidogrel in patients with recent ACS who undergo PCI.⁵⁷ In this trial, 13,608 patients with moderate- to high-risk ACS and a scheduled PCI were randomized to receive, in addition to aspirin 75 mg/d, prasugrel (60-mg loading dose followed by 10 mg/d) or clopidogrel (300-mg loading dose followed by 75 mg/d) for 6 to 15 months. Ninety-nine percent of patients had PCI at the time of randomization, and 94% received intracoronary stents. Prasugrel significantly reduced MI but increased major bleeding, including life-threatening and fatal bleeds. Prasugrel was associated with a possible reduction in vascular mortality. Results failed to demonstrate or exclude an effect on nonfatal stroke. The quality of evidence is rated down because of imprecision in vascular mortality, nonfatal stroke, and major extracranial bleeding.

Post hoc exploratory subgroup analyses spurred by these observations suggested that patients with a history of stroke or TIA before enrollment had net harm from prasugrel treatment, whereas elderly (aged > 75 years) patients and patients with a body weight < 60 kg had no net benefit from prasugrel (composite outcome of all-cause mortality, MI, stroke, and non-CABG-related TIMI major bleeding) (tests for interaction P = .06 for both). We judged the claimed subgroup effects to be of moderate credibility. The Food and Drug Administration labeling includes a boxed warning that the drug should not be used in patients with a history of TIA or stroke or urgent need for surgery, including CABG. The manufacturer recommends a decreased maintenance dose of 5 mg/d for patients weighing < 60 kg, although this particular recommendation is ba