Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome: Still Sacrosanct or Is Reappraisal Warranted?

Alan P. Jacobsen, MB, BCh, BAO; Inbar Raber, MD; Cian P. McCarthy, MB, BCh, BAO; Roger S. Blumenthal, MD; Deepak L. Bhatt, MD, MPH; Ronan W. Cusack, BM, BS, BSc; Patrick W.J.C. Serruys, MD, PhD; William Wijns, MD, PhD; John W. McEvoy, MB, BCh, BAO, MHS

Disclosures

Circulation. 2020;142(16):1579-1590. 

In This Article

Discussion

Although the role of aspirin in the early treatment of ACS is well-established,[24] emerging evidence raises the possibility that contemporary patients with CCS might not obtain similar cardiovascular protection from aspirin as had heretofore been assumed based on historical data. In particular, whether the historical benefit seen for aspirin in ATT can be assumed to hold true in modern patients with CCS receiving contemporary ischemia prevention therapies remains unclear. Recent trials of aspirin in primary prevention suggest that such a broad assumption may be unjustified.[5]

Only 2 of the historical studies of aspirin for patients with CCS reported β-blocker or lipid-lowering medication use (with <20% of participants using either medication in those trials) and none of these historical trials used low-dose aspirin when defined as <150 mg/d (the mean daily dose of aspirin in the 6 trials was 941 mg). Although current guidelines for secondary prevention of CCS recommend lifelong antiplatelet therapy with aspirin,[19] the longest follow-up from these trials is 4 years and the mean duration of follow-up among the 6 trials was just 24.5 months. Thus, the efficacy of aspirin for lifelong secondary prevention of CCS in the contemporary era is not well-supported by these historic trials.

The possibility that historical evidence favoring aspirin use among patients with CCS is now outdated affords the opportunity to consider recent and related clinical trial evidence from a different perspective (Figure). A number of contemporary studies have enrolled patients with CCS into trial arms that did not include aspirin. Because all of these studies tested alternative antithrombotic therapies, the rationale for having no aspirin arms in these trials was to decrease bleeding.

Figure.

Lifelong aspirin for all in the secondary prevention of chronic coronary syndrome (CCS).
A house that is still standing but that is built on an unstable foundation of outdated trials and now threatened by a number of contemporary wrecking balls. DAPT indicates dual antiplatelet therapy; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; and RF, risk factors.

The emerging theme from these recent trials is that aspirin discontinuation has demonstrated no compelling evidence for excess ischemic risk in the selected subgroups of patients with CCS studied, as long as alternative antithrombotics are administered. However, replacing aspirin with an alternative, more expensive antithrombotic has economic implications that require further testing and is a strategy that may not be feasible in many countries around the world, largely owing to financial and insurance barriers. None of these recent trials can be directly extrapolated to a scenario where aspirin is discontinued in a patient with CCS not taking another antithrombotic agent. Nonetheless, they add to the argument that aspirin may no longer be as effective for preventing ischemic events in modern patients with CCS treated to contemporary risk factor goals (specifically, if aspirin was effective in reducing ischemia, one would expect to see a consistent signal for lower ischemic risk in the aspirin plus second antithrombotic arm of these trials).

An important caveat is that, whereas the results of the above studies encourage further research into the discontinuation of aspirin in stable CCS, the removal of aspirin in patients with CCS not taking a second antithrombotic may naturally be associated with risk. A 2006 analysis reported a 3-fold increase in cardiovascular events in patients who reported discontinuation or nonadherence to aspirin.[54] Similarly, a 2017 Swedish cohort study reported a >30% increase in cardiovascular events in long-term aspirin users who discontinued the medication.[55] However, both of these studies were observational in nature and nonadherence is subject to strong confounders favoring poor outcomes.

Despite the ischemic risk that may be inherent to any trial evaluating aspirin discontinuation among participants with CCS not on other antithrombotic therapies (even if the trial included only persons achieving optimal risk factor targets on contemporary preventive therapies), there are also potential benefits to aspirin discontinuation that make such trials worth considering. This would apply in particular to older patients with CCS who have been stable for many years and who are particularly prone to the adverse bleeding outcomes inherent to aspirin use. Therefore, it could be argued that a randomized trial of aspirin discontinuation in older stabilized patients with CCS not on a second antithrombotic who are well treated to contemporary risk factor targets is a natural next step in the evolution of recent trial evidence.[5,6] Because aspirin is generic, such trials of aspirin discontinuation are unlikely to be directly funded by the pharmaceutical industry; however, they could be funded by government research investment or, alternatively, aspirin discontinuation could be introduced as a factorial randomization into pharmaceutical trials testing other novel CCS therapies.

Similarly, contemporary data indicate that the efficacy of aspirin for secondary prevention is only evident early (within the first month) after the index event[56,57] and because recent trials of patients who have received an initial 3 months of DAPT after PCI have shown that it is safe to stop aspirin and to continue instead with a single P2Y12 inhibitor for the first year or more after the PCI,[58] uncertainties exist about how to best treat these patients with CCS in the longer term. Specifically, among patients who are receiving a single P2Y12 inhibitor a year or more after PCI, it remains unknown which of the following treatment strategies is most effective for the subsequent lifelong secondary prevention of CCS:

  1. Stop P2Y12 inhibition at 1 year and restart aspirin for an indefinite/lifelong duration

  2. Continue P2Y12 inhibition long-term and keep aspirin on hold (ie, do not switch P2Y12 inhibition for aspirin at 1 year)

  3. If risk factors are at target and particularly among older adults or those at risk for bleeding, simply stop P2Y12 and not restart aspirin, instead focusing on maintaining optimal secondary prevention risk factor targets.

Future trials, adequately powered for CVD outcomes (and if possible, stent thrombosis), are necessary to answer these important questions.

Conclusions

Although the role of aspirin in secondary prevention of CVD is generally regarded as sacrosanct, emerging data suggest that reappraisal of the efficacy of lifelong aspirin in some CCS situations may be warranted. Recent clinical trials have examined the safety of aspirin discontinuation in a number of clinical scenarios, focusing primarily on patients concomitantly prescribed other antiplatelet and anticoagulation agents. The evidence emerging from these trials enables physicians to deprescribe aspirin in certain patients who are at greater risk for harm from concomitant aspirin therapy. Further trials can inform whether stabilized contemporary patients with CCS without other antiplatelet or anticoagulation therapies might also benefit from aspirin discontinuation. Elderly individuals or those with either a known history of bleeding or high risk for bleeding would be ideal candidates for a randomized trial to assess discontinuing aspirin without starting an alternative antithrombotic, as long as the index coronary event is a year or more in the past and other CVD risk factors are well controlled. It will be challenging to design, fund, and conduct such trials, but patients and physicians deserve to know the answer.

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