https://orcid.org/0000-0002-3253-5961
This editorial refers to ‘Incidence of ischaemic stroke and mortality in patients with acute coronary syndrome and first-time detected atrial fibrillation: a nationwide study’, by J.K. Petersen et al.,https://doi.org/10.1093/eurheartj/ehab575.
Does new AF in ACS patients induce the same increased risk for stroke as known AF and thus require OAC therapy? ACS, acute coronary syndrome; AF, atrial fibrillation; OAC, oral anticoagulants.
A 54-year-old male without a previous medical history is brought by ambulance to the cardiac catheterization laboratory (CCL) with the diagnosis of ST-elevation myocardial infarction (STEMI). The ECGs in the ambulance and at the CCL both show atrial fibrillation (AF). The patient is treated with primary percutaneous coronary intervention (PCI) with a second-generation drug-eluting stent, and at the coronary care unit dual antiplatelet therapy (DAPT; aspirin and ticagrelor) is continued. After 12 h, the patient spontaneously converts to sinus rhythm.
Patients presenting with acute coronary syndrome (ACS) complicated by new AF pose several relevant questions to treating clinicians: does new AF affect the prognosis of ACS patients? Is AF due to ACS and, when ACS is treated by PCI, does the risk associated with AF disappear? Also, perhaps the most important question: should both diagnoses (ACS and AF) be treated even if AF spontaneously converts to sinus rhythm within 2 h, as happened in our patient?
Because coronary artery disease and AF share multiple risk factors, such as older age, obesity, hypertension, and diabetes mellitus, their co-existence in one patient seems inevitable. Coronary artery disease occurs in 25–35% of patients with AF, and ∼10% of patients with a recent PCI have AF.1 Antithrombotic management in these patients is complicated, as antiplatelet therapy is inferior to oral anticoagulants (OACs) in AF treatment, and OAC is inferior to antiplatelet therapy in ACS treatment.2 Combination therapy with OAC and DAPT causes a major increase in bleeding events, which are known to be associated with an increased risk of mortality.3 , 4 Therefore, before treating both conditions, it should be established that new AF in ACS patients confers a higher risk of thrombo-embolic events.
In this issue of the European Heart Journal, Petersen et al. describe a large cohort study on this topic of new (they use the definition ‘first-time detected’) AF in patients with ACS.5 Data from Danish nationwide registries are combined to describe the prognosis of patients surviving a first-time admission with ACS from 2000 to 2018, according to AF status: (i) patients without, (ii) patients with a history of, and (iii) patients with newly diagnosed AF. They found that amongst 161 266 ACS survivors, 11.8% had a history of AF, and in 4.0% AF was first detected during admission. Using multivariable adjusted Cox proportional hazards analysis, compared with patients without AF, both known and new AF was associated with worse outcomes of mortality [known AF, hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.21–1.31; new AF, HR 1.52, 95% CI 1.43–1.62], ischaemic stroke (known AF, HR 1.38, 95% CI 1.22–1.56; new AF, HR 1.67 [95% CI 1.38–2.01), and major bleeding events (known AF, HR 1.22, 95% CI 1.14–1.30; new AF, HR 1.28, 95% CI 1.15–1.43). Newly detected AF seemed numerically even more strongly associated with adverse outcomes than known AF.
Of the patients with known AF, 42.4% were treated with OAC before the ACS. Ninety days after discharge, amongst patients with new AF who underwent PCI, 5.8% received no antithrombotic therapy, 4.3% aspirin only, 8.1% a P2Y12 inhibitor only, 35.6% DAPT, 4.2% OAC only, 14.5% dual therapy (OAC plus aspirin or a P2Y12 inhibitor), and 27.6% triple therapy (OAC plus DAPT). These percentages were comparable in patients with known AF. The authors found a statistically significant lower mortality for known and newly diagnosed AF patients that were treated with OAC as compared with antiplatelet therapy (HR 0.75, 95% CI 0.68–0.84; and HR 0.75, 95% CI 0.61–0.91, respectively). Similarly—although not significantly different probably due to low numbers—ischaemic stroke was decreased in patients that were treated with OAC as compared with antiplatelet therapy (HR 0.87, 95% CI 0.67–1.74; and HR 0.78, 95% CI 0.41–1.47, respectively). With new AF, the associated stroke reduction was numerically stronger than amongst known AF patients. As the vast majority of patients in the registry had a CHA2DS2-VASc score ≥2 (prior myocardial infarction, and mean age of patients with prior and new AF was >75 years), OAC treatment is indicated according to current guidelines.6 With only roughly 50% of AF patients treated with OAC after discharge, this supposes a large incidence of undertreatment.
The increased risk of thrombo-embolic events in ACS patients with a newly diagnosed AF has been described earlier, which is also discussed by the authors. In addition to the papers cited by the authors, recently Madsen et al. reported 3.7% newly diagnosed AF amongst 7944 STEMI patients.7 New AF was associated with an increased risk of mortality (HR 1.48, 95% CI 1.20–1.82) and a non-significant increase in ischaemic stroke (HR 1.48, 95% CI 0.96–2.19), as well as recurrent myocardial infarction (MI) (HR 1.14, 95% CI 0.86–1.52). Similarly, Hofer et al. found that in a population of 1372 patients with MI, 10% showed new AF.8 Also in this study, newly diagnosed AF was associated with an increased risk of cardiovascular mortality (HR 1.45, 95% CI 1.19–2.57).
From a pathophysiological point of view, it is not surprising that new AF increases the risk of thrombo-embolic events similarly to known AF. Although the ACS may invoke triggers through acute ischaemic changes and a component of congestive heart failure, there still needs to be a pathological fibrotic substrate in the atria to sustain the episode of atrial fibrillation.9 As AF is asymptomatic in many patients, this first capturing of AF on ECG is likely not be their first episode.10 Therefore, the authors properly named it ‘first-time detected AF’. The fact that both known AF and new AF show worse outcomes supports the concept that first detection may not be new disease.
In line with Petersen et al., other studies also found reduced mortality in ACS patients with new AF treated with OAC as compared with treatment without OAC. Madsen et al. found significantly reduced long-term mortality (HR 0.69, 95% CI 0.47–1.00).7 Hofer et al. also reported reduced cardiovascular mortality for antithrombotic regimens containing OAC (with triple therapy: HR 0.86, 95% CI 0.45–0.92).8 Though all those results are based on small samples and thus are insufficiently powered to prove reduced ischaemic stroke, they all support the use of OAC for patients with new AF as the current study does.
Despite the clear guideline recommendations of OAC treatment for AF patients,6 undertreatment remains a serious issue. The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) showed that amongst 10 781 newly diagnosed AF patients with a CHA2DS2-VASc score ≥2, 17.7% did not receive OAC therapy.11 This tendency of undertreatment was even greater amongst patients with paroxysmal and minimally symptomatic or asymptomatic AF. Also in the current study by Petersen et al., undertreatment seems to be a large issue: even whilst all patients were treated in a contemporary healthcare system, only half were treated with OAC. These numbers were comparable amongst patients with known and new AF: 53.5% of the patients with known AF and 53.8% of the patients with newly diagnosed AF were not treated with OAC 90 days after discharge. Apparently, in this study, physicians do not seem to distinguish between new and known AF. This finding is in contrast to observations made in the MATATOR-PCI registry: patients with known AF and a class IA indication for OAC were treated with OAC in 90.8% of cases, whereas similar patients with new AF were treated with OAC in only 50% of cases.12 Hofer et al. also found less OAC prescription for new AF as compared with known AF: 42.5% vs. 78.9%.8 So there may be a tendency towards less OAC treatment in patients with new AF compared with known AF during ACS.
The study of Petersen et al. does not provide insight into the reason for not prescribing OAC to these patients. Data from the GLORIA-AF suggest that short paroxysms of AF are less frequently treated with OAC.11 Also, the perception that ischaemia might evoke AF, and thus resolving ischaemia resolves AF, might play a role. Possibly, the knowledge that adding OAC to the indicated ACS antiplatelet therapy increases the risk for bleeding leads to withholding prescription. Also, as ∼10–15% of ACS patients are usually treated with coronary artery bypass graft (CABG), post-operative AF might be treated as a different disease. All in all, reduction of events with anticoagulant therapy in these specific scenarios has never been well studied in a dedicated randomized controlled trial. However, based on evidence that OAC prevents ischaemic stroke in the broad population of patients with AF, until further evidence is provided, we believe that such therapy will lead to fewer thrombo-embolic events and thus OAC should be considered in ACS patients with newly diagnosed AF.
Finally, the study by Petersen et al. is an excellent example of how large registries, despite their margin of error, have the potential to identify weaknesses in our current treatment patterns. The study may leave us with some remaining questions regarding details about the episode of AF (e.g. timing and post-operative AF), which would be very interesting to scrutinize in dedicated studies. However, until then, the results of all the above-mentioned studies should encourage active consideration of the combination of OAC and antiplatelet therapy (preferably single antiplatelet therapy with clopidogrel) as the optimal antithrombotic therapy in ACS patients with newly diagnosed AF.
Conflict of interest: W.L.B. has no conflicts to declare. J.M.t.B. reports grants from the Netherlands Organization for Health Research and Development, and a Dutch government institution called ZonMw, and speaker fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, the Medicines Company, Accumetrics, Boehringer-Ingelheim, Bayer, BMS, Pfizer, and Ferrer.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
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