Another brick in the wall: The impact of ticagrelor use on the incidence of stroke in a large registry

The risk of ischaemic stroke is a common concern among physicians who care for patients with acute coronary syndrome (ACS). These patients typically have multiple cardiovascular risk factors and require treatment with a dedicated medical regimen. The interesting work of Ulvenstam and colleagues1 seeks to further explore the impact of recent changes in medical treatment following percutaneous coronary interventions (PCIs) on stroke, which is often considered a secondary endpoint in the field of interventional cardiology. In their manuscript, the authors retrospectively evaluated the one-year incidence of ischaemic stroke among 34,933 patients following PCI for acute myocardial infarction (AMI) from 2009 to 2013 in Sweden. They assessed the impact of ticagrelor on ischaemic stroke by dividing the population into two time-blocks based on the introduction of ticagrelor. The first period was from December 2009 to December 2011, during which only clopidogrel was used. During the second period, from December 2011 to December 2013, 40% of patients were treated with clopidogrel and 60% with ticagrelor. Interestingly, there was a 21% relative risk reduction of ischaemic stroke in the second time block with a significant absolute lower incidence of ischaemic stroke (2.2% vs. 1.8%, see Figure 1). Moreover, the authors identified several variables associated with increased stroke risk, including older age, hypertension, diabetes mellitus, atrial fibrillation, heart failure during hospitalization, previous ischaemic stroke, and STEMI. The authors concluded that ticagrelor was associated with a significant reduction of ischaemic stroke rate over the time. Incidence of ischaemic stroke according to dual anti-platelet therapy. 1: ticagrelor 90 mg b.i.d., follow-up 12 months. 2: ticagrelor 90 mg b.i.d., follow-up 12 months. 3: ticagrelor 60 mg b.i.d., follow-up 36 months. Dual anti-platelet therapy (DAPT) is considered a standard of care for patients with AMI treated with PCI.2 The favourable results of the randomized clinical trial PLATO (see Figure 1)3 led to a progressive replacement of clopidogrel with the newer P2Y12 receptor blocker ticagrelor in the setting of PCI for ACS. However, no difference was observed in ischaemic stroke at 12 months’ follow-up (1.1% in both groups). The difference between the paper of Ulvenstam and the PLATO trial lies in the different populations considered in the two studies, as the authors comprehensively discussed in their paper. In the modern era of evidence-based medicine, results from randomized controlled trials (RCTs) are promptly translated into guidelines that greatly impact our daily practice. Nevertheless, cohorts enrolled in RCTs are usually composed of highly selected patients, substantially different from that seen in real-world practice. Despite the presence of typical cardiovascular risk factors and a higher incidence of STEMI in the PLATO population, patients in the observational study by Ulvenstam et al. were older and more likely to have a history of prior ischaemic stroke, a recognized predictor of further ischaemic cerebral accidents. Moreover, patients with atrial fibrillation with an indication for oral anticoagulation were excluded from PLATO. On the other hand, physicians ordinarily deal with difficulties like the choice of a correct combination of anti-coagulant and anti-platelet drugs4 along with sub-optimal therapy regimens5 in patients suffering of both AF and other risk factors for cerebrovascular diseases. These baseline differences may make the real-world population at great risk for ischaemic stroke and help account for the beneficial effect of ticagrelor in regard to the reduction of ischaemic stroke in the real-world population. But there is another side of the coin. What is the impact of this finding on cost? It is important to note the findings of this study are hypothesis-generating and do not show a significant reduction of stroke in a higher risk population based on a randomized controlled trial. Therefore, extrapolation of this data may carry significant financial implications. The use of DAPT in the setting of acute ischaemic stroke (especially within the first three months) is effective and mostly safe as confirmed by a prior meta-analysis.6 Nevertheless, the long-term use of DAPT does not always offer a significant reduction in stroke recurrence compared with a single drug alone, but instead substantially increases the risk of bleeding complications.7,8 The MATCH trial7 enrolled 7599 patients with stroke or TIA, of whom 5% had prior AMI and 13% had angina pectoris. In this trial, aspirin plus clopidogrel treatment did not reduce the risk of ischaemic stroke compared with clopidogrel alone (8% of ischaemic stroke for both subgroups), whereas DAPT was associated with a significant increase in life-threatening bleeding complications over the 18 month observation period. The successive CHARISMA trial8 evaluated aspirin plus clopidogrel versus aspirin alone in 15,603 patients, 48% of whom had documented coronary disease. CHARISMA showed DAPT was associated with a significant increase in moderate bleeding compared with aspirin alone (2.1% vs. 1.3%), though only had a minor impact on ischaemic stroke incidence at follow up (1.7% vs. 2.1% respectively, p = 0.07). However, these data differ in part from that presented in a sub-analysis of PEGASUS-TIMI54 trial9 by Bonaca et al. comparing the outcomes of lower doses of ticagrelor (60 mg b.i.d.) plus aspirin versus aspirin alone for the prevention of stroke in patients with prior AMI (Figure 1). In this study, stroke of any kind was significantly reduced with ticagrelor, but the specific risk-reduction for ischaemic stroke was high but not significant (1.28% vs. 1.65%, p = 0.06). However, pooled data in a meta-analysis including four RCTs and 44,816 patients demonstrated that intensive anti-platelet therapy significantly reduced the incidence of ischaemic stroke compared with placebo. Nevertheless, the lower dose of ticagrelor was also associated with a significantly higher incidence of TIMI major bleeding, even though there was not an increase in intracranial or fatal bleeding. Importantly, ticagrelor was associated with a higher rate of fatal intracranial bleeding compared with clopidogrel in the PLATO trial.3 The work of Bonaca et al. stands out as it not only raises the question of what is the optimal duration of DAPT, but also the question regarding what are the optimal dosages.9 Based on the above data, physicians are still left with the challenge of weighing the benefit of long-term DAPT against the increased risk of bleeding. The possible positive impact of increased utilization of ticagrelor described by the authors has not been confirmed in the setting of acute stroke or TIA according to a previous RCT.10 In this trial, a population characterized by a high burden of cardiovascular risk factors and a high prevalence of previous ischaemic stroke (11.6%) was randomized to receive monotherapy with either aspirin or ticagrelor within 24 h from the index event. Within 90 days from randomization, ticagrelor was not superior to aspirin for the prevention of new ischaemic cerebrovascular accidents, AMI and death. Another crucial issue that must be pointed out regards the period in which the data were collected. The years between 2009 and 2013 were characterized by a major proliferation of studies concerning the aggressive management of cardiovascular risk factors, culminating in the publication of new guidelines on cardiovascular disease prevention in 2012. As compared with the previous guidelines of 2007, the most relevant change was in regard to the objectives of hyperlipidaemia treatment. The updated guidelines called for the goal of low-density lipoprotein cholesterol to be moved from 100 mg/dL to 70 mg/dL in people at ‘very high cardiovascular risk’ and a strong recommendation to start high-dose statin treatment in patients with ACS during the index hospitalization. Although dyslipidaemia was not associated with the incidence of ischaemic stroke in the multivariable model proposed by Ulvenstam and colleagues, the recommendations of the updated guidelines could have resulted in a more intensive treatment of cardiovascular risk factors in the second period of study. In conclusion, we strongly support the efforts of the authors to limit the occurrence of such a disabling condition as ischaemic stroke, especially in patients with a high cardiovascular risk. Although long-term DAPT is recommended for the prevention of recurrent cardiac events,11 the data do not support its unconditioned adoption with the specific aim to prevent ischaemic stroke because of an unclear risk–benefit ratio. For this reason, focus should remain on the control of cardiovascular risk factors and on improvements in the social and educational status of the population12 while adopting a patient-specific tailored strategy of antiplatelet therapy in ACS to prevent cardiac and neurological events. Further studies, conducted on real-world patients, may help definitively address the efficacy and safety of ticagrelor mono-therapy compared with aspirin monotherapy or a combination of both in preventing ischaemic cerebral events. The work of Ulvenstam et al. can be considered ‘another brick in the wall’ against recurrent ischaemic events after ACS. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.