Another brick in the wall: impact of use of ticagrelor on reduction of stroke in a large registry.
Ovidio de Filippo MD, Sergio Raposeiras Roubin MD, Mauro Rinaldi Prof, Emad Abu Assi MD, Fabrizio D’Ascenzo MD.
Corresponding author: Fabrizio D’Ascenzo, Division of Cardiology Department Of Internal Medicine.
The risk of ischemic stroke (IS) is a common consideration among physicians who takes care of patients with acute coronary syndrome (ACS),usually requiring a careful management of CV risk factors and treatment with dedicated drugs. The interests work of Ulvenstam et al. lies in this context and deserves the merit of exploring the impact of recent changes in medical treatment following percutaneous coronary interventions (PCI) on stroke, often considered instead a secondary endpoint in researche in this field. In their manuscript the authors retrospectively evaluated the incidence of IS among 34933 patients, within 1 year following PCI for AMI from 2009 to 2013 in Sweden. They divided two time blocks based on the introduction of ticagrelor (first period December 2009-December 2011, clopidogrel only; second period 2009-December 2011- 2009-December 2013, 40% of patients treated with Clopidogrel and 60% with ticagrelor) showing a 21% relative risk reduction of IS in the second one, resulting in a significant absolute lower incidence of this outcome (2.2% vs 1.8%, see Figure number 1). Moreover, authors identified several predictors of increased stroke risk as older age, hypertension, diabetes mellitus (DM), atrial fibrillation (AF), heart failure during hospitalization, previous IS and ST-segment elevation myocardial infarction (STEMI). The authors concluded underlying the influence of ticagrelor on the reduction of IS rate over the time.
Dual antiplatelet therapy is nowadays (DAPT) considered the standard approach for patients with AMI treated with PCI (1,2). Results of the randomized clinical trial PLATO (see Figure number 1, 3), determined a progressive replacement of Clopidogrel by the new P2Y12 receptor blocker Ticagrelor. However, no difference for IS at 12 months follow up was observed (1.1% in both groups). The difference between the paper of Ulvenstam and the PLATO lies in the different populations considered in the two studies, as the authors widely discussed in their paper. In the modern era of evidence-based medicine, results from RCTs are promptly translated in guidelines conditioning our daily practice. Nevertheless cohorts enrolled in RCTs are usually made of highly selected patients, substantially different from real-life ones. Despite the prevalence of all most notorious CV risk factors and of STEMI admission diagnosis was higher in PLATO population compared to the one observed by Ulvensteam et al, patients of this observational study were older and more likely to have in anamnesis a previous IS, which is recognized to be a predictor of further ischemic cerebral accidents. Moreover, patients with AF with an indication for OAC were excluded from PLATO. All these divergences could account for the disagreements regarding the incidence of IS and the potential beneficial effect of ticagrelor with regard to this outcome in a real-life population.
But there is another side of the coin. Which is the cost of this finding? The safety-effectiveness of such hypothesis remains undetermined.
The use of a DAPT in the setting of acute IS (and within the first three months) is effective and mostly safe as confirmed by a meta-analysis published in 2013 (4). Nevertheless, the long-term use of DAPT does not always offer greater benefit for stroke recurrence prevention than a single drug alone, but does substantially increase the risk of bleeding complications (5-6). What stated is mainly supported by the MATCH trial (5) enrolling 7599 patients with stroke or TIA, of which 5% with previous AMI and 13% with angina pectoris.
In this trial aspirin plus clopidogrel treatment did not reduce the risk of IS compared with clopidogrel alone (8% of IS for both subgroups), whereas the DAPT was associated with a significant increase in life-threatening bleeding complications, over a 18 months observation period. The successive CHARISMA trial (6) evaluated aspirin plus clopidogrel versus aspirin alone in 15,603 patients (48% with a documented coronary disease). Also in this case DAPT compared with aspirin alone was associated with a significant increase in moderate bleeding (2.1 versus 1.3 percent), despite a minor impact on IS incidence at follow up (1.7% vs 2.1% , p=0.07). However, these data partially dissent from the ones presented in a sub-analysis of PEGASUS-TIMI54 trial (7) by Bonaca et al., comparing the outcomes of low doses of Ticagrelor (60mg bid) plus aspirin vs aspirin alone for the prevention of stroke in patients with previous AMI (see Figure number 1). In this study, stroke of any kind was significantly reduced with ticagrelor, but the specific risk-reduction for IS was high but not significant (1.28% vs 1.65%, p=0.06). Authors anyhow pooled their data in a meta-analysis including 4 RCT and 44816 patients, demonstrating a final benefit of intensive anti-platelet therapy vs placebo with regard to IS occurrence. Nevertheless, low doses of ticagrelor determined as well a significant higher incidence of TIMI major bleeding, even though no increase in intracranial or fatal bleeding was reported. In Ticagrelor arm of PLATO there was instead an higher rate of fatal intracranial bleeding (3). The work of Bonaca et al. stands out for the relevance given not only to the choice of an adequate DAPT, but also of appropriate dosages. Based on what stated above, benefit of long-term DAPT with ticagrelor should be weighted against risk of bleeding, and low dose should be preferred.
The possible positive influence of ticagrelor spreading described by the authors is not confirmed in the setting of acute stroke or TIA according to a previous RCT of 2016 (8). In this trial a population characterized by an high burden of CV risk factors and an high
prevalence of previous IS (11.6%) was randomized to receive a mono-therapy of aspirin or ticagrelor within 24 hours from the index event. Within 90 days from randomization, ticagrelor did not show to be superior with regard to prevention of new ischemic cerebrovascular accidents, myocardial infarction and death. Another crucial issue that must be pointed out regards the period in which the data were collected.. Years between 2009 and 2013 were characterized by a thriving proliferations of studies concerning the aggressive management of CV risk factors, culminating in the publication of new guidelines on cardiovascular disease prevention in 2012. This document represented a revolution compared with the previous of 2007. The most relevant change regarded the objectives of hyperlipidemia treatment,as the goal of LDL cholesterol 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 was given. The effect of dyslipidemia on IS was not established in the multivariable model proposed in the paper, but the divulgation of those guidelines could have resulted in a more intensive treatment of CV risk factors in the second period of study The importance of these considerations lies in the fact that if a role played by ticagrelor can be supposed for the prevention of atherotrombotic strokes interesting large vessels, this is less obvious for strokes of cardioembolic origin or for ischemic events interesting small arteries (“lacunary infarcts”).
In conclusion, we believe that best efforts should be made to limit the occurrence of such a disabling condition as IS especially in patients with an high cardiovascular risk. Anyway current evidences, while confirming the importance of long term DAPT for the prevention of recurrent cardiac events (9), do not support its unconditioned adoption with the specific aim to prevent IS because of an unclear benefit-risk ratio. For this reason, the control of CV risk factors remains a priority, along with a tailored strategy suggesting kind of dose of
antiplatelet study in ACS setting to prevent cardiac and neurological events. Further studies, conduced on real-life patients, will probably definitively address the efficacy and safety of Ticagrelor mono-therapy compared with aspirin or a combination of both in preventing ischemic cerebral events. The work of Ulvenstam et al. can be considered “another brick in the wall” against recurrent ischemic events after ACS.
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