Secondary Prevention of Ischemic Stroke despite Oral Anticoagulation

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Roberto Galea	--	2245	2023-12-09 11:24:03	\|
2	format	Jason Zhu	Meta information modification	2245	2023-12-12 02:23:09	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12185784

Patients with atrial fibrillation (AF) experiencing ischemic stroke despite oral anticoagulation (OAC), i.e., breakthrough strokes, are not uncommon, and represent an important clinical subgroup in view of the consistently high risk of stroke recurrence and mortality. The understanding of the heterogenous potential mechanism underlying OAC failure is essential in order to implement specific therapeutic measures aimed at reducing the risk of recurrent ischemic stroke.

ischemic stroke breakthrough strokes OAC failure

1. Introduction

Secondary stroke prevention in AF patients experiencing ischemic cerebrovascular event despite OAC is challenging. There are several reasons for this, including the incomplete understanding of the mechanisms underlying the ischemic events and the heterogeneous and high-risk population treated. As reported above, the initial care should firstly focus on excluding alternative reasons for stroke and those cases where insufficient OAC (including both reduced patient compliance and OAC underdosing) was the most likely reason of the ischemic event. However, this patient subgroup, although it might be easily treated by optimization of their OAC therapy, represents only a minority (31.7%) of patients with a breakthrough stroke ^[1]. It is also unclear whether patient education and other interventions to improve compliance may reduce the risk of recurrence in this patient population. The latest American Heart Association/American Stroke Association guidelines recommend tailoring the secondary stroke prevention strategy according to the suspected stroke etiology and regardless the antithrombotic therapy ongoing at the moment of stroke ^[2]. However, no specific recommendations have been given by the American Cardiology and Neurology Society guidelines about how to prevent further ischemic events in the specific scenario with breakthrough stroke ^[2]^[3]. Several proposed strategies have been reported so far. Polymeris et al. showed that in a multicenter observational study of almost three thousands AF patients hospitalized in a stroke center due breakthrough stroke, a majority of cases (almost 85%) secondary stroke prevention entailed OAC continuation (including switch to another OAC type) whereas addition of antiplatelet therapy (in 12.8%) or left atrial appendage closure ([LAAC] in 1%) were considered only infrequently ^[1]. Available supporting evidence and limitations of each available strategies will be discussed below.

2. OAC Continuation

OAC is an efficient therapy for secondary prevention of ischemic stroke in patients with AF ^[4]. However, the clinical impact of OAC re-initiation timing on the risk of stroke recurrence and hemorrhagic transformation after an acute ischemic stroke was only recently studied, as in the phase III DOAC trials recent stroke was an exclusion criteria and since the few RCTs conducted on this topic had relevant limitations ^[5]. In the ELAN (early vs. late initiation of direct oral anticoagulants in post-ischemic stroke patients with atrial fibrillation) study ^[6], 2013 AF patients with recent ischemic stroke were randomly allocated to receiving in a 1:1 fashion either an early (within 48 h after a minor or moderate stroke or on day 6–7 after a major stroke) or later OAC (day 3–4 after a minor stroke, day 6–7 after a moderate stroke, or day 12–14 after a major stroke). The primary endpoint was the composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 day after the index event. Patients with hemorrhagic infarction were excluded from this trial. The primary endpoint occurred in 2.9% of patients receiving early and 4.1% of patients receiving later OAC (risk difference, −1.18 percentage points, 95%CI, −2.84 to 0.47). At 30 days, recurrent ischemic strokes were reported in 1.4% and 2.5% (odds ratio: 0.57; 95%CI, 0.29 to 1.07) of early and late groups, respectively. No difference in intracranial hemorrhage was noted (in both groups only two events were observed). Although in this trial no statistical hypothesis was tested, the provided risk estimates encourages early initiation of OAC ^[6].

In breakthrough strokes with no evidence of underdosing or malcompliance, a change in OAC type is often practiced. In particular, dabigatran 150mg twice daily is frequently preferred over others since in trials directly comparing DOACs with VKA it was the only drug reportedly superior in terms of stroke prevention as compared to VKA ^[7]. Notwithstanding these results, there is no available evidence to support this practice ^[8]^[9]^[10], i.e., no comparative trials confirmed superior efficacy of dabigatran 150mg in head-to-head trials against other DOACs. In addition, the Rely trial was criticized for the inclusion of a very low-risk AF population ^[7]. In a large retrospective national cohort including 2908 patients admitted to public hospitals in Hong Kong due to ischemic stroke despite DOAC, Bonaventure et al. observed that switching to another OAC was associated with an increased risk of stroke recurrence at 6 years after the index stroke (in the VKA switch group: adjusted HR; 1.96; 95%CI: 1.27–3.02; p = 0.002; in the DOAC switch group: adjusted HR: 1.62; 95%CI: 1.25–2.11; p-value < 0.001), as compared to the subgroups of patients who continued the same therapy ^[10]. Consistently, other multicenter observational studies did not show any benefit in terms of recurrent stroke reduction with OAC switching ^[1]. Overall, continuation of OAC therapy is still the standard secondary prevention strategy with a better level of evidence as compared to alternative strategies. Based on the available studies, the routine switch to other OAC medication does not seem justified unless particular clinical scenarios are present, such as reduced adherence related to a specific drug aspect (costs, number of pills, side effect), drug interactions, labile INR, concurrent antiphospholipid antibody syndrome, mechanical valves, hemodynamically significant mitral valve stenosis, or left ventricular thrombus.

3. Addition of Antiplatelet Therapy

Evidence suggests that some breakthrough strokes may be related to non-cardioembolic mechanisms, where OAC may not be an important factor in preventing the ischemic event. The addition of antiplatelet therapy is another therapeutic option, which has so far not been studied in a dedicated RCT including breakthrough strokes. Dentali et al. tested the complementary effect of antiplatelet and anticoagulant therapy in AF patients in a meta-analysis including ten RCTs comparing aspirin plus OAC with OAC therapy alone in patients with at least 3 months of follow-up. The authors observed similar thromboembolic event rates in more than 4000 patients for AF patients receiving combined aspirin-OAC therapy compared with OAC therapy alone. As expected, the rate of major bleeding was higher in patients receiving combined therapy compared with OAC therapy alone ^[11]. Similar results were shown by another meta-analyses derived from a general population with AF under OAC. The authors observed that use of antiplatelet therapy paradoxically increased the risk of stroke modestly (relative risk [RR]: 1.33; 95%CI: 0.98–1.79) and, as expected, also increased the risk of major bleeding (RR: 1.54; 95%CI: 1.35–1.77) including intracranial hemorrhage (RR: 1.64; 95%CI: 1.20–2.24) ^[12]. Consistently, studies including AF patients with breakthrough strokes showed that the addition of antiplatelets to anticoagulants was associated with higher odds for the stroke recurrence ^[1]^[10].

Collectively, the routine addition of antiplatelet therapy following breakthrough stroke may not be recommended, except possibly for short-term use in patients with arterial embolism from unstable atherosclerotic plaques ^[13]. However, dedicated RCTs are required to better understand if and in which AF patients the addition of antiplatelet therapy on top of OAC might reduce ischemic stroke recurrence.

4. Left Atrial Appendage Closure

Postmortem and echocardiographic studies have shown that the vast majority of all cardiac thrombi in patients with AF originate from the left atrial appendage (LAA) ^[14]. Thus, LAAC, consisting of exclusion of the LAA cavity from the circulation by implanting a cardiovascular device at LAA ostium, has been established in clinical practice as an attractive alternative to OAC for preventing stroke in AF patients ^[3]^[15]. A meta-analysis including 1114 AF patients randomized to either LAAC or VKA showed a similar incidence of composite of stroke, cardiovascular death, or systemic embolism (HR: 0.82; 95%CI: 0.58 to 1.17; p = 0.27) and lower rates of mortality (HR: 0.73; CI: 0.54–0.98; p = 0.035) and haemorrhagic stroke (HR: 0.20; CI: 0.07–0.56; p = 0.002) in LAAC as compared to VKA groups ^[16] at a follow-up of 4343 patient-years. However, the advent of DOACs and their widespread use in clinical practice as first-line therapy for stroke prevention in AF led international guidelines to recommend LAAC only in selected AF patients with contraindication to long-term OAC ^[3]^[15]^[17]^[18]. However, no specific recommendations were given about performance of LAAC for preventing stroke recurrence in AF patients experiencing cerebrovascular ischemic events despite OAC. The available evidence related to the benefit of LAAC in such high-risk patients is based on a few small observational studies ^[19]^[20]^[21]^[22]. The largest one is a sub-study of the Amplatzer Cardiac Plug multicenter registry including 115 AF patients undergoing LAAC following a breakthrough stroke ^[19]. After a mean follow-up of 1349 patient years, the observed annual cerebrovascular ischemic events rate was 2.6% (a 65% relative reduction according to the CHA2DS2-VASc score) whereas the observed annual major bleeding rate was 0% (a 100% relative reduction according to the HAS-BLED score) ^[19]. Interestingly, the majority of patients discharged under either single (SAPT) or dual antiplatelet therapy (DAPT) whereas only a few patients (7.8%) were discharged under OAC ^[19]. Similarly, a recent prospective single-center observational study including 39 patients undergoing Watchman or Amulet implantation due to OAC failure and discharged under DAPT showed a reduction from scores predicted to observed annual rates of both thromboembolic (−14%) and bleeding (−100%) events ^[23]. On the other hand, Freixa et al. showed, in a retrospective analysis of 22 breakthrough stroke patients submitted to LAAC and continued OAC, a significant reduction in cerebrovascular events 2 years after the procedure as compared to the pre-LAAC events rates (0.1 ± 0.3 vs. 2.0 ± 1.0 events; p < 0.01) ^[20]. Reassuringly, the so far conducted observational studies on breakthrough stroke patients undergoing LAAC showed similar rates of technical success, procedure-related complications, and device-related thrombus as compared to other studies conducted on patients submitted to LAAC with other clinical indications ^[19]^[20]^[21]^[22]. A recently presented unpublished propensity score matching analysis comparing 433 patients receiving LAAC after thromboembolic event despite OAC with 433 patients continuing/switching OAC after breakthrough stroke showed a significantly reduced risk of the primary composite outcome in LAAC as compared to OAC groups (composite of recurrent stroke, systemic embolism, and cardiovascular death: HR 0.33; 95%CI 0.19–0.58) ^[24].

LAA thrombus can be observed in patients experiencing ischemic stroke despite OAC. This finding has been considered an absolute contraindication to LAAC for years, due to the potentially increased thromboembolic risk associated with the intervention and due to the exclusion of such patients from the pivotal RCTs comparing LAAC to VKA ^[16]. However, the procedural iteration occurred in the last few years in terms of procedural planning ^[25], procedural guidance ^[26], and devices used ^[27]^[28] led researchers to consider LAAC even in patients at higher risk, including those with LAA thrombus.

The post-LAAC antithrombotic drug regimen to be prescribed in patients with breakthrough stroke is unclear. The studies so far conducted suggest that OAC ^[20]^[21], antiplatelet therapy ^[19], or both ^[22] might be considered at discharge after a successful LAAC procedure. However, the relevant studies’ limitations, including the small size, the retrospective design, the lack of OAC adherence assessment, and the inherent selection bias do not allow people to draw any definitive conclusions. The limited evidence available on patients with breakthrough strokes undergoing LAAC suggest that either OAC alone or in addition to short-term aspirin or clopidogrel or DAPT for a few months followed by long-term SAPT may be appropriate strategies to prevent thromboembolic events after successful LAAC ^[17]^[18]. Sondergaard et al. reported a propensity score matching analysis including 1527 AF patients undergoing LAAC and discharged under OAC plus aspirin vs. antiplatelet therapy (91% on DAPT) and showed no differences between groups in terms of freedom from non-procedural thromboembolic conditions (98.8% vs. 99.4%; p = 0.089) at 6 months after procedure, although a higher DRT rate was observed in the antiplatelet group (3.1% vs. 1.4%; p = 0.014) ^[29]. Recently, LAAOS III reported the outcomes of a multicenter RCT testing the effect of additional surgical LAA exclusion in almost 5000 AF patients scheduled to undergo cardiac surgery for another indication. At a mean follow-up of 3.8 years, surgical LAAC on top of standard OAC reduced the risk of stroke or systemic embolism by 33% (4.8% vs. 7.0%; HR: 0.67; 95%CI: 0.53–0.85; p = 0.001) compared with no LAAC (OAC only) suggesting a synergistic benefit of surgical LAAC and OAC ^[30]. Based on these observations and on the high stroke risk of these patients, long-term OAC appears to be an appropriate therapy after LAAC for patients with breakthrough strokes. However, patients with breakthrough strokes seem to often have not only a very high ischemic risk but also a high bleeding risk, as recently reported by RENO-EXTEND study investigators (5.8% rate of major bleedings at a mean follow-up of 15.0 ± 10.9 months) ^[31], suggesting that a treatment regimen including DAPT or OAC/SAPT following LAAC may increase bleeding.

Collectively, the little available evidence suggests that LAAC might be an efficient strategy to further reduce the risk of stroke recurrence in patients with breakthrough stroke. However, further evidence is needed to better assess both the clinical benefit of LAAC and the ideal antithrombotic regimen following LAAC in such high-risk patients.

5. Rhythm Control

Rhythm control therapy is an emerging approach to potentially reduce stroke recurrence beyond the effect of anticoagulation alone in patients with AF. The evidence about the benefit of this strategy on reducing stroke risk in the overall AF population is still controversial ^[32]. However, very few studies have so far investigated the effects of early rhythm control in AF patients with recent ischemic stroke. The RAFAS (Risks and Benefits of Early Rhythm Control in Patients With Acute Strokes and Atrial Fibrillation: A Multicenter, Prospective, Randomized Study) trial compared a strategy of early rhythm control within 2 months after an acute stroke with standard care in a total of 300 patients ^[33]. Rates of stroke recurrence were lower at 12 months in the early rhythm control group (1.7%) compared with the standard care group (6.3%, p = 0.034). While antiarrhythmic drugs were used early following acute stroke (<10 days), pulmonary vein ablation was performed later during the study course (>3 months), and no safety signals were observed ^[33].

As a conclusion, rhythm control following breakthrough strokes is a strategy that might be considered in patients without particularly high-risk characteristics. Clearly, further studies testing the impact of this strategy on stroke recurrence in patients with breakthrough strokes are required.

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