Silent Brain Infarction After TAVR: Common but of Unclear Significance

Grant W. Reed; Amar Krishnaswamy; Samir R. Kapadia

Disclosures

Eur Heart J. 2021;42(10):1016-1018. 

Listen to Silence. It has much to say.

Rumi

Aside from death, stroke is the most important complication from transcatheter aortic valve replacement (TAVR). Stroke risk has steadily declined as randomized trials have progressed from high to low surgical risk,[1–3] and is generally lower for transfemoral (TF) AVR compared with surgical AVR.[3,4] Nonetheless, in real-world practice, the incidence of stroke has remained steady at ~2.3% in recent years, and is higher in certain subgroups.[5] Stroke prevention remains a key opportunity to improve TAVR outcomes, and there is intense interest in cerebral embolic protection devices (CEPDs) to mitigate this risk.

It is well understood that silent brain infarction (SBI) discovered incidentally on magnetic resonance imaging (MRI) after TAVR is more common than stroke.[6] Although frequent, there is debate regarding the significance of these asymptomatic brain lesions. It is timely that in this issue of the European Heart Journal, Woldendorp et al. report results from a meta-analysis of 2171 patients who underwent diffusion-weighted MRI imaging (DWI) post-TAVR, demonstrating that SBI was seen in 73.7%, while clinical stroke was much lower at 3%.[7] Interestingly, though CEPD use was associated with lower mean brain lesion volume and total lesion volume on DWI, the number of SBIs did not differ with CEPD use. Further, a higher mean number of SBIs was associated with an increased risk of post-procedural cognitive dysfunction (PCD) [19.93 SBI, 95% confidence interval (CI) 10.37–29.53, P < 0.001]. This is a potentially important finding—as it may indicate that there is a threshold at which SBIs are no longer 'silent', and translate to at least transient cognitive decline.

This and other analyses raise the question of what importance should be placed on SBIs in patient care and as an endpoint in clinical trials (Figure 1).[8] While there is increasing recognition that 'overt' stroke is a separate entity from 'covert' (or silent) brain injury (similar to how type 1 and type 2 MI are considered), it should likewise be appreciated that 'spontaneous' SBI may be more clinically meaningful than 'procedural' SBI.[8] Conceptually, procedural SBI may be less prognostic, as the inciting reason is episodic or may be once in a lifetime, while spontaneous SBIs may be due to underlying cerebrovascular disease and comorbidities, may be more likely to be recurrent, and accumulate over time. Procedural SBI may in fact be more impactful in a patient who has had spontaneous SBI in the past. On this point, in an analysis of the SENTINEL trial, spontaneous SBI assessed by T2-fluid-attenuated inversion recovery (FLAIR) before TAVR was correlated with cognitive outcomes, while incident procedural SBI was not.[6] This speaks to the importance of baseline MRI assessment in trials of post-procedure neurocognition. Few studies have been this thorough, which weakens the proposed association between SBI and PCD.

Figure 1.

Key points regarding SBI post-TAVR. Abbreviations are as defined in the text.

Further complicating the use of SBI as an endpoint, the diagnosis of SBI is highly dependent on the strength, timing, and type of MRI (DWI, T1-FLAIR, or T2-FLAIR). It is frequently observed that DWI lesions do not translate into scar on T2-FLAIR imaging 2–7 days after TAVR. This emphasizes the importance of pre-TAVR baseline imaging to determine the pre-TAVR T2-FLAIR lesion burden, because while it may be assumed that new lesions on DWI represent SBI, these may not translate into scar on T2-FLAIR imaging especially if the post-TAVR study is done too early or too late.[8,9]

Other limitations of the current analysis should be appreciated. The lack of an association between CEPD use and number of SBI lesions should be considered speculative, as only seven studies including CEPD use were available, resulting in wide CIs and possibly an effect bias for this comparison. Intuitively, the most emphasis should be placed on results from randomized controlled trials, given their close follow-up and adjudication of events. With this in mind, in the CLEAN TAVI trial of 100 patients, there was a significant reduction in the number of SBIs (4 vs. 10 lesions; P < 0.001) and volume of SBIs (242 mm2 vs. 527 mm2; P = 0.001) with TAVR + Sentinel CEP vs. TAVR alone. Similarly, in the SENTINEL trial, 240 patients were included in the imaging arms of the study and were randomized to TAVR + Sentinel CEP vs. TAVR alone. While there was a trend toward reduced lesion volume on DWI with Sentinel in the unadjusted analysis, the adjusted analysis demonstrated a significant reduction in new lesion volume in protected territories with Sentinel (P = 0.025).

It is also crucially important to recognize that SBI is ubiquitous among catheter-based procedures and surgeries—and is not a risk unique to TAVR. Upwards of 10–12% of patients have SBI after diagnostic catheterization; SBI is higher after percutaneous coronary intervention, and elevations of neuron-specific enolase (NSE) can be seen post-catheterization—even in asymptomatic patients.[10–12] In comparison with a similar procedure, >60% of patients have an SBI after transcatheter endovascular aortic repair; this suggests that aortic valve manipulation may not be the main source of SBI after endovascular procedures, and that embolization from the aorta or transient hypotension may be causative.[13] In direct comparison with surgical AVR, studies report a variable incidence of SBI ranging from ~15% to 59%,[14–16] with high rates of PCD approaching 12.4% at 4–6 weeks.[17] Thus, the premise that because SBI is frequent TAVR should be avoided in low-risk patients ignores the fact that SBI is also common after surgical AVR, that surgical AVR carries a high risk of PCD, and that trials thus far have demonstrated equivalent or higher risk of stroke from surgical AVR.

In light of the above, a large, well-powered clinical trial is needed to fully understand the short- and long-term clinical significance of SBI post-TAVR, and whether the risk of SBI and stroke can be reduced with CEPDs. Similarly, as the stroke reduction benefit of CEPDs has been debated, stroke appears to be an easier endpoint to adjudicate in the short term. To this end, the PROTECED TAVR (Stroke PROTECTion With Sentinel During Transcatheter Aortic Valve Replacement) (NCT04149535) trial is currently enrolling (with a goal of 3000 patients), randomized 1:1 to TAVR with vs. without Sentinel, with a primary endpoint of clinical stroke within 72 h of TAVR or discharge (as adjudicated by a neurology specialist). Until the results of such trials are known, in light of the safety of CEPDs and signals of a reduced volume of SBI post-TAVR, it is intuitive and reasonable to offer CEPDs to patients during TAVR.

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