ADVANCE Published: Stroke Rate Diminishing as TAVR Evolves

Stroke is relatively uncommon after TAVR with a self-expanding device, and its predictors differ depending on the timing of the event, according to a study published in the July 21, 2015, issue of the Journal of the American College of Cardiology.

The ADVANCE study, originally presented at the American Heart Association Scientific Sessions in November 2014, enrolled 1,015 high-risk patients (mean age 81.1 years; 51% women) scheduled to be implanted with the CoreValve device (Medtronic) at 44 experienced centers in Europe, Colombia, and Israel between March 2010 and July 2011.

Take Home: ADVANCE Published: Stroke Rate Diminishing as TAVR Evolves

Researchers led by Johan Bosmans MD, PhD, of Antwerp University Hospital (Edegem, Belgium), recorded neurological events in this population by time of first occurrence:

  • Periprocedural (0 to 1 day post-TAVR)
  • Early (2 to 30 days post-TAVR)
  • Late (31 to 730 days post-TAVR)

Most patients (79.6%) had NYHA class III/IV symptoms at baseline, and 13.1% had cerebrovascular disease. There were no differences between patients who developed stroke and those who did not, but patients with early stroke were more often women (P = .02), had higher STS scores (P = .04), and more often had a major vascular complication (P = .01). Those with late stroke were more likely to have had CABG (P = .047).

Timing of Events Makes a Difference

Overall, the stroke rate was 1.4% in the periprocedural period, accumulating to 3.0% by 30 days and 5.6% by 2 years. Corresponding rates of TIA were 0.2%, 0.3%, and 1.6%, respectively. Most strokes were ischemic, and there were no differences in stroke rate by access choice. Patients who did not have a stroke in the first 30 days were more likely to be alive at 2 years (75.1% vs 52.2%; P = .002).

While multivariate analysis did not determine any predictors of periprocedural stroke, early stroke was associated with female sex, acute kidney injury (AKI), and occurrence of a major vascular complication. Late stroke was linked to prior CABG (table 1).

Table 1. Independent Predictors of Stroke in TAVR Patients

The factors associated with having either stroke or TIA were generally similar, with prior A-fib emerging as a predictor of early stroke or TIA.

Breaking Down the Causes

The stroke rates published in ADVANCE are lower than those seen in PARTNER and the CoreValve US Pivotal Trial, according to the authors, who say this could be due to the lower-risk population studied in the newer trial. “Also, the relatively good survival, even in the patient cohort that sustained a neurological complication, compared to that in the PARTNER studies, may reflect the fact that ADVANCE patients were less sick, frail, or debilitated,” they note.

Additionally, Dr. Bosmans and colleagues write, all centers included in ADVANCE were high-volume TAVR sites—which was not always the case in the high-risk cohort of the CoreValve trial. This could have “exclude[d] the effect of possible ‘learning curve’ influences,” they say.

Due to the “multifactorial etiology” of periprocedural stroke, it was not surprising that predictive factors were identified, the authors assert. “However, most probably, catheter manipulations of the calcified and diseased aortic valve and aortic arch cause embolization of aortic debris or thrombotic material, resulting in stroke or TIA,” they say, adding that embolic protection devices may help reduce these complications.

Because half of recorded strokes were deemed early, this “strongly [suggests] that other determinants, apart from procedural aspects, are significantly related to final neurological outcome,” the authors write. Female sex (likely because of smaller vessels and higher vascular complication risk), A-fib history, AKI, and major vascular complications should all be on a TAVR operator’s radar, they say.

One potential solution to the A-fib issue would be to start anticoagulation therapy immediately after A-fib diagnosis and continue it for several months, the authors suggest. Although no clear guidelines outline what to do in this case, “a more aggressive antithrombotic treatment should probably be implemented,” they argue.

With regard to late stroke, a history of CABG most likely indicates complex atherosclerotic disease, they write, adding that late events “seem to be mostly related to patient-dependent characteristics and not to valve- or procedure-related factors, at least through 2 years.”

Encouraging Results, Though Caution Needed

In an accompanying editorial, Vinod H. Thourani, MD, of Emory University Hospital (Atlanta, GA), and colleagues say “these data come at an intriguing time. The field is currently seeing reports from randomized controlled trials in which a survival benefit and a reduction in the rate of major adverse cardiovascular and cerebrovascular events in TAVR patients is suggested, for the first time, compared with surgical aortic valve replacement.”

Moreover, third-generation balloon-expandable systems have almost eliminated paravalvular leak and clinical trials are recruiting intermediate-risk patients, which would not have been done “only 5 short years ago,” they write. “Rare innovations in cardiac surgery have had the momentum of TAVR, equally complemented and driven by the constant, fluid evolution of valve systems and delivery devices. Robust, structured, and monitored research must sprint to keep up.”

They note that “there was cause for alarm in terms of neurological outcomes” after PARTNER was published but that “more contemporary comparisons have largely mitigated the difference in stroke risk in TAVR compared with [surgery].”

While stroke rates among TAVR patients are becoming lower with experience, “it is undeniable that permanent neurological injury is the single most significant and most feared morbidity of cardiac interventions. A debilitating stroke is viewed by many as the greater evil, even compared with operative death.” Thus, they continue, efforts should be taken to further identify predictors of stroke as the TAVR population expands.

Though ADVANCE contributes to this goal, the editorialists caution against applying these results to a sicker cohort of patients or to those treated at lower-volume centers. They also highlight the fact that neurological events “were not actively sought; they were reported when identified.”

Dr. Thourani and colleagues conclude, “In the quickly developing arena of TAVR, we must also remember that even a year can make a difference, because not only do devices and technology evolve, [but] patient selection by TAVR centers becomes more refined, and alternative TAVR access routes are identified and used with increasing safety and feasibility. It will also be extremely interesting to learn how embolic protection devices influence neurological outcomes.”

Future studies, they add, “like the evolution of TAVR itself, must maintain a continuous, stringent drive to identify, prevent, and treat neurological dysfunction in this susceptible and often vulnerable patient population.”


1. Bosmans J, Bleiziffer S, Gerckens U, et al. The incidence and predictors of early- and mid-term clinically relevant neurological events after transcatheter aortic valve replacement in real-world patients. J Am Coll Cardiol. 2015;66:209-217.
2. Thourani VH, Tsai L, Jensen H. The heart and the head: neurological implications of transcatheter aortic valve replacement [editorial]. J Am Coll Cardiol. 2015;66:218-20. 


  • The CoreValve ADVANCE study was sponsored and funded by Medtronic.
  • Dr. Bosmans reports serving as a proctor for Medtronic.
  • Dr. Thourani reports serving on advisory boards for Abbott Medical, Boston Scientific, Edwards Lifesciences, and St. Jude Medical and receiving research support from Direct Flow Medical, Edwards Lifesciences, Medtronic, Sorin Medical, and St. Jude Medical.

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