Cryoballoon ablation of atrial fibrillation in octogenarians: one year outcomes from the cryo global registry

Background Limited information is available on the safety and efficacy of cryoballoon ablation (CBA) in elderly patients with atrial fibrillation (AF). Moreover, global utilization of CBA in this population (≥ 80 years old) has not been reported. This study’s objectives were to determine the use, efficacy, and safety of CBA to treat octogenarians suffering from AF. Methods In this sub-analysis of the Cryo Global Registry, 12-month outcomes of treating AF via CBA in octogenarians were compared to patients < 80 years old. Efficacy was evaluated as time to a ≥ 30 s atrial arrhythmia (AA) recurrence. Healthcare utilization was determined via repeat ablations and hospitalizations. Improvement upon disease burden was evaluated through patient reporting of symptoms and the EQ-5D-3L quality of life (QoL) survey. Results The octogenarian cohort (n = 101) had a higher prevalence of females (51.5% vs 35.7%) and CHA2DS2-VASc scores (4.2 ± 1.3 vs 2.0 ± 1.5) compared to the control cohort (n = 1573, both p < 0.01). Even when adjusting for baseline characteristics and antiarrhythmic drug usage, freedom from AA recurrence at 12 months (80.6% vs 78.9%, HRadj:0.97 [95% CI:0.59–1.58], p = 0.90) was comparable between octogenarians and control, respectively. Similar serious adverse event rates were observed between octogenarians (5.0%) and control (3.2%, p = 0.38). The groups did not differ in healthcare utilization nor reduction of AF-related symptoms from baseline to follow-up, but both experienced an improvement in QoL at 12 months. Conclusions Despite more age-related comorbidities, CBA is a safe and effective treatment for AF in octogenarians, with efficacy and adverse events rates akin to ablations performed in younger patients. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT02752737 Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10840-023-01680-z.


Introduction
In 2017, the approximate global prevalence of atrial fibrillation (AF) was 37.6 million, and it was forecasted to increase by more than 60% by 2050 [1].A growing elder population has contributed to this escalation of AF prevalence.Presently, AF impacts 10-17% of people 80 years and older [2].Managing AF in elderly patients can be difficult due to numerous comorbidities [2].Therefore, some physicians are hesitant to perform minimally invasive procedures, such as cryoballoon ablation (CBA), in this population [3].Furthermore, large clinical trials evaluating the safety and efficacy of CBA typically have not included octogenarians, even though they comprise a substantial proportion of the AF population [4][5][6][7].
Smaller studies have demonstrated the safety and efficacy of CBA in patients ≥ 75 years old with AF [3,6,[8][9][10].However, these studies involved one or multiple centers from the same country, and thus lacked diversity in patient demographics, standard of care protocols, and physician experience [3,6,[8][9][10].To address these evidence gaps, this sub-study from the Cryo AF Global Registry reports real-world efficacy, safety, healthcare utilization, and quality of life (QoL) outcomes in octogenarian AF patients treated via CBA.

Study Design
The Cryo Global Registry (NCT02752737) is an ongoing, prospective, multicenter, post-market, Medtronic-sponsored registry which evaluates AF ablation using the Arctic Front family of cryoablation catheters (Medtronic, Inc).An international physician steering committee supervised data quality and collection, analyses, and publication timelines.The principles defined in the Declaration of Helsinki and Good Clinical Practice guidelines drove data collection methods.Each site obtained authorization from local institutional/ethics review boards and acquired consent from patients preceding study enrollment.

Patient Population
All patients were required to be ≥ 18 years old with a planned CBA procedure and were not disqualified for any preexisting characteristics nor medical conditions.In this examination, patients with paroxysmal or persistent AF enrolled between May 2016 and May 2020 at global centers who treated at least one patient with an age ≥ 80 years were included.This sub-analysis compares two cohorts: patients ≥ 80 years of age (octogenarian group) and patients < 80 years of age (control group) at the time of enrollment.

Cryoballoon Ablation Procedure
At each site, operators conducted the CBA procedure according to local standard-of-care and current guidelines.Briefly, transeptal puncture was used to gain access to the left atrium (LA).To deliver a 23-or 28-mm CBA catheter (Arctic Front Advance; Medtronic, Inc.) into the LA, a specialized 15-F outer diameter steerable sheath was employed (FlexCath Advance Steerable Sheath; Medtronic, Inc.).A J-tip guidewire or a dedicated inner-lumen octopolar/decapolar circular mapping catheter (Achieve or Achieve Advance; Medtronic, Inc.) was used to deliver the cryoballoon catheter and sheath to the desired pulmonary vein (PV).The cryoballoon was inflated and advanced toward the PV before each ablation.Freezing was initiated after antral occlusion of the targeted PV was validated by selective angiography.Operators dictated the number and length of cyroapplications per PV, and pulmonary vein isolation (PVI) was verified by entrance and/ or exit block.
During right-sided CBA, pacing the diaphragm with a diagnostic catheter inserted into the right subclavian vein (or superior vena cava) and monitoring nerve function with manual and/or adjunctive diaphragmatic movement detection was recommended.All freezes were halted upon detection of a weakened diaphragmatic response.Operators independently decided on sedation method, pre-and intraprocedural imaging, esophageal temperature monitoring, chemical assessment of acute PVI, and placement of adjunctive ablation lesions.Patients were prescribed periprocedural anticoagulation and anti-arrhythmic drugs (AADs) and were discharged according to local standard-of-care procedures.

Patient Follow-up and Study Endpoints
Patients were monitored post ablation according to each center's standard-of-care, which included a mandatory 12-month post-procedure visit.Following a 90-day blanking period, efficacy was evaluated by the 12-month freedom from ≥ 30 s of documented AF/atrial flutter (AFL)/atrial tachycardia (AT).The rate of serious procedure-related adverse events was the primary safety endpoint.Serious events were defined as events that resulted in death or a serious deterioration in health.
Secondary endpoints included procedural characteristics, change in AF-related symptoms, QoL, and freedom from repeat ablation and rehospitalizations at 12 months.At baseline and 12-month follow-up, predefined AF-related symptoms and QoL were assessed.The European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) questionnaire was utilized to evaluate QoL.All-cause and cardiovascular (CV)-related hospitalization and repeat ablation rates were analyzed throughout 12 months of follow-up.Class I or III AAD prescription was collected at discharge and 12 months post-ablation.

Statistical Analysis
Continuous variables were summarized as mean and standard deviation, and categorical variables were summarized as counts and percentages.Kaplan-Meier methods were used to estimate 12-month freedom from atrial arrhythmia (AA) recurrence, repeat ablation, and rehospitalization.Standard error was approximated with Greenwood's formula.Cox regression models were employed to compute hazard ratios for efficacy outcomes between cohorts.Propensity score methods were utilized to evaluate an adjusted hazard ratio to account for dissimilarities in baseline characteristics between the octogenarian and control groups.With the classification of octogenarian serving as the dependent variable, a logistic regression model that encompasses all baseline characteristics (excluding CHA 2 DS 2 -VASc scores and age) as covariates was developed to calculate propensity scores.AAD usage following ablation was included as a covariate as well.To approximate adjusted hazard ratios, the Cox regression model comprised propensity score as a covariate.Distinct Cox regression models were utilized for each efficacy and healthcare utilization endpoint.Changes in number of symptoms and QoL from baseline to 12 months were assessed with linear models accounting for differences at baseline.Post-ablation AAD prescription at discharge (between octogenarians and control groups) was assessed with a Chi-Square test of independence, while change in the post-ablation AAD prescription from discharge to 12 months was assessed with a logistic model accounting for differences at discharge.P-values of < 0.05 were considered statistically significant.

Procedural Characteristic
Table 2 displays procedural characteristics.The majority of patients underwent CBA using a 28-mm Arctic Front Advance (98.7%).Total procedure, LA dwell, and fluoroscopy times did not differ between groups (p > 0.05).On average, octogenarians were administered 1.5 ± 0.8 freezes per PV for a mean duration of 184 ± 52 secs in comparison to the control group who received 1.6 ± 1.0 freezes per PV for a mean duration of 177 ± 52 secs (p = 0.02 for applications and p < 0.01 for duration).Overall acute PVI was high (95.0% in the octogenarian vs. 96.2% in the control, p = 0.59).Following CBA, the number of days until discharge were higher in the octogenarian patients (2.6 ± 4.1 days) compared to controls (1.8 ± 2.8 days, p < 0.01), and 2.0% of octogenarians vs 8.9% of control patients were discharged the same day of the index procedure.

Quality of Life and Arrhythmia Symptoms
The distribution of each AF-related symptom at baseline and 12-month visit is shown in Fig. 4. At baseline, palpitations were the most prevalent symptom, present in 67.0% of the octogenarians and 70.9% of the control group.Despite poorer cardiovascular health, there was no significant difference in symptom burden for octogenarians in comparison to controls at baseline (p = 0.23).Twelve months post ablation, 72.5% of the octogenarians and 78.4% of the control group indicated no symptoms.There was no difference between groups in the reduction of AF-related symptoms from baseline to follow-up (p = 0.37).Octogenarians suffered from a significantly lower overall QoL at baseline (0.83 vs 0.89, p < 0.01) and experienced a smaller mean improvement in QoL at 12 months after CBA (0.020 vs 0.033, p < 0.01; Table 4).

Discussion
Real-world evidence of the clinical outcomes after CBA in the octogenarian population is sparse.Thus, our study aimed to assess the efficacy and safety of CBA to treat AF in octogenarians, and to the best of our knowledge, this study evaluates the largest cohort of octogenarians treated with CBA, globally.This work is the first real-world analysis of a large global dataset of CBA procedures in octogenarians, including regions with scarce CBA evidence (i.e., Southeast Asia, Middle East, etc.), performed by a vast variety of operators from world-wide healthcare systems.The data indicated high efficacy for CBA in octogenarians, with comparable 12-month freedom from AA recurrence compared to patients < 80 years of age.Even when accounting for differences seen in baseline characteristics and AAD usage by propensity score methods; octogenarians had similar efficacy, safety, and healthcare utilization outcomes in comparison to control.Moreover, both cohorts experienced a decrease in AAD utilization post-ablation and improvement in QoL at 12 months.Of note, these results are based on a high proportion of completed follow-ups of more than 90% of the overall cohort.These findings are supported by smaller non-global studies.Liu et al. reported that 74% of octogenarians who underwent CBA experienced freedom from AA at 12 months [11].After a one-year follow-up, Abugattas et al.and Heeger et al.observed 81.1% and 80% of their elder cohort to be in sinus rhythm post CBA (respectively), with no significant difference to controls [12,13].However, previous studies evaluating the impact of age on the efficacy of CBA over longer follow-up periods have been Fig. 3 Freedom from Repeat Ablations, Hospitalization, and Antiarrhythmic Drug Usage.Kaplan-Meier estimate of (A) freedom from repeat ablation at 12 months, (B) freedom from all-cause hospitalization at 12 months, and (C) freedom from CV-related hospitalization at 12 months in octogenarians (red lines) or controls (blue lines) treated with CBA.Hazard ratios are presented from unad-justed (HR unadj ) and adjusted (HR adj ) Cox regression models, where the adjusted model include all subject characteristics from Table 1 with the exception of CHA 2 DS 2 -VASc score and age.(D) AAD prescription in octogenarians and controls at discharge (blue) and at 12 months (gray) Fig. 4 Atrial Fibrillation-Related Symptoms.Distribution of AF-related symptoms in octogenarians at baseline (blue) and 12 months (gray) and in controls at baseline (turquoise) and 12 months (black).A total of 1512/1674 patients reported symptoms less consistent.Vermeersch et al.found that after a median follow-up of 24 months post-CBA, patients ≥ 75 years old with PsAF had more AA recurrences compared to PsAF patients < 75 years old (p = 0.03) [14].Although the freedom from AF was similar between the two groups after a year, the success rate remained consistent in the younger cohort but continued to decline in the older group [14].Hartl et al.found that freedom from arrhythmia was not age dependent at the 12-month follow-up, but it was significantly different between age groups following 36 months post CBA [10].However, a 2019 CBA study discovered no differences in AF recurrence between ≥ 75 years old patients and the control cohort after three years [13].Together these findings suggest that more investigation is needed into the durability of CBA in older AF patients.
Overall, it is surprising that (despite the higher rate of comorbidities in the octogenarians) efficacy rates were similar compared to the younger patients.Through propensity score methods, CBA was determined to be just as effective in octogenarians as in the control group despite these differences in cardiovascular health and all other baseline characteristics.Furthermore, this logistic regression model demonstrated that AAD treatment from discharge to 12 months did not contribute to arrythmia recurrence in octogenarians.These results reinforce that CBA is an efficacious treatment for AF in the octogenarian population.It is of note, that there was a trend of a lower rate of repeat ablations performed in the octogenarians, but without full statistical significance.It is likely that physicians were reluctant to perform a second minimally invasive procedure in the elderly and treated them with AADs instead.Bunch et al. found that the need for AADs following ablation is more common with increasing patient age [15].Of note, in our analysis, AFrelated symptoms improved as much as in the younger cohort.A recently published randomized trial indicated a reduction of cardiovascular events by early restoration of sinus rhythm in AF patients [16]; however, this is of less relevance for clinical decision making in octogenarians, and instead, indication for rhythm therapy in elder AF patients should be driven by symptoms.
The study data show that CBA was feasible in patients ≥ 80 years of age with similar procedure times and success rates for acute PVI compared to younger patients.Although the elderly suffered from more comorbidities, indicated by higher CHA 2 DS 2 -VASc scores, being more hypertensive, higher NYHA classification, and more frequent prior myocardial infarctions; CBA did not result in a higher rate of serious procedure-related adverse events nor rehospitalizations compared to the control group in this large, global, multicenter registry.Of note, although CHA 2 DS 2 -VASc scores were higher in octogenarians, these patients had a relatively good health status for their age, suggesting that elder patients were selected for PVI based on favorable baseline characteristics and that some physicians were reluctant to perform PVI in more frail patients.In fact, frailty in AF patients is significantly associated with increased symptom severity, incidence of stroke and mortality, and prolonged hospitalization [17,18].In this regard, patient selection in the elder population of who may benefit from ablation becomes critical.This should be considered when interpreting the outcomes of this real-life registry.
However, there was a trend for octogenarians to remain in the hospital longer following CBA.This is aligned with previous findings of octogenarians being hospitalized for more than a mean of 2.5 days, and longer hospitalization is often necessary for elder patients in order to enhance fluid levels and improve mobility [15,19].Moreover, there may be some fear about delayed complications after PVI in elderly patients, which is why physicians may have been generous in keeping octogenarians in the hospital longer after PVI.Nevertheless, our data indicate that PVI can be safely performed in octogenarians (when selected properly), and thus, discharge does not need to be postponed as a standard practice.
These global results confirm earlier findings from several smaller single center trials [3,6,[8][9][10] and multicenter studies in smaller geographies [11-13, 19, 20] in terms of similar complication rates in elder patients despite a higher prevalence of cardiovascular diseases compared to control [3, 6, 8-13, 15, 19-22].Similar to our results, Abin et al.and Hartl et al.reported no procedure-related deaths or atrioesophageal fistulas in elder AF patients treated with CBA [9,10].However, Hartl et al.found that transient ischemic attacks occurred only in the elder group, the opposite result from our study [10].Even in a study in which two patients from the elder cohort died from cardiovascular complications; there was no significant difference in mortality compared to the control cohort [3].A 2022 meta-analysis review of 20 studies found that older patients suffered significantly more overall, major, and cerebrovascular complications in comparison to the control group [23].However, when the investigators analyzed adverse events from solely CBA studies, there were no longer differences in the complication rates between the elder and non-elder cohorts.This observation may be due to the fact that cryoballoon ablation provides procedural standardization, allowing for more consistent clinical outcomes.Furthermore, the most common scenario in which phrenic nerve injury occurs is with CBA, with an incidence of transient phrenic nerve palsy of 3.5% to 11.2% [24][25][26][27][28]; however, no phrenic nerve injuries occurred in the octogenarian cohort.These results support CBA as a safe treatment for octogenarians suffering from AF disease.It is well established that the incidence of AF increases with age [1].Surprisingly, octogenarians only made up 2.4% (101/4210) of patients enrolled in the Cryo Global Registry.Excluding Germany, octogenarians across various geographies (Supplemental Table 1) rarely underwent CBA in this large, real-world registry.This novel finding demonstrates that octogenarians are perhaps an underserved AF population, and the results from this study support CBA in older patients.

Study Limitations
Our study has some limitations.A mandatory, universal protocol for rhythm monitoring was not used across centers.Intermittent monitoring was employed for most patients, and consequentially, AF recurrence may have been underreported.However, patients in both cohorts were monitored on average three times over 12 months, primarily with Holter and 12-lead ECG monitoring, and there was no statistical difference in the proportion of unmonitored patients between groups.Also, this was a real-world registry accompanied with a selection bias that is common to any observational trial.To circumvent this issue, Cox proportional hazards modeling was utilized to account for differences in baseline characteristics between cohorts.Based on the overall reserved treatment of elders with invasive therapies, only octogenarians of relatively good physical condition may have been treated with CBA and may not reflect the broader population of octogenarians with AF.

Conclusions
This study establishes CBA as a safe and effective treatment for octogenarians suffering from PAF and PsAF, with efficacy and complication rates comparable to younger patients.Still, when considering older people's greater risk for comorbidities; great care should be taken when deciding what treatment options for AF to pursue.Therapy options should consider the general health of the patient and life expectancy, the physician's medical guidance, and the patient's desire for maintaining physical activity and QoL.

Table 4
Quality of Life † 1428 /1674 completed a 12 month visit and completed EQ5D at baseline and 12 months ‡ Linear model, dependent variable change in EQ5D, covariates = Age group, baseline, ED5D § Improvement from baseline to 12 months p = 0.54 ¶ Improvement from baseline to 12 months p < 0.01