Abstract
Background
The ThermoCool STSF catheter is used for ablation of ischemic ventricular tachycardia (VT) in routine clinical practice, although outcomes have not been studied and the catheter does not have Food and Drug Administration (FDA) approval for this indication. We used real-world health system data to evaluate its safety and effectiveness for this indication.
Methods
Among patients undergoing ischemic VT ablation with the ThermoCool STSF catheter pooled across two health systems (Mercy Health and Mayo Clinic), the primary safety composite outcome of death, thromboembolic events, and procedural complications within 7 days was compared to a performance goal of 15%, which is twice the expected proportion of the primary composite safety outcome based on prior studies. The exploratory effectiveness outcome of rehospitalization for VT or heart failure or repeat VT ablation at up to 1 year was averaged across health systems among patients treated with the ThermoCool STSF vs ST catheters.
Results
Seventy total patients received ablation for ischemic VT using the ThermoCool STSF catheter. The primary safety composite outcome occurred in 3/70 (4.3%; 90% CI, 1.2% – 10.7%) patients, meeting the pre-specified performance goal, p=0.0045. At 1 year, the effectiveness outcome risk difference (STSF - ST) at Mercy was −0.4% (90% CI: −25.2%, 24.3%) and at Mayo Clinic was 12.6% (90% CI: −13.0%, 38.4%); the average risk difference across both institutions was 5.8% (90% CI: −12.0, 23.7).
Conclusion
The ThermoCool STSF catheter was safe and appeared effective for ischemic VT ablation, supporting continued use of the catheter and informing possible FDA label expansion. Health system data hold promise for real-world safety and effectiveness evaluation of cardiovascular devices.
Keywords: ventricular tachycardia, ablation, real-world data, routine clinical practice, comparative effectiveness
1. Background
Ventricular tachycardia (VT) is a potentially lethal cardiac arrhythmia often precipitated by ischemic heart disease, including prior myocardial infarction (MI). Catheter ablation of monomorphic VT is recommended in multiple clinical contexts by professional society expert consensus because ablation improves clinical outcomes, particularly among patients with recurrent VT despite anti-arrhythmic drug therapy [1].
The ThermoCool ST ablation catheter was approved by the Food and Drug Administration (FDA) for ablation of refractory sustained monomorphic VT due to prior MI on February 11, 2014. This catheter is also approved for treatment of type I atrial flutter and drug-refractory recurrent symptomatic paroxysmal atrial fibrillation. A newer model of the catheter, ThermoCool STSF, has a 56-hole irrigation of its tip versus the earlier 6-hole tip irrigation. Thus, the STSF catheter requires less fluid volume for catheter tip irrigation, [2] so may be less likely to precipitate heart failure, and improves cooling of the catheter tip during ablation [3]. This catheter is approved for treatment of type I atrial flutter, drug refractory recurrent symptomatic paroxysmal atrial fibrillation, and drug refractory recurrent symptomatic persistent atrial fibrillation. Both catheter models are used for ablation of ischemic VT in clinical practice. A better understanding of the safety and effectiveness of the ThermoCool STSF catheter for VT ablation is needed to support ongoing clinical use and possible label expansion.
In recent years, propelled by the 21st Century Cures Act of 2016, [4] there has been interest in leveraging real-world data (RWD) sources to inform regulatory decision-making. FDA guidance [5] indicates that label expansion studies of medical devices may be supported by RWD. This contrasts with traditional standards for regulatory approval for high-risk devices regulated through the premarket approval pathway, [6] including ablation catheters, which typically require an investigational device exemption (IDE) clinical trial [7] in addition to non-clinical data such as bench testing.
Our prior research has demonstrated the feasibility of leveraging electronic health record (EHR) data to support clinical use and label expansion [8–10]. Accordingly, in order to provide evidence to support ongoing clinical use and regulatory submission for label expansion, we examined outcomes among patients treated for ischemic VT with the ThermoCool STSF catheter using data from two large U.S. health systems.
2. Methods
2.1. Study Conception
This study was funded by the National Evaluation System for health Technology Coordinating Center (NESTcc), which is funded by the FDA’s Center for Devices and Radiologic Health (CDRH) to support generation of real-world evidence (RWE) about medical device safety and effectiveness through partnerships with research data network partners, which include Mercy Health and Mayo Clinic. The industry partner in this study, Johnson and Johnson, chose an example of a test case that was clinically relevant to patients who are treated for VT after MI with the newer 56-hole STSF catheter, as compared to the 6-hole ST catheter. An inter-disciplinary team developed the study protocol and statistical analysis plan (SAP), with modifications based on FDA input through two Q-submission meetings and two sets of written comments from the FDA and written responses to FDA comments.
2.2. Study Design
This study compares the rate of safety events experienced with the ThermoCool STSF to a performance goal. The initial plan was a comparison of the ThermoCool STSF and ThermoCool ST catheters. However, covariate balance conducted by an independent statistician with no access to study outcome data did not result in an adequate balance of covariates (the best covariate balancing results: the absolute standardized difference was > 0.20 for 11 variables for the Mercy cohort and 7 for the Mayo Clinic cohort). Subsequently, the study protocol was revised before any outcome analysis was performed to a single-arm retrospective cohort analysis comparing the cumulative incidence of the primary composite safety outcome among patients treated with the device of interest (ThermoCool STSF) to a pre-specified performance goal using combined unadjusted data from two health systems. This study protocol and SAP were posted publicly on the European Network of Centres in Pharmacoepidemiology and Pharmacovigilance (ENCePP) post-authorisation studies Register [11] prior to hypothesis testing. This study was deemed exempt from institutional review board review at Mercy Health and was deemed minimal risk research with a waiver of informed consent at Mayo Clinic.
2.3. Data Sources and Distributed Analytic Model
Data were obtained for the period from January 1, 2014 to April 30, 2021 from the health information technology systems at Mercy and Mayo Clinic, including device data from supply chain systems and clinical data from EHRs.
Analyses were conducted using a distributed analysis model in which each healthcare system analyzed its data using a common analysis plan and common data model, the observational medical outcomes partnership (OMOP) version 5.3.1 for EHR data. This allowed for standardized definition, capture, and integration of all study data elements while allowing each organization to maintain data for the patients who received care within that health care system behind its own firewall and, thus, streamlining the analytic process by averting the need for sharing personal health information. Quality assurance analyses demonstrated identical results between the source and OMOP data at both health systems.
2.4. Inclusion and Exclusion Criteria
We identified patients aged 18 years and older undergoing a first VT ablation (Current Procedural Terminology [CPT] Code 93654 or International Classification of Diseases [ICD]-10-Procedural Coding System [PCS] codes 025K3ZZ, 025L3ZZ, or 025M3ZZ) with coincident codes in any position during the same catheter ablation procedure encounter for VT (ICD-9-Clinical Modification [CM] diagnosis code 427.1 and ICD-10-CM diagnosis code I47.2) as well as a history of MI at any time prior to the index ablation. Use of the ThermoCool STSF or ST catheter was also a requirement; catheters were identified using the unique device identifier in supply chain data. At Mercy, a combination of Healthcare Common Procedure Coding System codes and Mercy-specific charge codes for device billing was also used for devices used before 2016. All patients were required to have ≥ 6 months of encounter history within the EHR of the respective health system prior to the index ablation procedure.
We excluded patients who had undergone prior ablation, had prior heart transplant or long-term heart assist system implantation, whose procedural records indicated use of both study catheters, or for whom the difference between the latest date of follow-up and date of index procedure was < 7 days.
2.5. Outcomes
The primary safety outcome was a composite endpoint of 11 safety events occurring within 7 days post-ablation: death, acute MI, acute stroke, deep venous thrombosis, pulmonary embolus, complete heart block, pericardial effusion with hemodynamic compromise, cardiac perforation, new acute severe mitral or aortic regurgitation, arterial dissection, and/or vascular injury. This 7-day safety composite outcome was based on a clinical trial that evaluated an earlier version of the ThermoCool catheter to treat VT [12].
The primary study objective was to assess safety, not effectiveness. FDA indicated the primary objective should be safety because differences between the two catheters were not expected to affect device effectiveness, while improved cooling irrigation technology of the catheter tip with the ThermoCool STSF could lead to better safety outcomes than with the ThermoCool ST catheter. However, given the anticipated clinical interest in the findings, we examined an exploratory effectiveness outcome: a composite of rehospitalization for VT or heart failure (using primary diagnosis codes) or repeat VT ablation at 6 months and 1 year. This outcome was identified using algorithms of ICD-9 and 10 or CPT codes validated by clinician chart review on a random sample at each health system of patients in a dataset that did not include the study analytic population. Effectiveness outcomes were only ascertained among patients followed within the health system for up to 1 year, as evidenced by encounter records [8].
2.6. Physician-led Safety Event Identification
Patients with any components of this composite safety outcome event were identified by physician chart review after an algorithm of three criteria sensitive for detection of these safety events was applied to the data; criteria were intentionally broad to ensure comprehensive ascertainment of all possible safety outcome events. First, the chart of any patient with a hospitalization/readmission or emergency department visit within 7 days after index ablation was included. Second, the chart of any patient with a length of stay ≥ 48 hours after index ablation was included, since prolonged hospitalization could indicate a complication. Third, the chart of any patient with a diagnosis or procedure code for any event in the composite safety outcome that would not be expected to always lead to a hospitalization/readmission or emergency department visit or length of stay ≥48 hours was included (i.e., deep venous thrombosis, pulmonary embolus, complete heart block, or hematoma and hemorrhage [a component of vascular injury]). A standardized data abstraction form with specific criteria was used for this physician review.
2.7. Covariates
Covariates were patient demographic variables, including age, sex, and race; patient medical history variables based on all available information prior to the index procedure; most current patient body mass index prior to the index procedure; medication-related variables within the 6 months prior to the index procedure; and operator VT ablation volume during the 12 months prior to the index procedure (Table 1).
Table 1.
Baseline Characteristics of Patients Treated with Catheter Ablation for Ischemic Ventricular Tachycardia, Stratified by Health System
| Mercy | Mayo Clinic | |||
|---|---|---|---|---|
| Characteristic | ThermoCool STSF (n=35) | ThermoCool ST (n=23) | ThermoCool STSF (n=35) | ThermoCool ST (n=84) |
| Patient Demographics | ||||
| Age, years | ||||
| <65 | 8 (22.9%) | 11 (47.8%) | 11 (31.4%) | 31 (36.9%) |
| 65–74 | 19 (54.3%) | 7 (30.4%) | 13 (37.1%) | 35 (41.7%) |
| ≥75 | 8 (22.9%) | 5 (21.7%) | 11 (31.4%) | 18 (21.4%) |
| Sex | ||||
| Male | 33 (94.3%) | 19 (82.6%) | 31 (88.6%) | 72 (85.7%) |
| Female | 2 (5.7%) | 4 (17.4%) | 4 (11.4%) | 12 (14.3%) |
| Race | ||||
| White | 34 (97.1%) | 22 (95.7%) | 33 (94.3%) | 79 (94.0%) |
| Non-White | 1 (2.9%) | 1 (4.3%) | 2 (5.7%) | 5 (6.0%) |
| Medical History and Arrhythmia-related Information | ||||
| Elixhauser comorbidity index | ||||
| ≤3 | 0 (0.0%) | 2 (8.7%) | 1 (2.9%) | 5 (6.0%) |
| >3 | 35 (100.0%) | 21 (91.3%) | 34 (97.1%) | 79 (94.0%) |
| Body mass index, kg/m2 | 31.2 (6.1) | 32.1 (5.5) | 32.0 (7.0) | 30.6 (6.7) |
| Body mass index missing | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 5 (6.0%) |
| Congestive heart failure | 35 (100.0%) | 19 (82.6%) | 33 (94.3%) | 74 (88.1%) |
| Stroke, transient ischemic attack, or thromboembolism | 7 (20.0%) | 3 (13.0%) | 7 (20.0%) | 26 (31.0%) |
| Atrial fibrillation | 17 (48.6%) | 13 (56.5%) | 21 (60.0%) | 43 (51.2%) |
| Hypertension | 34 (97.1%) | 20 (87.0%) | 30 (85.7%) | 73 (86.9%) |
| Diabetes mellitus | 16 (45.7%) | 9 (39.1%) | 9 (25.7%) | 24 (28.6%) |
| Anemia | 6 (17.1%) | 3 (13.0%) | 5 (14.3%) | 15 (17.9%) |
| Valve replacement | 1 (2.9%) | 1 (4.3%) | 4 (11.4%) | 10 (11.9%) |
| Ventricular tachycardia-related hospitalizations | 24 (68.6%) | 12 (52.2%) | 26 (74.3%) | 57 (67.9%) |
| Implantable cardioverter defibrillator or pacemaker | 33 (94.3%) | 12 (52.2%) | 31 (88.6%) | 58 (69.0%) |
| Medications Within 6 Months Prior to Index Ablation | ||||
| Class I or III antiarrhythmic drugs | 34 (97.1%) | 17 (73.9%) | 25 (71.4%) | 66 (78.6%) |
| Anticoagulants | 29 (82.9%) | 16 (69.6%) | 21 (60.0%) | 40 (47.6%) |
| Operator and Procedural Characteristics | ||||
| Index year | ||||
| 2014–2018 | 10 (28.6%) | 14 (60.9%) | 5 (14.3%) | 68 (81.0%) |
| 2019–2021 | 25 (71.4%) | 9 (39.1%) | 30 (85.7%) | 16 (19.0%) |
| Operator volume in the 12 months prior to the index procedure | ||||
| <10 | 18 (66.7%*) | 6 (46.2%*) | 16 (45.7%) | 21 (25.0%) |
| ≥10 | 9 (33.3%*) | 7 (53.8%*) | 19 (54.3%) | 63 (75.0%) |
| Missing | 8 (22.9%) | 10 (43.5%) | 0 (0.0%) | 0 (0.0%) |
The percentage was based on data with known values.
2.8. Statistical Analysis
We summarized patient characteristics, overall and by study site. As noted above, the original goal was to conduct a comparative safety study of the ThermoCool ST and STSF catheters. However, none of the covariate balancing approaches achieved acceptable balance using the criteria of the number of covariates with absolute standardized difference ≤0.2 and the average of all covariates’ absolute standardized difference. Therefore, we used an approach previously described [13] for when an appropriate control group cannot be identified; specifically, a single-arm approach comparing the cumulative incidence of the primary composite safety outcome to a performance goal was conducted, with the comparative analysis as exploratory. A performance goal of 15% was chosen for the safety outcome using data pooled across both Mercy and Mayo Clinic; this value represents twice the expected proportion of the primary composite safety outcome in the ThermoCool ST group based on existing clinical and RWE studies [14,15]. The comparison to the performance goal was performed using a simple proportion with exact confidence intervals.
For the exploratory effectiveness outcome, we compared the Kaplan-Meier cumulative incidences of the ThermoCool ST and STSF catheter groups within each health system separately such that the comparative analyses were health system-specific and subsequently averaged across systems using a fixed-effects model with inverse variance weighting. We reported cumulative incidences at 6 and 12 months, as well as the risk differences between the two groups. Patients were censored for loss to follow-up, death, or administrative censoring.
2.9. Sensitivity Analysis
We conducted three sensitivity analyses for the primary composite safety outcome given potential interest in various VT populations. Within both health system’s data, we examined the safety outcome among patients treated with either catheter for VT ablation, regardless of history of prior MI (i.e., the overall VT population). We performed an additional sensitivity analysis among a subgroup of VT patients with history of MI that excluded patients with dilated or other primary cardiomyopathies, with the goal of excluding patients who may have a mixed cardiomyopathy. Additionally, we analyzed the primary safety outcome comparing the ThermoCool STSF group to the ST group using propensity score balanced data using the average treatment effect on the treated weights, with weights trimmed at the 95th percentile. Covariate weighting was performed using Stata, v17 (StataCorp LLC) and outcome analyses using R Studio, v1.4 (R Foundation for Statistical Computing).
3. Results
3.1. Baseline Characteristics
A total of 220 patients met inclusion criteria between January 1, 2014 and April 30, 2021 and 43 were excluded, primarily because they had undergone prior catheter ablation (Supplementary Appendix Tables 1 and 2). The remaining 177 patients, 58 at Mercy and 119 at Mayo Clinic, who underwent ischemic VT ablation were included; 70 received ablation using the ThermoCool STSF catheter (35 at each site) and 107 using the ThermoCool ST catheter.
The mean age was approximately 67 years, 155 (87.6%) were male, and 168 (94.9%) were White (Table 1 and Supplementary Appendix Table 3). One hundred sixty-one (91.0%) had a history of congestive heart failure, 94 (53.1%) atrial fibrillation, 119 (67.2%) prior VT-related hospitalization, and 134 (75.7%) an implantable cardioverter-defibrillator or pacemaker. Overall, of 641 total patients undergoing ablation, including those with ischemic VT or non-ischemic VT, the charts of 160 (25.0%) were reviewed (Supplementary Appendix Table 4).
3.2. Primary Safety Outcome
A primary safety composite outcome event was identified among 3 patients (4.3%; 90% CI, 1.2% – 10.7%), meeting the pre-specified performance goal, p=0.0045 (Table 2). One patient experienced a deep venous thrombosis, one vascular injury, and one pericardial tamponade (Table 3).
Table 2.
Cumulative Incidences of the Primary Composite Safety Outcome Among Patients Undergoing Ablation for Ischemic Ventricular Tachycardia within Unadjusted Data
| Study Group | Safety Events | N | Cumulative Incidence (90% CI) |
|---|---|---|---|
| Mercy | |||
| ThermoCool STSF | 0 | 35 | 0 (0.0%, 8.2%) |
| ThermoCool ST | 0 | 23 | 0 (0.0%, 12.2%) |
| Mayo Clinic | |||
| ThermoCool STSF | 3 | 35 | 8.5% (2.3%, 20.6%) |
| ThermoCool ST | 1 | 84 | 1.1% (0.0%, 5.5%) |
| Mercy and Mayo Clinic combined in the ThermoCool STSF group | |||
| 3 | 70 | 4.3% (1.2%, 10.7%) | |
| P value compared to the performance goal of 15% | 0.0045 | ||
Table 3.
Safety Events Included in the Composite Safety Outcome by Ablation Catheter (covariate-unadjusted data)
| Mercy | Mayo Clinic | |||
|---|---|---|---|---|
| ThermoCool STSF (n=35) | ThermoCool ST (n=23) | ThermoCool STSF (n=35) | ThermoCool ST (n=84) | |
| Safety Events | N (%) | N (%) | N (%) | N (%) |
| Death | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Acute myocardial infarction | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Acute stroke | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Deep venous thrombosis | 0 (0.0%) | 0 (0.0%) | 1 (2.9%) | 0 (0.0%) |
| Pulmonary embolus | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Complete heart block | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Pericardial effusion with hemodynamic compromise | 0 (0.0%) | 0 (0.0%) | 1 (2.9%) | 0 (0.0%) |
| Cardiac perforation | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| New acute severe mitral or aortic regurgitation | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Arterial dissection | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Vascular injury | 0 (0.0%) | 0 (0.0%) | 1 (2.9%) | 1 (1.2%) |
| Number of safety events within 7 days | 0 (0.0%) | 0 (0.0%) | 3 (8.6%) | 1 (1.2%) |
| Number of patients who had safety events within 7 days | 0 (0.0%) | 0 (0.0%) | 3 (8.6%) | 1 (1.2%) |
3.3. Effectiveness Outcome
Within 12-months post-ablation, 5 of 23 patients in the ThermoCool ST group at Mercy were identified as experiencing an effectiveness outcome event (Table 4), with corresponding cumulative incidence of 22.7% (90% CI: 7.9%, 37.4%) (Table 5). Among patients treated with ThermoCool STSF, 7 of 35 patients at Mercy, with a corresponding cumulative incidence of 22.2% (90% CI, 9.9%, 34.5%). The effectiveness outcome risk difference (STSF – ST) at Mercy was −0.4% (90% CI: −25.2%, 24.3%). Similarly, within 12-months post-ablation, 15 of 84 patients in the ThermoCool ST group at Mayo Clinic experiencing an effectiveness outcome event (Table 4), with a corresponding cumulative incidence of 20.2% (90% CI: 12.5%, 27.9%) (Table 5). Among patients treated with ThermoCool STSF, 8 out of 35, with a corresponding cumulative incidence of 32.9% (16.9%, 48.9%). The effectiveness outcome risk difference (STSF – ST) at Mayo Clinic was 12.6% (90% CI: −13.0%, 38.4%). The most common events for patients treated with ThermoCool STSF were rehospitalization for VT and rehospitalization for heart failure (8 of 70 patients for each event). The average risk difference across both institutions was 5.8% (90% CI: −12.0%, 23.7%). Six-month outcomes are also presented in Tables 4 and 5.
Table 4.
Effectiveness Outcome Events by Ablation Catheter (covariate-unadjusted data)
| Mercy | Mayo Clinic | |||
|---|---|---|---|---|
| ThermoCool STSF (n=35) | ThermoCool ST (n=23) | ThermoCool STSF (n=35) | ThermoCool ST (n=84) | |
| Effectiveness Outcome Events | N (%) | N (%) | N (%) | N (%) |
| Within 6 months post index ablation | ||||
| Rehospitalization for VT | 3 (8.6%) | 2 (8.7%) | 2 (5.7%) | 5 (6.0%) |
| Rehospitalization for heart failure | 2 (5.7%) | 2 (8.7%) | 2 (5.7%) | 5 (6.0%) |
| Repeat ablation for VT | 2 (5.7%) | 0 (0.0%) | 2 (5.7%) | 4 (4.8%) |
| Number of effectiveness events † | 7 (20.0%) | 4 (17.4%) | 6 (17.1%) | 14 (16.7%) |
| Number of patients who had effectiveness events | 6 (17.1%) | 4 (17.4%) | 4 (11.4%) | 8 (9.5%) |
| Within 1 year post index ablation | ||||
| Rehospitalization for VT | 3 (8.6%) | 2 (8.7%) | 5 (14.3%) | 10 (11.9%) |
| Rehospitalization for heart failure | 3 (8.6%) | 3 (13.0%) | 5 (14.3%) | 8 (9.5%) |
| Repeat ablation for VT | 2 (5.7%) | 0 (0.0%) | 4 (11.4%) | 5 (6.0%) |
| Number of effectiveness events † | 8 (22.9%) | 5 (21.7%) | 14 (40.0%) | 23 (27.4%) |
| Number of patients who had effectiveness events | 7 (20.0%) | 5 (21.7%) | 8 (22.9%) | 15 (17.9%) |
Duplicate patients may be included due to multiple events in a patient.
Table 5.
Cumulative Incidences and Risk Differences of Composite Effectiveness Outcome between the ThermoCool STSF and ThermoCool ST Catheters at 6 and 12 Months (covariate-unadjusted data)
| Catheter Group | Cumulative Incidence, % (90% CI) |
|---|---|
|
| |
| 6 months | |
| Mercy | |
| ThermoCool STSF | 18.5 (7.2, 29.8) |
| ThermoCool ST | 17.8 (4.5, 31.1) |
| Difference | 0.7 (−20.6, 22.0) |
| Mayo Clinic | |
| ThermoCool STSF | 15.0 (3.6, 26.4) |
| ThermoCool ST | 10.2 (4.6, 15.9) |
| Difference | 4.7 (−10.0, 19.6) |
|
| |
| Mean Difference across both Mercy and Mayo Clinic | 3.4 (−8.8, 15.6) |
| 12 months | |
| Mercy | |
| ThermoCool STSF | 22.2 (9.9, 34.5) |
| ThermoCool ST | 22.7 (7.9, 37.4) |
| Difference | −0.4 (−25.2, 24.3) |
| Mayo Clinic | |
| ThermoCool STSF | 32.9 (16.9, 48.9) |
| ThermoCool ST | 20.2 (12.5, 27.9) |
| Difference | 12.6 (−13.0, 38.4) |
|
| |
| Mean Difference across both Mercy and Mayo Clinic | 5.8 (−12.0, 23.7) |
3.4. Sensitivity Analyses
Among patients receiving VT ablation, regardless of history of prior MI, the combined (Mercy and Mayo Clinic) number of combined safety outcome events in the ThermoCool STSF group was 6 of 150 patients, with a cumulative incidence of 4.0% (90% CI: 1.8%, 7.7%, Supplementary Appendix Table 5). Among the patient subgroup excluding those with dilated or other primary cardiomyopathies, the number of combined safety outcome events in the ThermoCool STSF group was 3 of 53 patients, with a cumulative incidence of 5.7% (90% CI: 1.6%, 14.0%, Supplementary Appendix Table 6). Both analyses demonstrated that the upper bound of the two-sided 90% CI was below 15%.
In the comparative analysis of ThermoCool STSF and ST safety outcomes using propensity score balanced data, the weighted average difference (STSF – ST) across Mercy and Mayo Clinic was 5.6% (Supplementary Appendix Table 7). Confidence intervals could not be calculated because no safety outcome events were identified at Mercy.
4. Discussion
Using data generated in routine clinical care at two large health systems, we determined that the ThermoCool STSF catheter was safe for ablation of ischemic VT relative to a 7-day performance goal derived from the expected rate in the ThermoCool ST catheter group (which is labelled for this indication) based on prior studies. Additionally, the STSF catheter appeared similarly effective at 6 and 12 months as the ThermoCool ST catheter on an exploratory composite effectiveness outcome of rehospitalization for VT or heart failure or repeat VT ablation. These results support continued use of the STSF catheter for ablation of ischemic VT. Further, although data elements can be identified through manual chart review, these results show the strength of leveraging health information technology systems to efficiently evaluate the safety and effectiveness of cardiovascular devices.
Cardiac electrophysiology has seen significant innovation in recent years [7]. FDA seeks to balance patient access to new and developing technology while maintaining public safety [16]. We found that ablations for ischemic VT are being performed with the newer catheter, ThermoCool STSF, despite its lacking an FDA-approved indication. Clinicians may have adopted this catheter in practice for ischemic VT ablation since it offers potential benefits in reducing fluid overload and, potentially, heart failure exacerbation as well as more effective ablation. In our study, rates of rehospitalization for heart failure were numerically lower with the ThermoCool STSF at 6 months compared with the ThermoCool ST. In our study, this device met pre-established safety criteria when used for ischemic VT ablation; the overall safety event rate of 4.3% at 7-days post-ablation compares favorably with a 6.0% rate at 30-days in a large single-center study [17], 9.4% acute complication rate in VT ablation populations with ischemic cardiomyopathy in a meta-analysis of 29 studies [18], and an 11.2% in-hospital rate using national data [15]. This evaluation therefore provides helpful clinical information about safety and effectiveness to physicians considering use of the catheter as well as patients who are being treated with it off-label for ischemic VT ablation.
This study is unique in its use of RWD from both EHR and supply chain data sources to inform a premarket regulatory submission. RWD sources are used in cardiac electrophysiology to inform post-market surveillance [19]; however, premarket indications face different challenges and traditionally have required an investigational device exemption clinical trial application. These studies generally use structured case report forms, which are time-consuming and costly to complete. We estimate that a formal label expansion clinical trial would take at least 3 years and cost at least $10 million, as well as require significant staff time. Additionally, prospective trials focused on clinical outcomes in VT ablation have been prematurely terminated because of challenges in patient enrollment [20]. Although VT ablation is not common and our study population was limited, a strength is that we could examine larger patient populations by pooling health system data. Similar evaluations, even when there is no post-market requirement, through collaborations between industry and health systems can strengthen the medical device ecosystem by ensuring that new indications for use are formally evaluated to ensure that patients are not being exposed to ineffective or unsafe care.
Of the 90 examples of RWE published by FDA that were used for regulatory decision-making, none used electronically extracted EHR data as the only data source for premarket approval devices [21]. Thus, our study advances current scientific approaches through use of RWD, leveraging computable phenotypes for identification of study populations, covariates, and effectiveness outcomes; chart review was only required for safety event identification, thus allowing for a focused, efficient review. Further, our use of a sensitive algorithm for safety event identification only required review, which is time-consuming and labor-intensive, of 25% of charts (instead of all). By developing these processes, the application of large bodies of EHR data to address medical device research questions may be enhanced through common data models that enable distributed analytics. Importantly, the study protocol was registered and posted publicly prior to hypothesis testing [22]. Future studies could also leverage these methods to compare the safety and effectiveness of different ablation catheters.
Our study should be considered in the context of its limitations. First, we defined ischemic VT as based on a history of prior MI; some patients may have had VT that was not due to a prior MI or may have had a mixed (ischemic and non-ischemic) cardiomyopathy that precipitated VT. Our definition differs from definitions used in some clinical trials, which require ischemic VT secondary to a prior myocardial infarction. However, such ascertainments are not possible using RWD without detailed chart review and a history of MI should be a reliable indicator of risk. Additionally, some clinical trials of VT have relied only on a history of MI [23]. Furthermore, results were similar after excluding those with dilated cardiomyopathy in a sensitivity analysis. Second, although safety events might be missed, we used multiple approaches to ensure sensitivity of detection, and physicians subsequently reviewed approximately 25% of all charts for determination of outcome events. Further, the accuracy of the algorithms should not differ between the ThermoCool ST and STSF. Because most safety events were severe and occurred only out to 7 days post-ablation, our criteria, which emphasized detection through hospitalizations and prolonged length of stay, would not be expected to miss such outcomes. Third, we did not perform chart review for effectiveness outcomes because these were exploratory outcomes; however, we employed coding algorithms with acceptable positive predictive value. Fourth, the findings are limited to the catheters examined in this study; other catheters used for VT ablation may have different clinical performance in routine care and be associated with different rates of outcomes for patients.
In conclusion, analysis of health system data demonstrate that the ThermoCool STSF catheter was safe as measuring using a 7-day performance goal and appeared effective for ablation of ischemic VT, supporting continued use and informing possible FDA label expansion.
Supplementary Material
Acknowledgements
This project was supported by a research grant from the Medical Device Innovation Consortium (MDIC) as part of the National Evaluation System for health Technology (NEST), an initiative funded by the U.S. Food and Drug Administration (FDA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views nor the endorsements of the Department of Health and Human Services or the FDA. While MDIC provided feedback on project conception and design, the organization played no role in collection, management, analysis and interpretation of the data. The research team, not the funder, made the decision to submit the manuscript for publication.
Funding for this publication was made possible, in part, by the FDA through grant 1U01FD006292-01. Views expressed in written materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.
We thank Eric Brandt and Sunthosh Parvathaneni, MD, FHRS for their support of this study.
Footnotes
Statements and Declarations
Dr. Dhruva reports research funding from the Medical Device Innovation Consortium (MDIC), Arnold Ventures, National Institute for Health Care Management, and Department of Veterans Affairs. Drs. Zhang, Cafri, and Coplan are employees of Johnson & Johnson; the manufacturer of the ThermoCool catheters is Biosense Webster, which is part of the Johnson & Johnson Family of Companies. Dr. Noseworthy receives research funding from National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Aging, Agency for Healthcare Research and Quality (AHRQ), FDA, and the American Heart Association. He is a study investigator in an ablation trial sponsored by Medtronic. Dr. Noseworthy and Mayo Clinic are involved in potential equity/royalty relationship with AliveCor. Dr. Herrin receives support from the Centers for Medicare and Medicaid Services to develop quality measures; research support from NIH (1R01CA217889-01A1, 1UM1CA233033-01, and 1UG3AT010669-01), Patient-Centered Outcomes Research Institute, and AHRQ (R01 HS022882-02); and support from Delta Airlines. Dr. Ross received research support through Yale University from Johnson & Johnson to develop methods of clinical trial data sharing, FDA to establish Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) program (U01FD005938), MDIC, AHRQ (R01HS022882), NHLBI of the NIH (R01HS025164, R01HL144644), and the Laura and John Arnold Foundation to establish the Good Pharma Scorecard at Bioethics International and to establish the Collaboration for Research Integrity and Transparency at Yale; in addition, Dr. Ross is an expert witness at the request of Relator’s attorneys, the Greene Law Firm, in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen Inc. In the past 36 months, Dr. Drozda has received research support from MDIC, Medtronic, and Johnson & Johnson. His non-dependent son is an employee of Boston Scientific. The remaining authors have nothing to disclose.
Declarations
Ethical approval This study was deemed exempt from institutional review board review at Mercy Health and was deemed minimal risk research with a waiver of informed consent at Mayo Clinic.
Contributor Information
Sanket S. Dhruva, University of California, San Francisco School of Medicine, Section of Cardiology, Department of Medicine, San Francisco Veterans Affairs Medical Center, 4150 Clement St Building 203, 111C, San Francisco, CA 94121, USA.
Shumin Zhang, MedTech Epidemiology and Real-World Data Sciences, Office of the Chief Medical Officer, Johnson & Johnson, New Brunswick, NJ, USA.
Jiajing Chen, Mercy Research, Mercy, Chesterfield, MO, USA.
Peter A. Noseworthy, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Amit A. Doshi, Mercy Clinic, Mercy, St. Louis, MO, USA.
Kolade M. Agboola, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Jeph Herrin, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
Guoqian Jiang, Department of Artificial Intelligence and Informatics, Mayo Clinic, Rochester, MN, USA.
Yue Yu, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Guy Cafri, MedTech Epidemiology and Real-World Data Sciences, Office of the Chief Medical Officer, Johnson & Johnson, New Brunswick, NJ, USA.
Kimberly Collison Farr, Mercy Research, Mercy, Chesterfield, MO, USA.
Mwanatumu S. Mbwana, National Evaluation System for health Technology Coordinating Center (NESTcc), Medical Device Innovation Consortium, Arlington, VA, USA.
Joseph S. Ross, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA.
Paul M. Coplan, MedTech Epidemiology and Real-World Data Sciences, Office of the Chief Medical Officer, Johnson & Johnson, New Brunswick, NJ, USA.
Joseph P. Drozda, Jr., Mercy Research, Mercy, Chesterfield, MO, USA.
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