The First 4 Years of Postmarketing Safety Surveillance Related to the MitraClip Device: A United States Food and Drug Administration MAUDE Experience

Abstract: Objective. The MitraClip (Abbott) is a commercially available device to perform percutaneous transcatheter mitral valve repair (TMVR) for patients with symptomatic mitral regurgitation (MR). Recent data support its role in appropriately selected patients with functional MR, and its use is poised to increase. However, limited safety data in “real-world” practice are available after market introduction. Methods. We queried all available adverse event reports from the publicly available Manufacturer and User Facility Device Experience (MAUDE) database including “injuries” and “deaths” from October 2013 (date of Food and Drug Administration [FDA] premarket approval) to September 2017 using the following search limits: brand name (“MitraClip”) and product code (“NKM,” a unique FDA designation linked to MitraClip). Results. During the first 4 years after FDA approval, MAUDE received 200 death reports and 1666 injury reports containing 2974 unique adverse events. Of all death reports, 21% described deaths occurring >1 year post MitraClip and 30% included limited details. The top three known causes of death included complications requiring rescue high-risk surgery, clip detachment or unsuccessful clip placement, and damage to the valvular apparatus. Similar non-fatal events were reported. Additional procedures or surgical intervention were required in 227 injury events (8%). Conclusions. While injuries reported to the FDA have steadily increased with more widespread use of TMVR, device- or procedure-related death reports have accrued more slowly, corroborating a potential institutional or operator learning curve with this device. However, in light of incomplete and poor data quality, higher-fidelity systems of postmarketing safety surveillance are needed in the evaluation of emerging devices.

J INVASIVE CARDIOL 2020;32(5):E130-E132. Epub 2020 April 9.

Key words: device, mitral regurgitation, postmarketing surveillance, safety

The MitraClip (Abbott) is a commercially available device to perform percutaneous transcatheter mitral valve repair (TMVR) for patients with symptomatic mitral regurgitation (MR). The device was initially approved by the United States Food and Drug Administration (FDA) in October 2013 based on the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) for patients with primary MR at high risk for surgery.¹ Current guidelines recommend the percutaneous edge-to-edge repair in patients with symptomatic severe primary MR who are considered inoperable by the heart team (class IIb).² More recently, the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial demonstrated that TMVR with MitraClip resulted in lower rates of hospitalization for heart failure (HF) and all-cause mortality compared with medical therapy in patients with symptomatic HF and severe secondary MR.³ Subsequently, the FDA approved MitraClip for functional MR in March 2019.⁴ As the use of MitraClip is poised to increase in the United States and worldwide, limited safety data in “real-world” practice are available after market introduction. We leveraged data from the publicly available Manufacturer and User Facility Device Experience (MAUDE) database to identify adverse events complicating device implantation within the first 4 years of FDA approval.

Methods

The MAUDE passive surveillance system collects mandatory (from manufacturers, importers, and device-user facilities) and voluntary (from health-care professionals, patients, and consumers) reports of device-related malfunctions, injuries, or deaths received by the FDA within the last 10 years.⁵ Mandatory reporting is required for deaths or serious injury potentially related to a device. We queried all available adverse event reports including “injuries” and “deaths” from October 2013 (date of FDA premarket approval) to September 2017 using the following search limits: brand name (“MitraClip”) and product code (“NKM,” a unique FDA designation linked to MitraClip).

Results

During the first 4 years after FDA approval, MAUDE received 200 death reports and 1666 injury reports containing 2947 unique adverse events (Figure 1). A single injury report was also submitted as a death report. Median time from death to reporting was 26 days (range, 23-58 days), with 122 (61%) reported within 1 month. Time from injury adverse event to reporting was 23 days (range, 21-25 days), with 1386 (83%) reported within 1 month. Of the 200 death reports, 21% described deaths occurring >1 year post MitraClip and 30% included too few details to ascertain a clear cause of death. The top three known postdevice or postprocedural causes of death included complications requiring rescue high-risk surgery, clip detachment or unsuccessful clip placement, and damage to the valvular apparatus (Figure 2). Similarly, the most common events described in injury reports were single leaflet device attachment, clip detachment, and entanglement in chordae tendineae. Additional procedures or surgical intervention were required in 227 injury events (8%). Less common adverse events included vascular injury (n = 81; 3%), mitral stenosis (n = 36; 1%), and periprocedural stroke or myocardial infarction (n = 26; 1%).

Discussion

In the EVEREST II trial, rates of adverse events occurred at a lower frequency in the MitraClip arm compared with the surgical group. Over 1-year follow-up in the trial, seven cases of leaflet or chordae tears were confirmed on subsequent surgical examination, and no cases of device embolization or significant mitral stenosis were noted.¹ Within the limits of this passive reporting system, these regulatory data highlight the breadth of potential initial adverse events encountered by operators in the first 4 years after market introduction.

Institutional or operator learning curve. While injury reports have steadily increased with more widespread use of TMVR (estimated >12,000 devices used in United States during the study timeframe),⁶ reports of device- or procedure-related deaths have accrued more slowly or even plateaued. Similar to observations with other novel devices or procedures,⁷ ongoing institutional or operator experience may attenuate observed risks of more serious adverse events. Recent data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy registry have corroborated this apparent learning curve. Among 12,334 TMVR procedures performed at 275 sites between November 2013 and September 2017, increasing institutional volume was associated with greater success, shorter procedure duration, and fewer complications.⁶ National initiatives are underway to accredit centers with sufficient experience in performing TMVR.⁸

Study limitations. The MAUDE database is limited given self-reported data, lack of formal event adjudication, delayed and selective reporting, and under-reporting. Unfortunately, current serious adverse event capture is incomplete, with more than half of death reports in our experience reporting deaths occurring >1 year after MitraClip or with limited circumstantial details to facilitate process improvement. Since the exact total number of MitraClip procedures performed in the United States during this period is unknown, we could not report the actual incidence of these adverse events. Based on reported information, it was not possible to determine how many adverse events were related to the off-label use of MitraClip for secondary MR.

Conclusion

In the context of COAPT results and subsequent FDA approval, the MitraClip procedure is likely to be performed at an increasing number of centers with a wide range of operators. These regulatory data from the FDA-MAUDE system corroborate a potential learning curve, with plateauing of serious adverse events (including death) related to TMVR as its use increases nationally. Higher-fidelity, less-selective capture of real-world use and related procedural outcomes are providing parallel information regarding device safety.^9,10 

^*Joint first authors.

From the ¹Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; ²Division of Cardiology, Columbia University Irving Medical Center, New York, New York; ³Division of Cardiology, Ascension Borgess Medical Center, Kalamazoo, Michigan; ⁴Department of Internal Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, Michigan; ⁵Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts; ⁶Division of Cardiovascular Medicine, Massachusetts General Hospital, Boston, Massachusetts; and ⁷Division of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, Nebraska. 

Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Qamar reports support by the NHLBI T32 postdoctoral training grant (T32HL007604) and the American Heart Association Strategically Focused Research Network in Vascular Disease grant (18SFRN3390085 and 18SFRN33960262); grant support through Brigham and Women’s Hospital from Daiichi-Sankyo; personal fees for educational activities from American College of Cardiology, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine, Janssen Pharmaceuticals, Pfizer, Medscape, and Clinical Exercise Physiology Association. Dr Vaduganathan reports support by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541); advisory board income from Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, and Relypsa; clinical endpoint committees for studies sponsored by Novartis and the NIH. The remaining authors report no conflicts of interest regarding the content herein. 

Manuscript submitted September 22, 2019, final version accepted October 2, 2019.

Address for correspondence: Muthiah Vaduganathan, MD, MPH; Brigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School; 75 Francis St, Boston MA 02115. Email: mvaduganathan@bwh.harvard.edu     

1. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study. J Am Coll Cardiol. 2014;64:172-181. 
2. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2017;135:e1159-e1195.
3. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med. 2018;379:2307-2318. 
4. U.S. Food and Drug Administration. FDA approves new indication for valve repair device to treat certain heart failure patients with mitral regurgitation. Available at https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-valve-repair-device-treat-certain-heart-failure-patients-mitral. Published March 14, 2019. Accessed on April 8, 2020.
5. U.S. Food and Drug Administration. MAUDE - manufacturer and user facility device experience. Available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm. Accessed on April 8, 2020.
6. Chhatriwalla AK, Vemulapalli S, Holmes DR Jr, et al. Institutional experience with transcatheter mitral valve repair and clinical outcomes: insights from the TVT registry. JACC Cardiovasc Interv. 2019;12:1342-1352.
7. Vaduganathan M, DeFilippis EM, Fonarow GC, Butler J, Mehra MR. Postmarketing adverse events related to the CardioMEMS HF system. JAMA Cardiol. 2017;2:1277-1279.
8. American College of Cardiology. Transcatheter valve certification. Available at https://cvquality.acc.org/accreditation/services/TCV. Accessed on April 8, 2020.
9. Sorajja P, Mack M, Vemulapalli S, et al. Initial experience with commercial transcatheter mitral valve repair in the United States. J Am Coll Cardiol. 2016;67:1129-1140.
10. Ailawadi G, Lim DS, Mack MJ, et al. One-year outcomes after MitraClip for functional mitral regurgitation. Circulation. 2019;139:37-47.