Letters

1. Goldberg AE, Vijenthira A, Wong BM. Failure to cancel tests: a case of an unnecessary joint arthrocentesis: a teachable moment. JAMA Intern Med. 2015; 175(6):891-892.

The True Environmental Cost of Chlorofluorocarbon-Based Inhalers To the Editor It was with apprehension that I read the interesting and sobering analysis by Jena et al1 and commentaries2,3 on the health care and/or cost consequences of the decision of the US Food and Drug Administration (FDA) to ban chlorofluorocarbon (CFC)-based metered-dose inhalers (MDI) in order for the United States to comply fully with the Montreal Protocol. I participated as a panel member of the FDA advisory committee meeting in 2004 and chaired a follow-up meeting in 2005 convened to discuss the issues ahead of their final ruling later that year. The panel members and I were quite concerned about the implications of placing the cost of this laudable environmental goal on the backs of economically disadvantaged Americans with little or no health insurance given the fractured and chaotic state of health care access in the United States and the anticipated higher price of alternative non-CFC MDIs. The goal of complete cessation of CFC use had become a high priority of the government (in particular, the US State Department and Environmental Protection Agency) and was strongly supported by those pharmaceutical manufacturers, which already had more expensive hydrofluorocarbon and other nonCFC propellant-driven MDIs on the market. The FDA was tasked with finding CFC alternatives unless 3 essential aspects were met: (1) that no technically feasible alternative existed, (2) a substantial health benefit was being met, and (3) the release of CFCs was small. No considerations of price, adverse health consequences, or an exact definition of “small” were included in the criteria. Other Western or first-world countries with more comprehensive health insurance coverage and cost controls could readily afford to switch to inhalers with non-CFC propellants, but we in the United States had to rely on the goodwill of the several pharmaceutical manufacturers who individually proposed that they would make their newer MDIs readily available and affordable to poor Americans through vouchers and rebates. These, however, would necessitate physicians and patients having to apply and seek this price relief, which is a difficult hurdle for busy physicians and poor patients. As a member of the advisory committee, I voted to support to phase out CFC MDIs where alternatives existed with the hope that access and affordability would not be problematic. To gain a better perspective on the environmental consequence of such a small health-use exemption, I asked the following question to the experts at the meeting who claimed that it would take 50 years for the Austral ozone hole to completely close after all use of CFCs in refrigeration, air conditioning, and other industrial uses in the United States and elsewhere had been eliminated. “How much longer would it take if the quantitatively trivial use of CFCs in MDIs were continued until non-CFC generics might become available?” The answer: roughly another week. Erik R. Swenson, MD jamainternalmedicine.com

Author Affiliation: Pulmonary and Critical Care Medicine, VA Puget Sound Health Care System, University of Washington, Seattle. Corresponding Author: Erik R. Swenson, MD, VA Puget Sound Health Care System, Department of Medicine, 1660 S Columbian Way, Seattle, WA 98108 ([email protected]). Conflict of Interest Disclosures: None reported. Editorial Note: This letter was shown to the corresponding author of the original article, who declined to reply on behalf of the authors. 1. Jena AB, Ho O, Goldman DP, Karaca-Mandic P. The impact of the US Food and Drug Administration chlorofluorocarbon ban on out-of-pocket costs and use of albuterol inhalers among individuals with asthma. JAMA Intern Med. 2015;175 (7):1171-1179. 2. Ross JS, Redberg RF. On chlorofluorocarbon bans and inhaled albuterol prices. JAMA Intern Med. 2015;175(7):1179. 3. Redberg RF. Not breathing easier with the US FDAs ban on chlorofluorocarbon use in inhalers. JAMA Intern Med. 2015;175(7):1086.

LESS IS MORE

The Lariat for Left Atrial Appendage Closure: Rehash of Known Literature or a True Analysis? To the Editor We read with great interest the recent review of a small body of literature in JAMA Internal Medicine by Chatterjee et al.1 The implication by Chatterjee et al that somehow the US Food and Drug Administration (FDA) was lax in their approval of 510(k) class II status for the Lariat snare device (SentreHeart Inc) is perplexing. It is not unusual for device manufacturers to obtain marketing authorization for one use and then seek additional indications for a different use based on clinical need. Clinical scenarios often force physicians to make choices using clinical tools based on medical necessity. Those of us who have seen devastating bleeding complications from oral anticoagulation or strokes from failed anticoagulation strategies have chosen to close the left atrial appendage (LAA) with a device that is capable of doing the job with a high rate of complete closure.2 Many patients we have ligated with a Lariat had no choice other than open heart surgery or to stop their anticoagulation, which would leave them vulnerable to an atrial fibrillation (AF)-related stroke. Most cases where the Lariat is used off-label are “compassionate” cases that have no other FDA-approved alternative. Pulmonary vein isolation had similar issues when AF ablation started with 20% to 30% complications related to a radiofrequency ablation catheter that had not been approved for AF ablation at the time. Angioplasty endured decades of trials and tribulations to advance to where it is today. New data have been reported at major meetings demonstrating the merits of LAA ligation and stroke prevention in AF patients with contraindications to oral anticoagulation therapy.3-5 Additionally, the merits of LAA ligation to improve catheter ablation in treating persistent AF has been reported. Based on this growing body of beneficial evidence of LAA ligation, engagement with the FDA to initiate pivotal clinical trials to warrant labeling of the device beyond the soft tissue closure of the LAA are currently being undertaken. As with any new technology, there is a learning curve time period when the periprocedural difficulties get worked out. Improvements in techniques, micropuncture needles for access, and postprocedure management have markedly improved outcomes.6 (Reprinted) JAMA Internal Medicine November 2015 Volume 175, Number 11

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Using any device off-label is solely the responsibility of the physician and his or her relationship with the patient. In many contexts, using a device off-label is appropriate, regardless of the lack of randomized clinical trial data. Personal confidence in the tool, proper patient selection, and the right skill set are all requisite. However, we do agree with the authors that robust, prospective data, which are fortunately forthcoming, are needed. It is premature to conclude that Lariat is not safe and effective. Hosakote Nagaraj, MD David Wilber, MD Dhanunjaya R. Lakkireddy, MD Author Affiliations: Nebraska Heart Institute, Lincoln (Nagaraj); Division of Cardiovascular Medicine, Loyola University Medical Center, Chicago, Illinois (Wilber); Cardiovascular Research Institute, University of Kansas Hospital, Kansas City (Lakkireddy). Corresponding Author: Dhanunjaya R. Lakkireddy, MD University of Kansas Cardiovascular Research Institute, University of Kansas Hospital, 3901 Rainbow Blvd, Kansas City, KS 66160 ([email protected]). Conflict of Interest Disclosures: Dr Wilber is an advisory board member and a steering committee member with SentreHeart Inc. Dr Lakkireddy is a consultant for St Jude Medical, Biosense Webster, Janssen, Pfizer, Bristol-Myers Squibb, and is an advisory board member and a steering committee member with SentreHeart Inc. No other conflicts are reported. 1. Chatterjee S, Herrmann HC, Wilensky RL, et al. Safety and procedural success of left atrial appendage exclusion with the lariat device: a systematic review of published reports and analytic review of the FDA MAUDE database. JAMA Intern Med. 2015;175(7):1104-1109. 2. Pillarisetti J, Reddy YM, Gunda S, et al. Endocardial (Watchman) vs epicardial (Lariat) left atrial appendage exclusion devices: understanding the differences in the location and type of leaks and their clinical implications. Heart Rhythm. 2015;12(7):1501-1507. 3. Lee RJ, Rasekh A, Bartus K, et al Atrial fibrillation patients with contraindications to oral anticoagulation therapy treated with LAA ligation: initial long-term clinical outcomes. Paper presented at: Heart Rhythm Meeting; May 7 to May 10, 2014; San Francisco, CA. 4. Gafoor S, Sievert H, Franke J, et al LARIAT experience in patients contraindicated to anticoagulation. Paper presented at: Transcatheter Cardiovascular Therapeutics; November 14, 2014; Washington, DC. 5. Lakkireddy D, Sridhar AM, Kanmanthareddy A, et al. Left atrial appendage ligation and ablation for persistent atrial fibrillation: the LAALA-AF registry. JACCCEP. 2015;1(3):153-160. 6. Gunda S, Reddy M, Pillarisetti J, et al. Differences in complication rates between large bore needle and a long micropuncture needle during epicardial access: time to change clinical practice? May 15, 2015. http://www.researchgate .net/publication/278732334_Differences_in_Complication_Rates_between _Large_Bore_Needle_and_a_Long_Micropuncture_Needle_during_Epicardial _Access_-_Time_to_Change_Clinical_Practice. Accessed September 8, 2015.

To the Editor In their systematic review of the Lariat (SentreHeart Inc) left atrial appendage (LAA) ligation system, Chatterjee et al1 question the safety classification of the device, citing adverse events recorded in the US Food and Drug Administration’s (FDA) Manufacturer and User Facility Device Experience (MAUDE) database.1 While true complication rates cannot be ascertained from the MAUDE database, more than 3000 Lariat devices have been implanted in the United States since FDA approval in 2008 (email communication with a SentreHeart Inc representative, July 22, 2015), providing some perspective for the magnitude of adverse events reported by Chatterjee et al. Further1868

more, review of the MAUDE database for Lariat-related adverse events through June 2015 implicates operator error in 6 of 45 case reports (13%), including 3 LAA transections resulting from device withdrawal against resistance or before suture cutting, suggesting that inadequate operator training likely contributed to events. Surgery was required in another patient after Lariat ligation was attempted despite anatomical contraindications. This indicates that rigorous operator training protocols and improved patient selectivity would readily effect complication rates. Safety concerns of the WATCHMAN (Boston Scientific) device were addressed by implementing similar measures, accomplishing step-wise improvements in procedural safety, reflected in the PREVAIL trial of the WATCHMAN.2 The critique by Chatterjee et al of the FDA’s 510(k) process for Lariat approval relies heavily on their MAUDE database analysis. Interestingly, since FDA approval in March 2015, 5 WATCHMAN device embolizations and 3 procedural deaths have been recorded in the MAUDE database. Comparatively, in the randomized clinical PREVAIL trial of the WATCHMAN device, only 2 device embolizations and no procedural deaths were reported after 252 implants, reflecting that real-world use risks are not readily identified in clinical trials. Reviewing approximately 3000 510(k) applications annually, the FDA balances prompt integration of scientific innovations with ensuring safety of approved devices, recognizing that all offlabel device uses cannot be contemplated within their framework.3 Nevertheless, system safeguards like the MAUDE database are an effective mechanism for continued device surveillance. Current MAUDE database information regarding Lariat events, however, appears inconclusive and inadequate to make new determinations regarding the device. The Lariat’s epicardial approach provides unique benefits compared with endocardial occlusion. Lariat ligation achieves both mechanical and electrical isolation of the LAA and a reduction in atrial fibrillation burden with implications for affecting the underlying disease process.4 A lesser residual jet compared with successful WATCHMAN closure is accomplished with Lariat ligation.2,4 The availability of complementary LAA exclusion devices best serves the clinically and anatomically diverse spectrum of atrial fibrillation patients and provides the greatest opportunity for advancement of LAAdirected stroke prevention therapy. Mukta C. Srivastava, MD Vincent Y. See, MD Author Affiliations: Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore. Corresponding Author: Mukta C. Srivastava, MD, Department of Medicine, Division of Cardiovascular Medicine, University of Maryland School of Medicine, 110 South Paca St, Baltimore, MD 21201 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Chatterjee S, Herrmann HC, Wilensky RL, et al. Safety and procedural success of left atrial appendage exclusion with the lariat device: a systematic review of published reports and analytic review of the FDA MAUDE database. JAMA Intern Med. 2015;175(7):1104-1109. 2. Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64(1):1-12.

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3. Wizemann T. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press; 2010. 4. Afzal MR, Kanmanthareddy A, Earnest M, et al. Impact of left atrial appendage exclusion using an epicardial ligation system (LARIAT) on atrial fibrillation burden in patients with cardiac implantable electronic devices. Heart Rhythm. 2015;12(1):52-59.

In Reply We thank Nagaraj et al for their interest and thoughtful commentary. We do not feel that the US Food and Drug Administration (FDA) was lax in their clearance of the Lariat (SentreHeart Inc) device as a 510(k) class II device. Rather, the organization appears to have been misinformed regarding the primary intended use of the device—closure of the left atrial appendage (LAA)—and unfortunately did not yet have a mechanism in place to track real-world usage of the device to discover this primary intended use. The FDA has set prior precedent that novel LAA closure devices are class III (ie, high-risk) devices and require full premarket approval supported by clinical data derived from investigational device exemption (IDE) trials.1 Nagaraj et al state that most Lariat procedures were used for compassionate cases where no other treatment alternative was available. While this may be true in their practice, published literature2 has demonstrated that a large proportion of Lariat patients had not reported a prior complication of anticoagulation therapy, calling into question this assumed practice pattern. Additionally, the FDA has a mechanism in place for compassionate use of investigational devices prior to formal approval for a given indication. Importantly, clearance of the Lariat through the 510(k) pathway allowed the manufacturer to avoid seeking an investigational device exemption for their product. Hence, even for physicians who may have sought to use the device under compassionate use circumstances, there was no mechanism for consultation with the FDA regarding this because the product was not considered an investigational device. Nagaraj et al cite examples of other cardiac procedures whose early evolutions took place in the absence of formal FDA premarket approval studies. It is our contention that patients, physicians, and society benefit from rigorous safety and efficacy evaluations of novel high-risk cardiovascular devices prior to their widespread usage. When evidence is unavailable, as in the case of the Lariat, physicians are impaired in their ability to make optimal clinical decisions and properly inform patients of the risks and/or benefits of high-risk procedures. While we agree with Nagaraj et al that the safety of the Lariat procedure may improve with operator experience, we are not aware of any adequately powered analyses evaluating the “learning curve” associated with this procedure. We also agree that it is premature to comment on safety and efficacy of the Lariat in comparison to alternative therapeutic modalities, as there have been no comparative effectiveness studies of the device performed to date. We were gratified to see that 7 weeks after publication of our article, the first randomized IDE trial3 evaluating the Lariat device for LAA occlusion was announced by the manufacturer and congratulate Dr Lakkireddy et al on leading this important effort. As the Lariat will soon enter the FDA IDE trial process, a mechanism for compassionate use of the device should also soon exist with possible FDA preapproval of individual cases. jamainternalmedicine.com

We thank Drs Srivastava and See for their interest and clarifying the total number (>3000) of Lariat procedures performed domestically over the past 7 years. We continue to be alarmed that a novel high-risk cardiovascular procedure achieved such widespread use prior to evaluation of its safety and efficacy. Srivastava and See point out that some device complications may have been caused by inadequate operator training. Given the complexity of the Lariat procedure, this is a reasonable assumption. Universal off-label use of the device may contribute to this issue as a formal infrastructure for device training may be nonexistent or slow to develop. The authors state that current Manufacturer and User Facility Device Experience database information regarding Lariat events is inadequate and inconclusive. While we agree that commentary regarding the relative risks and/or benefits of the device in comparison to alternative therapies is currently impossible, the data presented in our manuscript strongly call into question the 510(k) clearance of the device under an intermediate-risk designation. This contention has recently been validated with the issuance of an FDA safety communication regarding use of the Lariat for LAA closure.4 Srivastava and See point out that greater risks are sometimes seen in real-world clinical practice than in clinical trials with novel devices. We agree with this important point and support the recently published consensus statement from several cardiology societies that recommend ongoing surveillance of the field of LAA closure within a multidevice national registry similar to that already in existence for transcatheter heart valve therapies.5 Finally, we agree that future patients may benefit from alternative therapies to close the LAA tailored to their unique anatomical and clinical circumstances. We are hopeful that the Lariat and other future investigational devices prove safe and effective in randomized trials justifying their use for this indication. Saurav Chatterjee, MD Jay Giri, MD, MPH Author Affiliations: Division of Cardiology, St Luke’s-Roosevelt Hospital, Mount Sinai Health System, New York, New York (Chatterjee); Cardiovascular Medicine Division, University of Pennsylvania Perelman School of Medicine, Philadelphia (Giri). Corresponding Author: Jay Giri, MD, MPH, Cardiovascular Medicine Division, Hospital of the University of Pennsylvania, 3400 Spruce St, Gates Pavilion, Ninth Floor, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Department of Health & Human Services. WATCHMAN FDA approval letter. http://www.accessdata.fda.gov/cdrh_docs/pdf13/p130013a.pdf 2015. Accessed August 16, 2015. 2. Chatterjee S, Herrmann HC, Wilensky RL, et al. Safety and procedural success of left atrial appendage exclusion with the lariat device: a systematic review of published reports and analytic review of the FDA MAUDE database. JAMA Intern Med. 2015;175(7):1104-1109. 3. Lakkireddy D, Sridhar AM, Kanmanthareddy A, et al. Left atrial appendage ligation and ablation for persistent atrial fibrillation: the LAALA-AF registry. JACCCEP. 2015;1(3):153-160. 4. US Food and Drug Administration. FDA public health notification: radiofrequency ablation of lung tumors - clarification of regulatory status. http://www.fda.gov /MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm061985 .htm. Updated August 6, 2015. Accessed August 9, 2015.

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5. Masoudi FA, Calkins H, Kavinsky CJ, et al. 2015 ACC/HRS/SCAI left atrial appendage occlusion device societal overview: a professional societal overview from the American College of Cardiology, Heart Rhythm Society, and Society for Cardiovascular Angiography and Interventions. Catheter Cardiovasc Interv. 2015;2015(Aug):7.

US Department of Veterans Affairs Primary Care Provider Turnover and Patient Satisfaction To the Editor Reddy et al1 found no clinical quality effect, but a modest reduction in patient satisfaction, associated with a US Department of Veterans Affairs (VA) patient experiencing primary care provider (PCP) turnover. On average, the PCP change occurred 1.5 years before quality and satisfaction were measured in 2010 to 2012. Relevant alternative policy explanations other than those offered by Reddy et al should be considered. First, fewer than 30% of VA enrollees are exclusively reliant on the VA for ambulatory care,2,3 and even patients who obtain primary care within the VA get more of their primary care outside of the VA, through other insurance.4 Because testing performed, cancer screening done, and effective care management provided outside of the VA all contribute to VA quality scores, it should not be surprising that changing a patient’s VA PCP did not affect quality metrics. Second, during the study’s duration, VA PCP turnover rates were about 15% per year, excluding transfers of PCPs to a different VA. Turnover rates also accelerated, in part because of implementation of a new patient-centered medical home initiative.5 Also, between 2010 and 2012, VA enrollees’ satisfaction with the VA declined. In national surveys,2,3 the proportion of respondents who agreed or completely agreed that “veterans like me are satisfied with the health care they receive” dropped from 73.7% to 67.5% and those who agreed that “VA health care providers treat their patients with respect” declined from 83.5% to 78.9%. Perhaps the new VA PCPs to whom patients are reassigned actually interact with patients less effectively than previous PCPs did. The Veterans’ Access to Care Through Choice, Accountability, and Transparency Act of 2014 seeks to improve veterans’ access to care by filling long-standing PCP shortages and improving private sector care access for some VA users. The study by Reddy et al1 suggests that VA administrators should ensure that newly hired PCPs are respectful and customer oriented. Furthermore, the study might encourage VA policy makers to consider adopting recently suggested insurer roles vis-à-vis their patient population by outsourcing more care.6 Because VA PCP changes do not appear to affect quality, their replacement with private sector PCPs might not either. Nonetheless, studies exploring how satisfaction and quality scores change among VA enrollees who obtain free, local, high-quality, private sector primary care through the 2014 Act are needed to determine the best future role for the VA from VA patients’ perspective. William B. Weeks, MD, PhD, MBA Author Affiliation: The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, New Hampshire. Corresponding Author: William B. Weeks, MD, PhD, MBA, The Dartmouth Institute for Health Policy and Clinical Practice, 307 River Rd, Rm 3264, Lyme, NH 03768 ([email protected]). 1870

Conflict of Interest Disclosures: None reported. 1. Reddy A, Pollack CE, Asch DA, Canamucio A, Werner RM. The effect of primary care provider turnover on patient experience of care and ambulatory quality of care. JAMA Intern Med. 2015;175(7):1157-1162. 2. Veterans Health Administration Office of the Assistant Deputy for Health for Policy and Planning. 2011 Survey of Veteran Enrollees' Health and Reliance upon VA. http://www.va.gov/HEALTHPOLICYPLANNING/SOE2011/SoE2011_Report.pdf. 2011. Accessed May 19, 2015. 3. Veterans Health Administration Office of the Assistant Deputy for Health for Policy and Planning. 2013 Survey of Veteran Enrollees' Health and Reliance upon VA. http://www.va.gov/HEALTHPOLICYPLANNING/SOE2013/2013_VHA _SoE_Full_Findings_Report_062414.pdf. 2013. Accessed May 19, 2015. 4. Weeks WB, Mahar PJ, Wright SM. Utilization of VA and Medicare services by Medicare-eligible veterans: the impact of additional access points in a rural setting. J Healthc Manag. 2005;50(2):95-106. 5. Sylling PW, Wong ES, Liu CF, et al. Patient-centered medical home implementation and primary care provider turnover. Med Care. 2014;52(12): 1017-1022. 6. Weeks WB, Auerbach D. A VA exit strategy. N Engl J Med. 2014;371(9):789-791.

In Reply Dr Weeks raises important points about limitations of our article and interpretation of results. First, there are many possible explanations for our findings. Dr Week’s assertion that veterans are not solely reliant on the US Department of Veterans Affairs (VA) for primary care services is a notable concern. This suggests that our measure of continuity of care may be incomplete due to care received outside of the VA. When an outside primary care provider (PCP) completes a quality measure, such as a cancer screening, it must be transmitted and recorded in the VA electronic health record. But we have no measure of the continuity of care received outside of the VA. If veterans received more continuous care outside of the VA, the correlation between continuity and ambulatory quality could be higher than we estimated. Second, PCP turnover was high and increased during our study period. Evidence from other large-scale patient-center medical home demonstration projects has also shown increasing burnout and turnover during initial implementation.1 At the same time veteran experience of care was declining. To our knowledge, ours is the first study to tie these 2 events together— when a veteran experiences a PCP turnover, their experience of care was lower. Finally, Dr Weeks presents the question of how the Veterans’ Access to Care Through Choice, Accountability, and Transparency Act of 2014 will affect veteran experience of care, suggesting our study implies that newly hired PCPs should be respectful and consumer oriented. We agree that all PCPs should be respectful and consumer oriented. We also think that the VA could do more to decrease PCP turnover by focusing on interventions that reduce PCP burnout. Recent evidence suggests that key elements of team-based care are associated with lower burnout in the VA, including appropriate staffing, having staff work at the top of their competency, and putting an emphasis on participatory decision making. Instilling these standards could help reduce PCP burnout and improve patient quality and experience of care.2 Ashok Reddy, MD, MSPH Rachel Werner, MD, PhD

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The Lariat for Left Atrial Appendage Closure: Rehash of Known Literature or a True Analysis?

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