NCA - Cardiac Pacemakers: Single-Chamber and Dual-Chamber Permanent Cardiac Pacemakers (CAG-00063R3) - Decision Memo

V. Food and Drug Administration (FDA) StatusThe class to which a device is assigned determines, among other things, the type of premarketing submission/application required for FDA clearance to market.  If a device is classified as Class I or II, and if it is not exempt, a 510k will be required for marketing.  For Class III devices, a premarket approval application (PMA) is required for marketing.  Pacemakers that are currently developed which are considered similar to predicate devices are cleared through the 510k process.  The FDA approves pacemakers for sino-atrial node dysfunction (e.g. sinus bradycardia, sinus arrest) and AV node dysfunction including second or third degree AV node block.VI.  General Methodological PrinciplesWhen making national coverage determinations under 1862(a)(1)(A), CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.  The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.  An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.A detailed account of the methodological principles of study design that the agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.  In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, the blinding of readers of the index test, and reference test results.  Public comments sometimes cite the published clinical evidence and give CMS useful information.  Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination.  Public comments that contain personal health information (PHI) will be redacted and the PHI will not be made available to the public.  CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum.VII.  EvidenceA.IntroductionIn this coverage analysis, we considered evidence for single or dual chamber permanent cardiac pacemakers for the treatment of symptomatic bradycardia.  Important health outcomes include mortality, morbidity (including adverse events), and quality of life (QOL).  Increased survival has been demonstrated with initial use of single chamber pacemakers.  The first patient to receive an implanted pacemaker was able to leave the hospital and lead a moderately active life for more than two years after receiving the implant.  Given the past research and evidence on survival from use of permanent pacemakers, our analysis focuses on mortality, but also emphasizes other health outcomes.  We note that while quality of life is an important health outcome, it is more difficult to objectively measure and discern potential bias in the reported studies.B. Literature SearchCMS searched PubMed from February 2004 (date of the last NCD) to December 2012 using key words pacemakers, single and dual.  We initially focused our search on randomized controlled trials (RCTs) and large prospective observational studies that evaluated adults  65 years.  Observational studies with sample sizes less than 50 cases were excluded as they may have inherent biases that substantially limit generalizability.  Abstracts, presentations, and articles not written in English were also excluded. In addition to our search, the requestors submitted 100 article summaries which were reviewed; seventeen articles met our criteria and were included in our review (five randomized trials, one randomized controlled comparison, one technology appraisal, one meta-analysis, two evidence reviews, one follow-up analysis of a randomized trial, one registry analysis, one secondary outcome analysis, three evidence-based guidelines, and one consensus statement).CMS does not consider cost when developing NCDs under 1862(a)(1)(A).  Some of the studies included in our review evaluated cost-effectiveness; however, CMS analysis did not rely on cost-effectiveness, nor did any cost effectiveness information impact the decision.C. Discussion of Evidence ReviewedQuestion:Is the evidence sufficient to determine that implantation and use of permanent single chamber or dual chamber cardiac pacemakers improve health outcomes in Medicare beneficiaries?1. External technology assessmentCastelnuovo E, Stein K, Pitt M, Garside R, Payne E. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation. Health Technol Assess 2005;9(43).Castelnuovo and colleagues reported the results of an evidence review (UK HTA:  United Kingdom health technology assessment) to estimate the effectiveness and cost effectiveness of dual-chamber pacemakers versus single-chamber atrial or single-chamber ventricular pacemakers in the treatment of bradycardia due to sick sinus syndrome (SSS) or atrioventricular block (AVB).  Patients with a primary diagnosis of acquired symptomatic bradycardia, secondary to SSS, AVB, or chronic bifascicular block, and individuals with symptomatic bradycardia in secondary and tertiary care centers were included.  Eligible studies were systematic reviews and randomized trials.  Non-randomized studies, case control, and cohort studies were excluded.  Outcomes were mortality (all-cause and cardiovascular), stroke, atrial fibrillation (AF), heart failure, exercise capacity, symptoms of breathlessness, fatigue, chest pain, dizziness, palpitations, sleep disturbance, functional status, QOL, adverse events of implantation (perioperative mortality and non-fatal complications), and pacemaker syndrome.Two evidence reviews, four parallel group randomized controlled trials (RCTs) (the Canadian Trial of Physiologic Pacing (CTOPP), the Mode Selection Trial (MOST), the Pacemaker Selection in the Elderly (PASE), and United Kingdom Pacing and Cardiovascular Events (UKPACE)) and 28 cross-over trials were included in the evidence review.  The authors reported: Dual chamber pacing was associated with lower rates of atrial fibrillation, particularly in SSS, than ventricular pacing, and prevents pacemaker syndrome.  Higher rates of atrial fibrillation were seen with dual-chamber pacing than with atrial pacing.  Complications occurred more frequently in dual-chamber pacemaker insertion.  They concluded: Dual-chamber pacing results in small but potentially important benefits in populations with SSS and/or AVB compared with ventricular pacemakers.Dretzke J, Toff WD, Lip GYH, Raftery J, Fry-Smith A, Taylor RRS. Dual chamber versus single chamber ventricular pacemakers for sick sinus syndrome and atrioventricular block. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.:CD003710. DOI: 10.1002/14651858.CD003710.pub2.Dretzke and colleagues reported the results of an evidence review (the Cochrane review) to assess the short- and long-term clinical effectiveness of dual chamber pacemakers compared to single chamber ventricular pacemakers in adults with AV block, sick sinus syndrome or both.  Patients 18 years and older with SSS and/or AVB were included.  Eligible studies were randomised controlled trials of either parallel group or crossover design comparing single chamber ventricular pacing with dual chamber pacing, or single chamber atrial pacing with dual chamber pacing.  Primary outcomes were cardiovascular mortality or all-cause mortality and cardiovascular morbidity (pacemaker syndrome, AF, stroke or heart failure).Up to year 2002, five parallel (CTOPP, MOST, PASE, 1 trial on tachyarrhythmia, 1 trial on AF) and 26 cross-over randomized controlled trials were included in the review.  The authors noted that quality of reporting was found to be poor and reported: Pooled data from parallel studies shows a statistically non-significant preference for physiologic pacing (primarily dual chamber pacing) for the prevention of stroke, heart failure and mortality, and a statistically significant beneficial effect regarding the prevention of atrial fibrillation (odds ratio (OR) 0.79, 95% CI 0.68 to 0.93).  Both parallel and crossover studies favour dual chamber pacing with regard to pacemaker syndrome (parallel: Peto OR 0.11, 95% CI 0.08 to 0.14; crossover: standardised mean difference (SMD) -0.74, 95% CI -0.95 to -0.52).  Pooled data from crossover studies shows a statistically significant trend towards dual chamber pacing being more favourable in terms of exercise capacity (SMD -0.24, 95% CI -0.03 to -0.45).  No individual studies reported a significantly more favourable outcome with single chamber ventricular pacing.  They concluded: This review shows a trend towards greater effectiveness with dual chamber pacing compared to single chamber ventricular pacing, which supports the current British Pacing and Electrophysiology Groups Guidelines regarding atrioventricular block.  Additional randomised controlled trial evidence from ongoing trials in this area will further inform the debate.Grenouilleau-Albertini A, Copie X, Mabo P, et al. Single or dual-chamber pacemakers? The guidelines of the HAS. Archives of Cardiovascular Diseases Supplements. 2010; 2: 61-74.Grenouilleau-Albertini and colleagues (HAS: Haute Autorit de Sand (French:  High Authority for Health)) reported the results of a technology appraisal to assess single and dual-chamber pacemakers with a view to updating their reimbursement conditions by French National Health Insurance.  They analyzed 1 health technology assessment, 1 meta-analysis, 3 guidelines and 3 randomised controlled trials.  Inclusion and exclusion criteria were not reported.  They found: Pacing mode did not reduce mortality or heart failure hospitalizations.  Compared with ventricular pacing, atrial-based pacing (physiologic modes) reduced stroke and atrial fibrillation (AF).  There was a significant reduction in the composite outcome of stroke or cardiovascular mortality, but only among patients with SSS.  Results of QOL, exercise capacity, functional status and pacemaker syndrome are variable.  They concluded: HAS recommends generally implanting a single chamber pacemaker for the management of bradycardia. Dual-chamber pacemakers (DDDR) have to be reserved for 2 situations: (i) SSS with evidence of impaired atrioventricular conduction, (ii) permanent AVB without AF.  HAS will not recommend that pacemakers with specific algorithms for minimal ventricular pacing be systematically used instead of single-chamber pacemakers in patients presenting with SSS or paroxysmal AVB, unless more clinical trials are performed.Healey JS, Toff WD, Lamas GA, Andersen HR, Thorpe KE, Ellenbogen KA, Lee KL, Skene AM, Schron EB, Skehan JD, Goldman L, Roberts RS, Camm AJ, Yusuf S, Connolly SJ. Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data. Circulation. 2006 Jul 4;114(1):11-7. Epub 2006 Jun 26.Healey and colleagues reported the results of a meta-analysis to determine whether atrial-based pacing prevents major cardiovascular events compared to ventricular pacing.  Randomized trials from 1990 were included.  Trials on multisite pacing and follow-up less than six months were excluded.  Outcomes were clinical events, mortality, stroke, heart failure, and AF.  Of the eight trials that met inclusion criteria, five trials had available patient level data and were included in the analysis (n = 758 patients with average follow-up of two years; 35000 patient years of follow-up).  Mean age of participants in the trials ranged from 73 to 80 years.  The authors reported: There was no significant reduction in mortality (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.87 to 1.03; P 0.19) or heart failure (HR, 0.89; 95% CI, 0.77 to 1.03; P 0.15) with atrial-based pacing.  There was a significant reduction in atrial fibrillation (HR, 0.80; 95% CI, 0.72 to 0.89; P 0.00003) and a reduction in stroke that was of borderline significance (HR, 0.81; 95% CI, 0.67 to 0.99; P 0.035).  They concluded: Compared with ventricular pacing, the use of atrial-based pacing does not improve survival or reduce heart failure or cardiovascular death.  However, atrial-based pacing reduces the incidence of atrial fibrillation and may modestly reduce stroke.2.Internal technology assessmentConnolly SJ, Kerr CR, Gent M, Roberts RS, Yusuf S, Gillis AM, Sami MH, Talajic M, Tang AS, Klein GJ, Lau C, Newman DM. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med. 2000 May 11;342(19):1385-91.