Cardiac resynchronization therapy: A regulatory perspective

Editorial

Cardiac resynchronization therapy: A regulatory perspective Warren K. Laskey, MD,a and William H. Maisel, MD, MPHb Albuquerque, NM; and Boston, MA

Despite remarkable advances in the pharmacological treatment of patients with severe congestive heart failure (HF), persistently high rates of mortality and repeat hospitalizations have stimulated the need for additional therapies. It is on this background of best medical therapy that electromechanical modalities for the treatment of patients with chronic HF are undergoing intense evaluation. Implantable cardioverter defibrillators (ICDs) have been shown to reduce mortality in selected high-risk patients with reduced left ventricular ejection fraction in multiple randomized controlled trials.1- 4 Cardiac resynchronization therapy (CRT) offers the additional potential for further improvement in morbidity and mortality in selected patients with HF.5 The United States Food and Drug Administration (FDA) is charged with the evaluation of devices for the treatment of human diseases. As such, the agency is required by law to assess device efficacy and safety. Valid scientific evidence must be provided (by the device sponsor) as a sine qua non for approval. Furthermore, these efficacy and safety data are applicable only in the context of the use of a device as intended (as specified in the instructions for use or label). The development of CRT has been characterized by a number of challenges relating to both the design and interpretation of clinical trials performed to evaluate its efficacy and safety. The last several years have seen an exponential increase in both the use of and interest in CRT in a diversity of clinical situations. As noted above, regulatory approval of a device for the treatment of human disease is predicated on sound scientific principles and specific indications for use. Therefore, to better interpret the

From the aDivision of Cardiology, Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM, and bCardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Dr. Laskey is the immediate past chairperson and Dr. Maisel is the current chairperson of the Food and Drug Administration Circulatory System Medical Devices Advisory Panel. The opinions expressed in the article are those of the authors and not necessarily those of the Food and Drug Administration. Submitted April 20, 2005; accepted May 17, 2005. Reprint requests: Warren K. Laskey, MD, Division of Cardiology, Department of Medicine, MSC10-5550, 1 University of New Mexico, Albuquerque, NM 87131-0001. E-mail: [email protected] Am Heart J 2006;151:757-61. 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2005.05.023

many forthcoming claims of safety and efficacy of CRT over a wide spectrum of clinical disease, it is worth reviewing the processes of regulatory approval of the initial CRT devices as seen from the perspective of the FDA Circulatory System Medical Devices Advisory Panel.

Efficacy Trial design, selection of control groups, and choice of end points The importance of clinical trial design and choice of end points is highlighted by the data from the InSync-ICD Pre-Market Application (PMA) presented by Medtronic on March 5, 2002 (Table I). This study initially enrolled 659 patients who met inclusion criteria. However, the inclusion of patients with New York Heart Association (NYHA) class II congestive HF was disallowed by the FDA after it was established that the pooling of data from the parent MUSTIC trial6 was not appropriate. Thus, the PMA presented to the panel reported the findings from 362 patients with NYHA class III/IV congestive HF who were randomized to the 2 treatment arms (CRT on and CRT off) after successful device implantation. The results of this study demonstrated statistically significant improvement in 2 of the co-primary end points (quality of life and NYHA class) but not in the third (6-minute walk) at 6 months (Table II). However, 20% of the data were censored and complete follow-up at 6 months was available in only 257 patients. There was considerable discussion at the advisory panel meeting, which focused on study design and the strength of the evidence supporting the claim of device efficacy. With respect to study design, the choice of a 6-month follow-up was of concern, as was the proportion of patients with complete follow-up data at 6 months. In addition, the adequacy of maintaining that all involved parties are blinded was questioned. With respect to the strength of the evidence, although the prespecified criteria for statistical significance were met (ie, at least one end point with an associated P b .0167) (Table II), the differences between treatment arms were of marginal clinical significance. Of note, the improvement in the 6-minute walk scores in both the control and CRT groups underscores the critical importance of an appropriate comparator group and emphasizes the inadequacy of using patients’ baseline status as a control. Similar observations were made for corresponding, albeit secondary, end points in the Guidant Contak CD-ICD

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Table I. Cardiac resynchronization therapy pivotal trials Intended patient population

Trial design

NYHA class

Indication for ICD required

QRS duration (ms)

Left ventricular ejection fraction

InSync ICD/P010031/Medtronic

III/IV

Yes

z130

V0.35

Contak CD-ICD/P010012/Guidant

III/IV

Yes

z120

V0.35

InSync Atrial Synchronous Biventricular Pacing Device/P010015/Medtronic CRT-defibrillator/P01012 supplement 26/Guidant (COMPANION)

III/IV

No

z130

V0.35

III/IV

Yes

z120

V0.35

Study/PMA no./sponsor

PMA (Table I). The use of end points subject to observer or measurement bias also raised concerns regarding the implications of clinically versus statistically significant trial results. The panel ultimately voted to approve this Medtronic PMA for the stated intended use (Table I) with, however, several conditions. Among these were a request for an analysis of mortality at 12 months in the pivotal study population and a separate analysis of longer-term (ie, 3 years) mortality and lead performance in a larger consecutive patient registry. More recently, a PMA submitted by Guidant Corporation and presented to the panel on July 28, 2004, (Table I) represented the first application for a CRT seeking approval for a reduction in the composite risk of all-cause hospitalization or all-cause mortality. Enrollment was stopped at just N1500 randomized patients with NYHA class III/IV congestive HF when the prespecified number of primary end point events had been reached. The PMA was based on the outcomes in patients receiving CRT and ICD therapy compared with outcomes in patients receiving optimal pharmacological therapy (OPT). This pairwise comparison differs somewhat from the analysis in the published COMPANION trial in which the primary end point was compared among 3 groups—CRT-only, CRT and ICD, and OPT-only patients.7 The PMA reported a statistically significant reduction in the risk of all-cause mortality or all-cause hospitalization at 1 year (Table II) in the patients assigned to the CRT and ICD arms (HR 0.80, 95% CI 0.68-0.95). The panel voted unanimously to approve this PMA with, however, several conditions. These reflected concerns over the definition and adjudication of allcause hospitalization; the changing definition of hospitalization over the course of the study; differential withdrawal of patients in the OPT arm (as a result of increasing commercial availability of CRT devices over the course of the trial); and the interpretations of the differences in mortality between groups beyond 1 year.

Randomized (n) 0-7 d after successful implant (362) 30 d after successful implant (501) 0-3 d after successful implant (532) Before implant (903)

Follow-up (mo) 6 6 6 12

Magnitude of treatment effect In the context of the evaluation of device efficacy, the magnitude of benefits must be clinically relevant; that is, the acute improvements in dyssynchronous cardiac contraction, stroke volume, cardiac output, and normalization of the prolonged QRS complex seen with CRT 8-10 should translate into meaningful long-term clinical improvement. Recognizing differences in study design, patient populations, end points, and duration of follow-up, the magnitude of the differences in functional end points and their statistical significance for the pivotal CRT trials submitted to the FDA are shown in Table II. Despite favorable directional trends for each of the component measures, the prespecified composite primary end point at 6 months in the Contak CD-ICD and the 6-minute walk component end point at 6 months in the InSync ICD PMA were not significantly different between groups. Secondary end points reflecting more objective improvement in functional capacity (eg, peak maximum minute oxygen consumption) exhibited directionally favorable (although not consistently statistically significant) trends in the CRT groups of both of these PMAs. Also noted were greater (favorable) responses in primary end points in the post hoc–defined CRT subgroup, with the most severe functional compromise in the Contak CD-ICD study. However, there was substantial variability in the measures chosen as end points and concern regarding the number of actual data points at the 6-month evaluation. Although the panel voted for nonapproval of the Guidant Contak CD PMA, additional data supporting device efficacy were subsequently submitted to the FDA and the application was approved. The co-primary end points in the Medtronic InSync Atrial Synchronous Biventricular Pacing Device study (6-minute walk, quality of life measure, and NYHA functional class) were each significantly different between treatment and control arms at 6 months despite significant interpatient variability in these measures. Directionally similar and statistically significant findings

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Table II. Cardiac resynchronization therapy pivotal trial results End point 1 Treatment

End point 2 Control

Trial

NYHA class (median)

InSync ICD Baseline 6 months

3 2

Treatment

End point 3

Control

QOL score (median)

3 3

55 33

P = .027

57 44

Treatment

Control

Six-minute walk (ms)

260 342

275 333

P = .009

P = .407

QOL score (median)

Six-minute walk (ms)

All-cause mortality, HF hospitalization, or ventricular tachycardia/ventricular fibrillation Contak CD-ICD All-cause mortality (%) HF hospitalization (%) Ventricular tachycardia/ ventricular fibrillation (%)

4.5 12.0 13.5

6.5 15.1 15.1

For combined end point, P = .21

NYHA class (median) InSync Atrial Synchronous Biventricular Pacing Device

2

3

P b .001

All-cause mortality or hospitalization (%)

40.5 P = .003

46.0

371

321

P = .003

All-cause mortality (%)

CRT-defibrillator (COMPANION) 56

68

P = .011

were reported for multiple secondary end points, with the latter reflecting more fundamental hemodynamic and physiological changes. The panel voted for approval with several conditions of the Medtronic PMA. The conditions reflected the panel’s desire for additional longer-term data, with most panel members feeling that 6 months was an insufficient period to meaningfully assess the persistence of device efficacy and reliability. The strong placebo effect noted in the control arm of the Medtronic study emphasized the need for bharder,Q less subjective end points in such nonmortality trials.

Competing risks The absolute mortality rate in patients with HF remains substantial.11 Furthermore, the mortality rate in patients randomized to receive active device therapy in CRT clinical trials also remains substantial. For example, mortality by 1 year in the CRT group in the COMPANION trial exceeded 10%.7 Although it is clear that ICDs reduce cardiovascular mortality in the setting of ischemic heart disease and reduced left ventricular systolic function, primarily as a result of reducing the risk of sudden cardiac death,1-3 the reduction in risk for cardiovascular mortality from progressive CHF is unlikely to be affected by ICDs.

12

19

P = .004

This progression of CHF, and the mortality risk it confers, is a potent competing force in trials designed to evaluate the clinical efficacy of CRT. Typically, the estimation of crude HRs from multivariate models of competing risk outcomes is based on meeting the assumption of proportional hazards. However, these estimates are often discordant with conclusions drawn from cumulative incidence plots for each (competing) level of risk factor. In addition, causespecific mortality in patients with HF may vary with the extent of clinical compromise: mortality in patients with NYHA class I/II symptoms is more likely to be classified as arrhythmic in etiology (sudden cardiac death) whereas that in patients with more severe functional compromise is more likely to be classified as progressive HF.12 These considerations also have important implications for the extrapolation of the clinical benefit of CRT to the most severely compromised (class IV, hospitalized, pressor dependent) patients as well as minimally compromised (asymptomatic or mildly depressed left ventricular systolic dysfunction) patients. The utility of CRT in these and other patient populations cannot be assumed. Furthermore, it is precisely as the result of competing risks that functional outcomes will

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be difficult to assess in patients with the most severe HF (and highest risk of overall mortality).

Safety Although efficacy is a requisite component of any new therapy, ba reasonable assurance of safetyQ13 is equally important and often more difficult to measure. Clinical trials involving thousands of patients can often demonstrate efficacy but are substantially underpowered and/or poorly controlled to adequately quantify important, albeit infrequent, safety issues. Cardiac resynchronization therapy trials are no different. Although prespecified safety end points were met in the abovementioned trials, the panel debated issues related to the safety of the initial implant (eg, coronary sinus injury) as well as the frequent need for repeat procedures to correct left ventricular lead dislodgment. The lack of long-term safety data prompted the panel to recommend a patient/device registry to track longer-term mortality and to evaluate lead performance over years rather than several months. Several safety issues such as the ability to remove coronary sinus leads years after implant owing to infection have yet to be adequately addressed. These issues may become increasingly relevant as manufacturers develop left ventricular leads with novel fixation mechanisms to better secure the leads in the coronary sinus.

Lessons learned and challenges for the future An inherent feature of the regulatory process for device approval is the requirement for randomized controlled trials. The results of the latter, of necessity because of stringent inclusion and exclusion criteria, can then only be applied to real-world patients with similar characteristics. Thus, although the regulatory process ensures a well-defined, relatively homogeneous patient population in which device safety and efficacy can be properly interpreted, it is this very insistence on the bpurityQ of the data set that may limit the generalizability and applicability of results to patients with characteristics specifically excluded or not adequately represented in the pivotal trials. This issue, although of relevance in matters of efficacy, is critical in matters of safety where underestimation of adverse outcomes is likely in lower-risk populations. The increasing spectrum of disease complexity and severity, the expanding capabilities of implantable devices, and the dynamic background of optimum medical therapy render scientifically sound, timely, and clinically relevant evaluation of device safety and efficacy of a difficult task. To commercially market a device, manufacturers must provide valid scientific evidence that their device is safe and effective when used as intended. As CRT expands to new patient populations (eg, patients with atrial fibrillation14 or

those with mildly symptomatic HF15), it is critical that scientific studies continue to provide the necessary evidence of benefit and safety. Demonstration of clinical benefits must be of sufficient magnitude to justify invasive intervention. Thus, postmarketing clinical trials such as the recently published CARE-HF study, in which CRT was shown to confer a survival advantage over medical management,16 are essential. The challenges in substantiating such benefits—competing risks in critically ill patients with HF, assessing the magnitude of benefits derived from CRT, the use of end points unlikely to reflect observer bias to assess device efficacy, and the design of scientifically sound clinical trials with appropriate control subjects—have driven and will continue to drive the debate of the utility of CRT in more diverse patient populations. Factors such as the use of surrogate end points to assess device efficacy, trial design including the difficulties in blinding physicians and patients to implantable devices, and the selection of appropriate control subjects make the device evaluation process particularly challenging. Furthermore, the assessment of real-world outcomes, particularly with respect to safety and reliability, will be necessary (but not sufficient) elements of the premarketing and postmarketing evaluation process. We thank Dr Bram Zuckerman (Director, Division of Cardiovascular Devices, Office of Device Evaluation, FDA/CDRH) for his thoughtful review of this article.

References 1. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmias. N Engl J Med 1996;335:1933 - 40. 2. Buxton AE, Lee KL, Josephson ME, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882 - 90. 3. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877 - 83. 4. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225 - 37. 5. McAlister FA, Ezekowitz JA, Wiebe N, et al. Systematic review: cardiac resynchronization in patients with symptomatic heart failure. Ann Intern Med 2004;141:381 - 90. 6. Linde C, Braunschweig F, Gadler F, et al. Long term improvements in quality of life by biventricular pacing in patients with chronic heart failure: results from the Multi-site Stimulation in Cardiomyopathy study (MUSTIC). Am J Cardiol 2003;91:1090 - 9. 7. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced heart failure. N Engl J Med 2004;350:2140 - 50. 8. Nelson GS, Berger RD, Fetics BJ, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle branch block. Circulation 2000;102:3053 - 9.

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9. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the Multisite Stimulation In Cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111 - 8. 10. St John Sutton MG, Plapper T, Abraham WT, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985 - 90. 11. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of survival with heart failure. N Engl J Med 2002;347:1397 - 402. 12. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001 - 7. 13. U.S. Food and Drug Administration Center for Devices and Radiological Health. Premarket Approval Application Filing Review-

Guidance for Industry and FDA Staff. Available at http://www.fda.gov/cdrh/ode [Assessed May 13, 2005]. 14. Hay I, Melenovksy V, Fetics BJ, et al. Short-term effects of right-left heart sequential cardiac resynchronization in patients with heart failure, chronic atrial fibrillation and atrioventricular nodal block. Circulation 2004;110:3404 - 10. 15. Abraham WT, Young JB, Leon AR, et al. Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator and mildly symptomatic chronic heart failure. Circulation 2004;110:2864 - 8. 16. Cleland JGF, Daubert J-C, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539 - 49.

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