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The Right Thing To Do With the Wrong Thing Eugene H. Blackstone, MD Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio The Right Thing To Do C ontemporary clinical trial design, of which the paper from Edwards Lifesciences is but one example [1], seeks to expose the fewest patients to a less safe or less effective treatment, including prosthetic heart valve ther- apy [2]. For this reason, it is the right thing to apply more efficient trial designs to heart valve assessment, including to those designs using objective performance criteria (OPCs) rather than randomized arms to establish nonin- feriority. For related article, see page 1162 That said, I am disappointed that the rationale given by the industry authors is not along the lines of patient safety. Rather, they emphasize and illustrate advantages to industry: such designs can somewhat speed the de- vice-to-market cycle. I concede this secondary, if perhaps self-serving, rationale. The Wrong Thing At the time OPCs were proposed, my assigned aspect of the debate was to argue in favor of randomized trials [3]. The primary argument against this was that decades of data— going back to the 1960s—that well-characterized heart valves and their safety were sufficient to serve as benchmarks (OPCs) to simplify and reduce cost of new heart valve device approval [4]. Today, and in the fore- seeable future, there is an explosion of new device technology that has not been seen for decades. Edwards Lifesciences is in the vanguard of such technology. Ad- vocates for new devices are not surgeons, but interven- tional cardiologists who know little about OPCs. Instead, they have lived through three decades of randomized trials of comparative safety and efficacy of percutaneous coronary intervention devices. Percutaneous valve tech- nology is young and rapidly improving (or at least changing). I would argue that the ideal standard for at least the near future is randomized clinical trials per- formed using contemporary trial designs that expose the fewest patients to less safe or less effective devices, including modification of these devices and their meth- ods of deployment [5]. Randomized Trials Pragmatically, randomized trials of heart valves pose challenges not present when different coronary stents or modifications thereof are being compared. The number of patients being stented is nearly an order of magnitude greater than those receiving heart valves. Sample sizes for comparing infrequently occurring clinical end points are huge, and thus the cost of trials huge. Meaningful composite safety and efficacy end points must be sought as proposed by the Valve Academic Research Consor- tium (VARC) [6]. A number of clever analytic designs using composite end points have been devised [7], but there are well-recognized dangers in using composite end points [8]. Arguments may also be leveled against contemporary efficient outcome-adaptive trial designs [9 –12]. These designs are based on accruing outcome data early enough in a trial to allow adaptation. Therefore, long- term outcomes generally cannot be used, although short- term safety end points could be used with substantial increase in sample size requirements. This suggests that such trials need, in addition to short-term data, long- term comparative data. Currently, surveillance registries are being planned and implemented for transcatheter aortic valve replacement without a surgical arm that would permit comparative effectiveness studies to be performed to assess comparative long-term safety and clinical effectiveness. Are the Objective Performance Criteria Outdated? I also question the basis and value of current OPCs for heart valve assessment. A huge advantage of the contemporary scene is that cardiologists and cardiac surgeons are now thrown into the same arena. Inter- ventional cardiologists bring a new perspective. They are mystified by surgeons’ well-established phrases and ideas, such as the definition of structural and nonstructural valve deterioration. Surgeons, in turn, are mystified by cardiologists wishing to cast valve replacement into the rubric of ischemic heart disease end points. VARC has begun to establish a common organizing structure and language by bringing to- gether cardiologic and surgical expertise [6]. An important clarification of end points has resulted by organizing these in terms of (1) success (technical aspects of treatment achieved), (2) safety, and (3) efficacy or effectiveness. Elements of this organizing structure are far from comprehensive as yet, and the second wave of VARC work to fill these gaps is under way. For example, there are no VARC definitions as yet of efficiency, cost effectiveness, or functional health status. Nevertheless, using the current VARC rubric, OPCs comprise one measure of technical success: periprosthetic leakage. Ob- jective performance criteria address several measures of safety (thromboembolism, valve thrombosis, hemor- Address correspondence to Dr Blackstone, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Ave, JJ4, Cleve- land, OH 44195; e-mail: [email protected]. © 2012 Published by Elsevier Inc Ann Thorac Surg 2012;93:1025– 6 0003-4975/$36.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2012.01.099

The Right Thing To Do With the Wrong Thing

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The Right Thing To Do With the Wrong ThingEugene H. Blackstone, MD

Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, Ohio

The Right Thing To Do

Contemporary clinical trial design, of which the paperfrom Edwards Lifesciences is but one example [1],

seeks to expose the fewest patients to a less safe or lesseffective treatment, including prosthetic heart valve ther-apy [2]. For this reason, it is the right thing to apply moreefficient trial designs to heart valve assessment, includingto those designs using objective performance criteria(OPCs) rather than randomized arms to establish nonin-feriority.

For related article, see page 1162

That said, I am disappointed that the rationale given bythe industry authors is not along the lines of patientsafety. Rather, they emphasize and illustrate advantagesto industry: such designs can somewhat speed the de-vice-to-market cycle. I concede this secondary, if perhapsself-serving, rationale.

The Wrong Thing

At the time OPCs were proposed, my assigned aspect ofthe debate was to argue in favor of randomized trials [3].The primary argument against this was that decades ofdata—going back to the 1960s—that well-characterizedheart valves and their safety were sufficient to serve asbenchmarks (OPCs) to simplify and reduce cost of newheart valve device approval [4]. Today, and in the fore-seeable future, there is an explosion of new devicetechnology that has not been seen for decades. EdwardsLifesciences is in the vanguard of such technology. Ad-vocates for new devices are not surgeons, but interven-tional cardiologists who know little about OPCs. Instead,they have lived through three decades of randomizedtrials of comparative safety and efficacy of percutaneouscoronary intervention devices. Percutaneous valve tech-nology is young and rapidly improving (or at leastchanging). I would argue that the ideal standard for atleast the near future is randomized clinical trials per-formed using contemporary trial designs that expose thefewest patients to less safe or less effective devices,including modification of these devices and their meth-ods of deployment [5].

Randomized TrialsPragmatically, randomized trials of heart valves posechallenges not present when different coronary stents or

Address correspondence to Dr Blackstone, Department of Thoracic and

Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Ave, JJ4, Cleve-land, OH 44195; e-mail: [email protected].

© 2012 Published by Elsevier IncPublished by Elsevier Inc

modifications thereof are being compared. The numberof patients being stented is nearly an order of magnitudegreater than those receiving heart valves. Sample sizesfor comparing infrequently occurring clinical end pointsare huge, and thus the cost of trials huge. Meaningfulcomposite safety and efficacy end points must be soughtas proposed by the Valve Academic Research Consor-tium (VARC) [6]. A number of clever analytic designsusing composite end points have been devised [7], butthere are well-recognized dangers in using compositeend points [8].

Arguments may also be leveled against contemporaryefficient outcome-adaptive trial designs [9–12]. Thesedesigns are based on accruing outcome data earlyenough in a trial to allow adaptation. Therefore, long-term outcomes generally cannot be used, although short-term safety end points could be used with substantialincrease in sample size requirements. This suggests thatsuch trials need, in addition to short-term data, long-term comparative data. Currently, surveillance registriesare being planned and implemented for transcatheteraortic valve replacement without a surgical arm thatwould permit comparative effectiveness studies to beperformed to assess comparative long-term safety andclinical effectiveness.

Are the Objective Performance Criteria Outdated?I also question the basis and value of current OPCs forheart valve assessment. A huge advantage of thecontemporary scene is that cardiologists and cardiacsurgeons are now thrown into the same arena. Inter-ventional cardiologists bring a new perspective. Theyare mystified by surgeons’ well-established phrasesand ideas, such as the definition of structural andnonstructural valve deterioration. Surgeons, in turn,are mystified by cardiologists wishing to cast valvereplacement into the rubric of ischemic heart diseaseend points. VARC has begun to establish a commonorganizing structure and language by bringing to-gether cardiologic and surgical expertise [6].

An important clarification of end points has resulted byorganizing these in terms of (1) success (technical aspectsof treatment achieved), (2) safety, and (3) efficacy oreffectiveness. Elements of this organizing structure arefar from comprehensive as yet, and the second wave ofVARC work to fill these gaps is under way. For example,there are no VARC definitions as yet of efficiency, costeffectiveness, or functional health status. Nevertheless,using the current VARC rubric, OPCs comprise onemeasure of technical success: periprosthetic leakage. Ob-jective performance criteria address several measures of

safety (thromboembolism, valve thrombosis, hemor-

Ann Thorac Surg 2012;93:1025–6 • 0003-4975/$36.00doi:10.1016/j.athoracsur.2012.01.099

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1026 EDITORIAL BLACKSTONE Ann Thorac SurgTHE RIGHT THING TO DO WITH THE WRONG THING 2012;93:1025–6

rhage, and endocarditis), but few measures of efficacy orclinical effectiveness (survival and New York Heart As-sociation functional class only).

Let’s briefly examine two safety end points: thrombo-embolism and bleeding. In the early days of heart valvereplacement, particularly with thrombogenic mechanicaldevices placed in otherwise healthy individuals, it madesense to take a conservative view that all post–valvereplacement neurologic events were caused by valve-related thrombus. On the flip side, all bleeding wasassumed to be valve anticoagulation-related. As valvereplacement is performed using bioprostheses in in-creasingly elderly patients with substantial atheroscle-rotic burden and propensity for atrial fibrillation, theseassumptions make less sense than they once did.

Careful analysis of PARTNER 1A neurologic eventsreveals an early (within a couple of weeks) periprocedureincrease in events followed by a constant underlying riskthat is powerfully related to patient characteristics andless to the device or mode of aortic valve replacement [13,14]. It is possible, of course, that clots can form on varioussurfaces of bioprostheses. However, the resulting “sig-nal” may be buried in noise of naturally occurring strokesin the elderly. Thus, a perfectly nonthrombogenic devicecould fail the “thromboembolism” OPC simply on thebasis of its being used in an elderly population at highrisk of stroke. This is because present OPCs are not riskadjusted for patient characteristics, and they do notconsider the events occurring within the first 30 days,during which there may be true differences related to thedevice. It is time to abandon the word “thromboembo-lism” and adopt standard neurologic terminology that ismore descriptive. It is time to introduce risk adjustment.

Consequences of End PointsFinally, lacking in surgical guidelines [15] and OPCs is anevaluation of consequences of end points on a standard-ized scale. Decades ago, Nelson at General Electric intro-duced an actuarial method for weighted events that hetermed the cumulative cost function [16]. We proposedweighing neurologic events occurring after valve replace-ment by an ordinal scale of “permanent functional limi-tation,” which today could, for example, be the NationalInstitutes of Health Stroke Scale [17]. One could imaginea composite end point being standardized by such aweighting method so that a small periprosthetic leakagethat is inconsequential or causes a mild chronic anemiacan be analyzed along with a debilitating stroke orreintervention to remove a deteriorating tissue prosthesisbecause of stenosis. Because this variable associates acontinuous variable with a binary outcome, it can reducesample size. This is one example of breathing life into afield that has been relatively static.

Thus, it is time to rethink the evaluation methodology

for prosthetic heart valves, debate randomized trials

versus OPCs, explore efficient contemporary trial de-signs, adopt a VARC-type organizing structure for endpoints, embrace risk adjustment, and consider differingconsequences of safety events that are now weightedequally.

References

1. Hamilton C, Lu M, Lewis S, Anderson W. Sequential designfor clinical trials evaluating a prosthetic heart valve. AnnThorac Surg 2012;93:1162–6.

2. Parides MK, Moskowitz AJ, Ascheim DD, Rose EA, GelijnsAC. Progress versus precision: challenges in clinical trialdesign for left ventricular assist devices. Ann Thorac Surg2006;82:1140–6.

3. Blackstone EH. In response to: Grunkemeier GL, Starr A.Alternatives to randomization in surgical studies. J HeartValve Dis 1993;2:119–22.

4. Chen E, Sapirstein W, Ahn C, Swain J, Zuckerman B. FDAperspective on clinical trial design for cardiovascular de-vices. Ann Thorac Surg 2006;82:773–5.

5. Blackstone EH. Could it happen again? The Björk-Shileyconvexo-concave heart valve story. Circulation 2005;111:2717–9.

6. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpointdefinitions for transcatheter aortic valve implantation clini-cal trials: a consensus report from the Valve AcademicResearch Consortium. J Am Coll Cardiol 2011;57:253–69.

7. Huque MF, Alosh M. A consistency-adjusted strategy foraccommodating an underpowered primary endpoint. J Bio-pharm Stat 2012;22:160–79.

8. Neaton JD, Gray G, Zuckerman BD, Konstam MA. Keyissues in end point selection for heart failure trials: compos-ite end points. J Card Fail 2005;11:567–75.

9. Berry DA. Adaptive clinical trials: the promise and thecaution. J Clin Oncol 2011;29:606–9.

10. Zhou X, Liu S, Kim ES, Herbst RS, Lee JJ. Bayesianadaptive design for targeted therapy development in lungcancer—a step toward personalized medicine. Clin Trials2008;5:181–93.

11. Coffey CS, Kairalla JA. Adaptive clinical trials: progress andchallenges. Drugs R D 2008;9:229–42.

12. Piana R. Can Bayesian design streamline our sluggish clin-ical trial system? Available at http://www.ascopost.com/articles/october-15-2011/can-bayesian-design-streamline-our-sluggish-clinical-trial-system/. Accessed November 15,2011.

13. Miller DC, Blackstone EH, Mack MJ, et al. Transcatheter(TAVR) versus surgical (AVR) aortic valve replacement:occurrence, hazard, risk factors, and consequences of neu-rological events in the PARTNER trial. J Thorac CardiovascSurg 2012; In press.

14. Daneault B, Kirtane AJ, Kodali SK, et al. Stroke associatedwith surgical and transcatheter treatment of aortic stenosis:a comprehensive review. J Am Coll Cardiol 2011;58:2143–50.

15. Akins CW, Miller DC, Turina MI, et al. Guidelines forreporting mortality and morbidity after cardiac valve inter-ventions. Ann Thorac Surg 2008;85:1490–5.

16. Nelson W. Graphical analysis of system repair data. J QualTechnol 1988;20:24–35.

17. Blackstone EH. Analyses of thrombosis, thromboembolismand bleeding after heart valve replacement as time-relatedoutcome events. In: Butchart EG, Bodnar E, eds. Currentissues in heart valve disease: thrombosis, embolism and

bleeding. London: ICR Publishers; 1992:445–63.