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Prosthetic Heart Valves: Objective Performance Criteria Versus Randomized Clinical Trial

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The current Food and Drug Administration (FDA) heart valve guidance document uses an objective performance criteria (OPC) methodology to evaluate the clinical performance of prosthetic heart valves. OPC are essentially historical controls, but they have turned out to be an adequate, and perhaps optimal, study design in this situation. Heart valves have a simple open-and-close mechanism, device effectiveness is easy to document, and the common complications (thromboembolism, thrombosis, bleeding, leak, and infection) are well known and easily detected. Thus, randomized clinical trials (RCTs) have not been deemed necessary for the regulatory approval of prosthetic heart valves. The OPC are derived from the average complication rates of all approved heart valves. Studies based on OPC have been shown to work well; many different valve models have gained FDA market approval based on this methodology. Although heart valve RCTs are not required by the FDA, they have been done to compare valves or treatment regimens after approval. Recently, the Artificial Valve Endocarditis Reduction Trial (AVERT) was designed to compare a new Silzone sewing ring, designed to reduce infection, with the Standard sewing ring on a St. Jude Medical heart valve. This was the largest heart valve RCT ever proposed (4,400 valve patients, followed for as long as 4 years), but it was stopped prematurely because of a high leak rate associated with the Silzone valve. Examining the results showed that a much smaller, OPC-based study with 800 patient-years would have been sufficient to disclose this complication of the Silzone valve.

Section snippets

Prosthetic Heart Valves

A heart valve is a one-way check valve, opening to allow the flow of blood in one direction at the appropriate time during the cardiac cycle, and sealing the valve orifice otherwise, to prevent backward flow. The first successful heart valve was the simple Starr-Edwards caged-ball device implanted in 1960 [1]. Engineering principles could be applied to the design, laboratory testing to assess flow, leak, strength, durability, and animal implantations to study the effects in a biological

Regulatory Developments

The FDA began regulating medical devices in 1976. At first, there was no standard for clinical performance, marketing applications seemed to be judged primarily on the completeness of data. Then a 1993 guidance document (revised in 1994 [9]) gave requirements for in vitro, animal, and clinical data, including New York Heart Association (NYHA) class, blood and hemodynamic data, and cardiovascular complications [10, 11]. This document included the list of OPC for valve-related complications (

Heart Valve RCTs

Although RCTs of heart valves have not been required for FDA approval, many have been done to compare postapproval valves. We will briefly review a few of the most important ones. There are two major randomized studies of heart valves, both comparing mechanical to tissue valves. A recent RCT compared the most-used third-generation SJM bileaflet valve to the first-generation Starr-Edwards caged-ball valve. And the largest RCT of heart valves ever proposed, a recent comparison of a new sewing

Rationale for OPC: Drugs Versus Devices

There are major differences between drugs and heart valves, which may explain why RCTs are required for regulatory approval of the former, but not the latter. The evaluation stages of drug studies are (1) establish safety, (2) refine dosage, and (3) confirm efficacy. The last step is difficult because usually the mechanism of action is systemic, complex, and not well understood, and the endpoints are partly subjective. Consequently, many patients are needed, with randomization and blinding

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