Generalized pairwise comparison methods to analyze (non)prioritized composite endpoints.

In the analysis of composite endpoints in a clinical trial, time to first event analysis techniques such as the logrank test and Cox proportional hazard test do not take into account the multiplicity, importance, and the severity of events in the composite endpoint. Several generalized pairwise comparison analysis methods have been described recently that do allow to take these aspects into account. These methods have the additional benefit that all types of outcomes can be included, such as longitudinal quantitative outcomes, to evaluate the full treatment effect. Four of the generalized pairwise comparison methods, ie, the Finkelstein-Schoenfeld, the Buyse, unmatched Pocock, and adapted O'Brien test, are summarized. They are compared to each other and to the logrank test by means of simulations while specifically evaluating the effect of correlation between components of the composite endpoint on the power to detect a treatment difference. These simulations show that prioritized generalized pairwise comparison methods perform very similarly, are sensitive to the priority rank of the components in the composite endpoint, and do not measure the true treatment effect from the second priority-ranked component onward. The nonprioritized pairwise comparison test does not suffer from these limitations and correlation affects only its variance.

Actuarial versus actual freedom from structural valve deterioration with the Carpentier-Edwards porcine bioprostheses.

BACKGROUND: The clinical performance of porcine bioprostheses for valve replacement surgery has been evaluated for over three decades by actuarial analysis as the standard for reporting time-related results. The incidence of structural valve deterioration (SVD) is used for the selection of prostheses for various subsets of patients. Actual or cumulative incidence analysis may provide a superior method to determine durability of bioprostheses. OBJECTIVE: To compare actuarial versus actual methodology in determining the durability of porcine bioprostheses for aortic (AVR) and mitral valve replacement (MVR). PATIENTS AND METHODS: Carpentier-Edwards porcine bioprostheses were implanted between 1975 and 1995 in 2237 AVR and 1582 MVR. The mean age for AVR patients was 65.4+/-12 years and for MVR patients 61.7+/-12 years. The cumulative follow-up for AVR was 14,810 years (mean 6.6+/-4.7) and for MVR 9718 years (mean 6. 1+/-4.5). RESULTS: For AVR the actual freedom from SVD was 87.4+/-2. 0% and 95.6+/-1.8% in those aged 61 to 70 years and more than 70 years, respectively; the actuarial freedom was 75.9+/-4.2% and 82. 3+/-7.9%, respectively. For MVR the actual freedom from SVD was 69. 4+/-2.5% and 92.9+/-1.9% for those aged 61 to 70 years and more than 70 years, respectively; the actuarial freedom was 25.5+/-5.7% and 79. 5+/-6.0%, respectively. Predictors of freedom from SVD for AVR were identified as advancing age, falling into the age groups 61 to 70 and those older than 70 years, and intermediate valve sizes; predictors for MVR were advancing age and age older than 70 years. CONCLUSIONS: Comparison of methods of durability assessment revealed that actual freedom from SVD supports porcine bioprostheses for AVR in patients more than 60 years of age and for MVR in patients more than 70 years of age. This evaluation with experience to 15 years supports the indications for use of porcine bioprostheses.

Structural valve deterioration in mitral replacement surgery: comparison of Carpentier-Edwards supra-annular porcine and perimount pericardial bioprostheses.

BACKGROUND: Bioprostheses preserved with glutaraldehyde, both porcine and pericardial, have been available as second-generation prostheses for valve replacement surgery. The performance with regard to structural valve deterioration with the Carpentier-Edwards supra-annular (CE-SAV) porcine bioprosthesis and the Carpentier-Edwards Perimount (CE-P) pericardial bioprosthesis (Baxter Healthcare Corp, Edwards Division, Santa Ana, Calif) was evaluated to determine whether there was a difference in mitral valve replacement. METHODS: The CE-SAV bioprosthesis was implanted in 1266 overall mitral valve replacements (isolated mitral, 1066; mitral in multiple, 200) and the CE-P bioprosthesis in 429 overall mitral valve replacements (isolated mitral, 328; mitral in multiple, 101). The mean age of the CE-SAV population was 64.2 +/- 12.2 years and that of the CE-P population, 60.7 +/- 11.7 years (P =.0001). For the study, structural valve deterioration was diagnosed at reoperation for explantation. RESULTS: The freedom from structural valve deterioration was evaluated to 10 years, and the freedom rates reported are at 10 years. For the overall mitral valve replacement groups, the actuarial freedom from deterioration was significant (P =.0001): CE-P > CE-SAV for 40 years or younger, 80% versus 60%; 41 to 50 years, 91% versus 61%; 51 to 60 years, 84% versus 69%; 61 to 70 years, 95% versus 75%. The older than 70-year group was 100% versus 92% (no significant difference). The actual freedom from structural valve deterioration also demonstrated the same pattern at 10 years: 40 years or younger, CE-P 82% versus CE-SAV 68%; 41 to 50 years, 92% versus 70%; 51 to 60 years, 90% versus 80%; 61 to 70 years, 97% versus 88%; and older than 70 years, 100% versus 97%. The independent risk factors of structural valve deterioration for the overall mitral valve replacement group were age and age groups and prosthesis type (CE-SAV > CE-P). The prosthesis type either in isolated replacement or in multiple replacement was not predictive of structural valve deterioration. The pathology of structural valve deterioration was different: 70% of CE-P failures were due to calcification and 57% of CE-SAV failures were due to combined calcification and leaflet tear. CONCLUSION: The actuarial and actual freedom from structural valve deterioration, diagnosed at reoperation, is greater at 10 years for CE-P than for CE-SAV bioprostheses. The mode of failure is different, and the cause remains obscure. Long-term evaluation is recommended, because the different modes of failure may alter the clinical performance by 15 and 20 years.

Quality of life in patients with bioprostheses and mechanical prostheses. Evaluation of cohorts of patients aged 51 to 65 years at implantation.

BACKGROUND: The purpose of this study was 3-fold: to compare the quality of life (QOL) in age- and sex-matched patients who received biological and mechanical prosthetic valves in isolated aortic valve replacement, to compare the QOL of patients with aortic valve replacement with the general population, and to compare patients with biological and mechanical prostheses with certain valve-specific questions and relate these responses to overall QOL. METHODS AND RESULTS: Patient-perceived QOL was evaluated in 200 patients who were sampled from a population of 420 patients (age range 51 to 65 years) who underwent isolated aortic valve replacement in the period of 1986 to 1996. One hundred of the sampled patients had a mechanical valve inserted and an equal number had porcine bioprostheses. Three survey instruments were used to examine perceived QOL: the SF-12 form, a 7-valve specific question form, and the Lamy Smiley Faces form. The response to the questionnaires was 89.5% (179 patients). Patients with mechanical valves were more bothered by valve sounds (P < 0.01) and had a negative correlation (P < 0.01) between valve sound and QOL on the mental scale only. Patients with biological valves were more fearful of the need for reoperation (P < 0.01), but there was no correlation between fear and QOL. The mechanical valve group had a negative correlation (P < 0.01) between fear of reoperation and QOL on both the mental and physical scales. There was no difference between the 2 cohorts with respect to fear of valve failure. Patients with mechanical valves were more concerned about frequency of medical visits and blood tests (P < 0.01) as well as the possibility of anticoagulant-related bleeding events (P < 0.01). QOL was equivalent between the 2 groups and to the general population for the same age group. Ninety-seven percent of the patients indicated they would make the same surgical decision again with regard to valve replacement; there was no difference between the 2 valve groups on this question. CONCLUSIONS: Patient-perceived QOL is similar between patients with aortic mechanical and biological valve replacement in the studied age group and comparable to the general population of similar age. Although certain valve-specific differences exist between the 2 prosthetic types, these differences do not appear to affect overall QOL as described by these patients.

Clinical evaluation and analysis of heart valve substitutes.

We discuss the clinical assessment of heart valve substitutes, primarily with regard to pre-market evaluation. We concentrate on the current FDA heart valve guidance document. This guidance is self-acknowledged to be an evolving document, scheduled to be revised between three and five years after its initial release on December 1993. We outline the history and some of the strengths of the present system, and discuss areas for possible improvement. We selected one important statistical issue to address thoroughly how to compute the confidence limit of a linearized rate.

Spreadsheet method for determining sample sizes for heart valve studies.

Grunkemeier, Johnson, and Naftel have given a method for computing sample size requirements for a clinical study of a new heart valve. This paper gives an implementation of the method on a computer spreadsheet. Moreover, it computes the sample size for the most powerful test with exactly the prescribed level of significance and power; all other tests will necessarily have smaller power and will need larger sample sizes. All graphs and tables are produced on the spreadsheet, and no use of special statistical functions is necessary.

Passive surveillance of heart valve devices: Björk-Shiley outlet strut fracture rates.

The Björk-Shiley Convexo-Concave heart valve has a mechanical failure mode called outlet strut fracture (OSF). Previous analyses have found that the hazard function for OSF is constant over time. This article uses the valve manufacturers implant database to examine the shape of the hazard function over time, employing a previously developed model to impute patient survival times. Decisions about patient management (e.g., elective explant) are based on projecting this risk into the future. An analysis that incorporates the decrement of patients at risk due to death and explant provides estimates of the actual occurrences of OSF over calendar time.

Characterization of parallel subtraction.

Parallel subtraction is an operation defined on pairs of positive operators. In terms of electrical networks, one may pose the following problem: Given an electrical network, represented by a specified positive operator, determine the set of positive operators which when connected in parallel with the specified operator yield another prescribed operator. The set of solutions of this electrical network problem is shown to have a minimum. The minimum is termed "the parallel difference of the fixed operators," and the operation is termed "parallel subtraction." The parallel difference is used to obtain explicit error estimates for an iteration procedure which approximates the geometric mean of positive operators. This concept of the geometric mean reduces to the square root of the product of the operators if the operators commute. Finally, by using the geometric mean, an operator version of the Gaussian mean is presented.

Predator-prey patterns.

A graph-theoretic condition is given for the existence of stable solutions to the Volterra-Lotka equations.

Parallel subtraction of matrices.

A new Hermitian semidefinite matrix operation is studied. This operation-called parallel subtraction-is developed from the theory of parallel addition. Since the theory of parallel addition is motivated by the analysis of interconnected electrical networks, parallel subraction may be interpreted in terms of the synthesis of electrical networks. The idea of subtraction is also extended to hybrid addition.