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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Prognosis after aortic root replacement with cryopreserved allografts in adults

JJ Takkenberg, MJ Eijkemans, LA van Herwerden, EW Steyerberg, MM Lane, RC Elkins, JD Habbema, and AJ Bogers.

Review published: 2003.

CRD summary

This review used meta-analysis and modelling to predict age-specific long-term prognosis after allograft aortic replacement (ARR) in adults. The authors concluded that ARR has an age-related limited durability, which leads to an increased risk of lifetime structural valve failure that requires reoperation in younger patients. Limitations in the reporting of the review process and data used to populate the model mean that the results may not be reliable.

Authors' objectives

To estimate the age-specific long-term prognosis of patients following aortic root replacement (ARR) with cryopreserved aortic allografts.


The authors' own study was combined with a search of MEDLINE (January 1995 to June 2000) and a cross-check of the reference lists of selected articles. The search terms used were given.

Study selection

Study designs of evaluations included in the review

Studies that reported the long-term follow-up of 40 patients or more, and had outcome data available on at least 90% of patients, were included in the review.

Specific interventions included in the review

Studies evaluating the use of cryopreserved allograft ARR with reimplantation of the coronary arteries were eligible for inclusion.

Participants included in the review

Patients aged greater than 16 years at the time of surgery were eligible for inclusion. The participants in the included studies were predominantly male and had a mean age of 51 years (range: 13 to 77). The number of participants who had undergone prior cardiac surgery, had active endocarditis, or received concomitant coronary artery bypass grafting varied (further details were provided).

Outcomes assessed in the review

The outcomes of interest were events following cryopreserved allograft ARR. The outcomes used in the review were the occurrence of early or late mortality, valve thrombosis, thromboembolism, late bleeding endocarditis, non-structural valve failure and structural valve failure. The outcomes were defined according to Edmund's guidelines (see Other Publications of Related Interest).

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Data were extracted using a pre-defined spreadsheet. However, it was not stated how many reviewers performed the data extraction, or how any discrepancies were resolved.

Data on the occurrence of valve thrombosis, thromboembolism, bleeding, endocarditis, non-structural valve failure, and early and late mortality were extracted from each individual study. Where possible, the trial investigators provided individual patient data on patient age and the incidence of structural valve failure.

Methods of synthesis

How were the studies combined?

The results of five studies were combined using meta-analysis to obtain a pooled incidence of structural valve failure. Individual patient data on age-specific structural valve failure were obtained from two studies. These parameters were used to construct a Weibull model to obtain patient age-specific estimates for structural valve failure.

A microsimulation model was used to quantify estimates of life expectancy (LE) and actual risk of events and reoperations in patients after ARR with cryopreserved aortic allograft. The occurrences of frequent events were combined in a weighted meta-analysis, while the incidences of rare events were combined in an unweighted meta-analysis. Linearised annual occurrence rates were calculated for valve thrombosis, thromboembolism, bleeding, endocarditis and non-structural valve failure, and were pooled to give a rate per patient-year. Pooled events were input into the model and 10,000 hypothetical life histories, characterised by age and gender, were computed for each individual patient. LE and risks of events were calculated for men from adjusted estimates of age- and gender-specific mortality. Assumptions about the risk of bleeding, operative mortality, reoperation, and mortality after thromboembolism, bleeding and endocarditis, were obtained from the literature.

How were differences between studies investigated?

One-way sensitivity analyses were performed using lower and upper confidence intervals (CIs) to investigate uncertainty in the estimates used for thromboembolism, bleeding, endocarditis, non-structural valve failure and mortality on LE and event-free LE across different age groups.

Results of the review

Five studies (n=629) with a follow-up of 1,860 patient-years were included in the review. Of these, one was the authors' own study and the remaining four were identified by the literature search.

The annual risk of events after ARR with cryopreserved allografts was 0.6% (95% CI: 0.3, 1.07) for thromboembolism, 0.05% (95% CI: 0.001, 0.28) for bleeding, 0.5% (95% CI: 0.25, 0.9) for endocarditis and 0.5% (95% CI: 0.24, 0.92) for non-structural valve failure. Fifteen persons with structural valve failure required reoperation. The corresponding age- and gender-specific time to structural allograft failure was 11.1 years in a 25-year-old male and 17.5 years in a 65-year-old male.

The calculated LE varied from 27 years in a 25-year-old male to 12 years in a 65-year-old male who had undergone ARR with cryopreserved allograft. This corresponded to actual lifetime risks of reoperation of 89% and 35% in the respective age groups.

Sensitivity analyses demonstrated that varying the baseline estimates of the individual parameters did not have a significant impact on the total LE. However, varying the estimate time to structural valve failure had an effect on the event-free LE. Specifically, for a 25-year-old male, varying structural valve failure from lower to upper estimates changed the event-free LE from 7.8 to 11.6 years.

Authors' conclusions

ARR with cryopreserved allografts had an age-related limited durability. This resulted in an increased risk of lifetime structural valve failure that required reoperation in younger patients.

CRD commentary

The review addressed a clear question and the inclusion criteria appeared appropriate. The search for relevant studies was limited to one electronic database and no attempt was made to identify unpublished studies; therefore, there was a strong possibility of publication bias. In addition, methods to reduce bias and errors were not used in the study selection and data extraction processes. The validity of the included studies was not assessed systematically, which made it difficult to assess the strength of the evidence presented. This was of particular importance given the small amount of clinical data that was used to populate the Weibull and microsimulation models.

Details of the included studies were tabulated, and these indicated heterogeneity in patient age, pre-operative endocarditis and early mortality across the included studies. Moreover, the authors' main results were based on men only, whereas it appeared that the outcomes in each included study were for both males and females. These factors question the validity of the pooled estimates used in the models. Consequently, given the limitations of the review process and validity of the estimates used, the authors' conclusions should be viewed with caution.

Implications of the review for practice and research

Practice: The authors stated that an internet-based version of the microsimulation model would become accessible to clinicians, and could be used as part of patient counselling.

Research: The authors did not state any implications for further research. Instead, they highlighted the need to improve and regularly update the microsimulation model to provide valid estimates of prognosis following ARR with cryopreserved allograft. In addition, they stated that the microsimulation model provided a useful tool in prognostic research.


Board of Health Care Insurance (College voor Zorgverzekering), grant number 99141.

Bibliographic details

Takkenberg J J, Eijkemans M J, van Herwerden L A, Steyerberg E W, Lane M M, Elkins R C, Habbema J D, Bogers A J. Prognosis after aortic root replacement with cryopreserved allografts in adults. Annals of Thoracic Surgery 2003; 75(5): 1482-1489. [PubMed: 12735566]

Other publications of related interest

Edmunds LH, Clark RE, Cohn LH, Grunkemeier GL, Miller DC, Wiesel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. Ann Thorac Surg 1996;62:932-5.

Indexing Status

Subject indexing assigned by NLM


Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aortic Valve /transplantation; Cryopreservation; Disease-Free Survival; Female; Humans; Life Expectancy; Male; Middle Aged; Models, Statistical; Postoperative Complications; Prognosis; Proportional Hazards Models; Prosthesis Failure; Reoperation; Risk Factors



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 12735566