1115
under-refrigerated, inadequately cooked, or recontaminated and temperature abused after cooking. Proper cooking and refrigeration of seafoods are important factors in the prevention of V parahaemolyticus gastroenteritis. REFERENCES 1. Levine MM. Escherichia coli that
cause
diarrhea: enterotoxigenic,
and enteroinvasive, enteropathogenic, enterohemorrhagic, enteroadherent. J Infect Dis 1987; 155: 377-89. 2. Doyle MP, Padhye W. Escherichia coli. In: Doyle MP, ed. Foodborne bacterial pathogens. New York: Marcel Dekker, 1989: 236-81. 3. Karmali MA. Infection by verocytotoxin-producing Escherichia coli. Clin Microbiol Rev 1989; 2: 15-38
4. Robins-Browne RM. Traditional enteropathogenic Escherichia coli of infantile diarrhea. Rev Infect Dis 1987; 9: 28-53. 5. Moon HW, Whipp SC, Arzenio RA, Levine MM, Gianella RA. Attaching and effacing activities of rabbit and human enteropathogenic Escherichia coli in pig and rabbit intestines. Infect Immun 1983; 41: 1340-51.
6. Gross RJ, Rowe B. Escherichia coli diarrhoea. J Hyg 1985; 95: 531-50. 7. Doyle MP, Schoeni JL. Isolation of Escherichia coli O157:H7 from retail fresh meats and poultry. Appl Microbiol 1987; 53: 2394-96.
8. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989; 321: 16-24. 9. Doyle MP. Food-borne pathogens of recent concern. Ann Rev Nutr 1985; 5: 25-41. 10. Tauxe RV, Vandepitte J, Wauters G, et al. Yersinia enterocolitica infections and pork: the missing link. Lancet 1987; i: 1129-32. 11. Scheimann DA. Yersinia enterocolitica and Yersinia pseudotuberculosis. In: Doyle MP, ed. Foodborne bacterial pathogens. New York: Marcel Dekker, 1989: 601-72. 12. Hanna MO, Stewart JC, Zink DL, Carpenter ZL, Vanderzant. Development of Yersinia enterocolitica on raw and cooked beef and pork at different temperatures. J Food Protect 1977; 42: 1180-84. 13. Finlay BB, Falkow S. Common themes in microbial pathogenicity. Microbiol Rev 1989; 53: 210-30. 14. Twedt RM. Vibrio parahaemolyticus. In: Doyle MP, ed. Foodborne bacterial pathogens. New York: Marcel Dekker, 1989: 543-68. 15. West PA. The human pathogenic vibrios: a public health update with environmental perspectives. Epidemiol Infect 1989; 103: 1-34.
VIEWPOINT Which heart valves should
we
use?
TOM TREASURE Each year in the UK more than 4000 patients have an operation to replace a heart valve. The available substitutes can be usefully classed as mechanical or tissue valves: the former require life-long anticoagulation, the latter group carry the probability of valve degeneration severe enough to require reoperation at a median of perhaps 12 to 13 years. The mechanical valves include the longest standing prosthesis, the Starr-Edwards caged-ball device, and a range of single-leaflet and double-leaflet designs. The tissue valves are virtually all glutaraldehyde-preserved, framemounted pig aortic valves, apart from a few bovine pericardial and fresh or preserved human valves. How should we judge between these valves to choose the best valve for a given patient? Both types function satisfactorily as valves and relieve the symptoms and hazards of stenosis and regurgitation-but tissue and mechanical valves have inherent advantages and disadvantages. It has become extremely difficult to make these choices rationally.
Retrospective analysis Virtually all the available clinical data about valve durability and thromboembolic risk are from series evaluated retrospectively by a single surgeon or a single institution. This approach has been accepted as standard, and major journals of cardiothoracic surgery have published guidelines for the content and presentation of such data.12 Events must be defined as accurately as possible. Death might seem a clear and easily counted end-point, but the line between valve-related and non-valve-related death is
easily drawn, and is information from valves. In any
incomplete: thus,
not
very uncertain without necropsy
a pathologist used to examining heart large series, follow-up data may be
valve failure and both mild and fatal
thromboembolism may go undiagnosed and unrecorded. But above all, to what extent are observed differences in outcome attributable to the choice of valve itself, or to quite
independent factors?
Mechanical factors Some aspects are reasonably straightforward and amenable to measurement. As little space as possible should be occupied by the valve mechanism, and the height and size of the valve protruding beyond the plane of the annulus into the ventricle or the aorta-its profile-may be crucial in a small heart. The size of the orifice in relation to the external diameter, and the resulting pressure gradient in small valve sizes, varies between designs, and the larger the sewing ring the less room there is for bloodflow. These flow characteristics of a valve are reasonably predictable and can be measured directly in a pulse duplicator, tested in animals, and the haemodynamics confirmed in recipients. But, ultimately, the important issues of durability and thromboembolic risk can only be established empiricallyas shown by the history of valve surgery. As often as not, modifications introduced to improve a particular fault, such as a tendency to thrombosis or an unacceptable pattern of mechanical failure, have made things worse or introduced a new, unforseen problem.
Patient factors In a large study of survival after aortic valve replacement the Cleveland Clinic,3 probability of survival at 10 years fell with each decade of age at time of operation-from 79% in patients under 40 to 35% in patients over 69 years of age. This fmding may be unsurprising but would completely swamp and invalidate any comparison of non-age-matched series. The decline in probability of survival with poorer left ventricular function at the time of operation was almost as great: 73% 10-year survival in those with normal left ventricular function compared with 42% in those with severe dysfunction. It is hard enough to match series for patient age, but even more difficult to be sure like is compared with like when preoperative left ventricular
at
ADDRESS’ Department of Cardiothoracic Surgery, St George’s Hospital, London SW17 0QT, UK (Mr T Treasure, MS, FRCS)
1116
function
(in itself difficult to measure in a standardised and comparable manner) has such a profound effect on longsurvival-and is even more tenuous when we take into that left ventricular function and the state of the left atrium might also influence the recorded incidence of thromboembolic events. The difference in long-term survival between tissue and mechanical valves in the same series—66% 64% at 10 years-is trivial by comparison. Any attempt to extract valve-dependent factors from such data, however sophisticated the multivariate technique used, is not only unlikely to satisfy the sceptic but would seem flawed to even the most sympathetic reader because of the inescapable problem of covariance: the process of clinical choice may group age, poor left ventricular function, impaired renal function, and other adverse factors in ways which preclude any attempt to separate out valve-specific propensity for thromboembolism, valve tissue failure, or even that most obvious end-point, death. term
account
Patient/hospital factors There have been few attempts at prospective, randomised trials. One, done in Edinburgh from 1975 to 1979, compared use of mechanical tilting-disc valves with pig valves in 540 patients: at 10 years there was no significant difference in survival.4 Meanwhile, in Glasgow from 1970 to 1984, the same tilting-disc valve was implanted in 1171 patients-but the 10-year probability of survival for patients with this valve was over 20% higher in Glasgow than in Edinburgh (90% vs65%,aortic; 70% vs50%,mitral).4.5 If the two units had simply reported separate series, with different valves, one might have assumed that these two Scottish cities, only 45 miles apart, were operating on a similar population of patients, with similar cardiac pathology, and with similar indications, and attributed any difference in 10-year survival to the choice of valve. Not so: for a valve common to both studies there was a 20% difference in 10-year survival. This large discrepancy surely indicates that factors other than the choice of valve were important determinants of long-term survival: differences either of patient populations studied (eg, age and cardiac state) or related to undefined factors in their management.
Historical factors To complicate comparisons of trial results further, the era in which the valve was implanted influences thromboembolic risk. Starr and his colleagues6 found that the same model of the Starr-Edwards valve, implanted in the same hospital, often by the same surgeons, had a considerably reduced thromboembolic risk in 1973-1979 compared with their earlier experience from 1965-1972 (10% less for aortic, 38% less for mitral valves).
Practicalities of a prospective trial Thus age, cardiac state, operating hospital, and timing of the series can all influence outcome sufficiently to obscure any differences which might exist between different types of valve. Should we not look to prospective, randomised trials to answer specific questions? The major problem to be overcome would be the size of the trial needed to show such a difference. Comparison of a valve with an annual thromboembolic risk of 4% with a new mechanical valve with an expected annual risk of 1-5%,’’ even with ideally matched groups of patients, would require about 400 patients in each group to show a significant difference (6/400
0-049 by Fisher’s exact test), but some 2000 patients to exclude the possibility of a 0 error. Of course, patients would usually be followed up for longer than one year, and the numbers required would reduce proportionately. However, despite the tendency to talk in terms of patient/years as if all years and all patients were interchangeable, hazards are greatest in the first year-so patients who have survived into the second year without problems are at less risk, whereas patients who have had thromboembolism are at higher risk. The level of anticoagulation would have to be strictly comparable,9,10 and the trial would have to be very large and extremely well conducted to establish proof of even quite a striking vs
16/400, p
=
difference between the valves. One would have to agree with the sentiments expressed by a panel of leading American surgeons:" "The conclusions from these analyses are disquieting. Validation of a new device should be able to withstand the rigorous scrutiny of statistical analysis, perhaps including a randomized trial, but such an approach is probably impractical and needs to be tempered by the constraints implicit in a study requiring patient populations of such magnitude. With anticipated event rates as low as 4 per 100 patient-years, demonstrations of small but statistically significant differences between prostheses would require unrealistically large sample sizes. One can only attempt to require sufficient data to avoid the widespread use of valves with definitely inferior results".
The case-report fallacy Clinical reports of sporadic outbreaks of failure of particular types, models, or even batches of valves may indicate design faults or manufacturing problems. The recently publicised problem of outlet strut fracture of some Bjork-Shiley 60° convexoconcave valves (one of many tilting-disc valves, and one of several Bjork-Shiley models) is an example. But it would be surprising if a mechanical device which has to perform about 42 million cycles per year did not break eventually, and some must fail sooner than others by chance alone. Freedom from strut fracture at 5 years is over 99 % 12 which, it could be argued, are very good odds when compared with other risk factors such as age, left ventricular function, or hospital. Alas, sudden catastrophe attributable to mechanical failure of a device has an eloquence that shouts down any statistical arguments. Need for a prospective trial If freedom from mechanical failure is of paramount importance, the oldest available device, the Starr-Edwards caged ball valve (model 6120 mitral, model 1260 aortic) has an unrivalled record: it has no hinge mechanisms to wear on opening, and an infmitely variable closing position. But durability of the valve is not the only consideration otherwise tissue valves, where eventual failure is inevitable, would not be used. If it is considered likely that a tissue valve will "outlive" the patient then the advantages of much reduced thromboembolism and freedom from the need for anticoagulation may outweigh the risk of valve failure, especially in older patients. Such decisions rely on estimates of likely survival for both the valve and the patient, and when one or other surprises us we have to reoperate unexpectedly or, if a tissue valve is used for its specific advantages in a younger person, plan for reoperation in due course. But repeat valve operations can be difficult and dangerous. The most recent registry figures for perioperative mortality for all valve operations have been
1117
around 5-6% for mitral valve replacement, and 4-5% for It seems implausible that reoperations could carry a lower risk than this. Many questions remain unanswered. For patients in whom a tissue valve is selected to avoid the need for anticoagulation, which valve carries the lowest thromboembolic risk with the longest working life? What is the likely working life and probable mode of failure? Is it prone to calcification and stenosis, or cusp failure and regurgitation, or both? Survival at reoperation will be strongly influenced by the mode of failure, since a mild and slowly progressive defect would allow time for diagnosis and planned surgery; sudden
aortic valve
catastrophe would not. These questions cannot be answered on the drawing board, in the pulse duplicator, or in animals. A prospectivetrial seemed the correct and only way to prove superiority of one material and one design over another. Two randomised trials had recruited several hundred patients to compare frame-mounted porcine aortic valves with those fashioned from bovine pericardium, but have been abandoned because of concern about possible transmission of bovine spongiform encephalopathy. So dramatic events such as strut failure,13,14 and even the emergence of a novel brain disease in cattle, dictate clinical practice while we still make choices that
the more numerous and more of death without the benefit of any scientific evidence from comparative trials. Prospective, controlled, randomised trials of adequate size and quality may be a daunting and difficult long-term commitment, but claims for superiority of a new valve over an older one, based on uncontrolled clinical series and historical controls, fall short of scientific proof.
important
INFORMATION FOR AUTHORS
replacement.
concern
causes
REFERENCES 1. Edmunds LH, Clark RE, Cohn LH, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. Ann Thorac Surg 1988; 46: 257-59. 2. Edmunds LH, Clark RE, Cohn LH, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. J Thorac Cardiovasc Surg 1988; 96: 351-53. 3. Lytle BW, Cosgrove DM, Taylor PC, et al. Primary isolated aortic valve replacement. J Thorac Cardiovasc Surg 1989; 97: 675-94. 4. Bloomfield P, Wheatley DJ, Prescott RJ, Miller HC. Ten year result of a randomised trial of the Bjork-Shiley, Hancock, and CarpentierEdwards prostheses. Br Heart J 1989; 61: 452. 5. Sethia B, Turner MA, Lewis S, Rodger RA, Bain WH. Fourteen years’ experience with the Bjork-Shiley tilting disc prosthesis. J Thorac Cardiovasc Surg 1986; 91: 350-61. 6. Macmanus Q, Grunkemeier GL, Lambert LE, Teply JF, Harlan BJ, Starr A. Year of operation as a risk factor in the late results of valve
replacement. J Thorac Cardiovasc Surg 1980; 80: 834-41. 7. Butchart EG, Lewis PA, Grunkemeier GL, Kulatilake N, Breckenridge IM. Low risk of thrombosis and serious embolic events despite low-intensity anticoagulation. Experience with 1004 Medtronic Hall valves. Circulation 1988; 78 (suppl I): 166-77. 8. Kuntze CEE, Ebels T, Eijgelaar A, Homan van der Heide JN. Rates of thromboembolism with three different mechanical heart valve prostheses: randomised study. Lancet 1989; i: 514-17. 9. Butchart EG, Lewis PA, Kulitilake ENP, et al. Anticoagulation
variability between centres; implications for comparative prosthetic valve assessment. Eur J Cardiothorac Surg 1988; 2: 72-81. 10. Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-32. 11. Gersh BJ, Fisher LD, Schaff HV, et al. Issues concerning the clinical evaluation of prosthetic valves. J Thorac Cardiovasc Surg 1986; 91: 460-66. 12. Hiratzka LF, Kouchoukos NT, Grunkemeier GL, Miller C, Scully HE, Wechsler AS. Outlet strut fracture of the Bjork-Shiley 60° convexoconcave valve: current information and recommendations for patient care. J Am Coll Cardiol 1988; 11: 1130-37. 13. Editorial. Advising patients with artificial heart valves. Lancet 1990; 336: 152. 14. Brahams D. Bjork-Shiley heart-valve failures. Lancet 1990; 336: 619-20.
The Lancet does not refuse to look at papers that fail to the journal’s style requirements, but it much prefers to see submissions meeting the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, prepared by the International Committee of Medical Journal Editors, of which The Lancet is a member (see Br Med] 1988; 296: 401-05 or Ann Intern Med 1988; 108: 258-65). Especially important is the need for double-spaced typing on one side of the paper; for references to carry titles and final page numbers; and for three copies of submitted articles. Submissions by FAX are not welcome and will only be evaluated after prior agreement with the meet
journal. Length of contributions. Authors can improve their chances of success if they observe the following word limits: articles, not more than 3000 (roughly twelve pages of typescript on A4); preliminary reports and hypotheses, 1500; letters, 500. To these limits to the body of the text may be added a title page; a summary of not more than 150 words, tables, illustrations, and legends; and references (preferably not more than 30 for articles and 10 for letters). Addresses. Details of addresses of all authors, a single qualification such as MD or PhD, and full professorships are published as a footnote to papers, and this information should be provided on the title page of the manuscript. A full address should be provided for the corresponding author, and the journal will need to know if this author differs from the one for editorial communications, including proofs. Authorship. The journal may ask for justification of authorship (see Lancet 1985; ii: 595). Covering letter. Every reasonable effort should be made for all authors to sign the covering letter. In this letter authors may wish to indicate any concessions they are willing to make, such as the omission of tables, figures, references, or parts of the text. Single copies of work that is unpublished, submitted, or in press, and is important to the argument, should be enclosed. Dual publication. If material in a submitted article has been published before or is to appear in part or whole elsewhere, the Editor must be informed. Acknowledgment of receipt. The receipt of papers (but not letters) is acknowledged immediately, a reference number for future inquiries being provided. Peer review. Every paper submitted is read by two or more of The Lancet’s editorial team of physicians and scientists. All those shortlisted for publication in the section Medical Science are then sent to one or more external advisers. Peer review is used more selectively for other categories of article and for letters. Proofs. Authors should arrange for proofs of articles to be returned within 48 hours. When proofs of letters are sent, the journal needs to have corrections as quickly as possible. Reprints. Within a few days of publication of a paper 100 offprints are despatched free of charge. Reprints must be ordered through The Lancet’s Reprint Department in London or Baltimore (for inquiries from North America). Copyright. Authors are assumed, with exceptions such as certain government employees, to transfer to The Lancet the copyright in their words, and this will be confirmed formally at proof stage for articles. Single copies can be made by individual clinicians or research workers for personal use without permission or payment. Multiple copying can be done only with the agreement of the journal’s Permissions Department in London, to which any requests for republication or translation should be addressed.
under-refrigerated, inadequately cooked, or recontaminated and temperature abused after cooking. Proper cooking and refrigeration of seafoods are important factors in the prevention of V parahaemolyticus gastroenteritis. REFERENCES 1. Levine MM. Escherichia coli that
cause
diarrhea: enterotoxigenic,
and enteroinvasive, enteropathogenic, enterohemorrhagic, enteroadherent. J Infect Dis 1987; 155: 377-89. 2. Doyle MP, Padhye W. Escherichia coli. In: Doyle MP, ed. Foodborne bacterial pathogens. New York: Marcel Dekker, 1989: 236-81. 3. Karmali MA. Infection by verocytotoxin-producing Escherichia coli. Clin Microbiol Rev 1989; 2: 15-38
4. Robins-Browne RM. Traditional enteropathogenic Escherichia coli of infantile diarrhea. Rev Infect Dis 1987; 9: 28-53. 5. Moon HW, Whipp SC, Arzenio RA, Levine MM, Gianella RA. Attaching and effacing activities of rabbit and human enteropathogenic Escherichia coli in pig and rabbit intestines. Infect Immun 1983; 41: 1340-51.
6. Gross RJ, Rowe B. Escherichia coli diarrhoea. J Hyg 1985; 95: 531-50. 7. Doyle MP, Schoeni JL. Isolation of Escherichia coli O157:H7 from retail fresh meats and poultry. Appl Microbiol 1987; 53: 2394-96.
8. Cover TL, Aber RC. Yersinia enterocolitica. N Engl J Med 1989; 321: 16-24. 9. Doyle MP. Food-borne pathogens of recent concern. Ann Rev Nutr 1985; 5: 25-41. 10. Tauxe RV, Vandepitte J, Wauters G, et al. Yersinia enterocolitica infections and pork: the missing link. Lancet 1987; i: 1129-32. 11. Scheimann DA. Yersinia enterocolitica and Yersinia pseudotuberculosis. In: Doyle MP, ed. Foodborne bacterial pathogens. New York: Marcel Dekker, 1989: 601-72. 12. Hanna MO, Stewart JC, Zink DL, Carpenter ZL, Vanderzant. Development of Yersinia enterocolitica on raw and cooked beef and pork at different temperatures. J Food Protect 1977; 42: 1180-84. 13. Finlay BB, Falkow S. Common themes in microbial pathogenicity. Microbiol Rev 1989; 53: 210-30. 14. Twedt RM. Vibrio parahaemolyticus. In: Doyle MP, ed. Foodborne bacterial pathogens. New York: Marcel Dekker, 1989: 543-68. 15. West PA. The human pathogenic vibrios: a public health update with environmental perspectives. Epidemiol Infect 1989; 103: 1-34.
VIEWPOINT Which heart valves should
we
use?
TOM TREASURE Each year in the UK more than 4000 patients have an operation to replace a heart valve. The available substitutes can be usefully classed as mechanical or tissue valves: the former require life-long anticoagulation, the latter group carry the probability of valve degeneration severe enough to require reoperation at a median of perhaps 12 to 13 years. The mechanical valves include the longest standing prosthesis, the Starr-Edwards caged-ball device, and a range of single-leaflet and double-leaflet designs. The tissue valves are virtually all glutaraldehyde-preserved, framemounted pig aortic valves, apart from a few bovine pericardial and fresh or preserved human valves. How should we judge between these valves to choose the best valve for a given patient? Both types function satisfactorily as valves and relieve the symptoms and hazards of stenosis and regurgitation-but tissue and mechanical valves have inherent advantages and disadvantages. It has become extremely difficult to make these choices rationally.
Retrospective analysis Virtually all the available clinical data about valve durability and thromboembolic risk are from series evaluated retrospectively by a single surgeon or a single institution. This approach has been accepted as standard, and major journals of cardiothoracic surgery have published guidelines for the content and presentation of such data.12 Events must be defined as accurately as possible. Death might seem a clear and easily counted end-point, but the line between valve-related and non-valve-related death is
easily drawn, and is information from valves. In any
incomplete: thus,
not
very uncertain without necropsy
a pathologist used to examining heart large series, follow-up data may be
valve failure and both mild and fatal
thromboembolism may go undiagnosed and unrecorded. But above all, to what extent are observed differences in outcome attributable to the choice of valve itself, or to quite
independent factors?
Mechanical factors Some aspects are reasonably straightforward and amenable to measurement. As little space as possible should be occupied by the valve mechanism, and the height and size of the valve protruding beyond the plane of the annulus into the ventricle or the aorta-its profile-may be crucial in a small heart. The size of the orifice in relation to the external diameter, and the resulting pressure gradient in small valve sizes, varies between designs, and the larger the sewing ring the less room there is for bloodflow. These flow characteristics of a valve are reasonably predictable and can be measured directly in a pulse duplicator, tested in animals, and the haemodynamics confirmed in recipients. But, ultimately, the important issues of durability and thromboembolic risk can only be established empiricallyas shown by the history of valve surgery. As often as not, modifications introduced to improve a particular fault, such as a tendency to thrombosis or an unacceptable pattern of mechanical failure, have made things worse or introduced a new, unforseen problem.
Patient factors In a large study of survival after aortic valve replacement the Cleveland Clinic,3 probability of survival at 10 years fell with each decade of age at time of operation-from 79% in patients under 40 to 35% in patients over 69 years of age. This fmding may be unsurprising but would completely swamp and invalidate any comparison of non-age-matched series. The decline in probability of survival with poorer left ventricular function at the time of operation was almost as great: 73% 10-year survival in those with normal left ventricular function compared with 42% in those with severe dysfunction. It is hard enough to match series for patient age, but even more difficult to be sure like is compared with like when preoperative left ventricular
at
ADDRESS’ Department of Cardiothoracic Surgery, St George’s Hospital, London SW17 0QT, UK (Mr T Treasure, MS, FRCS)
1116
function
(in itself difficult to measure in a standardised and comparable manner) has such a profound effect on longsurvival-and is even more tenuous when we take into that left ventricular function and the state of the left atrium might also influence the recorded incidence of thromboembolic events. The difference in long-term survival between tissue and mechanical valves in the same series—66% 64% at 10 years-is trivial by comparison. Any attempt to extract valve-dependent factors from such data, however sophisticated the multivariate technique used, is not only unlikely to satisfy the sceptic but would seem flawed to even the most sympathetic reader because of the inescapable problem of covariance: the process of clinical choice may group age, poor left ventricular function, impaired renal function, and other adverse factors in ways which preclude any attempt to separate out valve-specific propensity for thromboembolism, valve tissue failure, or even that most obvious end-point, death. term
account
Patient/hospital factors There have been few attempts at prospective, randomised trials. One, done in Edinburgh from 1975 to 1979, compared use of mechanical tilting-disc valves with pig valves in 540 patients: at 10 years there was no significant difference in survival.4 Meanwhile, in Glasgow from 1970 to 1984, the same tilting-disc valve was implanted in 1171 patients-but the 10-year probability of survival for patients with this valve was over 20% higher in Glasgow than in Edinburgh (90% vs65%,aortic; 70% vs50%,mitral).4.5 If the two units had simply reported separate series, with different valves, one might have assumed that these two Scottish cities, only 45 miles apart, were operating on a similar population of patients, with similar cardiac pathology, and with similar indications, and attributed any difference in 10-year survival to the choice of valve. Not so: for a valve common to both studies there was a 20% difference in 10-year survival. This large discrepancy surely indicates that factors other than the choice of valve were important determinants of long-term survival: differences either of patient populations studied (eg, age and cardiac state) or related to undefined factors in their management.
Historical factors To complicate comparisons of trial results further, the era in which the valve was implanted influences thromboembolic risk. Starr and his colleagues6 found that the same model of the Starr-Edwards valve, implanted in the same hospital, often by the same surgeons, had a considerably reduced thromboembolic risk in 1973-1979 compared with their earlier experience from 1965-1972 (10% less for aortic, 38% less for mitral valves).
Practicalities of a prospective trial Thus age, cardiac state, operating hospital, and timing of the series can all influence outcome sufficiently to obscure any differences which might exist between different types of valve. Should we not look to prospective, randomised trials to answer specific questions? The major problem to be overcome would be the size of the trial needed to show such a difference. Comparison of a valve with an annual thromboembolic risk of 4% with a new mechanical valve with an expected annual risk of 1-5%,’’ even with ideally matched groups of patients, would require about 400 patients in each group to show a significant difference (6/400
0-049 by Fisher’s exact test), but some 2000 patients to exclude the possibility of a 0 error. Of course, patients would usually be followed up for longer than one year, and the numbers required would reduce proportionately. However, despite the tendency to talk in terms of patient/years as if all years and all patients were interchangeable, hazards are greatest in the first year-so patients who have survived into the second year without problems are at less risk, whereas patients who have had thromboembolism are at higher risk. The level of anticoagulation would have to be strictly comparable,9,10 and the trial would have to be very large and extremely well conducted to establish proof of even quite a striking vs
16/400, p
=
difference between the valves. One would have to agree with the sentiments expressed by a panel of leading American surgeons:" "The conclusions from these analyses are disquieting. Validation of a new device should be able to withstand the rigorous scrutiny of statistical analysis, perhaps including a randomized trial, but such an approach is probably impractical and needs to be tempered by the constraints implicit in a study requiring patient populations of such magnitude. With anticipated event rates as low as 4 per 100 patient-years, demonstrations of small but statistically significant differences between prostheses would require unrealistically large sample sizes. One can only attempt to require sufficient data to avoid the widespread use of valves with definitely inferior results".
The case-report fallacy Clinical reports of sporadic outbreaks of failure of particular types, models, or even batches of valves may indicate design faults or manufacturing problems. The recently publicised problem of outlet strut fracture of some Bjork-Shiley 60° convexoconcave valves (one of many tilting-disc valves, and one of several Bjork-Shiley models) is an example. But it would be surprising if a mechanical device which has to perform about 42 million cycles per year did not break eventually, and some must fail sooner than others by chance alone. Freedom from strut fracture at 5 years is over 99 % 12 which, it could be argued, are very good odds when compared with other risk factors such as age, left ventricular function, or hospital. Alas, sudden catastrophe attributable to mechanical failure of a device has an eloquence that shouts down any statistical arguments. Need for a prospective trial If freedom from mechanical failure is of paramount importance, the oldest available device, the Starr-Edwards caged ball valve (model 6120 mitral, model 1260 aortic) has an unrivalled record: it has no hinge mechanisms to wear on opening, and an infmitely variable closing position. But durability of the valve is not the only consideration otherwise tissue valves, where eventual failure is inevitable, would not be used. If it is considered likely that a tissue valve will "outlive" the patient then the advantages of much reduced thromboembolism and freedom from the need for anticoagulation may outweigh the risk of valve failure, especially in older patients. Such decisions rely on estimates of likely survival for both the valve and the patient, and when one or other surprises us we have to reoperate unexpectedly or, if a tissue valve is used for its specific advantages in a younger person, plan for reoperation in due course. But repeat valve operations can be difficult and dangerous. The most recent registry figures for perioperative mortality for all valve operations have been
1117
around 5-6% for mitral valve replacement, and 4-5% for It seems implausible that reoperations could carry a lower risk than this. Many questions remain unanswered. For patients in whom a tissue valve is selected to avoid the need for anticoagulation, which valve carries the lowest thromboembolic risk with the longest working life? What is the likely working life and probable mode of failure? Is it prone to calcification and stenosis, or cusp failure and regurgitation, or both? Survival at reoperation will be strongly influenced by the mode of failure, since a mild and slowly progressive defect would allow time for diagnosis and planned surgery; sudden
aortic valve
catastrophe would not. These questions cannot be answered on the drawing board, in the pulse duplicator, or in animals. A prospectivetrial seemed the correct and only way to prove superiority of one material and one design over another. Two randomised trials had recruited several hundred patients to compare frame-mounted porcine aortic valves with those fashioned from bovine pericardium, but have been abandoned because of concern about possible transmission of bovine spongiform encephalopathy. So dramatic events such as strut failure,13,14 and even the emergence of a novel brain disease in cattle, dictate clinical practice while we still make choices that
the more numerous and more of death without the benefit of any scientific evidence from comparative trials. Prospective, controlled, randomised trials of adequate size and quality may be a daunting and difficult long-term commitment, but claims for superiority of a new valve over an older one, based on uncontrolled clinical series and historical controls, fall short of scientific proof.
important
INFORMATION FOR AUTHORS
replacement.
concern
causes
REFERENCES 1. Edmunds LH, Clark RE, Cohn LH, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. Ann Thorac Surg 1988; 46: 257-59. 2. Edmunds LH, Clark RE, Cohn LH, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. J Thorac Cardiovasc Surg 1988; 96: 351-53. 3. Lytle BW, Cosgrove DM, Taylor PC, et al. Primary isolated aortic valve replacement. J Thorac Cardiovasc Surg 1989; 97: 675-94. 4. Bloomfield P, Wheatley DJ, Prescott RJ, Miller HC. Ten year result of a randomised trial of the Bjork-Shiley, Hancock, and CarpentierEdwards prostheses. Br Heart J 1989; 61: 452. 5. Sethia B, Turner MA, Lewis S, Rodger RA, Bain WH. Fourteen years’ experience with the Bjork-Shiley tilting disc prosthesis. J Thorac Cardiovasc Surg 1986; 91: 350-61. 6. Macmanus Q, Grunkemeier GL, Lambert LE, Teply JF, Harlan BJ, Starr A. Year of operation as a risk factor in the late results of valve
replacement. J Thorac Cardiovasc Surg 1980; 80: 834-41. 7. Butchart EG, Lewis PA, Grunkemeier GL, Kulatilake N, Breckenridge IM. Low risk of thrombosis and serious embolic events despite low-intensity anticoagulation. Experience with 1004 Medtronic Hall valves. Circulation 1988; 78 (suppl I): 166-77. 8. Kuntze CEE, Ebels T, Eijgelaar A, Homan van der Heide JN. Rates of thromboembolism with three different mechanical heart valve prostheses: randomised study. Lancet 1989; i: 514-17. 9. Butchart EG, Lewis PA, Kulitilake ENP, et al. Anticoagulation
variability between centres; implications for comparative prosthetic valve assessment. Eur J Cardiothorac Surg 1988; 2: 72-81. 10. Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-32. 11. Gersh BJ, Fisher LD, Schaff HV, et al. Issues concerning the clinical evaluation of prosthetic valves. J Thorac Cardiovasc Surg 1986; 91: 460-66. 12. Hiratzka LF, Kouchoukos NT, Grunkemeier GL, Miller C, Scully HE, Wechsler AS. Outlet strut fracture of the Bjork-Shiley 60° convexoconcave valve: current information and recommendations for patient care. J Am Coll Cardiol 1988; 11: 1130-37. 13. Editorial. Advising patients with artificial heart valves. Lancet 1990; 336: 152. 14. Brahams D. Bjork-Shiley heart-valve failures. Lancet 1990; 336: 619-20.
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