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J Thorac Cardiovasc Surg 1994;107:1136-1145
© 1994 Mosby, Inc.
SURGERY FOR ACQUIRED HEART DISEASE |
Düsseldorf, Germany
From the Department of Cardiology, Pneumology and Angiology, Heinrich-Heine-University, Düsseldorf, Germany.
Address for reprints: Dieter Horstkotte, MD, Department of Cardiology, Pneumology and Angiology, Heinrich-Heine-University, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Abstract
Six hundred consecutive patients were operated on between September 1978 and October 1982 for isolated aortic (n = 298), mitral (n = 215), or multiple valve replacement (n = 87) with the St. Jude Medical bileaflet prosthesis. Mean age of the 303 female and 297 male patients was 50.7 ± 9.6 (range 12 to 83) years. All patients were followed up prospectively; follow-up was complete and averaged 122.2 ± 1.1 months for operative survivors. Total follow-up for aortic patients was 2904.1 patient-years, for mitral replacement 1859.5 patient-years, and for multiple valve replacement 736 patient-years. When the prothrombin times measured with different thromboplastins were converted into an international normalized ratio, four patient groups could be separated; that is, the groups comprised patients whose anticoagulation was maintained during the follow-up within an international normalized ratio corridor of 4.0 to 6.0, 3.0 to 4.5, 2.5 to 3.5, or 1.75 to 2.75. Less intensive anticoagulation in terms of the international normalized ratio values caused only a mild increase in the incidence of thromboembolic complications but a highly significant decrease in the rate of bleeding. Severe bleeding complications in the aortic valve group were highest with an international normalized ratio of 4.0 to 6.0 (1.15 per patient-year) and lowest with an international normalized ratio of 1.75 to 2.75 (0.24 per patient-year). The same held true for patients with single St. Jude Medical mitral valve replacement (2.09 per patient-year versus 0.72 per patient-year) and multiple valve replacements (4.45 per patient-year versus 1.20 per patient-year). These results suggest that the generally recommended international normalized ratio of 3.0 to 4.5 may be too high for patients with St. Jude Medical aortic valve replacement and also for patients with St. Jude Medical prostheses in the mitral position if, with respect to the thromboembolic hazard, there is not a predominating patient-related comorbidity. A large multicenter prospective randomized study is therefore proposed to establish the safe international normalized ratio levels accompanied by the lowest complication rates for both bleeding and thromboembolic events after St. Jude Medical prosthesis implanation (German experience with low intensity anticoagulation study). (J THORAC CARDIOVASC SURG 1994;107:1136-45)
Intracardiac thrombosis and consequent embolism have remained a constant source for late morbidity and mortality, 
1-3 necessitating life-long anticoagulation treatment, which itself carries a significant complication hazard. 4 Although there have been no clinical trials comparing the outcome of patients with mechanical heart valves who receive anticoagulation with patients with mechanical heart valves who receive no anticoagulation, level II evidence 5 has confirmed that anticoagula tion is more effective than treatment with platelet-active drugs for patients with Starr-Edwards ball valve prostheses. 6
For patients with mechanical heart valve prostheses, it has been recommended that oral anticoagulation be managed to maintain an international normalized ratio (INR) between 3.0 and 4.5 7-10 or between 3.6 and 4.8. 11 These recommendations are arbitrary and based on the clinical results of first- and second-generation mechanical prostheses, which had relatively high thromboembolic prevalences, 1 and do not take into account that improvements in the design and materials of more modern prostheses may have reduced thrombogenicity. 12,13 Moreover, despite implantation of the same type of prosthesis, the risk of intracardiac thrombus formation may vary from one patient to another because of the underlying cardiac morphologic and physiologic conditions. 14
Recent comparative studies that analyzed different anticoagulation intensities have revealed that thromboembolic and hemorrhagic complications are less prevalent with an intensity of oral anticoagulation below the hitherto recommended therapeutic ranges (INR 3.0 to 4.5). 15-20 However, the safety and efficacy of lowerintensity anticoagulation have not been proved so far. 21
This 10-year prospective observation of 600 consecutive patients in whom the St. Jude Medical bileaflet prosthesis (St. Jude Medical, Inc., St. Paul, Minn.) was implanted may contribute to the ongoing debate.
PATIENTS AND METHODS
Between September 1978 and October 1982, consecutive patients were operated on for isolated aortic (n = 298), mitral (n = 215), aortic plus mitral (n = 86), or triple (n = 1) valve replacement with the St. Jude Medical bileaflet prosthesis. There were 303 female and 297 male patients with a mean age of 50.7 ± 9.6 years, ranging from 12 to 83 years. Further, 24.2% of the single mitral valve replacements (n = 52) and 19.5% of the double valve replacements (n = 17) were reoperations after commissurotomy. Twenty-seven patients with isolated aortic valve replacements had undergone previous cardiac surgical intervention. Patients were followed up prospectively by the Düsseldorf system, which incorporates patient self-reporting of complications in addition to two outpatient examinations each year. 21 The mean interval between follow-up examinations was 7.4 ± 4.1 (range 1 to 13) months and the median interval was 7.9 months (10% of intervals were shorter than 3.2 months, 10% were longer than 10.3 months). The average number of examinations per patient during this follow-up period was 17.4 ± 5.7, ranging from 12 to 33. The median number of examinations was 15.6 with 10% of patients having fewer than 13.9 and 10% having more than 24.9 examinations during this period.
Average total follow-up was 113.6 ± 9.6 months, including patients who died in the early postoperative period or during the late follow-up. If only late survivors are considered, average follow-up was 122.2 ± 1.1 months. None of the late survivors had a follow-up less than 10 years. Total follow-up for patients with aortic valve replacement was 2904.1 patient-years, for mitral replacement 1859.5 patient-years, and for multiple valve replacements 736 patient-years.
All information gathered during the outpatient examinations and from the patient report forms was collected prospectively. No intermediate analysis of these data was done subsequent to the initial analysis of the preliminary clinical and hemodynamic results completed in 1982, 2,22 thus avoiding the risk of treatment bias.
Thromboembolic events and anticoagulant-related bleedings are reported in this paper according to the current guidelines for reporting morbidity and mortality after valve replacement operations. 23 In addition, thromboembolic and bleeding complications have been graded from I to III (TE I to III and BL I to III) using a modified performance status scale (Table I). 24
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25 The recommended target Quick range (15% to 25%), when measured by human thromboplastin containing calcium (Thromborel S'), was coincident with an INR of 3.0 to 4.5. Patients and their family doctors were advised to continue the therapy indefinitely. During the follow-up, 132,453 measurements of the anticoagulation intensity were documented. The median number of anticoagulation measurements per patient was 198 ± 71. The distribution of these measurements was calculated per patient and is presented as a Box and Whisker plot. 26
Statistics.
The usual test statistics of the SAS* and BMDP
software were used. Data are presented as mean plus or minus the standard deviation. Where it is indicated that a median value is given, this represents the 50th percentile and is accompanied by the 10th and 90th percentiles. Actuarial analysis of the event-free survival was done by the Kaplan-Meier product limit method. 27 The log rank test was used for the comparison of two event-free curves. 28 The substantial statistical analysis was done by an independent biostatistical institute.
RESULTS
Early and late mortality.
Early and late mortality is not a primary subject of this publication. It may, however, be important for the interpretation of the results. A more detailed analysis of this cohort's early and late mortality, as well as of late morbidity, has been published elsewhere. 17
Thromboembolic and bleeding complications.
The thromboembolic and bleeding prevalences in the present series are much higher than are usually reported for mechanical heart valves, especially for the St. Jude Medical prosthesis. This can be explained by the unique follow-up method used by our institution (previously described herein), which includes regular outpatient examination plus a system in which patients report all unusual events, even mild events such as a nosebleed or a hematoma of more than 3 cm in diameter, with a special documentation card. They also report all Quick measurements that have been done. Recent information suggests that most series claiming to report exact complication rates by follow-up methods different from this standard may miss the majority of minor events and even a significant percentage of more severe events. 29,30 This may be especially true when follow-up methods consist only of questionnaires or telephone calls. Because the current guidelines for reporting thromboembolism and bleeding complications dictate that all events be reported regardless of their severity, 23 it is obvious that the complication rates of two series of patients are dependent on the quality of the follow-up method and the frequency of follow-up examinations and interviews.
In the current situation, with nonstandardized follow-up techniques being used around the world, to make our data comparable with those of other series it may be more appropriate not to report all thromboembolic and bleeding events after valve replacement operations, but to report only moderate to severe complications (in our definition, complications graded II and III) and disregard so-called transient or minor episodes, as we have recommended earlier. 2 However, inclusion of all events makes possible a better statistical comparison, within our cohort, of different-intensity anticoagulation regimens.
Aortic valve replacement.
There were 19 thromboembolic and 27 bleeding episodes in the first 3 months after surgical intervention (Table II). The risk functions revealed a nonlinear prevalence for both thromboembolic and bleeding complications for this period. The thromboembolic and bleeding risk, therefore, was calculated only for the late (>3 months) postoperative period, during which a linear incidence for both complications was seen.
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Table II).
The linearized incidence for late thromboembolic events was 3.82%/pt-yr taking all thromboembolic events into account and 2.69%/pt-yr taking only the first or most severe of several events into account (Table II). The linearized incidence for all bleeding complications was 6.65%/pt-yr and 4.09%/pt-yr if only the first or most severe event is counted. Comparing late thromboembolic and bleeding complications of comparable severity, the bleeding-to-thromboembolism ratios were 2.6 (BL III/TE III), 1.6 (BL II/TE II), and 1.4 (BL I/TE I).
Mitral valve replacement.
In the first 3 postoperative months, 19 thromboembolic and 23 bleeding episodes were documented. Applying the same criteria described for the aortic valve group (events more than 3 months after operation), there were 114 thromboembolic events in 82 patients and 149 bleeding events in 119 patients in the later course. Eleven patients had severe (TE III) thromboembolic events, four being fatal. Twelve patients had grade II and 59 patients transient (TE I) thromboembolic episodes. Twelve patients had severe (BL III) bleeding complications, four being fatal. Twenty-five patients had grade II and 82 had minor (BL I) bleeding events (Table II).
The linearized incidence of thromboembolism in the late follow-up was 4.41%/pt-yr and the incidence of bleeding was 6.40%/pt-yr if only the first or most severe episodes were considered (Table II). Bleeding-to-thromboembolic ratios for comparable events were calculated as follows: 1.1 (BL III/TE III), 2.1 (BL II/TE II), and 1.4 (BL I/TE I).
Although the influence of patient-related factors (that is, cardiac morphologic and physiologic conditions) is not routinely analyzed when reporting on the thromboembolic risk after valve replacement operation, these factors are generally considered to be important incremental risk factors predisposing patients to intracardiac thrombosis and consequent embolization. A separate analysis of the thromboembolic and bleeding complications for patients with or without active atrial contraction and for three patient groups with progressing left atrial enlargement was done (Table III). Although there were no differences in the prevalence of bleeding complications or in the intensity of anticoagulation among these groups, the comparison demonstrates that the loss of active atrial contraction has a more significant influence on thromboembolic occurrences than does the left atrial dimension.
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Table II). Six of the 12 grade III complications (three thromboembolic and three bleeding) had a fatal outcome. The linearized incidence was 5.30%/pt-yr for thromboembolism and 6.11%/pt-yr for bleeding. Bleeding-to-thromboembolic ratios for comparable events were 1.4 (BL III/TE III) and 1.1 (BL II/TE II) (Table II).
Influence of anticoagulation intensity on the frequency of thromboembolic and bleeding complications.
For historical reasons, anticoagulation intensities in Germany are measured by the method reported by Quick 25 and reported as Quick's level, which is the percentage of normal. The Quick method does not take into account the sensitivity of the thromboplastin reagent used for the test. Therefore, because of the use of different thromboplastin reagents, two measurements of the anticoagulation intensity done from the same blood sample by two different laboratories may result in different Quick values.
To compare our results with other results in the literature, we attempted to convert the 132,453 Quick values from all documents measured by 13 laboratories (two at our institution, four at community hospitals, seven at private laboratories) into the corresponding INR values. With the use of the appropriate international sensitivity index 31 or, for the earlier years of valve implantation, the calibration curves (if available), we were able to recalculate the INR for 85.9% of the Quick measurements.
The routine data analysis included a Box and Whisker plot for the distribution of measured intensities of anticoagulation throughout the 10-year period for each patient. Fig. 1 gives the distribution of the measured Quick level for 30 patients consecutively operated on who received St. Jude Medical mitral valve prostheses. These patients were picked by chance from the total cohort (Nos. 85 through 114). The Box and Whisker plot for the respective INR values recalculated from the Quick measurements is given in Fig. 2. The significant differences between the distribution of the Quick levels and the INR are striking. Because of the different sensitivities of the thromboplastins used by the laboratories and the lack of appropriate adjustment when anticoagulant dosages were determined, patients were treated with different intensities of anticoagulation throughout the follow-up period.
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Table II can be arranged and presented in terms of these different anticoagulation intensities in Tables IV through VI.
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Table VII. Somewhat more than one third of all measurements in the aortic, mitral, and multiple valve replacement groups were outside the patient's initial range, the highest percentage being in the replacement groups with a calculated INR ranging from 4.0 to 6.0 and from 3.0 to 4.5; the lowest percentage was in the group with a calculated INR ranging from 1.8 to 2.7.
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In recent years, an increasing number of articles have been devoted to the thrombogenicity of artificial heart valves, especially valves of the latest generation, and the optimum intensity of anticoagulation for an individual patient. The reason for this growing interest is evident: intracardiac thrombosis associated with mechanical heart valves, consequent embolic episodes, and the need for life-long anticoagulation are the major disadvantages of such devices.
Because patient selection for operation, surgical techniques, anticoagulation modalities, comedication, patient-related comorbidity, other incremental risk factors, and the quality of follow-up methods may vary distinctly from institution to institution and even between two nonrandomized patient groups treated in the same institution, thromboembolic incidences published by different authors are noncomparable and any conclusion drawn from such an analysis may be extremely misleading. 30,31
Recommendations for the optimum level of anticoagulation for patients with replacement heart valves are based on thromboembolic incidences reported for first- and second-generation devices. For many years, the target therapeutic INR range of 3.0 to 4.5, initially chosen arbitrarily, has been regarded as optimum to balance thromboembolic and bleeding complications for mechanical valves of any design. When the St. Jude Medical bileaflet design was first introduced in the late 1970s, its primary and secondary thrombogenicity was suspected to be lower than that of prosthetic devices already available. The lower thrombogenicity was expected because of the more central flow pattern that creates less shear-induced platelet activation, 33 the surface of the valve housing and the leaflets made from thromboresistant pyrolytic carbon, 34 and the special hinge design. Corresponding to these theoretic expectations, lower prevalences of thromboembolic events actually have been found after a relatively short follow-up period. 2
As discussed previously, the thromboembolic and bleeding incidences in the present series are much higher than usually reported for mechanical heart valves, especially for the St. Jude Medical prosthesis. This can be explained by the unique follow-up method used by our institution. In the current situation, with nonstandardized follow-up techniques being used by institutions around the world, it seems more appropriate to disregard so-called transient or minor episodes. 2
Our results demonstrate that to avoid misinterpretation and mismanagement, anticoagulation management should be based on the reproducible INR rather than the prothrombin time or the Quick level. Although the Box and Whisker plot showed a relatively close profile and homogenous distribution of Quick levels in the majority of patients, conversion into the INR revealed that the anticoagulation intensity was amazingly variable and discrepant to what we had recommended (target INR 3.0 to 4.5). This finding made possible the stratification of our patients according to the actual anticoagulation intensity. With use of the "box best fitting into corridor" model, four groups of patients were defined with an INR ranging from 4.0 to 6.0, 3.0 to 4.5, 2.5 to 3.5, or 1.75 to 2.75. The overlap of the INR corridors was necessary to guarantee that the vast majority of measurements in an individual patient actually fell into one of the corridors. The anticoagulation intensity (corridor) was allocated to each patient by chance, inasmuch as the patients were free to choose their home physicians and thereby the laboratory where the Quick levels were measured. For this reason, and because the patient population was relatively homogeneous throughout, our study is essentially close to a prospective randomized study. Finally, an accurate analysis of the incidence of thromboembolic and bleeding complications associated with different anticoagulation levels was made possible by the long follow-up period (10 years).
Aortic valve replacement.
Transient thromboembolic and hemorrhagic episodes are of minor importance in the overall prognosis of patients after valve replacement and are regularly missed by conventional follow-up techniques. 35,36 For these reasons, we disregarded those minor (grade I) events for the analysis of the thromboembolic and bleeding risk after aortic valve replacement. By this analysis, it became evident that with more intensive oral anticoagulation, the thromboembolic risk was reduced but the risk of hemorrhagic complications increased. 19,20,37,38 Neither the frequency of significant (grades II and III) thromboembolic events nor of significant (grades II and III) hemorrhagic complications was a linear function of the intensity of oral anticoagulation (Fig. 4). When compared with results in patients without oral anticoagulation therapy (INR 1.0), the thromboembolic hazard after St. Jude Medical aortic valve replacement is significantly reduced by oral anticoagulation treatment. Those patients grouped under INR 1.0 (Fig. 4) were 16 patients, out of a group of 2112, in whom oral anticoagulation was contraindicated and who instead received platelet function inhibitors. These patients do not belong in the present series because they have not completed 10 years of follow-up. With anticoagulation intensities higher than INR 2.25, however, there is only a slight additional decrease in the incidence of significant thromboembolic complications (from 0.95%/pt-yr with INR 1.75 to 2.75 to 0.28%/pt-yr with INR 4.0 to 6.0), whereas significant hemorrhagic complications increased exponentially (from 0.36%/pt-yr with INR 1.75 to 2.75 to 2.59%/pt-yr with INR 4.0 to 6.0) (Table IV).
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Mitral valve replacement.
By the same analysis methods, patients who received a St. Jude Medical mitral valve showed a constant increase in the incidence of significant bleeding complications with more intensive anticoagulation (from 0.72%/pt-yr with INR 1.75 to 2.75 to 3.16%/pt-yr with INR 4.0 to 6.0). Thromboembolic events were significantly reduced by anticoagulation (4.1% per year incidence in patients not receiving anticoagulation). The incidence of significant thromboembolic events was calculated to be 0.42%/pt-yr with INR 4.0 to 6.0, 0.90%/pt-yr with INR 3.0 to 4.5, 1.56%/pt-yr with INR 2.5 to 3.5, and 1.63%/pt-yr with INR 1.75 to 2.75 (Table V).
The lowest cumulative incidence for thromboembolic plus bleeding complications was found with an INR of 2.5 to 3.6; the optimum range was 2.9 to 3.1.
Thromboembolic complications were significantly higher in the mitral valve group when compared with the isolated aortic valve implant group. This may be attributed to the underlying cardiac morphologic and physiologic condition of patients with mitral valve replacement, who have a higher incidence of atrial fibrillation, left atrial dilation, and, eventually, more extensive endocardial damage because of the mostly rheumatic or degenerative etiology of mitral valve disease. 14
Patients with St. Jude Medical mitral plus aortic valve replacements were similar to those with single mitral valve replacements with respect to thromboembolic complications.
We conclude from our data that the expected, and now proven, low thrombogenicity of the St. Jude Medical prosthesis may allow use of lower intensity anticoagulation. Data from our prospective but nonrandomized 10-year follow-up study indicate that in patients with St. Jude Medical aortic valve prostheses, and in patients who were seen with active atrial contraction and no more than a moderately enlarged left atrium (26 mm/m 2 body surface) and who received a St. Jude Medical mitral prosthesis, target INRs close to 3.0 resulted in the lowest overall incidence of thromboembolic and bleeding complications. To investigate the optimal target anticoagulation level for oral anticoagulation therapy for an individual patient with a given comorbidity, in terms of cardiac morphologic and physiologic conditions, who will receive a St. Jude Medical prosthesis, a multicenter study is being conducted. 21
Appendix: DISCUSSION
Dr. Kit V. Arom (Minneapolis, Minn.).
I rise to make two comments. The first is to congratulate the authors for bringing us this information. The study was not a randomize one, but it carries a meaningful and important message. In 1989, after review of our own 10-year experience with the St. Jude Medical prosthesis, we recommended that the prothrombin time level be lowered for both aortic and mitral valve replacement. To date, we keep the prothrombin time level between 1.3 and 1.5 times the control for the aortic valve and 1.5 to 1.7 times for the mitral valve. From what we just learned today, we may be able to lower the prothrombin time even more.
With the international sensitivity index of 2.45, our recommended prothrombin time is equivalent to an INR of between 1.9 and 2.7 for the aortic valve and 2.7 and 3.6 for the mitral valve.
My second comment is that I would like to ask the Association to develop a guideline of how to report a meaningful coagulation level. In 1977 the INR was developed to standardize reporting of the prothrombin time assay test results. This was necessary because variability in responsiveness of the different thromboplastins used as reagents throughout the world has resulted in dosing differences. At the present time, most scientific papers do not state the source of thromboplastin used in monitoring the prothrombin time. Thus it is difficult to compare studies of the safety and efficacy of oral anticoagulants.
A joint policy statement of the International Committee for Thrombosis and Hemostasis and the International Committee for Standardization in Hematology recommended in 1985 that the scientific journals no longer accept for publication papers that do not also express prothrombin time results and equivalent INR. Subsequently, the second American College of Chest Physicians conference on antithrombolytic therapy endorsed that recommendation. Therefore the guidelines could be developed by The American Association for Thoracic Surgery or the Society of Thoracic Surgery by adopting the INR system of reporting prothrombin time results. The system would enable the researcher to report uniform results worldwide, regardless of the reagent used. Use of the INR system will enable us to rationalize and standardize oral anticoagulation therapy.
Dr. Ben Bidstrup (London, England).
I would agree with Dr. Arom that the most important message from this paper is that uniform reporting of all anticoagulation with the INR should be adopted throughout the world so that comparable results can be reported.
One of the things I think is interesting is that, by chance, there is an enormous variation in INRs for the patients who were treated with various forms of anticoagulation. Did the authors in their earlier study think of looking at some of the newer methods of evaluating activation of coagulation, such as prothrombin fragment 1 and 2, to see whether there was ongoing coagulation activation, and is this going to be part of the future study in trying to identify patients who perhaps might need slightly different anticoagulation regimens?
Dr. G. Frank O. Tyers (Vancouver, British Columbia, Canada).
Could the authors tell us whether the annual incidence of combined thromboembolic and bleeding episodes, major or minor, was different during the first 5 years and the second 5 years of the follow-up?
Dr. Horstkotte.
To answer the second question, we did testing on these patients and we found the incidence of thromboembolic complications and of hemorrhagic complications to be constant after 4 months from the operation; thus the incidence was not different in the first 5 years when compared with that in the second 5 years.
In answer to the previous question: we are studying at the moment the impact of the thrombin content and fragments 1 and 2 on the incidence of thromboembolic events, but these laboratory tests have only been available in the past few years, and of course they had no influence on this study.
Footnotes
Read at the Seventy-third Annual Meeting of The American Association for Thoracic Surgery, Chicago, Ill., April 25-28, 1993. 
*SAS/STAT user's guide. Release 6.03. SAS Institute Inc.: Cary, N.C., 1989.
BMDP manual. Statistical Software Inc.: Los Angeles, Calif., 1989.
Institute for Medical Informatics and Biostatistics, Riehen, Switzerland.
References
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D. N. Salem, P. D. Stein, A. Al-Ahmad, H. I. Bussey, D. Horstkotte, N. Miller, and S. G. Pauker Antithrombotic Therapy in Valvular Heart Disease--Native and Prosthetic: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 457S - 482S. [Abstract] [Full Text] [PDF]
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D. Horstkotte Problems with complication rate analysis J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1668 - 1670. [Full Text] [PDF]
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A. M. Gillinov, E. H. Blackstone, J. M. Alster, J. M. Craver, W. A. Baumgartner, S. A. Brewster, L. H. Kleinman, and N. G. Smedira The Carbomedics Top Hat supraannular aortic valve: a multicenter study Ann. Thorac. Surg., April 1, 2003; 75(4): 1175 - 1180. [Abstract] [Full Text] [PDF]
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G. L. Grunkemeier and Y. Wu "Our complication rates are lower than theirs": Statistical critique of heart valve comparisons J. Thorac. Cardiovasc. Surg., February 1, 2003; 125(2): 290 - 300. [Abstract] [Full Text] [PDF]
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T. Gudbjartsson, S. Aranki, and L. H. Cohn Mechanical/Bioprosthetic Mitral Valve Replacement Card. Surg. Adult, January 1, 2003; 2(2003): 951 - 986. [Full Text]
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H. V. Schaff and D. H. Marsh Multiple Valve Disease Card. Surg. Adult, January 1, 2003; 2(2003): 1017 - 1045. [Full Text]
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