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Address for reprints: W. R. Eric Jamieson, MD, Vancouver Coastal Health Research Institute, University of British Columbia, 272 Waterleigh Dr, Vancouver, British Columbia V5X 4T2, Canada.
Vancouver Coastal Health Research Institute, Vancouver General Hospital and St. Paul's Hospital, University of British Columbia, Vancouver, British Colombia, Canada
The Prospective Randomized On-X Mechanical Prosthesis Versus St Jude Medical Mechanical Prosthesis Evaluation (PROSE) trial purpose was to investigate whether a current-generation mechanical prosthesis (On-X; On-X Life Technologies/Artivion Inc) reduced the incidence of thromboembolic-related complications compared with a previous-generation mechanical prosthesis (St Jude Medical Mechanical Prosthesis; Abbott/St Jude Medical). This second report documents the valve-related complications by individual prostheses and by Western and Developing populations.
Methods
The PROSE trial study was conducted in 28 worldwide centers and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The study protocol, and analyses of 10 demographic variables and 24 risk factors were published in detail in 2021.
Results
The total patient population (N = 855) included patients receiving an On-X valve (n = 462) and a St Jude Medical valve (n = 393). The overall freedom evaluation showed no differences at 5 years between the prostheses for thromboembolism or for valve thrombosis. There were also no differences in mortality. There were several differences between Developing and Western populations. The freedom relations at 5 years for mortality favored Western over Developing populations. Valve thrombosis was differentiated by position and site: aortic < mitral (P = .007) and Western < Developing (P = .005). In the mitral position there were no cases in Western populations, whereas there were 8 in Developing populations (P = .217).
Conclusions
The On-X valve and St Jude Medical valve performed equally well in the study with no differences found. The only differentiation occurred with valve thrombosis in the mitral position more than the aortic position and occurring in Developing more than Western populations. The occurrence of valve thrombosis was also related to a younger population possibly due to anticoagulation compliance based on record review.
The study valves performed equally well in the study with no differences found. Valve thrombosis occurred more often in mitral valves, Developing populations, and younger patients.
This work documents the potential differences in thromboembolic event rates between 2 mechanical prostheses: an earlier-generation St Jude Medical valve and a more recent-generation On-X valve. The study assesses prostheses types and positions, as well as Western versus Developing countries based on the United Nations Human Development Index.
The purpose of the Prospective Randomized On-X Prosthesis Versus St Jude Medical Prosthesis Evaluation (PROSE) study was to investigate whether a current-generation mechanical prosthesis (On-X Life Technologies/Artivion Inc) (Figure 1) reduced the incidence of thromboembolism (TE)-related complications compared with a previous-generation mechanical prosthesis (St Jude Medical Mechanical Prosthesis; Abbott/St Jude Medical Inc). The study hypothesis assessed the null and alternative hypotheses for a reduction in rate from 2% to 1%.
Figure 1On-X Prosthetic Heart Valve (On-X Life Technologies/Artivion Inc).
The study design of the PROSE trial was a multicenter, randomized trial with enrollment in 28 worldwide centers incorporating Western and Developing countries. The study used the United Nations Development Programme value for the Human Development Index arbitrarily as 0.9 and above for Western (ie, developed) countries and 0.75 and below for Developing countries. This categorization resulted in essentially a 50–50 split in the total study population.
The study methods were published in detail in the Journal of Cardiothoracic Surgery in 2021,
PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: part 1(patient dynamics): preoperative demographics and preoperative and operative risk factors.
including inclusion/exclusion criteria, sample size calculations, and all study procedures. This resulted in a randomized total patient population of 855 with an On-X population of 462 (54%) and a St Jude Medical population of 393 (46%). As previously described, this apparent difference resulted from a 2:1 randomization in the Australian center shifting the expected On-X percentage to 52% and the difference is not statistically significant.
PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: part 1(patient dynamics): preoperative demographics and preoperative and operative risk factors.
Confirmation of randomness creating no clinically important bias was published in the prior paper. The study was registered with ClinicalTrials.gov as NCT000639782. The institutional review board or equivalent ethics committee of the University of British Columbia approved the study protocol and publication of data. The patient(s) provided informed written consent for the publication of the study data. All other sites were required to receive local ethics review before commencing enrollment. Renewals of ethics approvals were maintained throughout each center's participation.
Study enrollment began in the Western cites during March 2003 and was slowed by a general reluctance from physicians and patients to randomization. Additionally, the Western populations were contributing too few mitral position patients to allow for valid analyses, so Developing country populations were added during March 2012. Enrollment ended in November 2015 in the Western sites and in August 2016 at all sites.
The follow-up of patients occurred at discharge, 3 months, 6 months, at 1 year, and annually thereafter during the conduct of the study and the longitudinal evaluation to approximately 5 years, resulted in a total of 4078.1 patient-years of follow-up. Follow-up of patients was limited to 5 years for most patients, although data beyond 5 years was included when made available by an investigator. Data collected included information regarding adverse events as defined as the “Guidelines for reporting morbidity and mortality after cardiac valvular operations” of the Society of Thoracic Surgeons and the American Association for Thoracic Surgery.
The target anticoagulation level for both prostheses was: for aortic position prostheses international normalized ratio (INR) between 2.2 and 2.8, and for mitral position prostheses INR between 2.5 and 3.5. No special effort was made to track INR values for each patient and control was left to standard of care at each site as a means of testing real-world results. The data analysis was performed using intent to treat, with no crossovers allowed in the trial. For the data analysis, the patients were included in the treatment group in which they were assigned.
Primary end points were rate of major TE and valve thrombosis (VT), and secondary end points were rate of major hemorrhage and all-cause and valve-related mortality. Linearized occurrence rates were used to determine the performance of the prostheses regarding major TE events and major hemorrhage events. Kaplan-Meier analysis was used to evaluate the performance of the 2 prostheses regarding freedom from TE events at 5 years. A log-rank test was used to validate the significance of the Kaplan-Meier analysis. Multiple logistic regression analysis examined the relationship between important demographic variables and adverse event rates. The statistics features of Excel version 2202 (Microsoft) calculated rates, whereas all other statistics, including all P values, were performed by the authors using MedCalc Software Ltd version 20.023.
The current documented thromboembolic rates with the On-X prosthesis came from the regulatory trials conducted for the Food and Drug Administration of the United States, and clinical studies.
Decision-making in the choice of heart valve for replacement in patients aged 60-70 years: twenty-year follow-up of the St Jude Medical aortic valve prosthesis.
From the literature cited above, the weighted average of TE for all valve positions was 1.09% per patient-year On-X and 2.03% per patient-year for the St Jude Medical prosthesis. Thus, for the purpose of sample size calculations, the TE rate for the On-X prosthesis used was 1.0% per patient-year and that of the St Jude Medical prosthesis was 2.0% per patient-year. It was assumed that the treatment group (On-X prosthesis) would experience a 50% reduction in the incidence of major TE events relative to the St Jude Medical prosthesis group. An exponential maximum likelihood test of equality of survival curves with a 0.050 1-sided significance level would have 80% power to detect the difference between a rate of 0.0100 for the On-X prosthesis and a rate of 0.0200 for the St Jude Medical prosthesis, given a sample size of at least 250 patients in each group and follow-up of 5 years.
The Adjudication Committee of the PROSE study consisted of the Data Safety Monitoring Board and the coordinating center principal investigator for the PROSE study at the Vancouver site. The primary end point adjudication was conducted blinded to the committee. This method of adjudication blinding of end point events is the only achievable method in a heart valve prosthesis study. The PROSE study utilized Case Report Forms for collection of the data. Each principal investigator monitored his or her center for severe adverse events as defined by the Society of Thoracic Surgeons and the American Association for Thoracic Surgery guidelines.
The sponsor and each of the centers reported the serious adverse events to the appropriate governments, as required by each country's law for commercially distributed products. The PROSE study was performed according to the principals of the Helsinki Declaration and all patients received informed consent to those rules or more stringent rules as locally appropriate.
The risks of valve replacement with either of these mechanical prostheses are those associated with all prosthetic replacement surgery, including TE, which was the focus of this study. The risks versus benefits of participating in the study was that patients (50% of patients) could turn out to receive a prosthesis type that was associated with fewer TE events than the other prosthesis type they could have received. The study was designed to determine which prosthesis was safer in terms of TE. The relative safety of the 2 prosthesis types was unknown before the trial, although both prostheses are approved for commercial use by Canadian and United States governments, and all major worldwide governments. The determination of the relative safety was the reason for the study.
Results
The total population for analysis in the PROSE trial was 855 patients implanted between 2003 and 2016. There were 939 patients screened for the trial. Of the trial patients, 16 discontinued/withdrew and 84 were lost to follow-up. The total population of On-X prosthesis recipients was 462 patients and the St Jude Medical recipient population was 393 patients. Patient follow-up in the trial was 4078.1 patient-years total: On-X n = 2219.8 and St Jude Medical n = 1858.3; Western population n = 2213.3 and Developing country population n = 1864.8; and aortic valve position population n = 2519.4 and mitral valve position population n = 1558.7. On schedule, follow-up to protocol requirements was 91.4% (4224 out of 4620). A consolidated standards of reporting trials flow diagram is provided in Figure E1.
The preoperative demographic characteristics and risk factors for the total population and the preoperative demographic characteristics and risk factors by aortic and mitral valve positions are detailed elsewhere and are summarized here for convenience.
PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: part 1(patient dynamics): preoperative demographics and preoperative and operative risk factors.
The mean age of the total population was 49.0 ± 12.6 years. The gender distribution was 58.8% men. Rheumatic valve etiology was 41.6%, whereas calcific valvular disease was 29.8%. Sinus rhythm was present in 75.2% of patients and atrial fibrillation was present in 23.1% of patients. The mean age for aortic prostheses patients was 52.3 ± 11.4 years. Aortic position patients were 13.7% rheumatic and 46.9% were calcific valve disease. Of the aortic position patients, 92.4% were in sinus rhythm and only 5.6% were in atrial fibrillation. The mean age for mitral position prostheses patients was 44.4 ± 12.8 years. Mitral position patients had 81.7% rheumatic and 5.0% had calcific valve disease. Of the mitral position patients 51.3% were in sinus rhythm and 47.6% were in atrial fibrillation.
There were no significant differences between On-X and St Jude Medical prosthesis patients for all preoperative and operative risk factors. As expected, the Western and Developing country populations provided the most significant differences for both preoperative and operative demographic characteristics and for preoperative and operative risk factors. All statistically significant (P < .01), preoperative demographic characteristics revealed the patients in the Developing country populations were younger (43.3 ± 12.6 years vs 54.5 ± 9.8 years), predominantly female (54.0% vs 29.0%), predominantly presenting with rheumatic disease (70.1% vs 7.9%), and more frequently in atrial fibrillation (35.6% vs 10.1%). Aortic stenosis was more common in the Western populations (66.5% vs 26.1%), whereas aortic regurgitation was more common in the Developing country populations (27.7% vs 13.0%). Mixed mitral disease was more common in the Developing populations (60.7% vs 32.0%), whereas mitral regurgitation was more common in the Western populations (42.0% vs 15.9%).
The preoperative and operative risk factors for Western and Developing populations revealed a complete contrast for almost all risk factors with the significant factors predominantly in the Western populations. The comparative risk factors that had statistically significant (P < .01) higher occurrence rates or measured values in the Western world population were coronary artery disease (29.1% vs 4.3%), diabetes mellitus (15.1% vs 7.7%), hypercholesterolemia (44.2% vs 6.7%), preoperative creatinine (98.1 ± 91.0 μmol/L vs 82.9 ± 28.5 μmol/L), hypertension (55.6% vs 20.6%), chronic obstructive pulmonary disease (14.0% vs 4.8%), previous myocardial infarction (8.2% vs 1.2%), and angina pectoris (20.6% vs 6.2%). The aortic valve percentage was more common in the Western population (87.2% vs 29.0%). Intraoperative adverse events were more common in the Western world (12.8% vs 4.8%). Congestive heart failure, on the other hand, was more common in the Developing populations (29.3% vs 21.7%).
Study Comparison by Prosthesis Type (5-Year Event Rate [% ± SE])
Kaplan-Meier analysis showed freedom from all-cause mortality was 89.0% to 1.9% for the On-X prosthesis and 90.7% to 1.5% for the St Jude Medical prosthesis (P = .746); valve-related mortality and sudden death was 94.7% to 1.1% for the On-X prosthesis and 95.6% to 1.1% for the St Jude Medical prosthesis (P = .601); TE was 96.8% to 0.9% for the On-X prosthesis and 95.8% to 1.1% for the St Jude Medical prosthesis (P = .606) (Figure 2); and VT was 98.8% to 0.5% for the On-X prosthesis and 98.9% to 0.5% for the St Jude Medical prosthesis (Figure 3). The prosthesis type for aortic and mitral positions was nonsignificant for both life tables and linearized rates for all-cause mortality, valve-related mortality plus sudden death, TE, and VT.
Figure 2Freedom from thromboembolism by valve type with 95% CIs. Five-year event-free rate in percent ± SE and log rank P value. On-X Prosthetic Heart Valve (On-X Life Technologies [On-X]/Artivion Inc); St Jude Medical Mechanical Prosthesis (Abbott/St Jude Medical [SJM]). CI, Confidence Interval; SE, standard error.
Figure 3Freedom from Valve Thrombosis by Valve Type with 95% CIs. Five-year event-free rate in percent ± SE, and log rank P value. On-X Prosthetic Heart Valve (On-X Life Technologies [On-X]/Artivion Inc); St Jude Medical Mechanical Prosthesis (Abbott/St Jude Medical [SJM]). CI, Confidence interval; SE, standard error.
Study Comparison by Prosthesis Position (5-Year Event Rate [% ± SE])
Kaplan-Meier analysis showed freedom from all-cause mortality for the aortic position was 91.2% to 1.3% and for the mitral position was 90.1% to 1.6% (P = .153); valve-related mortality plus sudden death for aortic was 95.4% to 1.0% and for the mitral position was 94.6% to 1.3% (P = .174); TE for aortic was 96.0% to 0.9% and for the mitral position was 96.9% to 1.0% (P = .944); and VT for the aortic position was 96.6% to 0.3% and for the mitral position was 97.8% to 0.8% (P = .0217) (Figure 4).
Figure 4Freedom from valve thrombosis by valve position with 95% CIs. Five-year event-free rate in percent ± SE, and log rank P value. CI, Confidence interval; SE, standard error.
Study Comparison by Economic Development (5-Year Event Rate [% ± SE])
Kaplan-Meier analysis showed freedom from all-cause mortality for the Developing country population was 88.4% to 1.6% and for the Western population was 92.9% to 1.3% (P = .0055); valve-related mortality and sudden death for the Developing population was 93.3% to 1.3% and for the Western population was 96.8% to 0.9% (P = .0106); TE for the Developing population was 96.1% to 0.7% and for the Western population was 94.7% to 1.1% (P = .0201) (Figure 5); and VT for Developing countries was 97.9% to 0.7% and for the Western population was 99.8% to 0.2% (P = .0137) (Figure 6). The 5-year event rate for Developing and Western populations was nonsignificant for the aortic valve position patients for freedom from all-cause mortality, valve-related mortality and sudden death, TE, and VT.
Figure 5Freedom from thromboembolism by site with 95% CIs. Five-year event-free rate in percent ± SE, and log rank P-value. CI, Confidence interval; SE, standard error.
Figure 6Freedom from valve thrombosis by site with 95% CI. Five-year event-free rate in percent ± SE, and log rank P value. CI, Confidence interval; SE, standard error.
The 5-year event rate for Developing and Western populations for mitral valve position patients showed freedom from all-cause mortality for Developing populations was 88.4% to 1.9% and for Western populations was 100.0% to 0.0% (P = .0306); valve-related mortality and sudden death for Developing populations was 93.6% to 1.5% and for Western populations was 100.0% to 0.0% (P = .208); TE for Developing populations was 97.7% to 0.9% and for Western populations was 92.4% to 3.6% (P = .0072): and VT for Developing populations was 97.4% to 1.0% and for Western populations was 100.0% to 0.0% (P = .244).
The overall risk assessment was conducted for 7 parameters: age, body mass index (BMI), congestive heart failure (CHF), chronic obstructive pulmonary disease, cerebrovascular accident, New York Heart Association (NYHA) functional class, and cardiac rhythm. The significant predictors of all-cause mortality were increases in age, CHF, BMI, NYHA functional class, and CVAs, whereas for valve-related mortality and sudden death there were increases in CHF, BMI, and NYHA functional class. The only predictor of TE in the whole population was increasing age (P <.005, 95% CI 0.05-0.009). VT was predicted by younger age in the whole population (P <.0001, 95% CI 0.15-0.0001), as well as in the Developing country population, both valve prostheses, and both aortic and mitral valve positions. There was no predictor of VT in the Western population due to lack of events.
The major late hemorrhagic rate for the On-X prosthesis was 1.0% per patient-year (n = 23) and for the St Jude Medical prosthesis was 1.2% per patient-year (n = 23). The major hemorrhagic rates were not differentiated by prostheses overall, by aortic and mitral valve positions, or by economic development. The TE event rates were undifferentiated for the On-X prosthesis at 0.5% per patient-year (n = 12) and for the St Jude Medical prosthesis at 0.5% per patient-year (n = 10). There were TE events in the aortic valve (n = 14) and mitral valve (n = 8) position populations, and in patients in Western (n = 16) and Developing (n = 6) positions. The TE events were more prevalent with aortic versus mitral valve position prostheses, and with aortic valve position in Western versus Developing populations but not the mitral valve position by economic development. Figure 7 shows a breakout of the TE and VT event rates across the various study cohorts. Table E1, Table E10, Table E11, Table E12, Table E13, Table E14, Table E15, Table E16, Table E2, Table E3, Table E4, Table E5, Table E6, Table E7, Table E8, Table E9 show the TE and VT event rates across the various study cohorts for aortic and mitral valve position patients separately.
Figure 7Thromboembolism (TE) and valve thrombosis (VT) event rates by study cohort: Summary figure for TE and VT linearized rates in percent per patient-year for all cohorts analyzed with indicators for statistically significant differences at P < .05. Bold double-ended arrows indicate significant differences in VT. SJM, St Jude Medical; On-X, On-X Life Technologies.
The most prominent major complication was VT (10 events in 9 patients). Within the total population, the On-X prosthesis major complication rate was 0.2% per patient-year (n = 5) and St Jude Medical prosthesis major complication rate was 0.3% per patient-year (n = 5). The aortic valve position major complication rate was 0.1% per patient-year (n = 2) and the mitral valve position major complication rate was 0.5% per patient-year (n = 8) (P = .007). The thrombosis rate was differentiated by economic development: 0.04% per patient-year (n = 1) for the Western population versus 0.5% per patient-year (n = 9) in the Developing country population (P = .005). There were 2 aortic valve positions for the On-X prosthesis (0.1% per patient-year) and 0 in the aortic valve position for the St Jude Medical prosthesis (P = .199). There were 3 mitral valve position prostheses for the On-X (0.4% per patient-year) and 5 mitral valve position St Jude Medical prostheses (0.7% per patient-year) (P = .360). The rate of aortic VT by economic development was 0.05% per patient-year for the Western population (n = 1) and 0.2% per patient-year for the Developing country population (n = 1) (P = .340). Mitral valve thrombosis by economic development was 0 in the Western population, whereas it was 8 in the Developing country population (0.6% per patient-year) (P = .217). One might expect that the occurrence of 0 versus 8 events would be statistically significant, but the lack of mitral patients in the Western population prevents achieving significance here.
The mean age for prosthesis thrombosis was 28.8 ± 16.0 years, whereas the total population mean age was 45.0 ± 11.5 years. There were a total of 4 St Jude Medical prosthesis cases and 5 On-X prosthesis cases among the initial cases. There were 5 cases treated with thrombolysis, 2 experienced explant surgery, and 1 experienced explant surgery after thrombolysis. There were 2 primary deaths and 1 additional late sudden death. The 2 deaths were due to multisystem failure with shock syndromes. Review of anticoagulant therapy records in all VT patients showed that the INR status varied extensively or was not followed. The time postoperation from the original surgery was mostly relatively early (<1 year) but varied up to 4 years. One of the On-X prosthesis aortic position cases was not receiving anticoagulation therapy at all.
The postoperative patient status was very satisfactory in the total population, with 77.6% experiencing NYHA functional class improvement and 20.8% experiencing NYHA functional class stability. There was no significant differentiation in postoperative status by prosthesis type, prosthesis position, or economic development status. The cardiac rhythm status in the whole population was atrial fibrillation in 23.1% of patients preoperation and in 9.5% postoperation at 1 year (P < .0001). Similarly, the aortic position population was 5.6% and 2.4% (P = .0002), whereas the mitral valve population was 47.6% and 19.4% (P < .0001). The Western population rates were 10.6% and 5.6% (P < .0001) and in the Developing population 35.5% and 13.6% (P < .0001). In general, improvement in both NYHA functional class and sinus rhythm occurred across the entire trial.
Discussion
On-X Prosthesis-Specific Design Features
As shown in Table 1 and Figure 8, A and C, the On-X prosthesis is a pure pyrolytic carbon prosthesis with a supra-annular sewing ring. The prosthesis design facilitates pannus protection (pannus protection was not a comparative feature of the PROSE trial). The long, flared orifice of the On-X prosthesis facilitates organized flow through the prosthesis (height-to-diameter ratio of about 0.6). The actuated pivots of the On-X prosthesis allow the leaflets to follow the blood flow through the prosthesis. The pivot purge of the On-X prosthesis facilitates the elimination of blood stasis in the prosthesis. The leaflet swing angle through closure is 50°, reducing closing volume and allowing for more pivot purge. The 2-point closure of the On-X prosthesis reduces the impact of leaflet closure.
Table 1On-X valve (On-X Life Technologies [On-X]/Artivion Inc) versus St Jude Medical valve (St Jude Medical [SJM]) design comparison
Figure 8Prostheses used: A, On-X aortic valve (On-X Life Technologies/Artivion Inc). B, St Jude Medical aortic valve (Abbott/St Jude Medical). C, On-X mitral valve. D, St Jude Medical mitral valve.
St Jude Medical Prosthesis-Specific Design Features
As shown in Table 1 and Figure 8, B and D, the St Jude Medical prosthesis is made from a silicon-alloyed pyrolytic carbon that is less strong and more brittle than pure pyrolytic carbon. It also features a supra-annular sewing ring, but its orifice does not extend above and below the ring except at the pivot ears providing little barrier to pannus overgrowth. The height-to-diameter ratio of the housing is approximately 0.3. Its leaflets rotate on a fixed pivot with a leaflet swing of 55° increasing closing volume, thus limiting pivot purge. Its closing contact points are at the tips of the leaflets resulting in a higher likelihood of cavitation.
Although the results did not bear out the original hypothesis that TE event rates would be significantly lower for the On-X prosthetic valve than for the St Jude Medical prosthetic valve, they do establish that these valves both perform well across the many cohorts in the trial when managed on target anticoagulation levels for both prostheses (aortic prostheses INR, 2.2-2.8 and for mitral prostheses INR, 2.5-3.5). There are many limiting reasons for finding that the historic literature observations are not discovered to hold under a randomized trial, including but not limited to references not being contemporary such that practice can change to improve results, methods of follow-up can be slightly different even using the same event definitions, observer differences are likely, and the variability of results within studies and valves is large enough to mask the small difference being sought. This study attempted to look at these valves under as close to real-world conditions. A brief survey of the literature finds studies for both valves
with rates of TE <1% per patient-year, also conducted under real-world conditions, illustrating the difficulty of establishing small adverse event rate differences, which is a limitation of the study.
The lack of detailed INR follow-up limits the ability to discern potential effects of varying anticoagulation protocols. However, since this study was completed, a more recent study, Prospective Randomized On-X Anticoagulation Trial (PROACT), has found that for the On-X valve, warfarin anticoagulant therapy can be reduced to create a reduction in bleeding events without increase in thromboembolism for the aortic valve.
The currently underway PROACT Xa study (NCT04142658) should also determine whether patients with an On-X mechanical aortic valve can be effectively anticoagulated with apixaban as an alternative to warfarin.
Rationale and design of PROACT Xa: a randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with an On-X mechanical aortic valve.
This study allowed a direct comparison of Western and Developing populations but is also limited in comparative power for subset analyses by these same differences. Many of the differences between these 2 populations were assumed to exist based on literature reports, but this trial confirms these assumed differences, such as younger age, rheumatic etiology, mitral versus aortic positions and rates of atrial fibrillation. Unexpectedly, the study also showed that, although TE events increase with age as expected, VT events were associated with younger age. VT events also occurred in patients who had erratic INR results or were simply noncompliant to their therapy.
Conclusions
The PROSE trial revealed essentially equal performance for the On-X and St Jude Medical prostheses regarding influence of prosthesis type on major TE, VT, and major hemorrhage, as well as all-cause, valve-related, or unexpected mortality, when managed at target INR levels in the protocol representing standard of care. The only important differentiation occurred with VT occurring in the Developing country populations more than in the Western populations. The mitral thrombosis in the Developing populations occurred in a younger population, identified on multiple logistic regression, possibly due to anticoagulation compliance status because widely variable anticoagulation therapy was consistent in VT patients. The future evaluation of mechanical valve prostheses needs to include extensive randomized evaluation of anticoagulation protocols.
On-X Life Technologies (2003-2016)/Artivion Inc (2016 to present) provided reimbursement payments to each center's research department. All other authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
The authors thank Alanna Dyck, research coordinator, Division of Cardiovascular Surgery, Department of Surgery, University of British Columbia, British Columbia, Canada, who had responsibility throughout essentially the total length of the Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation study for the complete study.
The authors thank all research coordinators at all the study centers who provided extensive support throughout the extended length of the study. ClinicalTrials.gov registration No. NCT000639782.
Appendix E1
Table E1Adverse event rates for the whole population
Table E9New York Heart Association functional class cross-tabulation: Preoperation (Preop) to 1-year postoperation (Postop) for On-X (On-X Life Technologies/Artivion Inc) patients
Table E10New York Heart Association functional class cross-tabulation: Preoperation (Preop) to 1-year postoperation (Postop) for St Jude Medical patients
Table E13New York Heart Association functional class cross-tabulation: Preoperation (Preop) to 1-year postoperation (Postop) for the Western population
Table E14New York Heart Association functional class cross-tabulation: Preoperation (Preop) to 1-year postoperation (Postop) for the developing population
<.0001, BMI, .07 to .0005, CVA, 1.38 to .017, congestive HF, .93 to .010
.0004, BMI, .08 to .004, congestive HF, 1.29 to .008
No relationships
.027, age, –.12 to .043 inverse to age
No relationships
Mitral
.010, congestive HF, 0.93 to .010
No relationships
.01, age .06 to .016
.0004, age –0.12 to .003 inverse to age
No relationships
TE, Thromboembolism. VT, valve thrombosis; HF, heart failure; NYHA, New York Heart Association functional class; BMI, body mass index; CVA, cardiovascular accident.
∗ Values are presented as model P value, factor(s) coefficient P value.
Figure E1Consolidated standards of reporting trials flow diagram for randomized groups in the Prospective Randomized On-X Prosthesis Versus St Jude Medical Mechanical Prosthesis Evaluation trial.
Figure E2Thromboembolism (TE) and valve thrombosis (VT) rates for mitral patients by cohort. Summary figure for TE and VT linearized rates among mitral valve patients in percent per patient-year for all cohorts analyzed with indicators for statistically significant differences at P < .05. On-X, On-X Life Technologies; SJM, St Jude Medical.
Figure E3Thromboembolism (TE) and valve thrombosis (VT) rates for aortic patients by cohort. Summary figure for TE and VT linearized rates among aortic valve patients in percent per patient-year for all cohorts analyzed with indicators for statistically significant differences at P < .05. On-X, On-X Life Technologies; SJM, St Jude Medical.
PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: part 1(patient dynamics): preoperative demographics and preoperative and operative risk factors.
Decision-making in the choice of heart valve for replacement in patients aged 60-70 years: twenty-year follow-up of the St Jude Medical aortic valve prosthesis.
Rationale and design of PROACT Xa: a randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with an On-X mechanical aortic valve.
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