Background and Aim: We compared 23-year composites of valve-related reoperation, morbidity, and mortality following combined mitral and aortic mechanical and bioprostheses in young rheumatics aged <45years.

Methods: Retrospective comparative analysis of valve-related reoperations and survival data were performed from 498 consecutive propensity matched patients undergoing either bioprosthetic MVR (Group I, n=249) or mechanical MVR (Group II, n=249) between 1998 and 2022.

Results: The median age was 33 (IQR: 27-40) and 33 (IQR: 28-39) years for Group I and II respectively. The median follow-up was 134 months (IQR: 99.5-178.5) with 5281.8 patient-years data in both biological and mechanical arm. Bioprosthetic arm exhibited lesser cumulative mortality (3.6% vs 4.8%, SMD= -0.18, p=0.01). Hazard regression for mortality included (HR, 95% CI) included preoperative CHF on inotropes and ventilator 9.84  (4.54, 18.64), p<0.001, renal failure requiring peritoneal/hemodialysis 11.64, (6.57, 20.64), p<0.001, atrial fibrillation 3.83 (1.63, 8.98), p<0.002, reoperation for thrombosed mechanical and degenerated bioprostheses 5.38, (3.09, 9.35), p<0.001, previous operation 3.53, (1.93, 6.45), p<0.001, poor left ventricular function 4.25, (2.29, 7.88), p<0.001, prolonged aortic clamp time 3.84, (2.19, 6.78), p<0.001,  and prolonged CPB time 2.69, (1.84, 8.68), p<0.001. Propensity score matching did not exhibit any difference in reoperation between two groups (Group I vs Group II: 13.6% vs 17.6%, SMD= -0.110, p=0.21). At a median follow-up of 134 months (IQR: 99.5-178.5) months, actuarial survival was 92.3%±0.02% (group I vs 96.6%+0.01%) and there was no difference between the groups (p=0.90).

Conclusions: Bioprostheses are an acceptable alternative to mechanical prostheses in young rheumatics aged <45 years undergoing mitral and aortic valve replacements unwilling for mechanical valve, redo surgeries, life-long anticoagulation, and those desirous of pregnancy.

Current consensus guidelines of the American Heart Association and European Society of Cardiology, uniformly recommend either type of prosthetic valve for patients aged 60 to 70 years and mechanical prosthesis for patients less than 60 years. [1-6] These recommendations are based on the results of 4 randomized controlled trials that demonstrated no significant difference in late survival. [5-9Two of these trials compared mechanical and bioprosthetic valve models implanted in 1970s and 1980s. – [8-10] The other 2 trials included patients undergoing aortic valve replacement. [4,5] Contemporary data are limited to small single center studies. [10-12] 

Valve replacement in young adults entails a choice between a mechanical prosthesis with risks of anticoagulation-related bleeding/thrombosis versus bioprosthesis necessitating eventual reoperation. Over the last 20 years, there is a shift away from a clear cut age limit towards patients’ wish and lifestyle considerations. [5-10] This may be related to the enhanced durability of new-generation bioprostheses, improved outcomes of redo surgery, or development of valve-in-valve transcatheter valve implantation. [5-10]

In patients requiring combined aortic and mitral valve replacements (MAVR), the valve prosthesis of choice in patients younger than 60 years has traditionally been mechanical prostheses. [11-23] Prosthesis selection is determined by several competing factors, including the elevated hazard for structural deterioration of biologic prostheses in younger patients, anticoagulation related complications with mechanical prostheses, complexity and difficulty in performing redo valve replacements for bioprosthetic failure and the growing trend towards avoidance of warfarin in younger patients. [11-23]

The results of bileaflet and Starr Edwards mechanical prostheses with single valve surgery have been extensively reported. [11-23] There is limited documentation, however, on the late (15 years) and very late (> 20 years) composites of complications, namely, valve-related reoperations, morbidity, and mortality following combined mitral and aortic valve replacements using mechanical and bioprostheses in young rheumatics. [11-31]

In 2018, we published our preliminary observations on the result of mitral valve replacement (MVR) using Carpentier-Edwards PERIMOUNT bioprosthesis in young rheumatics aged less than 40 years. [13] Subsequently in 2021, we published long-term propensity-matched outcomes after bioprosthetic MVR in 260 young rheumatics. [20] We also compared 22-year composites of valve-related reoperations, morbidity and mortality following mitral mechanical and bioprostheses in young rheumatics aged less than 45 years. [32]

The primary objective of this study was to compare the very late-term (20 years) outcomes of composites of valve-related complications in young rheumatics aged less than 45 years, undergoing combined bioprosthetic or mechanical mitral and aortic valve replacements (MAVR). The secondary objectives were to: i) compare the short- and long-term hemodynamic performance of prostheses and structural valve deterioration of multivalvular bioprostheses, and ii) ascertain the duration and intensity of anticoagulation required in bioprosthetic group in immediate and late postoperative period and before re-replacement of degenerated bioprostheses, and iii) determine whether the risk of reoperative mortality for structural deterioration of bioprostheses was greater than the cumulative rate of lethal thrombotic and haemorrhagic complications in patients with mechanical prostheses.

This retrospective study conforms to the principles outlined in the declaration of Helsinki and was approved by the Institutional Ethics Committee.

Patient selection criteria

Choice of prosthesis for MAVR was determined by patients’ preference and surgeon’s judgement based on patients’ age and comorbidities, bleeding risk, life-style, and compliance to anticoagulation. Young rheumatics aged less than 45 years undergoing combined MAVR using either mechanical (St. Jude Medical or ATS Medical) or bioprosthesis (St. Jude Epic or Carpentier-Edwards PERIMOUNT) with or without tricuspid annuloplasty were included in this descriptive case series. Patients undergoing MAVR using prosthesis other than mentioned above, non-rheumatic etiology, and concomitant cardiac surgery were excluded. Young females desirous of pregnancy, patients coming from remote rural areas making follow-up and anticoagulant monitoring practically difficult, contraindications to use of anticoagulation, thrombosed mechanical mitral and/or aortic prosthesis, and patients’ choice were indications for bioprosthetic MAVR (Figures 1A, 1B).

Figure 1A: Graphic display (n=498) showing long-term valve-related actuarial survival of Group I and Group II patients.

Figure 1B: Consort diagram showing inclusion and exclusion criteria for young rheumatics aged <45>

In patients with mitral stenosis and a small left ventricle, the low-profile Epic bioprosthesis was chosen over PERIMOUNT prosthesis. There were no specific criteria for selection of mechanical prosthesis. We retrospectively reviewed medical records of young rheumatics aged less than 45 years who underwent either a bioprosthetic (Group I) or mechanical (Group II) MAVR from January 1998 to June 2022 by the corresponding author.

A total of 925 aortic and mitral prostheses [325 bioprostheses; (Carpentier-Edwards PERIMOUNT model 6900 (Edwards Lifesciences, Baxter Healthcare Corporation, Irvine, CA, USA, n=105; St. Jude Epic Porcine bioprosthesis, n=220)] and 600 mechanical prostheses (St. Jude Medical, n=300; ATS Medical, n=300) were implanted. 

Patients were matched one-to-one according to age, sex, preoperative thromboembolism, presence of atrial fibrillation (AF), advanced New York Heart Association (NYHA) status, preoperative congestive heart failure (CHF) requiring inotropes and ventilation, Left ventricular ejection fraction (LVEF) <0>65 mm, and presence of LA clot according to optimal match technique. A power calculation estimated that approximately 233 patients per group were required to have a minimum of 80% power to detect a 10% difference in mortality between the two groups with a 2-sided of 0.05 Table 1, Figures 2A, 2B).

Figures 2A, 2B:  Propensity density graph before (2A) and after (2B) propensity score matching.

Six-monthly follow-up data included clinical history, NYHA class assessment, and valve-related events. [33-35] If 6-monthly evaluation was not possible after repeated attempts to contact the patient, it was considered missing. If two consecutive evaluations were missing, the patient was considered lost to follow-up. Transthoracic two-dimensional (2D), colour flow and Doppler echocardiography was performed according to the American Society of Echocardiography criteria within first six months and then annually. [34,36]

In a developing country such as ours, where recognition of the need for information is a powerful asset in patient care, we spend time relating to three facets in the follow-up of patients: (1) instilling insight into the problem of chemoprophylaxis in preventing recurrent attacks of rheumatic fever (penicillin injections once every 3 weeks remain necessary until the age of 45 years); (2) advice regarding awareness about prevention of bacterial endocarditis particularly in relation to dental problems; and (3) education and counseling regarding low-intensity anticoagulation and the necessity for meticulous attention to its control. Follow-up was achieved by yearly outpatient clinic visits, mailed questionnaires, contact with the referring physicians, and use of social workers for direct patient contact.

Outcome measures

Valve-related mortality included death caused by thrombosis, thromboembolism, hemorrhage, structural valve deterioration, non-structural dysfunction, or prosthetic valve endocarditis and death related to reoperation for a valve related complication including sudden unexplained, unexpected deaths. Valve-related mortality was defined either as early/perioperative (i.e. in hospital or within 30 days of operation) or late (after 30 days) attributed to the explanted valve. [6,33,34],

Valve-related morbidity was defined as permanent valve-related impairment as a result of permanent neurologic or other functional deficits caused by valve thrombosis, thromboembolism, hemorrhage, structural valve deterioration, non-structural dysfunction, prosthetic valve endocarditis, or reoperation. 

Late reoperations were defined as reoperations that occurred more than 30 days after implant. Reoperations were defined as any subsequent mitral or aortic valve replacements. Reoperations that did not involve mitral or aortic valve replacement were excluded.[20]

Structural valve deterioration was diagnosed as clinically relevant valvular stenosis or insufficiency by Doppler echocardiography, reoperation, or necropsy. Examples included cuspal perforation, tear, thickening, calcification, stiffness, stretching, wear and abrasions, thinning, leaflet escape, stent creep, or stress fracture. Structural deterioration that resulted from endocarditis, paravalvular leak, or thrombosis was not included in the structural valve deterioration category. [4,6]

Stroke was defined as any cerebrovascular accident documented during the index hospitalization as well as any subsequent hospital admission in including transient ischemic attacks). [4,6]

A major bleeding event was defined as any subsequent hospital admission in which the principal diagnosis was intracerebral hemorrhage, hemopericardium/cardiac tamponade, gastrointestinal hemorrhage, hematuria, hemarthrosis, hemoptysis, or retinal hemorrhage. Bleeding events were classified as major (i.e. requiring hospital admission or transfusion, of intracranial location, or causing death), or minor (i.e. prospectively recorded but not major).4,6 Heart failure was defined as per previous publications as the composite end-point of (i) New York Heart Association (NYHA) functional class 3 or 4 for more than 4 consecutive weeks, corroborated with physical examination, chest X-Ray, ECG and echocardiography findings when available, or (ii) death where the primary or main contributing diagnosis was heart failure.[4,34,36]

Anticoagulation

Patients with bioprosthetic MAVR were started on warfarin and aspirin (100mg/day) on first postoperative day maintaining an INR between 2.0 and 2.5. After discharge, patients were reviewed at one week, one month, three months, then subsequently at six months interval. Anticoagulation was stopped in patients with bioprosthetic MAVR and normal sinus rhythm at 12 weeks of follow-up.

Patients with a preoperative LA/left atrial appendage (LAA) clot, history of recent thromboembolism, aneurysmal LA, AF, and degenerated bioprosthesis were maintained on anticoagulation with an INR between 1.5 and 1.8. All patients received aspirin life-long, unless contraindicated.

Patients undergoing mechanical MVR received life-long warfarin and aspirin (100mg/day) maintaining INR between 2.5 to 3.5. The three study end-points were the composites of valve-related complications (mortality, morbidity and reoperations), explantation due to thrombosed mechanical prosthesis and structural valve deterioration (SVD).

Selection of a balanced cohort

Table 1 shows the significant imbalances in baseline characteristics between patients treated with mechanical and biological mitral and aortic prostheses before matching. To assemble a balance cohort of patients with mechanical and biological mitral and aortic prostheses, we used propensity-score matching method on those with mechanical and biological prostheses on measured baseline characteristics. For this purpose, we estimated propensity scores for treatment (group) for each of the 925 patients using multivariable logistic regression model. Group was used as the dependent variable and baseline characteristics namely- LA reduction, aortic cross-clamp time, thromboembolism, dyspnoea, previous operation, LVEF, chordal preservation, type of mitral valve disease were included as covariates to find the best optimal match set. Here, model’s effectiveness are not important because propensity-score based models are sample-specific adjusters and are not intended to be used for out-of sample prediction, discrimination or estimation of coefficients. The efficacy of propensity-score models is best assessed by estimating post-match absolute standardized differences between baseline covariates that directly quantifies the bias in the means or proportions of covariates across the groups. Therefore, we presented before and after propensity match standardized differences and its findings in Love plots (Figure 3). 

Figure 3: Love plot depicting standardized mean of difference (SMD) for covariates balancing before and after propensity score matching

An absolute standardized difference of 0% indicates no residual bias and less than 15% is considered of inconsequential bias. Greedy nearest neighbouring matching method was used for matching protocol with a caliper of 0.1 to match 1: 1 patients with mechanical and biological mitral and aortic prostheses. We were able to match 249 of the 325 biological prostheses and 249 of 600 patients of mechanical mitral and aortic prostheses.

For descriptive analyses, we used Pearson Chi-square/Fisher’s exact test and t-test/Wilcoxon rank-sum tests for before match and McNemar’s test and paired sample t-test/sign-rank test for after match comparisons of baseline covariates between patients with mechanical and biological mitral and aortic prostheses. Kaplan–Meier curve with 95% confidence interval and matched Cox regression analyses were used to determine the associations of group with various outcomes during months of follow-up. All statistical analyses were done using STATA 14.0 Software (College Station, Texas, USA) and two-sided tests with a p-value of < 0>

(mortality, reoperation and adverse postoperative events) were calculated by Kaplan-Meier actuarial methods and compared with log-rank statistic (Fig. 4A, 4B, 5A, 5B, 6A, 6B).

Results

Study population

After matching as described previously, our final study population consisted of a total of 498 patients aged between 11 and 70 (Group I: mean 33.32±7.80, median 33.0 (IQR: 27-40) years; Group II: mean 33.22±7.95, median 33.0 (IQR: 28-39) years (SMD 0.012, p=0.19). As presented in Table 1, after propensity matching, there were no differences among the 249 matched pairs in preoperative characteristics and both groups were fairly homogenous. Our institutional policy is to use bioprostheses beyond 18-years of age after bone growth and maturation are completed. In this study, one patient aged 12-years with a thrombosed mechanical prosthesis and another patient aged 13-year with thalassemia and hemolysis underwent bioprosthetic mitral and aortic valve replacements.

Table 1: Preoperative and intraoperative characteristics of patients undergoing mitral and aortic valve replacements (MAVR) before and after propensity score matching

The technical details of the surgical steps of combined mitral and aortic bioprosthetic and mechanical valve replacements have been enumerated in the video presentation (Video Presentation) as well as in our earlier publication.20,32 Every attempt was made to preserve the chordopapillary apparatus ensuring implantation of an appropriate sized prosthesis without leaflet entrapment or left ventricular outflow tract obstruction (LVOTO).

In patients with predominantly stenotic lesions with severe chordopapillary fusion, MVR was performed without chordal preservation. Intraoperative transesophageal echocardiography was performed to confirm satisfactory prosthetic valve function immediately after surgery.

Total chordo-papillary apparatus was preserved using Milki’s technique whenever feasible (Group I, n=149, 59.8%; Group II, n=160, 64.2%). In patients with calcified leaflets with annular extension and severe subvalvular fusion, the mitral apparatus was completely excised (Group I, n=40, 16.1%; Group II, n=39, 15.7%). The remaining patients had only posterior chordal preservation (Group I, n=60, 24.1%; Group II, n=50, 20.1%). 

The technical details of chordal preservation, annulus decalcification and its effect on regional and global ventricular function have been addressed in our previous publications. [13,23,37,38] Size of the bioprosthetic valve ranged from 25 mm to 33 mm [Group I, valve size: 33 mm n=21); 31 mm (n=38); 29 mm (n=94); 27 mm (n=74); 25 mm (n=22)]. The sizes of the implanted mechanical mitral prosthesis in group II ranged from 24 mm to 31 mm [St. Jude Medical Inc. St. Paul, Minn. mechanical size 31 mm (n=30); 29 mm (n=67); 27 mm (n=56); Medtronic Open PivotTM AP360° Apex and AP, Medtronic Inc. Mx USA; size 28 mm (n=38), 26 mm (n=52), 24 mm (n=6).

Size of the bioprosthetic aortic valve ranged from 19 mm to 25 mm (size 25 mm, n=44; 23 mm, n=57; 21 mm, n=109; 19 mm, n=39). The sizes of the mechanical St. Jude Medical Inc. were 19 mm, n=17; 21 mm, n=53; 23 mm, n=49; 25 mm, n=39). The ATS medical sizes were 20 mm, n=19; 22 mm, n=50 and 24 mm, n=22. 

Patients undergoing redo MAVR for degenerated bioprostheses (n=34) or thrombosed mechanical prostheses (n=44) were subjected to a uniform surgical protocol in all patients undergoing explantation of the degenerated bioprostheses and thrombosed mechanical prostheses standardised by the corresponding author. There were no instances of paravalvular leak on any patients. A mechanical mitral valve [(Medtronic Open PivotTM AP360° Apex and AP, Medtronic Inc., Mx, USA); size 24mm (n=17), 26 mm (n=19); St. Jude Medical Inc. St. Paul, Minn, 27mm (n=21), 29 mm (n=21) was used in patients undergoing explantation for SVD, (Figure 7A-7D). The sizes of the mechanical aortic valve were [St. Jude Medical Mechanical 19mm, n=8; 21 mm, n=24; 23mm, n=28; 25mm, n=18].

Median ischemic time for group I patients was 42 minutes (IQR: 35-70); and for group II was 46 minutes (IQR: 36-70), (SMD= -0.098, p=0.27). Median cardiopulmonary bypass (CPB) time for group I was 59 minutes (IQR: 46-86); and for group II was 59 minutes (IQR: 47-84), (SMD= -0.032, p=0.72) respectively. Ninety-five (36.5%) patients underwent LA reduction for giant LA. No surgery was performed for atrial fibrillation. One hundred and seventeen (23.5%) patients with organic tricuspid valve disease underwent tricuspid valve reconstruction using commissurtomy and Kay’s or DeVega’s annuloplasty.

Operative mortality and morbidity

There were 5 (2%) hospital deaths in group I and 8 (3.2%) in group II due to low cardiac output syndrome (LCOS) after reoperation for thrombosed mechanical prosthesis (n=4)/failed mitral valve reconstruction (n=5), intractable ventricular arrhythmias (n=2) and sepsis (n=2) with left ventricular and renal failure. Comparative assessment of early complications between the two groups revealed no differences in incidence of perioperative mortality and morbidities.

Late outcomes 

Late mortality was 1.6% (n=4) in group I and 1.6% (n=4) in group II (p=1). The causes were persistent congestive heart failure (CHF) (n=2), intractable ventricular arrhythmias (n=5), and renal failure (n=1) between 45 days and 215 months following surgery. A combination of persistent CHF, intractable ventricular arrhythmias and renal failure were the causes of death of 12 (15.4%) patients undergoing redo MAVR (Group I; n=3: Group II; n=3). The other causes were anticoagulant-related massive intracerebral haemorrhage (n=4), and sepsis (n=2). On hazard regression analysis, the risk of cumulative mortality was equal in both groups [HR 0.86 (95% CI 0.35, 2.08), p=0.73].

Four patients were lost to follow-up. Follow-up was complete in 473 (99.1%) patients and yielded 5281.8 patient-years data. Four hundred and thirty-one (91.1%) patients were in NYHA class I, while 42 (8.8%) were in NYHA class II. The actuarial survival at a median follow-up of 134 months (IQR: 99.5-178.5) was 96.6%±0.01% (95% CI: 93.31-98.30). There was no difference in actuarial survival between the two groups (log rank, p=0.90, Figures 5A, 5B).

Thromboembolic complications occurred in 46 patients (Group I: n=25; Group II: n=21): transient ischemic attack (n=21), dysarthria (n=14), and hemiplegia (n=11). Two patients in Group I and one patient in group II developed prosthetic valve endocarditis and were managed conservatively. Although cumulative mortality was more in mechanical arm (Group I: 3.2% vs Group II: 4.4%), there was no difference in actuarial survival between two groups (Group I: 92.3%+/0.02% vs Group II: 96.6%±0.01 (log-rank: unmatched p=0.1, matched p=0.90), (Figures 4A, 4B)
 

Figures 4A, 4B: Survival probability from Kaplan-Meier curve before (4A) and after (4B) propensity score matching (Log rank: group I vs group II, unmatched p=0.58; matched p=0.90).

Requirement for redo valve replacements was similar between the two propensity matched groups (SMD= -0.11, p=0.21). Patients undergoing reoperation were associated with 5.38 (95% CI 3.09, 9.35) times increased risk of death compared to non-reoperated group (p<0>

Figures 5A, 5B: Survival probability from Kaplan-Meier curve of patients undergoing reoperation. Figure 5A compares survival probability between reoperation vs no reoperation. Figure 5B depicts survival probability of patients undergoing reoperation between Group I and Group II.

At a median follow up of 134 months (IQR: 79-199), 13.6% (n=34) of group I, and 17.6% (n=44) of group II patients underwent redo MAVR using mechanical prosthesis, and there was no difference in actuarial survival between the two groups (log rank, unmatched p=0.58; matched p=0.90) (Figure 5B). Valve leaflet thickening with mild prosthetic valve stenosis (Epic; mitral n=8, aortic n=3, PERIMOUNT; mitral n=4, aortic n=5) was seen between 88 and 110 months of follow-up and being closely followed-up.

The composites of valve-related cumulative events were similar between the two propensity matched groups [Group I: 19.3% (n=48) vs Group II 24% (n=60), (SMD= -0.117, p=0.19). The actuarial event free survival at a median follow-up of 134 months was 92.3%±0.02% (Group I) vs 96.6%±0.01% (Group II: log rank p=0.90), (Figures 6A, 6B).

Figures 6A, 6B: Survival probability from Kaplan-Meier curve of patients undergoing reoperation. Figure 5A compares survival probability between reoperation vs no reoperation. Figure 5B depicts survival probability of patients undergoing reoperation between Group I and Group II.

Figures 7A-7D: Photographs of explanted St. Jude mechanical valve with thrombotic occlusion of leaflets (A, B) and PERIMOUNT bioprostheses (C, D) showing structural valve deterioration (Cuspal perforation, tear, thickening, calcification, stiffness, wear and abrasions, creep, and stress fracture).

Hemorrhagic complications necessitating hospitalisation occurred in 7 (2.8%) patients in group II. Twenty-five (10.04%) patients of group I and 21 (8.43%) patients of group II experienced thromboembolic complications. The linearized valve-related adverse postoperative cumulative events were 1.37 events/100 patient-years for group I and 1.38 events/100 patient years (p=0.89) for group II. At late follow-up, more patients were in atrial fibrillation in mechanical arm (Group I: 60.0% vs Group II: 72.0%, p=0.17) (Table 2B)

*Variables with increased risk

Table 2:  Risk of 0- to 23-years mortality after combined mitral and aortic bioprosthetic and mechanical valve replacement by Hazard regression analysis

The hazard regression model of risk factors for cumulative mortality included preoperative CHF on inotropes and ventilator (HR 9.84, 95% CI: 4.54, 18.64, p<0 xss=removed p=0.21).>

Comparative data as late (15 years) and very late-term (20 years) performances of bioprostheses and mechanical prostheses in young rheumatics undergoing combined mitral-aortic valve replacements are limited and conflicting. [15-19,24-31,39-41] This is the first propensity matched comparative study on very late-term performance of bioprostheses and mechanical prostheses following combined aortic and mitral valve replacements. The important findings of this retrospective study were:

1. Propensity score matching and multivariable modelling minimised the biases and demonstrated similar long-term survival upto 22 years in both groups of patients.
2. Composites of valve-related mortality, morbidity, defined as per neurologic and functional impairment favored bioprosthesis in selected individuals.
3. Both groups exhibited almost similar valve-related reoperation rates (group I: 13.65% vs group II: 17.6%, SMD-0.11, p = 0.21), and
4. Bioprosthetic arm exhibited lesser cumulative mortality [3.2% (n=8) vs 4.4% (n=11), SMD= -0.18, p=0.01)] and was statistically significant (Table 1).

Unlike other published series, patients in this study were carefully matched with regard to age, NYHA functional status, atrial fibrillation, and other variables as enumerated in table 1. Because combined MAVR was performed more often using mechanical prosthesis than bioprostheses in this study, maximum patients treated with bioprostheses were included and matched with the mechanical prostheses group. 

Shared decision-making about the choice of prosthetic valve type is influenced by several factors, as enumerated under. According to American College of Cardiology/American Heart Association 2020 guidelines, a mechanical prosthetic valve may be favored in patients aged less than 50 years under the following circumstances:

• Patient preference (avoid risk of reintervention).
• Complaint patient with either home monitoring or close access to INR monitoring.
• Presence of other indication for long-term anticoagulation (e.g. atrial fibrillation).
• High-risk reintervention (e.g. porcelain aorta, prior radiation therapy).
• Small aortic root size for aortic valve replacement (may preclude valve-in-valve procedure in future).

Implantation of a bioprosthesis in this age group is associated with a lower risk of anticoagulation but there is an increased incidence of structural deterioration with bioprosthesis (15-year risk- 30% for age 40 year, 50% for age 20 year). [1]

A bioprosthetic valve may be favored in patients aged more than 65 years under the following circumstances: 

• Patient preference (avoid risk and inconvenience of anticoagulation.
• High risk of long-term anticoagulation.
• Limited access to medical care or inability to regulate vitamin K dependent antagonist.
• Access to surgical centers with low reoperation mortality rate.
• Access to transcatheter valve-in-valve replacement.
• Transcatheter aortic valves have larger effective orifice areas for smaller valve sizes (avoid patient-prosthesis mismatch).1

Published data indicate that strong consideration should be given to choosing a tissue over a mechanical prosthesis in patients aged >60 years, but the issue remains largely unsettled in patients aged <60>

Although, these studies have helped define the recommendations for prosthesis selection according to patient’s age, they compared valve models implanted in 1970s and 1980s, had a considerable proportion of redo-thoracotomy/sternotomy patients at initial valve implantation, and reported perioperative mortalities at initial operation and at reoperation that were high (>14%) by modern standards, thus potentially biasing against use of bioprosthesis. [7,14,34]

Thirdly, data with sufficient follow-up duration to adequately capture tissue prosthesis, reoperations, and long-term mortality in younger patients is lacking. Fourthly, a rapid development is witnessed in the field of bioprosthesis, with newly introduced devices every year. The production of some of the devices was even stopped before the long-term results were obtainable which indeed is mandatory for every new device.

The rationale for these studies is based on improved durability of bioprostheses, anticipated low risk of reoperation, and avoidance of long-term anticoagulation. Data on long-term survival of patients with bioprostheses, however, are conflicting. [15-19,24-31,39-41]

Valvular heart diseases in developing countries resulting from rheumatic fever is disabling and if untreated leads to congestive heart failure and death. The severity and rapid progression of rheumatic valvular disease in pediatric and younger patients precludes repair in the great majority. Young patients face a difficult choice between a life time of anticoagulation and 1-3% per year bleeding risk with mechanical prosthesis and a significant risk of reoperation due to structural valve deterioration with bioprosthesis.[4,11-14,20-23,37,38] 

Whether reoperation is more hazardous than strokes and hemorrhage, long-term valve-related mortality may be the most important criterion for comparison and literature is divided on the recommendation in young rheumatics.[6,42-47 ]

In our previous propensity matched investigation on 466 consecutive patients undergoing either bioprosthetic MVR (n= 233) or mechanical MVR (n=233), we compared 22 – year composites of valve – related reoperation, obesity, and mortality in young rheumatics aged less than 45 years. At a median follow up of 136 months (IQR: 79-197), our reoperation rate was 17.6% for mechanical prostheses and 13.6% in bioprosthetic arm, while reoperation for structural valve deterioration was associated with 0.27 times lower risk of cumulative mortality than reoperation for thrombosed mechanical processes (p<0>

All biologic valves are at risk of structural valve deterioration. Any patient treated with a bioprosthesis may need reoperation for valve replacement if the individuals life expectancy exceeds that of the valve. In 1999, and 2001 the French investigators reported that the risk of reoperation for SVD of bioprostheses was 3 fold higher in cases involving patients older than 65 years of age (p=0.02) who had mitral-aortic valve replacement (p=0.02).[48,49]

On the basis of this finding, implantation of 2 bioprostheses would seem contraindicated in patients in whom structural degeneration requiring reoperation in likely to occur after age 65 years. However, alternative use of mechanical valves is associated with a significantly higher risk of potentially lethal haemorrhagic complications. [39,40,50]

In this review, the mean age of both groups of patients was 33.32 + 7.8 (range 11-70, median 33 years; bioprosthesis), and 33.32 + 7.95 (range 12-45; median 33 years; mechanical); SMD=0.012; p=0.19) respectively. Thus, the survival period of the study population was much longer than the life span of the bioprostheses. Therefore, follow-up of patients treated with bioprostheses was not artificially shortened. Hence, we found that overall actuarial survival was slightly shorter in the bioprosthetic group, although statistically insignificant (group I: 92.3% + 0.02% vs group II: 96.6% + 0.01%; Logrank: p=0.90; Figures 4A, 4B). 

In general, the younger the patients are, the earlier the valve degenerates.[43,46,50] Freedom for SVD-related reoperation rates at 10 and 15 years in patients aged less than 60 years in the published literature has been reported between 71-84% and 62.6%-87.4% respectively.[43,46,50] In our previous investigation on 260 young rheumatics aged less than 45 years undergoing isolated mitral valve replacement, we had demonstrated that at a median follow up of 134 months, our reoperation rate was 8.5% in Epic and 14.6% in PERIMOUNT arm, while reoperation for structural valve deterioration was associated with 3.82 times increased risk of death.[20]

A number of recent articles supported the use of bioprostheses in patients aged less than 60 years with the argument that bioprostheses reduced the postoperative valve-related complications including SVD and mortality. Myken and associates studied Biocor MVR in 1712 patients with a mean follow-up of 6.2 years.43 The 20-year freedom from actuarial valve related mortality was 92.8% and freedom from SVD was 79.3%. They concluded that bleeding was more hazardous than reoperation.43 The Biocor MVR durability reported by Pomerant Zeff and associates in 2006 on 546 patients (mean age 48 years) at 15 years was 51.8% for those aged <50>

Our findings in this review are in accordance with the published investigations of 15-years survival of 53% - 84.4% with mechanical prosthesis and 42% - 58.8% with bioprosthetic combined aortic and mitral valve replacements.[16,17,24-31] The striking variability in the results using the same prosthetic devices is also known to occur from the experience of other centers. Armenti and colleagues cited an actuarial survival of only 76% and 62% at 3 and 5 years, respectively, using St Jude Medical prostheses and their experience was a variance from that of Brown and colleagues whose results were most favourable with this combination.[31,40,53]

Our hospital mortality of 3.2% in the biologic arm and 4.4% in the mechanical arm following propensity matching compares favourably with 2.5% to 12% of other investigators and is not substantially higher than patients with isolated valve replacement in several investigations.15,19,24-31 Bernal and colleagues from Spain reported a mortality of 10.7

Although our study is limited by its retrospective nature, propensity score analysis provides a balance of two compared groups and attempt to control for the most of the bias in assignment of valve type.

Randomized controlled trials themselves are limited because randomization requires stratification on many prognostic variables and thus often leads to selection of very specific groups of patients with results that lack generalizability. In addition, randomization is based on few variables that the investigators consider as most significant predictors of outcome. 

Thirdly, like other observational cohorts, our results may not be generalizable to all young adults undergoing MAVR in other centers.

This study adds equipoise to the notion of valve choice in young rheumatics aged less than 45 years. Bioprostheses for combined mitral and aortic valve replacements are valid alternative to mechanical prostheses in patients from remote rural areas, those desirous of pregnancy, patients with bleeding risk, and those with thrombosed mechanical prostheses. Bioprostheses were undifferentiated in terms of composites of valve-related reoperation and mortality.

Survival from reoperation in bioprosthetic arm was superior to mechanical arm because of planned elective intervention, mostly when the patients were in functional class I/II. In light of this data, we conclude that choice of prosthesis for mitral and aortic valve replacements should be based on patient’s preference, ability to take anticoagulation, and the likelihood of reoperation.

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