Performance of Mechanical and Biological Mitral Prostheses in Young Rheumatics Aged Below 45 Years

Lakshmi Kumari Sankhyan, Ujjwal Kumar Chowdhury, Diplomate NB, Niwin George, Sushamagayatri B, Srikant Sharma, Diplomate NB, Sai Divya Yadavalli, Devanish KNH, Maroof A. Khan, All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh All India Institute of Medical Sciences, New Delhi *Corresponding Author: Ujjwal Kumar Chowdhury, MCh, Diplomate NB Professor Department of CTVS AIIMS, New Delhi-110029, INDIA Received Date: February 11, 2021; Accepted Date: March 29, 2021; Published Date: April 02, 2021 Citation: Lakshmi K. Sankhyan., Ujjwal K. Chowdhury., Diplomate NB, Niwin George, Sushamagayatri B, et al. (2021) Performance of Mechanical and Biological Mitral Prostheses in Young Rheumatics Aged Below 45 Years. J. Clinical Cardiology and Cardiovascular Interventions, 4(7); Doi:10.31579/2641-0419/149 Copyright: © 2021 Ujjwal Kumar Chowdhury, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

: Graphic display (n=466) showing long-term valve-related actuarial survival of Group I and Group II patients. literature at 10, 20 and 30 years is 61-75%, 36.5-39%, and 22.6% respectively. [2][3][4]12] Over the last 20 years, there is a shift away from a clear cut age limit towards patients' wish and lifestyle considerations. [6,11,12] This may be related to the enhanced durability of newgeneration bioprostheses, improved outcomes of redo surgery, or development of transcatheter valve-in-valve implantation. [6,11] Although investigators have evaluated survival and valve-related complications, little information is available regarding composites of complications, namely valve-related reoperations, morbidity, and mortality in young rheumatics. [12,13] In 2018, we published our preliminary observations on the result of MVR using Carpentier-Edwards PERIMOUNT bioprosthesis in young rheumatics aged <40 years. [14] 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 <45 years, undergoing bioprosthetic or mechanical MVR. The secondary objectives were to: i) compare the short-and longterm hemodynamic performance of prosthesis and SVD of 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.

Materials and Methods
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 MVR 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 <45 years undergoing isolated MVR 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 MVR 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 prosthesis, and patients' choice were indications for bioprosthetic MVR.
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 <45 years who underwent either a bioprosthetic (Group I) or mechanical (Group II) MVR from January 1998 to December 2019 by the corresponding author.
A total of 600 mitral mechanical prostheses (SJM Mechanical, n=300; ATS Medical, n=300) and 295 bioprostheses (Carpentier-Edwards PERIMOUNT model 6900 (Edwards Lifesciences, Baxter Healthcare Corporation, Irvine, CA, USA, n=165; St. Jude Epic Porcine bioprosthesis, n=130) were implanted. Among these, 132 patients of PERIMOUNT were from our previous investigation, and 33 were new patients in Group I (Figure 1). [14] Patients were matched one-to-one according to age, sex, preoperative thromboembolism, presence of atrial fibrillation (AF), advanced NYHA status, preoperative CHF requiring inotropes and ventilation, LVEF <0.25, size of LA >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 2 groups with a 2-sided  of 0.05 Table 1 Six-monthly follow-up data included clinical history, NYHA class assessment, and valve-related events. [15] 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 within first six months and then annually. [16] Definitions

Outcome measures
Valve-related mortality included death caused by thrombosis, thromboembolism, hemorrhage, SVD, non-structural dysfunction, or prosthetic valve endocarditis and death related to reoperation for a valverelated 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. [17,18] 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 MVR. Reoperations that did not involve mitral valve replacement were excluded.
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.
Stroke was defined as any cerebrovascular accident documented during the index hospitalization as well as any subsequent hospital admission in Figure 3: Love plot depicting standardized mean of difference (SMD) for covariates balancing before and after propensity score matching which the principal diagnosis was hemorrhagic or ischemic stroke (not including transient ischemic attacks).
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).
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.

Anticoagulation
Patients with bioprosthetic MVR 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 MVR and normal sinus rhythm at 12 weeks of follow up.
Patients with a preoperative LA/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 SVD. Table 1 shows the significant imbalances in baseline characteristics between patients treated with mechanical and biological mitral prostheses before matching. To assemble a balance cohort of patients with mechanical and biological mitral prostheses, we used propensity-score matching method on those with mechanical and biological mitral prostheses on measured baseline characteristics. For this purpose, we estimated propensity scores for treatment (group) for each of the 895 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-ofsample prediction, discrimination or estimation of coefficients. The efficacy of propensity-score models is best assessed by estimating postmatch 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).

Selection of a balanced cohort
An absolute standardized difference of 0% indicates no residual bias and, 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 prostheses. We were able to match 233 of the 600 mechanical prostheses patients with 233 patients of biological mitral prostheses.

Statistical Analysis
For  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.  Figure 6A compares survival probability with and without adverse events in the study group. Figure 6B depicts survival probability of patients with and without adverse events between group I and group II. mitral 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 < 0.05 were considered statistically significant.
The freedom from the composites of valve-related complications (mortality, reoperation and adverse postoperative events) were calculated by Kaplan-Meier actuarial methods and compared with log-rank statistic (Figures 4A, 4B, 5A, 5B, 6A, 6B).
As presented in Table 1, after propensity matching, there were no differences among the 233 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 MVR.

Surgical techniques
The technical details of the surgical steps have been enumerated in the video presentation (Video Presentation) as well as in our earlier publication. [3,4] Every attempt was made to preserve the chordopapillary apparatus ensuring implantation of an appropriate sized prosthesis without leaflet entrapment or LVOTO.
In patients with predominantly stenotic lesions with severe chordopapillary fusion, MVR was performed without chordal preservation. [3,4] Intraoperative transoesophageal echocardiography was performed to confirm satisfactory prosthetic valve function immediately after surgery.

Operative mortality and morbidity
There were 5 (2.1%) hospital deaths in group I and 8 (3.4%) in group II due to 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 (  10.57) times increased risk of death compared to non-reoperated group (p=0.002) and there was significantly decreased probability of long-term survival (log rank p=0.0003) ( Table 3, Figures 5A, 5B). At a median follow up of 136 months (IQR: 76.0-197.0), 18.8% (n=44) of group I, and 13.3% (n=31) of group II patients underwent redo MVR using mechanical prosthesis, and there was no difference in actuarial survival between the two groups (log rank p=0.83) ( Figure 5B). Valve leaflet thickening with mild prosthetic valve stenosis (Epic n=6, PERIMOUNT n=2) was seen between 84 and 100 months of follow-up and being closely followed-up.

Discussion
Comparative data on late (15 years) and very late-term (20 years) performances of bioprostheses and mechanical prostheses in young rheumatics are limited and conflicting. [1][2][3][4]13,14,[17][18][19][20] The important findings of this retrospective study were:  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 years. Randomised trials comparing biological and mechanical prosthesis in younger patients are scanty. [1][2][3][4]13,14,[17][18][19][20] 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. [1,8,19] 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.
Although direct comparisons across many studies may be misleading, it is reasonable to review the data as a whole and make generalizable statement in favour or disfavour of a particular prosthesis.
Survival analysis on 575 patients at 15 years by Hammermeister and colleagues showed lower all-cause mortality with mechanical AVR but not MVR. Bioprostheses were associated with significantly lower bleeding rates but higher rates of SVD. [9] The Edinburgh trial studied 530 patients receiving either a Bjork-Shiley tilting disc valve or porcine bioprosthesis and concluded that mechanical prostheses had improved survival over bioprostheses at 12 years, but not at 20 years. Mechanical prostheses were associated with higher bleeding rate for both AVR and MVR. [2][3][4]8] Beyond these randomized trials, the consensus is that bioprosthesis are associated with increased SVD and reoperation but lower bleeding and thromboembolism rates. [1][2][3][4]14,[17][18][19][20] Several investigators have demonstrated conflicting data on valve-related reoperations between biologic and mechanical prostheses and mortality. [1][2][3][4]14,[17][18][19][20] Despite the divergence of data, at a median follow-up of 136 months (IQR:79-197), our reoperation rate was 18.8% for bioprosthesis and 13.3% in mechanical arm, while reoperation for SVD was associated with 0.27 times lower risk of cumulative mortality than reoperation for thrombosed mechanical prosthesis (p<0.001).
This study is one of the largest to compare bioprosthetic and mechanical MVR with a median follow-up of 11.3 years. Our study doesn't include multiple biologic or mechanical valve models and therefore provides a pure comparison of most commonly used prostheses. The study inferred that bioprostheses appeared to be favourable based on lower incidence of valve-related morbidity. Since, no significant difference in re-operation was observed between prostheses, bioprostheses appear to be the clear preference for young rheumatics; offering an improved morbidity profile, without sacrificing durability.

Study Limitations
Although it is a retrospective study, our statistical methods attempt to control for 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. In contrast, propensity score analysis provides a balance of two compared groups with weighted effects of the covariates on treatment variable and thus minimizing the bias related to imbalances in assignment of treatment type.
Secondly, like other observational cohorts, our results may not be generalizable to all young adults undergoing MVR in other centers.

Conclusions
This study adds equipoise to the notion of valve choice in young rheumatics aged <45 years. Bioprostheses 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 MVR should be based on patient's preference, ability to take anticoagulation, and the likelihood of reoperation.