Surgical valve replacement (SVR) remains the mainstay of treatment for valvular heart disease (VHD) affecting any of the four valves if they are not suitable for repair (1, 2). Over six decades, mechanical or tissue valve prostheses have been used for SVR, and the advantages and disadvantages of both are well documented (1, 3, 4). Newer surgical bioprosthetic heart valves (BHVs) have demonstrated a marked improvement in durability (2, 3, 5). The new-generation BHVs are made from corrosion-resistant frame material, subjected to anti-calcification/mineralization treatments, and have glutaraldehyde-fixed independent tissue leaflets (6). While there are substantial clinical data on the durability and hemodynamic performance of aortic tissue valves, their implantation in the mitral position remains less researched. However, there is comparatively limited recent evidence about the advantages of pericardial valve over a porcine prosthesis for mitral valve replacement (7).

An epidemiological report by the Centers for Disease Control and Prevention highlighted that of all deaths due to VHD in 2017, 61% and 15% deaths were attributed to aortic and mitral valve disease, respectively (8). Further, >90% patients with advanced VHD were aged <60 years in a study conducted in northern India (9).

SVR has become preferable over annuloplasty and/or valvuloplasty in patients aged <60 years with aortic and/or mitral valve disease, due to the improvements in BHVs (1, 10), and tissue valves composed of bovine pericardium or porcine tissue are preferred over mechanical valves (1, 2).

BHVs can be stented or stent-less, and made of porcine tissue or bovine pericardium. Stented valves provide a good structural frame that prevents damage during implantation and ensures long-term maintenance of the valve geometry (11). The Dafodil™ pericardial bioprosthesis (Meril Life Sciences Pvt Ltd., India) is a tri-leaflet bovine pericardial valve, which has been indigenously developed in India. It has a stented design with three independent laser-cut leaflets, providing better leaflet coaptation and tenacious protection against leaflet calcification (Figure 1). The Dafodil^TM valve is designed for supra-annular placement, which aims to provide a larger effective orifice area (EOA), as the stent and the sewing ring are positioned on top of the native annulus. The valve has a sewing ring with commissural markers that aim to facilitate its attachment with appropriate orientation, especially useful in mitral valve replacement (MVR). The three leaflets are treated with proprietary anti-calcification technology (AntiCa⁺), with an aim to prevent calcification and valve degeneration. The Dafodil™ valve offers a comprehensive range of sizes for both aortic and mitral valves, tailored to accommodate the diverse anatomical requirements of patients undergoing valve replacement procedures. Aortic valve sizes in the Dafodil™ range from 19 mm to 27 mm, with options such as 19 mm, 21 mm, 23 mm, 25 mm, and 27 mm available. Similarly, mitral valve sizes in the Dafodil™ typically include 23 mm, 25 mm, 27 mm, 29 mm, and 31 mm, providing a wide selection to match individual patient needs. These precise size variations enable cardiac surgeons to choose the most appropriate valve size for each patient, ensuring optimal post-surgical functionality and compatibility.

The first-in-human trial evaluated the safety and clinical efficacy of Dafodil™ pericardial bioprosthesis. In the previous publication data of first 60 patients at 1-year has been presented (12). The current investigation reports the 3-year outcomes of 136 patients enrolled in the Dafodil™-1 trial.

A total of 193 patients were screened, out of which 49 patients did not meet the eligibility criteria, 8 patients refused informed consent, hence a total of 136 patients were enrolled (aortic group: 67 and mitral group: 69). One patient in the AVR group withdrew consent prior to the 3-year follow-up and one patient from the MVR group was lost to follow-up prior to the 2-year follow-up. At the time of reporting, 134 patients had completed the 3-year follow-up (300 per 100 patient-years) including 66 and 68 patients in the AVR and MVR groups, respectively. The patient flow diagram according to the CONSORT (Consolidated Standards of Reporting Trials) guidelines is presented in Figure 2.

The results of the Dafodil™-1 trial showed favorable 3-year clinical safety and hemodynamic performance in patients who underwent AVR and MVR and received the Dafodil™ pericardial bioprosthesis. The MACE incidence was 2.3% per 100 patient-years (1.3% strokes per 100 patient-years and 1.3% deaths per 100 patient-years) for AVR group and 4.7% per 100 patient-years (0.6% strokes per 100 patient-years and 4.0% deaths per 100 patient-years) for MVR group. The Kaplan–Meier estimates of MACE-free survival for the AVR and MVR groups were 89.6% and 79.7% (p = 0.11). Previously, the 1-year results had reported favorable clinical safety and performance with the Dafodil™ prosthesis (12).

The hemodynamic performance of the AVR group in our study is comparable with that of the Inspiris Resilia™ aortic valve, which was investigated prospectively in a large multinational cohort by the COMMENCE trial investigators (16–18). Over the 5-year follow-up, similar hemodynamic improvements were observed for the overall study population; however, aortic root enlargement was concomitantly required for patients with SAA (16). The 4-year outcomes of the COMMENCE trial reported an all-cause mortality rate of 2.2% per patient-year, including 0.4% valve-related mortality per patient-year. In addition, the rate of thromboembolism events was 1.7% per patient-year (18). Our outcomes are comparable to these, thus demonstrating an acceptable device safety and performance. In the COMMENCE mitral cohort, the 5-year probability of event-free survival was 79.9% and all-cause mortality rate was 18.07%. There was one case of postoperative major paravalvular leak (PVL), which required reintervention with a PERIMOUNT Magna Mitral Ease valve and one case required reintervention (19).

In the PERIGON Pivotal trial, the estimated Kaplan-Meier cumulative probability of all late bleeding events and late major bleeding events at 3 years was 7.3% and 4.3%, respectively. The estimated Kaplan-Meier cumulative probability of all-deaths was 7.2% (95% confidence interval [CI]: 5.6–9.0) (20). In our study there were no major bleeding events. Moreover, 93.3% and 91.1% of patients in the AVR and MVR groups had NYHA class I status at the 3-year follow-up. Further, a significant impact on the health-related QoL was observed at the 3-year follow-up. In comparison, 75.3% patients were in class I in the PERIGON Pivotal trial at the 3-year follow-up following SAVR with the Avalus pericardial bioprosthesis (Medtronic Inc., Minneapolis, Minnesota, USA) [20]. This PERIGON trial also reported high transvalvular gradients in patients who received 19-mm (18.2 ± 6.1 mmHg at discharge, 18.3 ± 6.0 mmHg at 3-year) and 21-mm Avalus BHVs (15.2 ± 4.9 mmHg at discharge; 15.9 ± 5.5 mmHg at 3-year), while mild PVL was noted in 2.7% patients (21). Our outcomes are similar to these results.

Eichinger et al. conducted a study of 561 valve replacements (AVR: 461 and MVR: 100) (22) using the Mosaic™ bioprosthetic valve. They reported improvement in mean pressure gradients and EOA for AVR (12.8 ± 5.2 mmHg; 1.7 ± 0.5 cm²) and MVR (4.1 ± 1.4 mmHg; 1.7 ± 0.5 cm²) cohorts at the 5-year follow-up. Similar hemodynamic improvements were observed in the AVR and MVR groups in our study at the 3-year follow-up (AVR: 11.1 ± 6.0 mmHg, 1.8 ± 0.4 cm² and MVR: 4.4 ± 1.7 mmHg and 1.6 ± 0.5 cm²).

We noted that the CPB and aortic cross-clamp times were significantly higher in the Dafodil™-1 trial for patients who underwent AVR with concomitant procedures (CPB: 163.8 ± 63.0 min; Aortic cross-clamp: 116.7 ± 53.1 min). We believe that these durations will reduce considerably with improved learning curve in future years. The CPB (113.2 ± 29.8 min) and aortic cross-clamp time (79.4 ± 22.8 min) was significantly lower in the MVR patients who underwent isolated MVR. Even among those who underwent concomitant procedures with MVR, the CPB (125.7 ± 52.1 min) and aortic cross-clamp duration (86.5 ± 23.5 min) was remarkably lower, which proves the ease of implantation of the Dafodil™ mitral valve. The Dafodil™ mitral valve has dedicated black suture lines that aid in implantation and orientation of the valve, which is further supported by the commissural markers on the sewing ring.

Overall, our data are comparable to the data reported in contemporary studies of pericardial bioprosthetic valves. With these mid-term follow-up results from the Dafodil™-1 trial, the suitability of Dafodil™ pericardial valve for the Asian population is well demonstrated. The AVR cohort of the Dafodil™-1 trial faired consistently with the data of recent Indian studies that analyzed the outcomes of valve replacements using various models of the Carpentier—Edwards porcine bioprosthesis and PERIMOUNT pericardial bioprosthesis in South Asian patients (5, 10). Talwar et al. reported 2.4% early and 0.7% late mortality in a cohort of 559 patients who underwent MVR, AVR, tricuspid, and double valve replacements (10).

Furthermore, contrary to the observation by Freitas-Ferraz et al. that stented valves may not be the best choice for treating patients with a small aortic annulus (23), the Dafodil™-1 trial showed significantly improved outcomes for the SAA patients enrolled, including good improvements in the hemodynamics, NYHA functional class, and SF-12 scores. Future long-term evaluation of this patient group would be critically useful to aid in the device selection in routine clinical practice.

The Dafodil™ pericardial bioprosthesis, Inspiris Resilia™ aortic valve, Avalus™ bioprosthesis, and Perimount Magna Ease™ are new-generation bioprosthetic valves used in surgical valve replacement. All these valves are made up of bovine pericardium. The Dafodil™ valve, crafted from bovine pericardial tissue, features a tri-leaflet design within an elgiloy alloy stent and includes a proprietary AntiCa⁺ anti-calcification treatment, addressing concerns such as calcification. The black sutures help reduce the commissural profile and ease the implantation. On the other hand, the Inspiris Resilia™ aortic valve incorporates a stented tri-leaflet design made from Resilia™ bovine pericardial tissue, and it utilizes EIP™ technology for anti-calcification. In contrast to the Dafodil™ bioprostheses, the Inspiris Resilia™ has a distinct valve tailored for mitral positioning, whereas the Dafodil™ valve can be employed for both AVR and MVR surgeries. The Avalus™ bioprosthesis is similar to that of other stented aortic bioprosthetic valves. It has Proprietary AOA™ anti-calcification technology which mitigates calcification and protects the tissue, but this valve is not suitable for use in the mitral valve positioning. Lastly, Perimount Magna Ease™ valve, tri-leaflet bioprosthesis, available for both aortic and mitral positions, has Thermafix anti-calcification technology and suture markers aid in valve orientation and suture placement.

With the increased use of Bioprosthesis for patients who require surgical valve replacement, SVD and the need for reintervention remains a concern, particularly in younger patients with long-life expectancy. Other than the above-mentioned studies, the long-term durability studies of the Epic, Mosaic, and Perimount Magna Ease bioprostheses are available. These studies primarily focus on the incidences of major bleeding events, SVD, and need for reoperation. The long-term outcomes of these studies, are given in Table 4. The Epic and Perimount Magna Ease bioprostheses have demonstrated acceptable results in terms of freedom from all-cause mortality and valve related complications, whereas the SVD rates of Mosaic bioprosthesis are comparable with the Perimount Magna ease bioprosthesis. Like the long-term studies of other devices, further follow-up of Dafodil™-1 first-in-human trial is ongoing.

We note that the sample size of the trial was a major limitation. The reasons for this can be linked to the low accessibility to quality healthcare among diseased populations in India, which is a middle-income country. The current study is on-going trial, which is not sufficiently powered to address structural valve deterioration over time. Hence, the long-term follow-up is warranted. The socioeconomic factors play a considerable role in the patients' decision-making regarding invasive treatment for VHD. However, the effects of these nonclinical factors are expected to reduce in the forthcoming years, as the access to affordable healthcare increases and the availability of this indigenously designed prosthetic valve grows. We acknowledge that the data of MVR patients may serve critically to evaluate the clinical need of a viable mitral valve prosthesis in the South Asian population, where aortic and mitral valve diseases are highly prevalent, even though there were limited number of patients.

This is a first-in-man study of Dafodil™ pericardial bioprosthesis for AVR and MVR, which demonstrated favorable 3-year outcomes and hemodynamic improvements, and significantly enhanced patients' quality of life. Further large-scale randomized trials with longer follow-ups are required to corroborate the findings of this first-in-man study.