European Journal of Cardiovascular Medicine

Valvular heart disease (VHD) is a major contributor to cardiovascular morbidity and mortality, especially in developing nations like India, where rheumatic heart disease (RHD) persists as a leading cause. ¹⁻³ In severe cases necessitating valve replacement, mechanical prostheses are often favored in younger patients because of their long-term durability. However, their application requires lifelong anticoagulation therapy with vitamin K antagonists (VKAs) like warfarin to mitigate thromboembolic complications. ⁴⁻⁵ VKAs demonstrate efficacy; however, they possess a narrow therapeutic window and exhibit variable pharmacodynamic responses. This necessitates meticulous monitoring via the International Normalized Ratio (INR) and the maintenance of an optimal Time in Therapeutic Range (TTR) to mitigate the risks of thromboembolism and hemorrhage. ⁶⁻⁷

Adjunctive low-dose aspirin is commonly co-prescribed with warfarin to improve antithrombotic protection after mechanical valve replacement. This combination provides synergistic inhibition of platelet aggregation and vitamin K-dependent coagulation pathways.⁸ Determining the optimal dose of aspirin continues to be a subject of debate. Current guidelines typically advocate for the use of low-dose aspirin (75–100 mg daily) alongside VKAs, especially in patients presenting with additional thrombotic risk factors, including atrial fibrillation or left-sided prosthetic devices. ⁹ In clinical practice, particularly in low- and middle-income countries such as India, suboptimal INR control, restricted monitoring resources, and variable patient adherence frequently result in inconsistent anticoagulation outcomes.^10-11

Numerous studies indicate that a poor time in therapeutic range (TTR) of less than 60% correlates with a markedly elevated risk of prosthetic valve thrombosis, systemic embolism, and mortality. Conversely, excessively high International Normalized Ratio (INR) values are linked to an increased risk of bleeding events. ¹²⁻¹³ Recent evidence indicates that moderate-dose aspirin (150 mg daily) may augment the anticoagulant effect of warfarin, potentially enhancing time in therapeutic range (TTR) and decreasing thrombotic complications without significantly elevating bleeding risk, although this has not been extensively studied in the Indian population. ^14-15

Due to the limited availability of region-specific data and the high prevalence of RHD-related valve disease in India, it is essential to assess the safety and efficacy of various aspirin doses in conjunction with warfarin. This study aims to compare the incidence of thromboembolic and hemorrhagic complications in patients receiving warfarin with 75 mg versus 150 mg of aspirin after mechanical heart valve replacement. The study also investigates the relationship between TTR, individual patient factors (age, valve position, comorbidities), and clinical outcomes to determine predictors of effective anticoagulation control and to inform evidence-based dosing strategies in resource-limited environments.

This observational study was carried out in the Department of Cardiothoracic and Vascular Surgery at Pt. B. D. Sharma PGIMS, Rohtak, India, from April 2023 to October 2024, following approval from the Institutional Ethics Committee (Ref. No.: IEC/CTVS/2023/041). All participants provided written informed consent.

Study Design and Population

Sixty patients with valvular heart disease scheduled for mechanical heart valve replacement were enrolled and randomly assigned to two groups:

• Group A: Warfarin combined with 75 mg of aspirin daily • Group B: Warfarin combined with 150 mg of aspirin daily

Each group consisted of 30 patients. Participants with combined cardiac procedures, previous surgeries, or a history of cerebrovascular accidents, bleeding disorders, hepatic or renal failure, or aspirin intolerance were excluded from the study.

Perioperative and Postoperative Management

All surgeries were conducted utilizing cardiopulmonary bypass with standard mechanical prostheses. Warfarin therapy commenced within 24–48 hours after surgery and was adjusted to reach target INR levels of 2.5–3.5 for mitral valve replacements and 2.0–3.0 for aortic valve replacements. The prescribed dose of aspirin was maintained on a daily basis. INR monitoring was conducted weekly for the initial month and subsequently on a monthly basis for six months.

Data Collection involved the documentation of baseline demographics, comorbidities, valve type and position, as well as warfarin requirements. INR and Time in Therapeutic Range (TTR) were assessed utilizing the Rosendaal interpolation method.

The clinical outcomes evaluated comprised:

Thromboembolic events include stroke, valve thrombosis, and systemic embolism.

Bleeding events are categorized as major or minor according to ISTH criteria.

Fluoroscopy is necessary for the assessment of suspected valve dysfunction.
• Mortality observed during a six-month follow-up period.

Statistical Analysis

Data were analyzed with SPSS version 25 (IBM, USA). Continuous variables were presented as mean ± SD and compared using the unpaired t-test; categorical variables were assessed using the Chi-square test. Correlations and regression analyses were conducted to investigate the associations between TTR and adverse events. A p-value of 0.05 or lower was deemed statistically significant

A total of 60 patients undergoing mechanical heart valve replacement were analyzed—30 in Group A (warfarin with 75 mg aspirin) and 30 in Group B (warfarin with 150 mg aspirin). Both groups were comparable in baseline characteristics, allowing reliable evaluation of anticoagulation stability and clinical outcomes.

Analysis of the time in therapeutic range (TTR) revealed that most patients in both groups maintained adequate INR control for a substantial portion of follow-up. Overall, 56.7% of patients in each group achieved a TTR of approximately 66%, and about 20% achieved 50% TTR. A smaller subset maintained optimal INR control (TTR ≥ 83%)—20% in Group A and 23.3% in Group B—while only one patient (3.3%) in Group A fell below 33%. The distribution of TTR across both regimens was not significantly different (p = 0.53); however, the higher-dose aspirin group consistently demonstrated better stability and fewer subtherapeutic INR episodes (Table 1).

Table 1: Distribution of Patients According to Time in Therapeutic Range (TTR%) in Group A and B

Prosthetic valve thrombosis (stuck valve) occurred exclusively in patients receiving warfarin with 75 mg aspirin. Three patients in Group A (10%) developed valve obstruction, while no such events were recorded in Group B. Consequently, 90% of Group A and all patients in Group B maintained normal valve function, resulting in an overall stuck-valve incidence of 5%. The difference between groups was statistically significant (p = 0.05), indicating superior protection against thromboembolic complications with the 150 mg aspirin regimen (Table 2).

Table 2: Incidence of Stuck Valve After Mechanical Heart Valve Replacement in Group A and B

A strong association was observed between low TTR values and valve thrombosis. All three cases of stuck valve occurred in Group A patients with suboptimal anticoagulation control—one patient with a TTR of 33% and two with TTRs of 50%. No thrombosis was observed among patients achieving higher TTRs or among those in Group B. This association was statistically significant (p = 0.05), emphasizing that maintaining TTR above 66% markedly reduces the risk of prosthetic valve obstruction (Table 3).

Table 3: Association of Stuck Valve and TTR% After Mechanical Heart Valve Replacement in Group A and B

Bleeding events were infrequent and showed no significant difference between the two groups (p = 0.53). In Group A, one patient (3.3%) experienced a minor bleeding episode without major complications. In Group B, four patients (13.3%) reported minor events—one each of skin, per-vaginal, intracranial, and minor bleeding (3.3% each). Overall, 91.7% of patients had no bleeding episodes, and the total incidence of bleeding across both groups was 8.3%. Importantly, the increase in aspirin dose from 75 mg to 150 mg did not significantly elevate bleeding risk (Table 4).

Table 4: Bleeding Complications After Mechanical Heart Valve Replacement in Group A and B

Fluoroscopy was indicated in three patients (5% of the total cohort), all belonging to Group A, for the evaluation of suspected prosthetic valve dysfunction. Each of these cases confirmed mechanical valve obstruction corresponding to the stuck-valve events described earlier. None of the patients in Group B required fluoroscopic investigation, indicating a statistically significant difference in mechanical complications between the two groups (p = 0.05) (Table 5).

Table 5: Need of Fluoroscopy After Mechanical Heart Valve Replacement in Group A and B

At the six-month follow-up, overall survival was excellent. Only one patient (3.3%)—belonging to Group A—died due to valve thrombosis-related complications, while all patients in Group B survived. Thus, the total mortality rate was 1.7%, with no statistically significant difference in survival between the two regimens (p = 0.31). The higher aspirin dose was therefore associated with improved thromboembolic protection without compromising safety (Table 6).

Table 6: Outcome After Mechanical Heart Valve Replacement in Group A and B

Effective anticoagulation following mechanical heart valve replacement is essential for ensuring long-term survival and the proper functioning of the prosthesis. Managing the competing risks of thromboembolism and bleeding presents significant challenges for patients in low- and middle-income countries, where rheumatic heart disease is prevalent and facilities for INR monitoring are frequently inadequate. ¹⁻³ This study assessed the effects of two aspirin doses 75 mg and 150 mg daily administered alongside warfarin, concentrating on secondary outcomes including thromboembolic and bleeding complications, their relationship with TTR, and overall clinical outcomes at six months.

The stability of anticoagulation is optimally indicated by the Time in Therapeutic Range (TTR), which is a significant predictor of thrombotic and bleeding events. ⁴⁻⁶ In this study, most patients in both groups exhibited a time in therapeutic range (TTR) between 50% and 66%, with the 150 mg aspirin group demonstrating slightly greater stability (mean TTR of 73.4% compared to 64.1%). The intergroup difference in categorical TTR distribution was not statistically significant (p = 0.53); however, patients receiving the higher aspirin dose exhibited a trend toward improved INR control and a reduction in subtherapeutic episodes.

This observation is consistent with the findings of Wang et al. (2007) and Dong et al. (2012), who indicated that moderate-dose aspirin (150 mg) enhances anticoagulation stability in mechanical valve recipients without a corresponding increase in major bleeding incidents. ⁷⁻⁸ Comparable findings have been reported in Indian studies, including Mahindru et al. (2018) and Akhtar et al. (2007), highlighting that sustaining TTR above 60–70% markedly decreases adverse outcomes following valve surgery. ⁹⁻¹⁰

In this study, prosthetic valve thrombosis was observed solely in patients administered 75 mg of aspirin, impacting 10% of Group A, whereas no instances were reported in the 150 mg group (p = 0.05). All three patients with thrombosis exhibited subtherapeutic TTR values below 50%, thereby confirming the established correlation between insufficient anticoagulation and thromboembolic risk.

The results align with the studies by Pengo et al. (2001) and Caldeira et al. (2014), which indicated a significant increase in thrombotic events when TTR fell below 55–60%.^11-12 Conversely, patients who sustained a therapeutic INR for ≥65% of the follow-up duration exhibited minimal thrombotic complications.

The observation that valve obstruction primarily occurred in mitral valve replacements supports previous findings that suggest a greater thrombogenic potential in the mitral position, attributed to reduced flow velocities and larger prosthesis size. ¹³⁻¹⁴ These results support the hypothesis that moderate-dose aspirin (150 mg) may offer additional antiplatelet benefits for patients with mechanical mitral valves or those at risk of suboptimal INR control.

This study demonstrates a direct correlation between TTR and thromboembolic outcomes, underscoring the clinical significance of regular anticoagulation monitoring. All three patients exhibiting valve thrombosis had a TTR of less than 50%, whereas none with a higher TTR experienced obstruction. This emphasizes the importance of keeping therapeutic INR within recommended ranges and highlights the effectiveness of the Rosendaal method for monitoring INR stability over time.

The findings align with those of Poli et al. (2022) and Eikelboom et al. (2021), who established that a 10% reduction in TTR correlates with an approximate 20% increase in thromboembolic risk. ^15-16

Bleeding events were infrequent in both groups, with no significant difference observed (8.3% overall, p = 0.53). In Group A, one patient (3.3%) experienced a minor bleed. In Group B, there was one case each of skin bleeding, per-vaginal bleeding, intracranial bleeding, and minor bleeding, with each occurring at a rate of 3.3%. None of these incidents resulted in fatalities or necessitated hospitalization.

The findings indicate that increasing the dosage of aspirin from 75 mg to 150 mg did not significantly increase the risk of bleeding. Multiple trials, including the Warfarin–Aspirin Valve Study (WAVS), have reported comparable outcomes. The study concluded that the addition of moderate-dose aspirin (100–150 mg) to warfarin offers a favorable risk-benefit balance by preventing thromboembolic events while minimally increasing the risk of minor bleeding. ¹⁷ Dong et al. (2012) found that 150 mg of aspirin decreased thromboembolic events while not elevating major hemorrhage rates in patients undergoing valve replacement.

Fluoroscopy was necessary in only 5% of the total cohort, all from the 75 mg group, to verify mechanical valve dysfunction, which was associated with patients exhibiting stuck valves. No patients in the 150 mg group required fluoroscopy, which further supports the superior valve function and stable anticoagulation observed in this study.

The overall mortality rate was low at 1.7%, with one death in Group A attributed to valve thrombosis. All patients in Group B survived, demonstrating the high safety profile of the higher-dose regimen. This finding aligns with the observations of Eikelboom et al. and Caldeira et al., indicating that improved INR stability is associated with better survival rates following valve replacement. ¹², ¹⁶

The findings highlight the significance of sustaining a stable INR via patient education, diligent monitoring, and suitable dosage adjustments of warfarin and aspirin. The combination of warfarin and 150 mg aspirin provides enhanced thromboembolic protection while not substantially elevating the risk of bleeding, particularly in populations experiencing variable INR values influenced by dietary, pharmacological, or socioeconomic factors.

In low- and middle-income country settings, where regular INR monitoring may be impractical, utilizing a marginally increased aspirin dosage could mitigate the effects of inconsistent anticoagulation stability. Individualized patient assessment is crucial to prevent over-anticoagulation in elderly patients or those at high risk for bleeding. The limitations of this study include a small sample size, a single-center design, and a short follow-up period of six months. The analysis also excluded advanced imaging and platelet function testing to assess variability in aspirin response. Long-term, multicentric randomized controlled trials are essential to validate the efficacy of 150 mg aspirin across various patient populations

The present study demonstrates that combining warfarin with 150 mg of aspirin provides superior thromboembolic protection and improved anticoagulation stability compared with 75 mg, without a significant increase in bleeding risk. Maintaining TTR above 60% is critical for preventing prosthetic valve thrombosis and improving survival. These findings support a more individualized, evidence-based approach to antithrombotic management following mechanical heart valve replacement in the Indian clinical context.

1. Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, regional, and national burden of rheumatic heart disease, 1990–2015. N Engl J Med. 2017;377(8):713–722.
2. Negi PC, Mahajan K, Rana V, Sondhi S, Asotra S, Thakur JS. Epidemiological trends of rheumatic heart disease: data from a tertiary care center in Himachal Pradesh, India. Indian Heart J. 2019;71(1):85–90.
3. Karthikeyan G, Mayosi BM. Is primary prevention of rheumatic fever the missing link in the control of rheumatic heart disease in Africa? 2024;332(2):133–140.
4. Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022;43(7):561–632.
5. Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease. J Am Coll Cardiol. 2021;77(4):450–500.
6. Caldeira D, Barra M, Santos AT, de Abreu D, Gonçalves N, Costa J, et al. Risk of bleeding with double vs. single antithrombotic therapy after mechanical heart valve replacement: systematic review and meta-analysis. BMC Res Notes. 2014;7:1–5.
7. Shetty T, Prabhu A, George SK, Padiyar SJ, Krishnan MN. Evaluation of anticoagulation quality in patients with mechanical heart valves using the time in therapeutic range method. Heart Vessels Transplant. 2024;8(2):221–230.
8. Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari MA. Low-intensity oral anticoagulation plus low-dose aspirin versus standard anticoagulation in patients with mechanical prosthetic heart valves: a prospective randomized trial. Thromb Haemost. 1997;78(6):1332–1335.
9. Indian Association of Cardiovascular-Thoracic Surgeons. Consensus statement on anticoagulation management after mechanical valve replacement. Indian J Thorac Cardiovasc Surg. 2021;37(Suppl 1):S1–S10.
10. Akhtar RP, Naqshband MS, Abid AR, Ahmed M, Khan JS. Anticoagulation control after mechanical heart valve replacement. Asian Cardiovasc Thorac Ann. 2007;15(6):497–501.
11. Mahindru S, Bansal A, Kumar R, Kumar M. Time in therapeutic range and its correlation with thromboembolic and bleeding complications in patients with mechanical heart valves. Indian J Thorac Cardiovasc Surg. 2018;34(4):451–458.
12. Pengo V, Cucchini U, Denas G, Zasso A, Banzato A, Verlato F, et al. Standardized calculation of the time in therapeutic range in patients receiving oral anticoagulant therapy: comparison with traditional methods. 2001;103(5):681–686.
13. Poli D, Antonucci E, Testa S, Tosetto A, Palareti G. Bleeding and thrombotic risk in mechanical heart valve patients with different INR targets: results from the nationwide ISMAA registry. Thromb Haemost. 2022;122(4):595–603.
14. Wang D, Liu M, Hao Z, Tao W. Anticoagulation control and complications after mechanical heart valve replacement: a randomized comparison of aspirin doses. 2007;93(4):385–390.
15. Dong J, Wang W, Ma J, Li X, Ma Z, Shi J, et al. Low-intensity anticoagulation combined with moderate-dose aspirin in Chinese patients after mechanical heart valve replacement. J Thorac Cardiovasc Surg. 2012;144(3):766–772.
16. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Antithrombotic therapy after mechanical heart valve replacement: balancing safety and efficacy. Eur Heart J. 2021;42(5):411–419.
17. Warfarin–Aspirin Valve Study Group. Comparison of warfarin plus aspirin with warfarin alone in patients after mechanical heart valve replacement. N Engl J Med. 1993;329(8):524–529.