Pharmacological management of major complications following left ventricular assist device implantation in type 2 diabetes mellitus

Abstract

Left ventricular assist devices (LVADs) represent a cornerstone therapy for advanced heart failure. However, their efficacy in patients with type 2 diabetes mellitus (T2DM) is challenged by diabetes-exacerbated complications. To determine optimal pharmacological strategies to mitigate major LVAD-related complications in patients with T2DM. This review provides evidence for pharmacological strategies to mitigate major LVAD-related complications in T2DM, in which endothelial dysfunction (via impaired PI3K/Akt-NO signaling), chronic inflammation, and diabetic nephropathy amplify the risk of thrombosis, bleeding, infection, and right ventricular (RV) failure. For thromboembolism prevention, individualized warfarin management (international normalized ratio: 2.0-3.0) with intensified monitoring is essential, while aspirin omission in magnetically levitated devices (2 trials) reduces bleeding. Phosphodiesterase-5 inhibitors show promise for thrombosis reduction, but require bleeding risk assessment. Glycemic control necessitates the proactive de-escalation of insulin/sulfonylureas post-LVAD owing to improved insulin sensitivity and hypoglycemia risks, favoring SGLT-2 inhibitors/GLP-1 receptor agonists for cardiometabolic benefits. Driveline infection management requires renal-adjusted antimicrobial prophylaxis, culture-directed therapy, and novel approaches for drug-resistant cases. The prevention of RV failure depends on preoperative hemodynamic optimization and post-operative inotropic support. A multidisciplinary approach integrating anticoagulation precision, infection control, glycemic tailoring, and hemodynamic stabilization is critical to counter T2DM-pathophysiology interactions.

Key Words: Left ventricular assist devices; Type 2 diabetes mellitus; Heart failure; Pharmacological management; Bleeding

Core Tip: Type 2 diabetes mellitus exacerbates left ventricular assist device (LVAD)-related complications via endothelial dysfunction and inflammation. This review highlights tailored strategies, including precision warfarin dosing, aspirin omission from magnetically levitated LVADs, SGLT-2 inhibitors/GLP-1 agonists for glycemic control, and novel infection/right ventricular failure management to optimize outcomes.

INTRODUCTION

Left ventricular assist devices (LVADs) have transformed the therapeutic landscape for end-stage heart failure, serving as a critical bridge to transplantation or as a definitive destination therapy for patients ineligible for donor organ transplantation. Contemporary continuous-flow devices such as the HeartMate 3 (Abbott Laboratories) have achieved remarkable two-year survival rates exceeding 80% in clinical trials, underscoring their efficacy in sustaining life[1]. However, this therapeutic advancement is accompanied by a unique spectrum of complications including thrombosis, bleeding, driveline infections, and right ventricular (RV) dysfunction, necessitating sophisticated pharmacological management to optimize outcomes[2]. For patients with type 2 diabetes mellitus (T2DM), the risk is substantially amplified owing to underlying immune dysfunction and microvascular disease, which can impair host defenses and complicate treatment. Therefore, a pharmacologically centered approach for both prevention and treatment is imperative to mitigate the incidence and severity of these infections.

LVAD-related complications significantly increase in patients with T2DM, a comorbidity prevalent in up to 40% of LVAD recipients[3]. T2DM induces a pathophysiological cascade that exacerbates device-specific risks via multiple interconnected mechanisms. Chronic hyperglycemia promotes the formation of advanced glycation end products, which impair endothelial function and disrupt nitric oxide (NO)-mediated vasodilation, thereby creating a prothrombotic environment conducive to pump thrombosis[4]. Insulin resistance, a hallmark of T2DM, triggers chronic low-grade inflammation via elevated proinflammatory cytokines (TNF-α, IL-6), while simultaneously compromising neutrophil chemotaxis and phagocytic activity—factors that contribute to the 2-3 fold higher incidence of driveline infections observed in patients with diabetic LVAD[5]. Additionally, diabetic nephropathy, present in 30-50% of T2DM patients, complicates anticoagulation strategies by altering drug metabolism and increasing bleeding risks through uremic platelet dysfunction[6].

This metabolic milieu presents distinct therapeutic challenges that require tailored pharmacological approaches beyond the standard LVAD management protocols. Anticoagulation therapy, which prevents pump thrombosis, requires careful calibration in patients with T2DM owing to their dual vulnerability to thrombotic events and bleeding complications, which is exacerbated by potential drug-drug interactions between oral anticoagulants and common antidiabetic medications. Infection management in this population necessitates consideration of altered pharmacokinetics in renal impairment and increased antimicrobial resistance, while metabolic control itself becomes a therapeutic target, with emerging evidence supporting the cardiovascular benefits of newer glucose-lowering agents such as SGLT-2 inhibitors in LVAD-supported patients[7].

This review consolidates the current evidence from randomized trials, observational studies, and translational research to delineate pharmacotherapeutic strategies that specifically address the major complications of LVAD implantation in patients with T2DM. By focusing on the unique interplay between diabetes pathophysiology and device-related complications, this review aimed to provide a targeted framework for optimizing pharmacological interventions, including anticoagulation, infection control, metabolic regulation, and hemodynamic support, which account for the distinctive risks and treatment responses in this high-risk cohort. This, study aimed to bridge the gap between advancements in device technology and improved clinical outcomes in patients with T2DM receiving LVAD therapy.

PATHOGENIC SYNERGY: T2DM EXACERBATES LVAD THROMBOTIC RISK

LVAD implantation requires a critical balance between pump thrombosis prevention and the mitigation of bleeding risk. T2DM exacerbates this challenge via multiple mechanisms. Following LVAD implantation, balancing the prevention of pump thrombosis with the control of bleeding complications is a critical challenge. Recent research has revealed a close association between T2DM and vascular endothelial dysfunction, which is characterized by reduced NO production and availability. Insulin signaling, particularly via the PI3K/Akt pathway and subsequent NO activation, plays a vital role in maintaining endothelial function and inducing vasodilation[8]. In T2DM, this pathway may be compromised, leading to an imbalance between the vasodilatory and prothrombotic factors. This dysfunction, coupled with hyperglycemia, fosters an inflammatory state and elevates the production of adhesion molecules and reactive oxygen species, creating a prothrombotic milieu. This increased thrombotic propensity directly increases the risk of pump thrombosis and systemic thromboembolic events in patients with LVAD[9]. While continuous-flow LVAD, particularly fully magnetically levitated devices, have significantly enhanced long-term survival by reducing pump thrombosis and disabling strokes, addressing device-related blood compatibility issues remains crucial[10,11]. Careful management of antithrombotic regimens is essential to prevent device-related thromboembolic events, such as stroke, pump thrombosis, and peripheral embolism.

ANTICOAGULATION: PRECISION DOSING STRATEGIES

Warfarin

Vitamin K antagonists are established anticoagulant therapies post-LVAD implantation that mitigates pump thrombosis and thromboembolic events. The target international normalized ratio (INR) typically ranges between 2.0 and 3.0, with slight variations based on the specific LVAD device and institutional guidelines[12,13]. Although T2DM may not inherently increase thromboembolic risk, vascular dysfunction associated with T2DM increases the cardiovascular risk factors[14]. Henderson et al[15] demonstrated an independent association between T2DM and decreased time in therapeutic range (TTR), suggesting a potentially heightened baseline thrombotic and bleeding risk in patients with T2DM. Hence, meticulous INR monitoring and personalized warfarin dosing are imperative, considering factors such as dietary habits, concomitant medications, changes in diabetes management, and glycemic control[16]. Particularly for patients with T2DM with an elevated risk of reduced TTR, a judicious approach to vitamin K antagonist therapy is warranted. Direct oral anticoagulants (DOAC) such as rivaroxaban, apixaban (factor Xa inhibitors), and dabigatran (direct thrombin inhibitor) are emerging as alternatives to warfarin because of their predictable pharmacokinetics and pharmacodynamics, potentially simplifying management. However, their use in patients with LVAD is evolving, and the efficacy and safety of DOAC in patients with T2DM require further investigation[17]. It is necessary to consider the impact of renal and hepatic functions in patients with T2DM on the pharmacokinetics of DOAC when administering these novel anticoagulants. Given the substantial inter-individual variability and multifactorial considerations involved, this article refrains from delving into detailed strategies for utilizing warfarin or novel anticoagulants. Tailoring anticoagulant regimens for individual patients requires expertise from specialized medical teams in specific clinical contexts.

Aspirin

Aspirin is commonly used in conjunction with warfarin to mitigate the risk of pump thrombosis and thromboembolic events in patients with LVAD[18]. In some cases, the addition of a second antiplatelet agent such as clopidogrel may be necessary, particularly for high-risk patients or those with specific device considerations. However, in individuals with T2DM who face an elevated bleeding risk, the optimal antiplatelet regimen and the necessity of such therapy must be carefully evaluated[19]. The ARIES-HM3 trial, conducted in 2023, offered novel insights into the role of aspirin in LVAD-supported patients[20]. This randomized, double-blind, placebo-controlled study explored the safety and efficacy of omitting aspirin while maintaining vitamin K antagonist therapy in patients with advanced heart failure implanted with a fully magnetically levitated LVAD. This study demonstrated that abstaining from aspirin was not inferior to an aspirin-containing regimen in preventing major blood-clotting adverse events such as stroke and pump thrombosis. Avoiding aspirin has been linked to a notable decrease in non-surgical bleeding events without an increased risk of thromboembolism. This discovery challenged the traditional belief that aspirin is indispensable for favorable outcomes in all patients with LVAD, particularly after the introduction of magnetically levitated devices with enhanced blood compatibility. For patients with T2DM, current evidence suggests that aspirin may not be obligatory in the antithrombotic treatment regimen for those utilizing fully magnetically levitated LVAD, potentially lowering the risk of bleeding. Crucially, the aspirin avoidance group experienced a statistically significant and clinically relevant reduction in non-surgical bleeding events (absolute risk reduction 5.6%). This is paramount for patients with T2DM, who are inherently at a higher bleeding risk owing to factors such as diabetic nephropathy and uremic platelet dysfunction. Device-specific advancements: This benefit is attributed to the advanced fully magnetically levitated design (HeartMate 3), which minimizes blood shear stress and stasis, thereby reducing the device's intrinsic thrombogenicity. Therefore, the need for aggressive antiplatelet therapy has diminished. Potential high-risk subgroups in which Dual Antiplatelet Therapy may remain justified include patients with a history of arterial thrombotic events, recurrent history of ischemic stroke, myocardial infarction, or symptomatic peripheral artery disease prior to LVAD implantation. Active or Recent Venous Thromboembolism: History of deep vein thrombosis or pulmonary embolism around the time of implantation. Known hypercoagulable disorders include conditions such as Factor V Leiden, antiphospholipid syndrome, or protein C/S deficiency. Other high-risk scenarios: This includes patients with persistent atrial fibrillation and low TTR for warfarin (a known issue in some patients with T2DM) or those with device-related concerns for flow stagnation. Nevertheless, the decision to adjust or discontinue aspirin should be carefully deliberated, balancing the reduction in bleeding risk against potential thrombotic tendency and always involving consultation with a specialized LVAD medical team, taking into account individual risk factors and overall clinical benefits. The fundamental principles of risk-benefit assessment remain paramount.

Phosphodiesterase type 5 inhibitors

Recent studies have explored the potential of phosphodiesterase type 5 inhibitors (PDE-5i) for mitigating thrombotic complications[21]. A comprehensive registry study revealed that post-LVAD implantation and the utilization of PDE-5i correlated with a decreased occurrence of thrombotic events (such as pump thrombosis and ischemic stroke) and enhanced survival rates among patients with continuous-flow LVAD patients. This advantage was consistent across different LVAD types (axial or centrifugal) and was not influenced by concurrent antiplatelet therapy. Nevertheless, the administration of PDE-5i increases the susceptibility to gastrointestinal bleeding, which is a prevalent issue in LVAD recipients. Particularly, for individuals with T2DM who face higher risks of both complications, a thorough evaluation of individual circumstances is imperative to determine the potential bleeding hazards associated with PDE-5 inhibitors. It is plausible that, in comparison with conventional antithrombotic medications, the judicious use of PDE-5i could ameliorate the well-being and prognosis of this cohort. However, the long-term effects of this strategy require further investigation (Table 1).

Table 1 Focus on thrombosis, hemorrhage, and impact of diabetes & pharmacological interventions.

Variable	Thrombosis	Hemorrhage	Participants (n)	Time (year)	Design	Ref.
Centrifugal-flow LVAD	0.010	0.430	515	5	Prospective and observational study	Mehra et al[10], 2022
Axial-flow LVAD	0.108	0.765	505	5
Diabetes	0.223	0.101	129 with T2DM	7	Retrospective cohort study	Vest et al[12], 2016
Non-diabetes	0.234	0.053	171	7
Diabetes			131 with T2DM	9	Retrospective cohort study	Asleh et al[16], 2017
HbA1c ≥ 7.0%	0.183		60 with T2DM	9
HbA1c < 7.0%	0.183		71 with T2DM	9
Non-diabetes	0.171		210	9
Only use warfarin	0	0.225	296	1	RCT	Mehra et al[20], 2023
Combination aspirin	0	0.282	293	1
Use PDE-5i1	0.358		4950	4	Prospective cohort study	Xanthopoulos et al[21], 2020
No PDE-5i	0.381		8822	4
Use SGLT-2 inhibitors	Total 0188		16 patients with T2DM	0.5	Retrospective cohort study	Chavali et al[26], 2023
No SGLT-2 inhibitors	Total 0267		15 patients with T2DM	0.5
Apixaban	0.034	0.042	119	1	RCT or observational study	Tripoli et al[47], 2025
Warfarin	0.111	0.186	90	1

¹Compared to not using phosphodiesterase type 5 inhibitors, the risk of gastrointestinal bleeding increases by 14% with the same rate of cerebral hemorrhage.

LVAD: Left ventricular assist device; HbA1c: Glycated hemoglobin; T2DM: Type 2 diabetes mellitus; RCT: Randomized controlled trial; PDE-5i: Phosphodiesterase type 5 inhibitors.

DIABETES MEDICATIONS: CONTROL BLOOD SUGAR CONCENTRATION

SGLT2 inhibitors and GLP-1 receptor agonists

Reducing the thrombus burden in patients with T2DM supported by LVAD necessitates pharmacological management of cardiovascular risk factors common in T2DM[22,23]. Strategies such as statins for dyslipidemia, antihypertensive agents for blood pressure control, and meticulous glycemic control are paramount. LVAD implantation has shown promise in enhancing glycemic control by lowering glycated hemoglobin (HbA1c) levels and reducing the need for hypoglycemic agents including insulin[24]. This improvement was attributed to increased cardiac output, optimized hemodynamics, potential mitigation of inflammatory markers, and insulin resistance with LVAD support[25]. However, sustaining optimal glycemic control in patients with T2DM is vital for ameliorating endothelial dysfunction and reducing the prothrombotic state. The role of pharmacological interventions such as metformin, SGLT2 inhibitors (known for cardiovascular benefits in patients with heart failure), and GLP-1 receptor agonists (beneficial in heart failure and diabetes management) are being explored in patients with T2DM and LVAD[26]. T2DM is the primary driver of chronic kidney disease (CKD), and LVAD implantation further elevates renal stress via hemodynamic fluctuations and contrast-induced injury. This dual burden increases the risk of acute kidney injury during driveline infection (DLI) treatment. The renal protective effects of SGLT2 inhibitors—including reduced intraglomerular pressure, preserved glomerular filtration rate, and mitigation of tubulointerstitial fibrosis, are directly relevant to DLI management in patients with T2DM and LVAD. Although initial studies have demonstrated safety and potential glycemic improvement, the long-term effects require further investigation. The selection of specific agents should be guided by a specialized LVAD medical team, considering individual patient characteristics, and consultation with an endocrinologist (Figure 1).

Figure 1 Anticoagulation and combination medication algorithm for patients with type 2 diabetes mellitus: A flowchart guide. INR: International normalized ratio; PDE-5i: Phosphodiesterase type 5 inhibitors; T2DM: Type 2 diabetes mellitus.

Insulin and sulfonylureas

In the management of T2DM in patients with LVADs, the use of insulin and sulfonylureas requires a nuanced and cautious approach owing to the significant physiological changes post-implantation. Restoration of cardiac output after LVAD placement markedly improves insulin sensitivity and glucose homeostasis, leading to a substantial decrease in the requirement of insulin and other antidiabetic medications[27,28]. Multiple studies have documented this phenomenon, with one meta-analysis of 13 studies showing a significant reduction in daily insulin needs of approximately 18.8 units, along with a 1.23% reduction in HbA1c levels[29]. This enhances glycemic control while being beneficial and significantly elevates the risk of hypoglycemia if the medication dosages are not meticulously down titrated[30]. This risk is compounded in patients with CKD, which is a common comorbidity causing decreased insulin clearance. Although sulfonylureas can also be utilized, their safety profile in this specific population is of growing concern. Research suggests an association between sulfonylurea use and a higher risk of ventricular arrhythmias (VA) and sudden cardiac death than metformin use[31,32]. Therefore, LVAD therapy positively affects glycemic control; vigilant and proactive management of insulin and sulfonylurea therapy is necessary to mitigate the pronounced risks of hypoglycemia and potential adverse cardiovascular events. This study recommends reducing pre-operative insulin doses by 30%-50% on day 1. Sulfonylureas are better avoided. Acute phase: Use frequent point-of-care glucose checks or continuous glucose monitoring (CGM) to make further safety adjustments. Long-term: Use HbA1c and CGM-derived data (time-in-range, hypoglycemia events) to fine-tune therapy, often favoring agents with cardioprotective benefits and low hypoglycemia risk (e.g., SGLT2 inhibitors, GLP-1 receptor agonists, and metformin).

PHARMACOLOGICAL MANAGEMENT OF DLI

Perioperative antibiotic prophylaxis (renal-adjusted dosing)

DLI is a predominant and severe complication of LVAD implantation that contributes significantly to morbidity and mortality[33]. Because renal insufficiency is an independent predictor of LVAD infection, meticulous management of renal function, including dose adjustments of nephrotoxic agents and medications to preserve kidney health, is crucial[34]. Moreover, standard antibiotic prophylaxis during the perioperative phase typically involves drugs, such as cefamandole or piperacillin-tazobactam, necessitating vigilant monitoring of renal function during their administration.

Novel therapeutic modalities for resistant infections

Upon infection onset, prompt and appropriate broad-spectrum antibiotic therapy guided by culture and sensitivity test results is essential. Therefore, prolonged or recurrent antibiotic administration is necessary[35]. Localized antibacterial agents are used in cases of power transmission system infections, whereas systemic antibiotics are reserved for more extensive infections involving pumps or other components. Phage therapy has emerged as a viable option for treating severe antibiotic-resistant infections. Rojas et al[36] highlighted its successful application in the management of device-related infections in a study targeting specific bacterial strains. The use of viscous galenic formulations may enhance phage retention at wound site, thereby improving its efficacy. Negative pressure wound therapy combined with antiseptic irrigation shows promise for complex wound management and the promotion of healing in infected areas. Innovative technologies, such as the new wave membrane LVAD, reduce blood flow shear stress and decrease vascular damage and the risk of infection. Cold atmospheric argon plasma demonstrates cost-effectiveness and antibacterial properties in the treatment of superficial infections. Given the increased susceptibility of patients with diabetes to wound infections and delayed healing, these novel anti-infective modalities have potential benefits in individuals with T2DM supported by LVAD.

PHARMACOLOGICAL MANAGEMENT OF RV FAILURE

RV failure (RVF) is a frequent and devastating complication of LVAD implantation, with some reports indicating an incidence of approximately 20%. The development of RVF is associated with significantly worse outcomes, including prolonged intensive care unit and hospital stay, and reduced long-term survival rates[37,38]. The pathophysiology is complex and driven by an acute increase in RV preload from LVAD-mediated systemic blood flow, a leftward septal shift that distorts RV geometry and function, and a delayed reduction in RV afterload because the pulmonary artery pressure may not decrease for weeks[39]. In patients with T2DM, this risk is often magnified. Preexisting diabetic cardiomyopathy can compromise myocardial structure and function, rendering the right ventricle more susceptible to failure when faced with abrupt hemodynamic shifts imposed by the LVAD.

Pre-implantation pharmacological optimization

Prevention of post-operative RVF begins with meticulous preoperative pharmacological optimization, especially in patients with borderline RV function. The goal was to improve hemodynamics before the surgical stress of implantation.

Patients with borderline RV function may benefit from interventions such as diuretics, inotropic agents, and temporary mechanical support, such as an intra-aortic balloon pump to enhance hemodynamics before implantation. Vasodilators, including milrinone, hydralazine, and sodium nitroprusside, were used to decrease RV afterload. The vasodilator challenge test during right heart catheterization is valuable for assessing RV functional reserve and identifying candidates who could benefit from improved RV hemodynamics after left LVAD implantation. The pulmonary artery pulsatility index measured during this test is a promising predictor of RVF and can augment risk stratification models such as the EUROMACS-RHF score. In cases of elevated pulmonary vascular resistance, inhaled NO and PDE-5i can help manage pulmonary hypertension and reduce the RV afterload. Diuretics play a role in reducing the RV load, particularly in achieving a negative fluid balance post-operatively or when signs of right heart failure manifest. Continuous furosemide infusion is preferred over a bolus injection, whereas torsemide is advantageous in patients with renal insufficiency. In patients with T2DM, careful consideration of diuretic dosing is necessary because of its potential impact on electrolyte balance and blood glucose control[40]. Furthermore, when using medications to optimize hemodynamics, adjustments in LVAD speed and ventilation parameters should be considered to determine their effects on hemodynamics[41].

Post-implantation pharmacological support

Inotropic drug support is typically required during the early post-operative period to treat right-sided heart failure. This approach involves three key steps aligned with the underlying pathological mechanisms: Identifying appropriate candidates for inotropic therapy, selecting suitable medications, and adhering to the usage precautions. Dobutamine, a conventional inotropic agent, is effective in rapidly increasing blood pressure in patients with cardiogenic shock. The 2018 AHA Scientific Statement recommends milrinone for managing RHF because of its ability to reduce end-diastolic ventricular pressure and induce vasodilation in both systemic and pulmonary circulation, with a low risk of tachycardia[42]. Levosimendan, a calcium sensitizer and a KATP channel opener, has demonstrated favorable hepatic and renal safety profiles. It enhances right heart function parameters in patients with acute decompensated heart failure and benefits those with severe pulmonary hypertension complicated by right heart failure[43]. Novel agents, such as myosin activators, which do not increase calcium transients and lower arrhythmia risk, hold promise for future therapeutic interventions. Nonetheless, caution is warranted regarding prolonged or excessive inotropic drug use, as it may negatively impact myocardial energy metabolism, necessitating prudence in supporting RV function with these medications[44]. Recent research has indicated that enhancing cardiac output and hemodynamic parameters after LVAD implantation may lead to secondary enhancement of the RV function, thereby potentially decreasing the requirement for intensive pharmacological intervention[45].

PHARMACOLOGICAL MANAGEMENT OF ARRHYTHMIAS

While LVAD implantation can improve hemodynamics and consequently resolve some preexisting arrhythmias, it can also paradoxically trigger new-onset or persistent VA, most notably ventricular tachycardia (VT). The arrhythmogenic substrate can be complex, stemming from the interaction between the inflow cannula of the device and the myocardium, preexisting myocardial scarring, or underlying cardiac pathologies[46]. For patients with T2DM, this risk is inherently heightened. Diabetic cardiomyopathy, which is characterized by myocardial fibrosis and diabetes-related autonomic neuropathy, can create a more vulnerable substrate for arrhythmias, making aggressive pharmacological management a critical component of post-LVAD care (Figure 2).

Figure 2 Complications and management strategies for type 2 diabetes mellitus patients after left ventricular assist device implantation. RVF: Right ventricular failure; DLI: Driveline infection; T2DM: Type 2 diabetes mellitus; LVAD: Left ventricular assist device.

The primary goal of pharmacological intervention is to suppress VA to prevent hemodynamic instability and reduce the frequency of implantable cardioverter-defibrillator shocks. Key pharmacological strategies include beta-blockers as a cornerstone of guideline-directed medical therapy for heart failure and as foundational antiarrhythmic therapies. They are essential for neurohormonal blockade and play a crucial role in the management and prevention of VA in patients with LVAD. When beta-blockers are insufficient, specific antiarrhythmic drugs (AADs) are administered. Amiodarone (Class III) is the most commonly used AAD for treating VT in patients with LVAD owing to its efficacy and is often the first-line treatment for patients with recurrent or sustained VA. Procainamide (Class I) may also be used to manage VT/ventricular fibrillation, particularly in acute settings.

CONCLUSION

The management of complications after LVAD implantation in patients with T2DM requires a nuanced multidisciplinary approach that addresses the unique pathophysiological interplay between diabetic metabolic derangements and device-specific risks. T2DM exacerbates LVAD-related complications through mechanisms such as endothelial dysfunction driven by advanced glycation end products, chronic inflammation, insulin resistance, and comorbid renal impairment, which collectively increase the risk of thrombosis, bleeding, infection, and hemodynamic instability. Pharmacological strategies must be tailored to mitigate these risks, and anticoagulation regimens require the precise calibration of warfarin dosing with vigilant INR monitoring. Emerging data support the potential of PDE-5i in reducing thrombotic events, although their use necessitates careful balancing against increased gastrointestinal bleeding risks, particularly in patients with T2DM. Glycemic control remains paramount, with LVAD-induced improvements in insulin sensitivity mandating cautious adjustment of insulin and sulfonylureas to prevent hypoglycemia. SGLT2 inhibitors and GLP-1 receptor agonists show promise for cardiovascular and metabolic benefits, albeit with a need for long-term safety data. Additionally, targeted management of driveline infections through antibiotic stewardship, novel modalities, such as phage therapy, and proactive renal function preservation, along with the strategic use of vasodilators, inotropes, and diuretics can further optimize the prevention and treatment of RVF.