Background: Quadruple guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF)—composed of an angiotensin receptor-neprilysin inhibitor (ARNI) or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB), an evidence-based beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a sodium-glucose cotransporter 2 inhibitor (SGLT2i)—produces complementary reductions in cardiovascular mortality and rehospitalization. Yet implementation across Asian health systems remains highly inconsistent. Aim: To synthesize contemporary implementation data from East and Southeast Asia, identify phenotype-specific and health-system barriers, and propose a testable nurse- or pharmacist-led (NPL) implementation model adapted to HFrEF populations in this subregion. Methods: This article integrated published HFrEF registry, health-economic, and implementation-science literature primarily from Taiwan, Singapore, the Philippines, Vietnam, China, and Japan. The synthesis was narrative and hypothesis-generating; therefore, all projected trial tables are explicitly labeled as simulated planning projections for a proposed cluster-randomized trial. Results: HFrEF care in East and Southeast Asia is constrained by three interacting barriers: (i) out-of-pocket medication costs and reimbursement gaps; (ii) lower body size, lower baseline systolic blood pressure, frailty, and renal-electrolyte vulnerability; and (iii) overextended outpatient infrastructure. We proposed a 3-step predischarge-to-primary-care NPL co-management protocol that starts low-dose foundational therapy before discharge, provides algorithm-driven titration at weeks 2 and 4, and hands over stable patients to primary care by week 6. Conclusion: The HFrEF translational gap in East and Southeast Asia is fundamentally an implementation gap. A phenotype-adapted, protocolized NPL titration pathway deserves prospective testing as a scalable model for improving GDMT optimization across diverse health systems in the subregion. Relevance for patients: Safer and faster optimization of proven heart failure therapies may reduce avoidable rehospitalizations and premature mortality in vulnerable Asian HFrEF populations.