In a landmark study published in Nature Communications in 2025, researchers Guo, Wei, Lin, and colleagues have delivered compelling evidence on the cardiovascular benefits of two prominent antiviral therapies, nirmatrelvir/ritonavir and molnupiravir, in the context of COVID-19. Their investigation, employing a sophisticated target trial emulation design, reveals not only the immediate protective effects against severe COVID-19 outcomes but also highlights a substantial reduction in both short-term and long-term cardiovascular complications associated with the virus. This breakthrough comes at a crucial juncture where the global scientific community continues to grapple with the lingering, multifaceted consequences of the COVID-19 pandemic.
The cardiovascular system has emerged as a critical battlefield during and after COVID-19 infection, with patients frequently exhibiting a wide spectrum of complications, ranging from myocardial injury and arrhythmias to thromboembolic events. While the respiratory manifestations of SARS-CoV-2 infection were initially the primary focus, increasing clinical evidence has underscored the significant burden that COVID-19 imposes on the heart and vasculature. This interplay between viral pathology and cardiovascular sequelae has prompted urgent inquiries into strategies that might mitigate these risks, beyond the scope of antiviral efficacy alone.
Nirmatrelvir/ritonavir, a protease inhibitor combination, and molnupiravir, a ribonucleoside analog, have both garnered emergency use authorizations for COVID-19 treatment due to their antiviral capabilities. However, this study extends their utility into cardiovascular risk reduction. Utilizing a methodologically rigorous target trial emulation approach—a study design aimed to replicate the conditions of a randomized controlled trial using observational data—the team dissected large, real-world datasets to simulate and analyze outcomes in diverse patient populations receiving these agents.
The researchers meticulously adjusted for confounding variables such as age, comorbidities, and baseline cardiovascular risk, ensuring that the observed outcomes could be confidently attributed to the antiviral treatments themselves. This application of causal inference techniques to observational data fortifies the findings’ reliability and relevance, particularly in real-world clinical settings where randomized controlled trials may not be feasible for long-term outcomes.
Key findings demonstrate that both nirmatrelvir/ritonavir and molnupiravir significantly reduce the incidence of major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and heart failure exacerbations, within the first 30 days of treatment. More strikingly, these benefits were sustained over extended follow-up periods, suggesting protective mechanisms that transcend mere viral suppression and hint at modulation of inflammatory and thrombotic pathways triggered by SARS-CoV-2.
Mechanistically, the cardiovascular protection observed may derive from the antiviral regimens’ capacity to curtail viral replication early in infection, thus dampening the cytokine storm and systemic inflammation known to drive endothelial dysfunction and coagulopathy. Moreover, ritonavir’s known pharmacokinetic boosting properties may enhance nirmatrelvir’s bioavailability, optimizing viral clearance and attenuating cardiovascular insult. Molnupiravir’s incorporation of erroneous nucleotides during viral RNA synthesis may similarly interrupt the establishment of viral reservoirs that perpetuate inflammatory states.
These insights pave the way for reconsidering antiviral therapy not only as an acute intervention but also as a strategic component in the prevention of chronic cardiovascular morbidity linked to COVID-19. The study’s implications advocate for early antiviral administration in eligible patients, especially those with pre-existing cardiovascular risk factors, to preempt long-term heart disease post-COVID-19.
The authors also emphasize the importance of integrating such therapeutic strategies into broader COVID-19 management protocols, which currently prioritize vaccination and symptomatic treatment. The intersection of antiviral therapies with cardioprotective effects offers a promising avenue to mitigate the pandemic’s enduring legacy on global cardiovascular health.
While the study delivers robust evidence, the researchers acknowledge limitations inherent in the observational data sources, including potential residual confounding and variation in healthcare access across populations. They call for prospective randomized trials to further elucidate and validate these findings. Nonetheless, the target trial emulation framework provides a powerful tool to derive causal inferences rapidly, crucial during an evolving public health crisis.
Importantly, the study advances understanding of post-acute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as “long COVID,” which often encompasses persistent cardiovascular symptoms. These results suggest antiviral therapy might mitigate the development or severity of such symptoms by restraining early pathogenic pathways, thus improving patient quality of life and reducing healthcare burdens.
The comprehensive data analysis incorporated detailed patient demographics, viral variant considerations, and stratification by timing of antiviral initiation, all contributing to the nuanced appreciation of these drugs’ impact. Such granularity informs clinical decision-making, underscoring the need for prompt diagnosis and tailored treatment approaches.
Furthermore, the research indicates that the cardiovascular benefits of these antivirals extend beyond hospitalized patients, encompassing outpatient settings where early intervention may substantially alter disease trajectories. This broadened scope aligns with public health goals to reduce hospital admissions and long-term disability.
Of particular interest is the study’s suggestion that the antiviral regimens may interrupt the feedback loops between viral persistence, immune dysregulation, and endothelial injury. This hypothesis, if confirmed, positions these drugs as potentially transformative agents in managing not only infection but also its chronic inflammatory sequelae.
In sum, Guo and colleagues’ investigation enriches the therapeutic arsenal against COVID-19 by highlighting the dual antiviral and cardioprotective roles of nirmatrelvir/ritonavir and molnupiravir. Their findings bolster the rationale for widespread, equitable access to these medications and encourage further research into their multifaceted mechanisms.
As the world continues to adapt to the challenges posed by COVID-19 and its aftermath, this study exemplifies the power of innovative epidemiological methodologies combined with clinical insight. The nuanced understanding of viral and host interactions gleaned here not only informs immediate clinical practice but also charts a promising path towards mitigating one of the pandemic’s most pernicious complications: cardiovascular disease.
Subject of Research: Effectiveness of nirmatrelvir/ritonavir and molnupiravir in reducing short-term and long-term cardiovascular complications associated with COVID-19.
Article Title: Effectiveness of nirmatrelvir/ritonavir and molnupiravir in reducing the risk of short-term and long-term cardiovascular complications of COVID-19: a target trial emulation study.
Article References:
Guo, Z., Wei, Y., Lin, G. et al. Effectiveness of nirmatrelvir/ritonavir and molnupiravir in reducing the risk of short-term and long-term cardiovascular complications of COVID-19: a target trial emulation study. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67776-4
Image Credits: AI Generated
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