Highlights
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SSO₂ therapy reduced infarct size and microvascular obstruction after PCI.
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No significant difference in follow-up MACE, mortality, or reinfarction was observed.
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Early SSO₂ use (≤6h) in anterior STEMI showed a trend toward fewer repeat revascularizations.
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Supports SSO₂ as an adjunct to enhance myocardial salvage after STEMI.
ABSTRACT
Background
Supersaturated oxygen (SSO₂) therapy is an emerging intervention to minimize myocardial damage and improve outcomes in patients with ST-segment elevation myocardial infarction (STEMI). This meta-analysis evaluated the efficacy of SSO₂ therapy to reduce infarct size and microvascular obstruction (MVO).
Methods
PubMed, Embase, and Cochrane databases were systematically searched for studies comparing percutaneous coronary intervention (PCI) plus SSO 2 to PCI alone for STEMI. Outcomes of interest included infarct size, MVO, and subsequent major adverse cardiovascular events (MACE), all-cause mortality, re-infarction, and target vessel revascularization (TVR). Mean differences (MD) with 95% confidence intervals (CIs) were calculated using random-effects models.
Results
Six studies ( n = 1660) were included with 548 patients (33%) receiving SSO₂ therapy. Pooled analysis showed that PCI plus SSO₂ significantly reduced infarct size (MD −4.31; 95% CI −6.70 to −1.92; P <.01) and MVO (SMD −0.72; 95% CI −1.11 to −0.34; P <.01) compared with PCI alone. MACE, all-cause mortality, re-infarction, and TVR were comparable between the groups.
Conclusion
SSO₂ therapy significantly reduced infarct size and MVO in patients undergoing PCI for STEMI.
Background
ST-segment elevation myocardial infarction (STEMI) is a critical condition that requires prompt intervention to restore myocardial perfusion and minimize infarct size Primary percutaneous coronary intervention (PCI) is the standard of care for emergent revascularization in STEMI Despite mean door-to-balloon times consistently under 90 minutes and widespread use of guideline-directed medical therapies, the 30-day mortality rate for patients aged 65 and older with STEMI in the United States remains approximately 12%. Additionally, between 20% and 30% of patients with STEMI develop heart failure (HF) within 1 year. ,,
Despite successful PCI, myocardial salvage can be suboptimal due to microvascular obstruction (MVO), leading to significant infarct size, both of which are associated with adverse clinical outcomes. , A study by Stone et al. showed that a 5% increase in infarct size was associated with a 20% increase in the hazard of death or HF hospitalization, independent of other clinical factors. As larger infarcts are associated with worse long-term outcomes, including higher rates of HF and mortality, there is a strong clinical imperative to reduce infarct size.
Supersaturated oxygen (SSO₂) therapy has emerged as a novel adjunctive treatment aimed at reducing infarct size and MVO following PCI. Administered immediately following PCI, SSO₂ therapy enhances myocardial oxygenation and promotes tissue salvage This systematic review and meta-analysis comprehensively evaluated the effects of SSO₂ therapy on infarct size, MVO, and subsequent cardiovascular events in patients with STEMI undergoing primary PCI.
Methods
This systematic review and meta-analysis were conducted according to the recommendations of the Cochrane Collaboration Handbook and reported according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines (Supplementary Methods S1 and S2) The protocol for this study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; ID CRD420251039966).
Eligibility criteria
Studies were eligible for inclusion if they (1) were randomized controlled trials (RCTs), cohort studies, or case-control studies; (2) presented data on outcomes following PCI plus SSO₂ in patients with ACS; and (3) presented data on outcomes of interest such as infarct size and MVO.
Exclusion criteria were as follows: (1) nonoriginal studies (reviews, letters to the editor, and commentaries); (2) studies outside the population of interest; (3) case reports, case series, and animal studies; and (4) studies not reporting data on outcomes of interest.
Study selection and data extraction
PubMed/Medline, Embase, and the Cochrane Library were searched systematically from inception through March 2025. The search strategy included keywords of “supersaturated oxygen” OR “SSO2 therapy” OR “hyperoxemic therapy” AND “myocardial infarction.” After removing duplicates, 2 authors independently screened the abstracts based on the inclusion criteria. Potentially eligible studies underwent full text screening by the same 2 authors for inclusion in the meta-analysis. Conflicts were resolved in consultation with the senior author. Data were extracted from each study into prespecified data collection table including baseline characteristics and outcomes such as infarct size, MVO, and subsequent cardiovascular events. Details of the search strategy are reported in Supplementary Methods S3 .
Outcomes
Efficacy outcomes included infarct size, measured using cardiac magnetic resonance imaging (CMR) or technetium-99m sestamibi single-photon emission computed tomography (SPECT), and MVO, defined as a lack of gadolinium enhancement within the hyper enhancing infarct zone on CMR.
Safety outcomes included subsequent major adverse cardiovascular events (MACE; composite of death, reinfarction, and target vessel revascularization) and its individual components including all-cause mortality, reinfarction (defined per the Academic Research Consortium criteria), and target vessel revascularization (any repeat revascularization procedure of the target vessel). Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of this research.
Quality assessment
The methodological quality of the included studies was evaluated using risk of bias assessment tools. For RCTs, the Cochrane Risk of Bias 2.0 (RoB 2) tool was applied to assess each study across 5 domains to categorize studies as having a low, moderate, or high risk of bias nonrandomized studies were assessed using the ROBINS-I tool; each study was evaluated in 7 domains and categorized as having low, moderate, serious, or critical risk of bias Publication bias was assessed by funnel-plot analysis of point estimates according to study weights.
Sensitivity analyses
Two prespecified sensitivity analyses were performed: (1) subgrouping according to the timing of reperfusion from symptom onset (≤6 hours, <24 hours, and >12 hours) and the presence of anterior STEMI (Supplementary Figure 5) , and (2) leave-one-out sensitivity analysis. We assessed between-study heterogeneity using the R² statistic, considering a 2-tailed P value <.05 as the threshold for statistical significance.
Statistical analysis
All statistical analyses were conducted using R version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) The packages used were “meta” and “dmetar.” Continuous outcomes data were pooled using Mantel-Haenszel random-effects models to obtain mean differences (MDs), standard mean differences (SMDs), and 95% confidence intervals (CIs). Binary outcomes were aggregated using Mantel-Haenszel random-effects models to generate risk ratios (RRs) and 95% CIs. The DerSimonian and Laird method was used to calculate the heterogeneity variance tau² Heterogeneity was assessed using Cochrane’s Jackson method I² statistics The heterogeneity of the studies was described based on I² values of 0%, ≤25%, ≤50%, and >50%, corresponding to no observed, low, moderate, and substantial heterogeneity, respectively. Statistical significance was set at P <.05. A leave-one-out sensitivity analysis was performed to assess the influence of individual studies on the overall effect estimates and to identify potential sources of heterogeneity.
Results
The initial literature search yielded 244 articles ( Figure 1 ). After removing duplicates and screening titles and abstracts, 165 articles were retrieved, and full texts were reviewed for possible inclusion. Finally, 6 studies ,,,,, (2 RCTs and 4 observational studies) with a pooled population of 1,660 patients with STEMI were included in the analysis, with 548 patients (33%) receiving SSO₂ therapy following PCI. The mean age of the population was 59.2 years, and 78.9% of the patients were male. The baseline characteristics of the included studies are presented in Table I .
PRISMA flow diagram of study screening and selection.
Table I
Baseline and summary characteristics of included studies
| Study | Year | Study design | Sample size (PCI + SSO₂/PCI Alone) | Mean age (years) | Male, % | Time to reperfusion, hours | Primary PCI | SSO₂ duration, min | Infarct Size measurement | Outcome assessed |
|---|---|---|---|---|---|---|---|---|---|---|
| A. Schaefer et al. | 2024 | Observational | 22/22 | 57±12/58±11 | 95%/80% | ≤6 h | Yes | 60 min | CMR (4 ± 2 days post-PCI) | Infarct size and MVO |
| AMIHOT I | 2007 | RCT | 134/135 | 60 ± 13/60 ± 12 | 73.1%/73.3% | ≤24 h | Yes | >60 min | Tc-99m SPECT (14 days) | Infarct size and MACE |
| AMIHOT II | 2009 | RCT | 222/79 | 61±12/59±11 | 77%/87.3% | ≤6 h | Yes | 90 min | Tc-99m SPECT (14 days) | Infarct size and MACE |
| Falah et al. | 2024 | Observational | 90/784 | 58±11/58.5 ± 12 | 84.4%/80.5% | ≤6 h | Yes | 60 min | CMR (2-7 days post-PCI) | Infarct size and MVO |
| IC HOT | 2020 | Observational | 83/83 | 60 ± 10/60 ± 13 | 80.7%/81.9% | ≤6 h | Yes | 60 min | NA | MACE |
| Carlson et al. | 2025 | Observational | 19/31 | 59 ± 10/62 ± 21 | 63%/61% | >12 h | Yes | 60 min | CMR (2-4 days post-PCI) | Infarct size, MVO and MACE |
SSO₂: Supersaturated oxygen therapy; PCI: Percutaneous coronary intervention; CMR: Cardiac magnetic resonance imaging; MVO: Microvascular obstruction; SPECT: Single-photon emission computed tomography; Tc-99m: Technetium-99m; MACE: Major adverse cardiovascular events.
Efficacy outcomes
SSO₂ therapy following PCI for STEMI significantly reduced infarct size compared with PCI alone (MD −4.31%; 95% CI −6.70 to −1.92; P <.01; I² = 19%) ( Figure 2 A). Additionally, SSO2 therapy was associated with a significant reduction in MVO (SMD −0.72, 95% CI −1.11 to −0.34; P <.01; I² = 53%) ( Figure 2 B).
Forest plots showing A, the effect of supersaturated oxygen (SSO₂) therapy on infarct size (% of left ventricular mass) and B, standardized mean differences in microvascular obstruction (MVO) following SSO 2 + PCI compared with PCI alone. CI, confidence interval; IV, inverse variance; MD, mean difference; SD, standard deviation.
Safety outcomes
The pooled risk of subsequent MACE was comparable between the cohorts receiving PCI plus SSO₂ and PCI alone ( Figure 3 A). Similarly, the overall risks of all-cause mortality ( Figure 3 B), reinfarction ( Figure 3 C), and TVR ( Figure 3 D) were comparable.
