Aetna considers intra-coronary hyperoxemic therapy (also known as aqueous oxygen therapy, hyperoxemic reperfusion therapy, super-oxygenation therapy, and super-saturated oxygen infusion therapy) experimental and investigational for the treatment of the following indications (not an all-inclusive list) because of insufficient evidence of its effectiveness.
Coronary heart disease is the leading cause of death worldwide, with over 7 million deaths annually. Following an acute myocardial infarction (AMI), early restoration of blood flow through the the occluded coronary artery with the use of thrombolytic therapy or primary percutaneous coronary intervention (PCI) is the most effective approach to reduce the size of a myocardial infarct (MI) and improve clinical outcomes. However, reperfusion alone is insufficient to save endangered myocardium because complications resulting from loss of viable cardiac myocytes are still common following AMI even after myocardial blood flow has been restored. Furthermore, it has been reported that reperfusion following ischemia causes additional cell dealth and increases infarct size. This phenomenon is known as myocardial reperfusion injury or lethal reperfusion injury, which culminates in the death of cardiac myocytes that were viable immediately before myocardial reperfusion. This form of myocardial injury may partly explain why, despite optimal myocardial reperfusion, the mortality following an AMI approaches 10%, and the incidence of cardiac failure after an AMI is almost 25% (Yellon and Hausenloy, 2007).
Many cardiac interventional procedures have been employed to reduce myocardial reperfusion injury. One of the interventions is intracoronary hyperoxemic therapy, also known as aqueous oxygen (AO) therapy, hyperoxemic reperfusion therapy, super-oxygenation therapy, and super-saturated oxygen infusion therapy. Bartoli (2003) stated that experimental data support the hypothesis that reperfusion microvascular ischemia contributes to myocardial tissue injury over a prolonged time period, and hyperbaric oxygen attenuates microvascular dysfunction and reperfusion microvascular ischemia. However, treating patients with AMI in a hyperbaric oxygen (O2) chamber or with a conventional oxygenator is problematic. Aqueous oxygen is a crystalloid solution containing extremely high concentrations of O2 (1 to 3 ml O2/ml saline). The AO system mixes AO solution with a patient's blood from an arterial puncture and delivers the hyperoxemic blood to targeted ischemic myocardium via an infusion catheter for regional correction of hypoxemia and production of hyperoxemia. The system precisely controls the partial pressure of oxygen (pO2) without clinically significant microbubble formation (Creech et al, 2002). Hyperoxemic coronary infusion of AO in experimental models of AMI improved left ventricular (LV) function and reduced infarct size compared with normoxemic controls, very likely as a result of microvascular blood flow improvement. The first clinical experiences with intra-coronary infusion of AO solution demonstrated the therapy to be a safe and well-tolerated in the setting of AMI following successful primary percutaneous transluminal coronary angioplasty (PTCA). Its use was associated with significant progressive improvement in LV function as measured by ejection fraction (EF) and wall motion score index.
In a multi-center study, Dixon et al (2002) evaluated the feasibility and safety of intra-coronary hyperoxemic reperfusion after primary PTCA for AMI. Hyperoxemic blood (pO2: 600 to 800 mm Hg) was infused into the infarct-related artery for 60 to 90 mins after intervention. The primary end points were clinical, electrical and hemodynamic stability during hyperoxemic reperfusion and in-hospital major adverse cardiac events. Global and regional LV function was evaluated by serial echocardiography after PTCA, after AO infusion, at 24 hrs and at 1 and 3 months. A total of 29 patients were enrolled (mean age of 58.9 +/- 12.6 years). Hyperoxemic reperfusion was carried out successfully in all cases (mean infusion time of 80.8 +/- 18.2 mins; mean coronary perfusate pO2 of 631 +/- 235 mm Hg). There were no adverse events during hyperoxemic reperfusion or the in-hospital period. Compared with baseline, a significant improvement in global wall motion score index was observed at 24 hrs (1.68 +/- 0.24 versus 1.48 +/- 0.24, p < 0.001) with a trend toward an increase in EF (48.6 +/- 7.3 % versus 51.8 +/- 6.8 %, p = 0.08). Progressive improvement in LV function was observed at 1 and 3 months, primarily due to recovery of infarct zone function. The authors concluded that intra-coronary hyperoxemic reperfusion is safe and well-tolerated after primary PTCA. The authors said that these preliminary findings support the need for a randomized controlled trial to determine if hyperoxemic reperfusion enhances myocardial salvage or improves long-term outcomes.
Glazier (2005) stated that an increasing body of experimental and clinical data suggested a valuable role for high concentrations of O2, delivered directly to the coronary artery, in reducing microvascular injury. The author said that, recently, a catheter-based method has been developed for infusion of highly concentrated AO into blood without bubble formation to provide hyperoxemic treatment of tissue ischemia. In experimental studies, AO hyperoxemia has been found to improve LV function and electrocardiographic evidence of ischemia. This is thought to be the result of augmentation of O2 delivery in plasma. Marked improvement in myocardial flow has been consistently found. These observations may explain the improvement of LV function after AO treatment noted in these studies.
Trabattoni et al (2006) evaluated LV function recovery, ST-segment changes, and enzyme kinetic in ST-elevation AMI patients treated with intra-coronary hyperoxemic perfusion (IHP) after primary PCI and compared them with the results obtained in control patients. A total of 27 anterior ST-elevation AMI patients treated less than or equal to 12 hrs after symptom onset by primary PCI were subjected to selective IHP into the left anterior descending coronary artery for 90 mins. They were compared with 24 anterior ST-elevation AMI control patients matched in clinical and angiographic characteristics and treated with conventional primary PCI. Left ventricular function recovery was evaluated by serial 2-D contrast echocardiography. Left anterior descending coronary artery recanalization was successful in all patients. After IHP (100 % successful, duration 90 +/- 5.4 mins), patients showed a 4.8 +/- 2.2 hrs shorter time-to-peak creatine kinase release (p = 0.001), a shorter creatine kinase half-life period (23.4 +/- 8.9 hrs versus 30.5 +/- 5.8 hrs, p = 0.006), and a higher rate of complete ST-segment resolution (78 % versus 42 %, p = 0.01). A significant improvement of mean LVEF (from 44 +/- 9 % to 55 +/- 11 %, p < 0.001) and wall motion score index (from 1.77 +/- 0.2 to 1.39 +/- 0.4, p < 0.001) was observed at 3 months in IHP patients only. The authors concluded that after successful primary PCI, IHP is associated with significant LV function recovery when compared to conventional treatment. The authors said that enzyme kinetic and ST-segment changes suggest faster and more complete microvascular reperfusion and may explain the benefits of this new therapy on LV function.
In a prospective, randomized trial, O'Neil and associates (2007) determined if hyperoxemic reperfusion with AO improves recovery of ventricular function after PCI for AMI. A total of 269 patients with acute anterior or large inferior AMI undergoing primary or rescue PCI (less than 24 hrs from symptom onset) were randomly assigned after successful PCI to receive hyperoxemic reperfusion (treatment group) or normoxemic blood auto-reperfusion (control group). Hyperoxemic reperfusion was performed for 90 mins using intra-coronary AO. The primary end points were final infarct size at 14 days, ST-segment resolution, and delta regional wall motion score index of the infarct zone at 3 months. At 30 days, the incidence of major adverse cardiac events was similar between the control and AO groups (5.2 % versus 6.7 %, p = 0.62). There was no significant difference in the incidence of the primary end points between the study groups. In post-hoc analysis, anterior AMI patients reperfused less than 6 hrs who were treated with AO had a greater improvement in regional wall motion (delta wall motion score index = 0.54 in control group versus 0.75 in AO group, p = 0.03), smaller infarct size (23 % of left ventricle in control group versus 9 % of left ventricle in AO group, p = 0.04), and improved ST-segment resolution compared with normoxemic controls. The authors concluded that intra-coronary hyperoxemic reperfusion was safe and well-tolerated after PCI for AMI, but did not improve regional wall motion, ST-segment resolution, or final infarct size. A possible treatment effect was observed in anterior AMI patients reperfused less than 6 hrs of symptom onset.
In a prospective, multi-center trial (AMIHOT-II), Stone et al (2009) examined the effect of super-saturated oxygen (SSO2) delivery on infarct size after PCI in AMI. A total of 301 patients with anterior ST-segment elevation MI undergoing PCI within 6 hrs of symptom onset were randomized to a 90-min intra-coronary SSO2 infusion in the left anterior descending artery infarct territory (n = 222) or control (n = 79). The primary efficacy measure was infarct size in the intention-to-treat population (powered for superiority), and the primary safety measure was composite major adverse cardiovascular events at 30 days in the intention-to-treat and per-protocol populations (powered for non-inferiority), with Bayesian hierarchical modeling used to allow partial pooling of evidence from AMIHOT I. Among 281 randomized patients with tc-99m-sestamibi single-photon emission computed tomography data in AMIHOT II, median (inter-quartile range) infarct size was 26.5 % (8.5 %, 44 %) with control compared with 20 % (6 %, 37 %) after SSO2. The pooled adjusted infarct size was 25 % (7 %, 42 %) with control compared with 18.5 % (3.5 %, 34.5 %) after SSO2 (p(Wilcoxon) = 0.02; Bayesian posterior probability of superiority, 96.9 %). The Bayesian pooled 30-day mean (+/- SE) rates of major adverse cardiovascular events were 5.0 +/- 1.4 % for control and 5.9 +/- 1.4 % for SSO2 by intention-to-treat, and 5.1 +/- 1.5 % for control and 4.7 +/- 1.5 % for SSO2 by per-protocol analysis (posterior probability of non-inferiority, 99.5 % and 99.9 %, respectively). Adverse events in the AMIHOT II trial included four patient deaths in the treatment group within 30 days versus none for the controls, a statistically insignificant difference. The authors concluded that among patients with anterior ST-segment elevation MI undergoing PCI within 6 hrs of symptom onset, infusion of SSO2 into the left anterior descending artery infarct territory results in a significant reduction in infarct size with non-inferior rates of major adverse cardiovascular events at 30 days.
In a review on ischemic reperfusion injury of the heart, Pinto and colleaues (2009) stated that ischemic reperfusion injury is an important limitation to the effectiveness of primary reperfusion therapies in AMI. Clinical manifestations include arrhythmias, microvascular dysfunction, and myocyte dysfunction and death. Therapies specifically targeted to the prevention reperfusion injury are not available for clinical use. Despite ongoing improvements in the understanding of the underlying mechanisms and a wide range of potential treatments under investigation, effective therapies remain elusive.
The Downstream super-oxygenation therapy system (TherOx, Inc., Irvine, CA) is under development as a myocardial salvage intervention to be used in conjunction with standard treatment for AMI to reduce infarct size and salvage cardiac tissue. On March 18, 2009 the U.S. Food and Drug Administration’s Circulatory System Devices Panel voted to issue a “not approvable” letter in response to the pre-market application for the Downstream SSO2 device. The majority of the panel were unconvinced that the targeted oxygen therapy improves clinical patient outcomes, even though trial data from the AMIHOT-II trial showed the therapy created a statistically significant reduction in the surrogate endpoint of myocardial infarction size (FDC Reports, 2009). Several panelists pointed out that although the Downstream SS02 device produced statistically significant changes in infarct size, the differences were small. In addition, there was a trend toward an increased risk of adverse events and death in the treatment group.
While the findings of several published reports appear to be encouraging, the available evidence regarding intra-coronary hyperoxemic therapy for the treatment of AMI is insufficient to provide an adequate assessment of its effectiveness. Other potential applications of this technology include carbon monoxide poisoning, cardiogenic shock, radio-contrast nephropathy, and stroke. Moreover, there is a lack of published evidence to support the use of intra-coronary hyperoxemic therapy for these indications.
An UpToDate review on “Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Periprocedural management” (Gibson et al, 2013) states that “Based upon success in the reduction of infarct size in animal models, an infusion of blood mixed with aqueous oxygen into the coronary arteries after primary PCI has been shown to be safe and feasible in humans. However, benefit was not confirmed in the first outcome trial of this technology (AMIHOT) in which 269 patients with STEMI were randomly assigned after successful primary or rescue PCI to receive intracoronary hyperoxemic reperfusion or normoxemic blood autoreperfusion over 90 minutes. There was no difference between the two groups in any of the primary efficacy endpoints (final infarct size at 14 days, ST-segment resolution, or change in regional wall motion score index at three months). At 30 days, the incidence of major adverse cardiac events was not different between the two groups”.
|CPT Codes / HCPCS Codes / ICD-9 Codes|
|There are no specific CPT or HCPCS codes for hyperoxemic therapy
|ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):|
|410.00 - 411.10||Acute myocardial infarction|
|430 - 438.9||Transient cerebral ischemia|
|583.0 - 583.9||Nephritis and nephropathy [radio-contrast]|
|986||Toxic effect of carbon monoxide|
|997.02||Iatrogenic cerebrovascular infarction or hemorrhage|
|E867||Accidental poisoning by gas distribution by pipeline [carbon monoxide]|
|E868.0 - E868.9||Accidental poisoning by other utility gas and other carbon monoxide|
|E890.2||Other smoke and fumes from conflagration in private dwelling [carbon monoxide]|
|E891.2||Other smoke and fumes from conflagration in other and unspecified building or structure [carbon monoxide]|
|E947.8||Other drugs and medicinal substances causing adverse effects in therapeutic use [radio-contrast nephropathy]|
|E952.1||Suicide and self-inflicted poisoning by other carbon monoxide|
|E982.1||Poisoning by other carbon monoxide, undetermined whether accidentally or purposely inflicted|
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|ICD-10 codes will become effective as of October 1, 2015:|
|There are no specific CPT or HCPCS codes for hyperoxemic therapy
|ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):|
|G45.0 - G45.2
G45.4 - G45.9
|Transient cerebral ischemic attacks and related syndromes|
|I21.01 - I22.9||ST (STEMI) & non-ST (NSTEMI) elevation myocardial infarction|
|I60.00 - I67.2
I67.4 - I69.998
|I97.810 - I97.821||Intraoperative/postprocedural cerebrovascular infarction during surgery|
|N04.0 - N05.9
N07.0 - N07.0
|Nephritis and nephropathy [radio-contrast]|
|T50.8X5+||Adverse effects of diagnostic agents [radio-contrast nephrophathy]|
|T58.01X+ - T58.94X+||Toxic effect of carbon monoxide|
|T59.891+||Toxic effect of other specified gases, fumes and vapors, accidental (unintentional)|
|X00.1XX+, X02.1XX+||Exposure to smoke in fire in building or structure [carbon monoxide]|