AMIHOT II breathes new life into supersaturated oxygen strategy post-PCI

Shelley Wood

October 23, 2007

Washington, DC - Supersaturated oxygen therapy after PCI may not, in fact, have breathed its last gasp: results from the AMIHOT II study suggest that the infusion of supersaturated blood into an infarcted artery may indeed reduce infarct size in certain subsets of patients. The findings may resuscitate the experimental therapy that failed to show any benefit in the AMIHOT I trial, as reported by heart wire .

Other experts, however, pointed out that adverse events were actually numerically higher in the patients treated with the supersaturated blood and that further studies, in larger groups of patients, are critical.  

Dr Gregg Stone

Dr Gregg Stone (Columbia University, New York, NY) presented the AMIHOT II study here during the Tuesday late-breaking clinical-trials session at the TCT 2007 meeting.

AMIHOT II grew out of a post hoc subset analysis from the negative AMIHOT I trial that suggested patients with large infarcts who underwent PCI within the first six hours of symptoms experienced significant improvements following supersaturated oxygen therapy, something not seen in the trial as a whole. For AMIHOT II, Stone et al randomized 301 patients with large anterior infarcts who had undergone early reperfusion to either supersaturated oxygen therapy for 90 minutes following PCI or standard treatment. Findings from these patients were then combined with a similar subset of patients from AMIHOT I using a Bayesian hierarchical model, a strategy that Stone emphasized has the FDA's stamp of approval.

Reduction in infarct size, as measured by Tc-99m sestamibi SPECT at 14 days—the primary end point of the trial—was significantly greater among patients who underwent supersaturated oxygen therapy. After treatment, patients who received their own, supersaturated blood had an infarct size that was 6.5% smaller than patients who received standard therapy. The proportion of patients with immeasurable infarcts at 14 days—pointing to normal left ventricular function—was also significantly different between the two groups.

"Among high-risk patients with acute anterior MI undergoing successful PCI within six hours of symptom onset, infusion of supersaturated oxygen therapy into the myocardial infarct territory results in a significant reduction in infarct size," Stone concluded.

Incidence of 30-day MACE, a secondary end point, intended to assess whether there were any short-term adverse effects of infusing the oxygenated blood, was not statistically different between the two groups—although the MACE rate was numerically higher in the supersaturated-oxygen group. The trial, however, was underpowered to adequately assess safety. Low patient numbers also meant that the MACE results could not show that the therapy actually had an impact on clinical outcomes, Stone noted. Future studies with larger patient numbers and longer follow-up will be needed to assess whether the treatment can improve clinical outcomes.

Questions for future studies

Dr Harvey White

In a press conference discussing the results, Dr Harvey White (Auckland City Hospital, New Zealand) pointed out that the statistical methods used by Stone et al will need to be scrutinized to make sure the data are being pooled appropriately. "The question is whether you should start de novo for the second trial," he said.

But Stone staunchly defended the statistical methods used. "This isn't simple pooling; that's not what Bayesian analysis does. It would be wrong to just take the first subgroup, cherry-pick it, then just pool them together," he said. Instead, the statistical model allows data to be pooled if they are consistent with the randomized data and rejected if they are not, a form of "continuous blending."

Stone agreed, however, that further studies will need to be conducted to determine whether a reduction in infarct size would translate into clinical benefit: other studies have suggested that a reduction in infarct size of 5% would translate into a more than 17% reduction in mortality, he said; if the findings from AMIHOT II pan out, an even greater mortality benefit would be expected, given the 6.5% reduction in infarct size, he suggested.

Stone also emphasized that the treatment, should it ultimately be approved for use, would likely be cost-effective. "Patients with large infarcts who end up with heart failure and other complications of their infarcts certainly are expensive to care for by the medical community."

White, while emphasizing that this study should be "hypothesis-generating," acknowledged that the study is one of very few studies of myocardial protection strategies to have shown any benefit in a patient group in whom myriad experimental treatments have failed.

Bleeding rates need scrutiny

During the late-breaking clinical-trials session where Stone presented the AMIHOT II results, Dr Michael Haude (University Essen, Germany) also urged further follow-up and research. He identified two areas for concern that will need to be evaluated in future studies: for one, the high proportion of patients with immeasurable infarcts at 14 days, touted as a benefit of supersaturated oxygen, calls into question whether Tc-99m sestamibi SPECT is the best tool for tracking change in infarct size. He also pointed to the higher rates of bleeding in patients who received the supersaturated blood. "Bleeding complications were of particular concern," he said. "They were significantly more frequent with supersaturated oxygen therapy: almost every fourth patient had an adverse bleeding event," he noted. "We need to see long-term follow-up studies to definitively evaluate this therapy."

Stone disclosed receiving research support from TherOx, the company developing the supersaturated oxygen therapy used in AMIHOT II.


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