Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD.

Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).

Toward a Blood-Borne Biomarker of Chronic Hypoxemia: Red Cell Distribution Width and Respiratory Disease.

Hypoxemia (systemic oxygen desaturation) marks the presence, risk, and progression of many diseases. Episodic or nocturnal hypoxemia can be challenging to detect and quantify. A sensitive, specific, and convenient marker of recent oxygen desaturation represents an unmet medical need. Observations of acclimatization to high altitude in humans and animals reveals several proteosomic, ventilatory, and hematological responses to low oxygen tension. Of these, increased red cell distribution width (RDW) appears to have the longest persistence. Literature review and analyses of a 2M patient database across the full disease pathome revealed that increased RDW is predictive of poor outcome for certain diseases including many if not all hypoxigenic conditions. Comprehensive review of diseases impacting the respiratory axis show many are associated with increased RDW and no apparent counterexamples. The mechanism linking RDW to outcome is unknown. Conjectural roles for iron deficiency, inflammation, and oxidative stress have not been born out experimentally. Sports-doping studies show that erythropoietin (EPO) injection can induce formation of unusually large red blood cells (RBC) in sufficient numbers to increase RDW. Because endogenous EPO responds strongly to hypoxemia, this molecule could potentially mediate a long-lived RDW response to low oxygenation. RDW may be a guidepost signaling that unexploited information is embedded in subtle RBC variation. Applying modern techniques of measurement and analysis to certain RBC characteristics may yield a more specific and sensitive marker of chronic pulmonary and circulatory diseases, sleep apnea, and opioid inhibition of breathing.

Persistent increase in red cell size distribution width after acute diseases: A biomarker of hypoxemia?

BACKGROUND: A biomarker of hypoxic exposure would be useful in clinical diagnosis and prognosis. Acute hypoxia stimulates large increases in serum erythropoietin (EPO), and EPO induces formation of characteristic enlarged red blood cells (RBCs). The presence of large RBCs perturbs red cell distribution width (RDW). METHODS: Using a >2M patient medical claims database, the human pathome was scanned for diseases where RDW rose 0-50days following a new diagnosis. The course of RDW after selected diagnoses was visualized by registering RDW measurements by diagnosis date. RESULTS: Acute hemorrhage, which provokes EPO-driven erythropoiesis, is followed by increases in RDW but not mean cell volume (MCV). Similar RDW increases follow many acute diseases with risk of hypoxia, including heart failure, pneumonia, atelectasis, pulmonary embolism, pneumothorax, and sepsis. Elevations reach maximum within 1month after onset and subside to pre-disease levels about 6months later. Unlike the case with iron-deficiency anemia (IDA), RDW elevations after hypoxia-associated diseases are unaccompanied by discernible change in average RBC size. CONCLUSIONS: As predicted by a model risk pathway linking hypoxia to formation of enlarged RBCs via EPO, acute hypoxemia-related disease episodes induce change in RBC size distribution. Further study is needed to explore whether a more sensitive and specific signal can be extracted from the fine structure of the RBC size distribution routinely measured in automated hemocytometers.