Clinical trial NCT03810911: Mechanisms of EPO-induced Hypertension
Official title: Mechanisms of Erythropoietin Induced Hypertension
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Kidney Disease
Blood Pressure
Anemia
Keywords: Flow mediated dilatation
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2019-01-22
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: All subjects will receive darbepoetin during the study. One group, the immediate start group, will receive the drug the day of randomization. The other group, the delayed start group, will receive the drug 12 weeks later.
Primary purpose: TREATMENT

Brief summary: The investigators hypothesize that compared to untreated controls, erythropoietin (EPO) therapy in anemic patients with chronic kidney disease will raise diastolic blood pressure (BP). The magnitude of increase in diastolic BP at 12 weeks after treatment will be related to two factors. First, endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks and second, the change of forearm blood flow in response to breathing oxygen and the change in this measure from baseline to 4 weeks. Study procedures include fasting blood draws, ambulatory blood pressure, urine collection, and forearm blood flow tests. The study hopes to accrue 160 subjects.

Detailed description: Hypertension is a common but frequently overlooked and underreported adverse effect of erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks associated with normalization of hemoglobin. The risk of strokes is strongly related to poorly controlled hypertension. Blood pressure was not measured the way it usually is in hypertension trials, so the investigators cannot be completely confident that the risk of strokes in this large randomized trial was not related to EPO-induced hypertension. New therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon but it remains to be seen whether these new drugs would have a lower or a higher risk for hypertension compared to EPO. Accordingly, understanding the mechanism of EPO-induced hypertension is urgent. The investigators hypothesize that compared to untreated controls, EPO therapy in anemic patients with chronic kidney disease (CKD) will raise diastolic blood pressure. The magnitude of increase in diastolic BP at 12 weeks after treatment will be related to endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks. If the investigators understood the time course, the magnitude, and the mechanisms of EPO-induced hypertension (EIH) the investigators will better be able to design studies to compare the vascular effects of EPO and HIF stabilizers in the future. Thus, this study has the potential of improving the investigators' understanding of a common side effect of EPO by precisely quantifying the magnitude of BP change, its effects on endothelial function, and discovering the biomarkers of these adverse effects. Thus, the investigators can in the future robustly compare these effects of EPO with HIF stabilizers. This study is innovative because it will focus on the potential mechanisms by which EPO induces an increase in BP. The time-course and magnitude of change in BP will be assessed using the gold-standard measurement of 24 hour ambulatory BP recordings. The more frequent clinic BP recordings using validated methods will better allow us to track changes in BP over time. The investigators' lab is uniquely qualified to carry out these experiments due to a large experience with such types of studies. The investigators will examine endothelial function using a reference method -- that of flow-mediated dilatation -- which is established in the investigators' laboratory. The investigators will directly test the hypothesis whether endothelial function is responsible for the BP increase.

Eligibility criteria: Inclusion Criteria:

* Stage 3 or 4 chronic kidney disease
* Controlled hypertension with 24 hour ambulatory blood pressure monitoring less than 140/90 mmHg at baseline and treatment with at least 1 antihypertensive medication
* Hemoglobin between 8 and 10 g/dL
* No treatment with erythropoiesis-stimulating agents (ESA) within 3 previous months

Exclusion Criteria:

* Need for packed red blood cells (RBC) transfusion in the previous 2 months
* Myocardial infarction, stroke or hospitalization for heart failure in the past 2 months
* In the assessment of the investigator, have hematologic, inflammatory, infectious, or other conditions that might interfere with the erythropoietic response

Primary outcomes:
measure: Change in diastolic blood pressure in EPO treated patients compared to delayed start controls
timeFrame: Baseline to 12 weeks
measure: Change in flow mediated dilatation (FMD)
timeFrame: Baseline to 4 weeks
measure: Predictors of change in flow mediated dilatation (FMD)
timeFrame: Baseline to 4 weeks
Secondary outcomes:
measure: Change in systolic blood pressure in EPO treated patients
timeFrame: Baseline to 12 weeks
measure: Between group change in hypertension status
timeFrame: Baseline to 12 weeks
measure: Within group change in hypertension status
timeFrame: baseline to 12 weeks vs 12 weeks to 24 weeks
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Richard L. Roudebush VA Medical Center, Indianapolis, IN
state: Indiana
Study officials:
affiliation: Richard L. Roudebush VA Medical Center, Indianapolis, IN
name: Rajiv Agarwal, MD MBBS
role: PRINCIPAL_INVESTIGATOR
References: