Amanda M. Smith

BACKGROUND: The objective of this cluster randomized controlled trial was to determine the feasibility and safety of an intensive (systolic blood pressure [SBP] <120 mm Hg) versus usual care (SBP <140 mm Hg) approach to SBP control in patients with renal cell or thyroid cancer initiating VEGFR (vascular endothelial growth factor)-tyrosine kinase inhibitors. METHODS: A phase II site–based cluster randomized controlled trial compared intensive SBP control to usual care, incorporating a centralized BP advisory core to guide BP management. Patients underwent home BP monitoring and study visits at baseline, 1, 2, 3, and 6 months. SBP was compared between the 2 study arms using bootstrapped CIs. Common Terminology Criteria for Adverse Events and patient-reported outcomes were summarized. RESULTS: Overall, 61 patients with renal cell (n=58) or thyroid cancer (n=3) from 10 sites were enrolled; 30 at 5 sites were randomized to intensive SBP control and 31 at 5 sites to usual care. A lower SBP was observed in the intensive SBP control arm compared with usual care, with mean differences of −12.2 (95% CI, −18.1 to −7.0) mm Hg at 1 month, −7.6 (95% CI, −15.3 to −0.4) mm Hg at 3 months, and −6.9 (95% CI, −19.3 to 6.0) mm Hg at 6 months. In the usual care arm, Grade 3 Common Terminology Criteria for Adverse Events for kidney injury (n=4), hypotension (n=3), and dyspnea (n=2) were numerically greater compared with the intensive SBP control (n=1, 2, and 0, respectively). Patient-reported outcomes were largely similar between the 2 groups. CONCLUSIONS: This first-ever randomized controlled trial of SBP control in an active cancer population demonstrates the feasibility, safety, and tolerability of intensive SBP control with VEGFR tyrosine kinase inhibitors. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04467021.

Supplemental Table S1: Study Representativeness Table

Supplemental Table S1: Study Representativeness Table

Supplemental Table S2: Factor Loadings for Biomarker Clusters in Principal Component Analysis

Supplemental Table S2: Factor Loadings for Biomarker Clusters in Principal Component Analysis

Purpose:Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT.Patients and Methods:Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine–nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF.Results:Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05).Conclusions:Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.

Purpose:Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT.Patients and Methods:Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine–nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF.Results:Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05).Conclusions:Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.

Purpose: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT; NCT01988571) randomized patients with breast cancer or lymphoma receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF (left ventricular ejection fraction) in PREVENT. Patients and Methods: Blood samples were collected and cardiac MRI was performed before doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers [arginine–nitric oxide metabolites, paraoxonase-1 (PON-1) activity, and myeloperoxidase] were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined whether biomarker clusters explained the lack of effect of atorvastatin on LVEF. Results: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (P = 0.081); Cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (P = 0.024). There were no significant changes in other biomarker clusters (P > 0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (P > 0.05). Conclusions: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.