Ignite Creation Date:
2024-10-26 @ 3:35 PM
Last Modification Date:
2024-10-26 @ 3:35 PM
Study NCT ID:
NCT06515678
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
None
First Post:
2024-07-04
Brief Title:
Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Bevacizumab-associated Hypertension
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Patients Treated With Bevacizumab Maintenance A Target Trial Emulation
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
IATRO
Brief Summary:
Antiangiogenic therapies like bevacizumab have notably improved cancer treatment including for gynecological cancers by inhibiting the vascular endothelial growth factor and thus limiting tumor growth In treating advanced ovarian cancer bevacizumab has been shown to extend progression-free survival by four months though it also induces or worsens hypertension in 2 to 19 of patients by affecting vascular nitric oxide production or by capillary rarefaction This hypertension may result in severe cardiovascular events necessitating the use of antihypertensive drugs like calcium channel blockers and RAAS inhibitors angiotensin converting enzyme - ACE - inhibitors mainly despite some concerns about their effects on VEGF secretion and CA125 levels Clinical guidelines vary with some favoring ACE inhibitors while others recommend calcium channel blockers underlining the need for comparative studies on these drugs oncological and cardiovascular impacts To address these issues this study utilizes an emulated trial approach leveraging comprehensive data from the French National Health Data System to compare the efficacy of these antihypertensive classes in reducing relapse and improving survival in ovarian cancer patients treated with bevacizumab
The investigators will emulate a target clinical trial to compare the impact of antihypertensive treatments on outcomes of patients with bevacizumab-associated hypertension by ACE inhibitors arm A versus calcium channel blockers CCBs arm B on the risk of ovarian cancer withdrawal after surgery
The investigators will emulate a target clinical trial to compare the impact of antihypertensive treatments on outcomes of patients with bevacizumab-associated hypertension by ACE inhibitors arm A versus calcium channel blockers CCBs arm B on the risk of ovarian cancer withdrawal after surgery
Detailed Description:
Antiangiogenic therapies such as bevacizumab have significantly improved the treatment landscape of various cancers including gynecological types Bevacizumab is a humanized monoclonal IgG1 antibody targeting all forms of human vascular endothelial growth factor-A VEGF essential for angiogenesis in healthy and cancerous tissues This drug inhibits angiogenesis primarily by blocking VEGF from activating its receptors VEGFR on endothelial cells thus limiting tumor growth by cutting off their blood supply and aiding the effectiveness of cytotoxic drugs by reducing tumor interstitial pressure and abnormal blood vessels
For advanced ovarian cancer bevacizumab was found to improve the median progression-free survival of 4 months However targeting tumor vessels will eventually modify the patients vasculature leading to hypertension in 2 to 19 of patients as per a meta-analysis VEGF-VEGFR pathway inhibition can cause hypertension by inhibiting the production of nitric oxide in the arterial wall or by capillary rarefaction and increased afterload Several retrospective studies support a correlation between the occurrence of a bevacizumab-associated hypertension BIH and outcomes highlighting the link between tumor and patient vasculature However bevacizumab-associated hypertension can lead in some rare cases to major adverse cardiovascular events MACE
Multiple treatments have been proposed to control this adverse reaction Calcium channel blockers CCBs such as amlodipine have been proposed and offers a way to control bevacizumab-associated hypertension Angiotensin-converting enzyme inhibitors ACEi which targets the renin-angiotensin-aldosterone system RAAS to control hypertension could also constitute an interesting option and could be more efficient
However there is both caution against the use of CCBs and ACEis since nifedipine has been shown to induce VEGF secretion in vitro and ACEi enalapril and perindopril have been associated in a case report with CA125 increase
Current guidelines vary on the preferred class of medication for initial management of antiangiogenic-associated hypertension The European Society of Cardiology ESC guidelines favor ACEis as the first-line treatment whereas guidelines for gynecological cancers suggest CCBs for managing BIH in patients without other comorbidities This discrepancy highlights the need for direct comparisons of oncologic and cardiologic outcomes in this context
Randomized controlled trials RCTs despite being the gold standard face practical and financial constraints that may limit their use In the absence of RCT observational data can serve as a crucial alternative for estimating real-world causal effects However observational studies come with challenges such as confounding factors due to the lack of randomization and the risk of immortal-time bias A recent advancement in addressing these challenges is the use of emulated trials which strive to replicate the conditions of a target RCT This approach employing propensity-score adjustment methods has shown promise in extracting the highest level of evidence from observational data The SNDS covering 988 of the French population offers extensive and detailed demographic health condition and healthcare utilization data enabling a thorough and representative analysis of healthcare outcomes in oncology
In this study to address measured confounding at baseline an exact copy of each patients record will be created and allocated to each arm of the study ensuring identical baseline characteristics across the study groups Clones will be artificially censored when their observed trajectories deviated from the treatment strategy of the arm to which they were assigned This informative artificial censoring introduces selection bias over time which will be addressed using inverse probability of censoring IPC weights Standardized mean differences SMDs will be derived to assess adjustment quality after IPC weighting
The per-protocol average treatment effect ATE will be estimated by the one- and three-year differences in PFS probability and three-year restricted mean survival time RMST differences in the IPC-weighted population This will be visually assessed using weighted Kaplan-Meier survival curves Similar steps will be performed for overall survival OS at one three and five years for survival probability differences and at five years for RMST
This study focuses on comparing the effects of antihypertensive drugs - ACEi vs CCBs- on the risk of relapse in patients undergoing adjuvant maintenance treatment with bevacizumab for ovarian cancer after debulking surgery It employs an emulation of a clinical trial using data from the French National Health Data System SNDS Secondary objectives will include examining the causal impact of these antihypertensive classes on overall survival the incidence of MACE and the time to treatment failure
For advanced ovarian cancer bevacizumab was found to improve the median progression-free survival of 4 months However targeting tumor vessels will eventually modify the patients vasculature leading to hypertension in 2 to 19 of patients as per a meta-analysis VEGF-VEGFR pathway inhibition can cause hypertension by inhibiting the production of nitric oxide in the arterial wall or by capillary rarefaction and increased afterload Several retrospective studies support a correlation between the occurrence of a bevacizumab-associated hypertension BIH and outcomes highlighting the link between tumor and patient vasculature However bevacizumab-associated hypertension can lead in some rare cases to major adverse cardiovascular events MACE
Multiple treatments have been proposed to control this adverse reaction Calcium channel blockers CCBs such as amlodipine have been proposed and offers a way to control bevacizumab-associated hypertension Angiotensin-converting enzyme inhibitors ACEi which targets the renin-angiotensin-aldosterone system RAAS to control hypertension could also constitute an interesting option and could be more efficient
However there is both caution against the use of CCBs and ACEis since nifedipine has been shown to induce VEGF secretion in vitro and ACEi enalapril and perindopril have been associated in a case report with CA125 increase
Current guidelines vary on the preferred class of medication for initial management of antiangiogenic-associated hypertension The European Society of Cardiology ESC guidelines favor ACEis as the first-line treatment whereas guidelines for gynecological cancers suggest CCBs for managing BIH in patients without other comorbidities This discrepancy highlights the need for direct comparisons of oncologic and cardiologic outcomes in this context
Randomized controlled trials RCTs despite being the gold standard face practical and financial constraints that may limit their use In the absence of RCT observational data can serve as a crucial alternative for estimating real-world causal effects However observational studies come with challenges such as confounding factors due to the lack of randomization and the risk of immortal-time bias A recent advancement in addressing these challenges is the use of emulated trials which strive to replicate the conditions of a target RCT This approach employing propensity-score adjustment methods has shown promise in extracting the highest level of evidence from observational data The SNDS covering 988 of the French population offers extensive and detailed demographic health condition and healthcare utilization data enabling a thorough and representative analysis of healthcare outcomes in oncology
In this study to address measured confounding at baseline an exact copy of each patients record will be created and allocated to each arm of the study ensuring identical baseline characteristics across the study groups Clones will be artificially censored when their observed trajectories deviated from the treatment strategy of the arm to which they were assigned This informative artificial censoring introduces selection bias over time which will be addressed using inverse probability of censoring IPC weights Standardized mean differences SMDs will be derived to assess adjustment quality after IPC weighting
The per-protocol average treatment effect ATE will be estimated by the one- and three-year differences in PFS probability and three-year restricted mean survival time RMST differences in the IPC-weighted population This will be visually assessed using weighted Kaplan-Meier survival curves Similar steps will be performed for overall survival OS at one three and five years for survival probability differences and at five years for RMST
This study focuses on comparing the effects of antihypertensive drugs - ACEi vs CCBs- on the risk of relapse in patients undergoing adjuvant maintenance treatment with bevacizumab for ovarian cancer after debulking surgery It employs an emulation of a clinical trial using data from the French National Health Data System SNDS Secondary objectives will include examining the causal impact of these antihypertensive classes on overall survival the incidence of MACE and the time to treatment failure
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None