Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Bevacizumab-associated Hypertension
NCT Number: NCT06515678
Acronym: IATRO
Status: ACTIVE_NOT_RECRUITING
Study Type: OBSERVATIONAL
Conditions: Ovarian Cancer|Antiangiogenic-Associated Hypertension|Adjuvant Bevacizumab|Hypertension
Interventions: DRUG: arm A - angiotensin converting enzyme inhibitors (ACEi)|DRUG: arm B - calcium channel blockers (CCBs)|DRUG: arm R - angiotensin receptor blockers ARB
Sponsor: Groupe Hospitalier Pitie-Salpetriere
Collaborators: Dr Floriane Jochum, Principal Investigator|Institut Curie
Sex: FEMALE
Age: ADULT, OLDER_ADULT
Enrollment: 9464
Study Design: Observational Model: |Time Perspective: p
Start Date: 2024-05-20
Completion Date: 2024-08-31
Locations: Institut Curie, Paris, 75005, France|Pitié-Salpêtrière, Paris, 75013, France

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.

Primary Outcome Measures: Progression-free survival for ovarian cancer, The per-protocol average treatment effect (ATE) will be estimated by the one-, two-, and three-year differences in PFS probability, and three-year restricted mean survival time (RMST) differences in the IPC-weighted population.

The main outcome will be at three-year.

Covariate adjustment :

Covariates included in the inverse probability weighting are: (i) age at trial inclusion, (ii) number and type of comorbidities, (iii) economic deprivation level, (iv) number of general practitioner consultations the year before, (v) number of gynecologist consultation the year before, (vi) number of cardiology consultation at inclusion, (vii) number of nephrology consultation at inclusion, (viii) FIGO stage, (ix) surgical strategy, (x) hospital annual ovarian cancer volume, and (xi) hospital academic status, PFS is defined as the time, from ovarian cancer first surgery to death, progression or recurrence, whichever occurres first, assessed up to 7 years
Secondary Outcome Measures: Overall survival, The per-protocol average treatment effect (ATE) will be estimated by the one-, two-, three-, and five-year differences in OS probability, and five-year restricted mean survival time (RMST) differences in the IPC-weighted population., OS is defined as the time, from ovarian cancer first surgery to death from any cause, assessed up to 7 years|Major Cardiovascular Event (MACE) - narrow definition, MACE-narrow is defined any acute myocardial infarction or cerebrovascular infarction. A competing risk model will be used for the occurrence of MACE narrow and broad, with death as a competing event. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who died. The death censoring mechanism may depend on the baseline and time-dependent factors. The IPCW method introduces weights to correct for this dependent censoring. The second step of the IPCW method is thus to use inverse probability of censoring weights with baseline covariates and time-dependent covariates : (i) Number of cardiology consultations, (ii) Number of nephrology consultations. MACE will be analyzed up to 36 months to assess the direct impact of bevacizumab use. Longer-term outcomes will be available in the supplemental only., Time from ovarian cancer first surgery to the time of MACE-narrow, assessed up to 7 years|Major Cardiovascular Event (MACE) - broad definition, MACE-narrow is defined any acute myocardial infarction or cerebrovascular infarction. A competing risk model will be used for the occurrence of MACE narrow and broad, with death as a competing event. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who died. The death censoring mechanism may depend on the baseline and time-dependent factors. The IPCW method introduces weights to correct for this dependent censoring. The second step of the IPCW method is thus to use inverse probability of censoring weights with baseline covariates and time-dependent covariates : (i) Number of cardiology consultations, (ii) Number of nephrology consultations. MACE will be analyzed up to 36 months to assess the direct impact of bevacizumab use. Longer-term outcomes will be available in the supplemental only., Time from ovarian cancer first surgery to the time of MACE-broad, assessed up to 7 years|Time to treatment failure (TTF), Treatment failure is defined as the necessity to switch antihypertensive therapy, add a new antihypertensive therapy (bitherapy), the occurrence of a MACE-broad, recurrence or death. Time to antihypertensive treatment failure (TTF) will be assessed by the median TTF in each study arm (CCBs and ACEi). Dose increase was not considered a treatment failure. TTF is censored at bevacizumab withdrawal., Time from bevacizumab initiation to the first antihypertensive treatment switch or change to bitherapy, assessed up to 7 years