Impact of Antihypertensive Therapy on Recurrence Risk of Ovarian Cancer for Bevacizumab-associated Hypertension

NCT06515678 | Active Not Recruiting FDA Drug

• 1 other identifier: CIC1421-24-09
• Study Type: observational
• Target: 9,464
• Locations: 1 country
• Sites: 2

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.

Conditions

Ovarian Cancer; Antiangiogenic-Associated Hypertension; Adjuvant Bevacizumab; Hypertension

Keywords

antiangiogenics; antihypertensive; ovarian cancer surgery; bevacizumab; calcium channel blockers; angiotensin-converting enzyme inhibitors

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Overall survival

  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

  Time from ovarian cancer first surgery to the time of MACE-narrow, assessed up to 7 years

• Major Cardiovascular Event (MACE) - broad definition

  Time from ovarian cancer first surgery to the time of MACE-broad, assessed up to 7 years

• Time to treatment failure (TTF)

  Time from bevacizumab initiation to the first antihypertensive treatment switch or change to bitherapy, assessed up to 7 years

Study Arms (5)

Main analysis - antihypertensive therapy with bevacizumab (ACEi or CCBs)

Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with monotherapy ACEi (arm A) or CCB (arm B) up to 6 months following debulking surgery

Drug: arm A - angiotensin converting enzyme inhibitors (ACEi); Drug: arm B - calcium channel blockers (CCBs)

Complementary group - arm C1 - bevacizumab without antihypertensive therapy

Patients treated with bevacizumab without initiation of antihypertensive treatment within 6 months following debulking surgery

Complementary group - arm C2 - standard chemotherapy alone

Patients who were only treated by standard chemotherapy within 6 months following debulking surgery without bevacizumab

Complementarity analysis - 1st-line CCB vs ACEi vs ARBs

Adjuvant/maintenance bevacizumab after ovarian cancer debulking surgery with antihypertensive therapy monotherapy. Any patients with bevacizumab treated with Renin Angiotensin Aldosterone System (RAAS) inhibitor drug among ACEi (arm A) versus angiotensin receptor blocker ARB (arm R) versus CCB (arm B)

Drug: arm A - angiotensin converting enzyme inhibitors (ACEi); Drug: arm B - calcium channel blockers (CCBs); Drug: arm R - angiotensin receptor blockers ARB

Sensitivity analysis

Sensitivity analysis S1 - Impact of Antihypertensive Treatment Switching. The investigators will utilize time-varying inverse probability of censoring weights (IPCW). The first step of the IPCW method consists in censoring patients who interrupt their initially assigned treatment. The second step of the IPCW method is thus to use IPCW with baseline covariates and time-dependent covariates linked to the treatment switching. (i) Number of cardiology consultations, (ii) Number of nephrology consultations or proteinuria, (iii) Number of cardiovascular events related to hypertension (MACE broad) Sensitivity analysis S2 - Exclusion of patients with isolated proteinuria or elevated proteinuria: The investigators will reproduce the main analysis, excluding patients with signs of isolated proteinuria or elevated proteinuria.

Drug: arm A - angiotensin converting enzyme inhibitors (ACEi); Drug: arm B - calcium channel blockers (CCBs)

Interventions

arm A - angiotensin converting enzyme inhibitors (ACEi) DRUG

Patients with ACEi monotherapy before or within 6 months following debulking surgery. ACEi will be defined as any drugs from the Anatomical Therapeutic Classification C09AA with an indication for hypertension, including but not limited to: captopril, enalapril, lisinopril, perindopril, ramipril, quinapril

Complementarity analysis - 1st-line CCB vs ACEi vs ARBs; Main analysis - antihypertensive therapy with bevacizumab (ACEi or CCBs); Sensitivity analysis

arm B - calcium channel blockers (CCBs) DRUG

Patients with CCB monotherapy before or within 6 months following debulking surgery. CCBs will be defined as any drugs from the Anatomical Therapeutic Classification C08CA with an indication for hypertension, including but not limited to: amlodipine, felodipine, isradipine, nicardipine, nifedipine

Complementarity analysis - 1st-line CCB vs ACEi vs ARBs; Main analysis - antihypertensive therapy with bevacizumab (ACEi or CCBs); Sensitivity analysis

arm R - angiotensin receptor blockers ARB DRUG

Patients with angiotensin receptor blocker (ARB) before or within 6 months following debulking surgery. ARBs will be defined as any drugs from the Anatomical Therapeutic Classification C09CA with an indication for hypertension, including but not limited to: losartan, valsartan, irbesartan, candesartan or olmesartan medoxomil.

Complementarity analysis - 1st-line CCB vs ACEi vs ARBs

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The study population consists of women over 18 diagnosed with ovarian cancer between January 1, 2011, and December 31, 2020, who undergone debulking surgery for ovarian cancer with adjuvant chemotherapy. In the main target emulated trial, all patients received an antihypertensive first-line monotherapy with either CCBs or ACEi as a stable treatment monotherapy treatment of hypertension prior to bevacizumab or for a bevacizumab-associated hypertension. 2 complementary cohorts are kept for interpretation and quality control purposes.

You may qualify if:

• women with newly ovarian cancer diagnosis (FIGO III to IV)
• age over 18 years old at time of ovarian cancer diagnosis
• diagnosed between January 1, 2011 and December 31, 2020
• with debulking ovarian cancer surgery and adjuvant chemotherapy

You may not qualify if:

• not in the "Regime general" "Sécurité Sociale" reimbursement system
• without standard chemotherapy protocol (carbotaxol every 3 weeks or weekly)
• history of heart failure or heart surgery, cardiovascular infarction or any coronaropathy disease, cerebro-vascular disease, arteriopathy of the lower limb, within the year before ovarian cancer surgery. Patients with history of hypertension without any complications were not excluded.
• bevacizumab initiation prior to debulking surgery
• combination of antihypertensive classes prior bevaizumab or as the first-line hypertensive therapy of bevacizumab-associated hypertension
• antihypertensive monotherapy from other classes than CCBs and ACEi (ARBs, beta-blockers, diuretics etc...) as the anti-hypertensive therapy. Therapy could be initiated before ovarian surgery.
• Complementary analysis :
• \- patients treated by ARBs

Sponsors & Collaborators

• Groupe Hospitalier Pitie-Salpetriere: lead
• Dr Floriane Jochum, Principal Investigator: collaborator
• Institut Curie: collaborator

Study Sites (2)

Institut Curie

Paris, 75005, France

Location

Pitié-Salpêtrière

Paris, 75013, France

Location

MeSH Terms

Conditions

Ovarian Neoplasms; Hypertension

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Vascular Diseases; Cardiovascular Diseases

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 4, 2024
• First Posted: July 23, 2024
• Study Start: May 20, 2024
• Primary Completion: August 1, 2024
• Study Completion: August 31, 2024
• Last Updated: July 26, 2024

Record last verified: 2024-07

Locations

FR (2)