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Hydrochlorothiazide and Risk of Skin Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04334824
Recruitment Status : Completed
First Posted : April 6, 2020
Last Update Posted : March 9, 2021
Sponsor:
Collaborators:
Drug Safety and Effectiveness Network, Canada
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Canadian Network for Observational Drug Effect Studies, CNODES

Brief Summary:

The purpose of this study is to determine whether the use of hydrochlorothiazide is associated with an increased risk of skin cancer compared with the use of angiotensin-converting enzyme (ACE) inhibitors. More specifically, the investigators will assess the risk of non-melanoma and melanoma skin cancer. The investigators hypothesize that the use of hydrochlorothiazide is associated with an increased risk of skin cancer compared with ACE inhibitors.

The investigators will carry out separate population-based cohort studies using administrative health databases from seven Canadian provinces and the United States. The study cohort will be defined by the initiation of hydrochlorothiazide or an ACE inhibitor, with follow-up until an incident diagnosis of non-melanoma or melanoma skin cancer. The results from the separate sites will be combined to provide an overall assessment of the risk of non-melanoma and melanoma skin cancer in users of hydrochlorothiazide.


Condition or disease Intervention/treatment
Non-melanoma Skin Cancer Melanoma Hypertension Drug: Hydrochlorothiazide Drug: Angiotensin-converting enzyme (ACE) inhibitors

Detailed Description:

The study objective is to determine whether the use of hydrochlorothiazide is associated with an increased risk of skin cancer compared with the use of angiotensin-converting enzyme (ACE) inhibitors. More specifically, the investigators will assess whether hydrochlorothiazide is associated with the risk of non-melanoma and melanoma skin cancer.

A common-protocol approach will be used to conduct retrospective cohort studies using administrative health data from seven Canadian provinces (Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec, and Saskatchewan) and the United States (US) MarketScan database. Briefly, the Canadian databases include population-level data on physician billing, diagnoses and procedures from hospital discharge abstracts, and dispensations for prescription drugs. Prescription drug data are limited to those aged 65 years old and older in Alberta, Nova Scotia, and Ontario. The US MarketScan database includes individuals and their dependents covered by large US employer health insurance plans, and government and public organizations.

A standardized mortality ratio weighted cohort analysis will be conducted. In each jurisdiction, the investigators will assemble a study cohort that includes all patients aged 40 years or older (or 66 years or older in Alberta, Nova Scotia, and Ontario) newly-treated with hydrochlorothiazide or an ACE inhibitor between April 1, 1995 and March 31, 2018 (or the latest date of data availability at each site). The date of study cohort entry will be defined by the dispensation date of the newly prescribed hydrochlorothiazide or ACE inhibitor. Patients will be followed starting 366 days after study cohort entry until an incident diagnosis of non-melanoma or melanoma, or censored upon switching to a study drug, death, end of coverage or end of the study period (March 31, 2018), whichever occurs first.

Exposure will be defined as a prescription for hydrochlorothiazide or an ACE inhibitor on the date of cohort entry. The exposures will be lagged by one year in order to consider a minimum cancer latency period between treatment initiation and the diagnosis of skin cancer. Analyses will be conducted using a modified intention-to-treat approach. The outcomes of interest will be non-melanoma and melanoma skin cancer.

Weighted Cox proportional hazards models with calendar year as a strata will be used to estimate site-specific adjusted hazard ratios (HR) and corresponding 95% confidence intervals (CI) for each outcome of interest among hydrochlorothiazide users compared to ACE inhibitor users. In order to reflect the Canadian context, the primary analysis will be restricted to Canadian data and the US MarketScan data will be used only in a secondary analysis. Secondary analyses will be conducted for each outcome of interest. These will include the following: 1) as-treated, 2) cumulative duration of use, 3) dose-response relation, 4) effect modification by age (≤65, 66-74, and ≥75 years), sex and immunosuppressive status, and 5) time since initiation of treatment (<3, 3-5, and >5 years). For non-melanoma, events will be further classified into basal cell carcinoma or squamous cell carcinoma sub-types in jurisdictions where data is available. Four sensitivity analyses will be performed to assess the robustness of study results and address some of the study limitations. Site-specific results from the Canadian sites will be combined by random-effects meta-analysis to provide an overall assessment of the risk of non-melanoma and melanoma skin cancer in hydrochlorothiazide users compared to ACE inhibitor users. Four additional analyses at the meta-analysis level will be conducted. These will include the following: 1) using fixed-effects model, 2) pooling results only from jurisdictions where non-melanoma sub-type differentiation is available, 3) pooling results from all sites including the US MarketScan data, and 4) pooling results by jurisdictions with and without cancer registry data.

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Study Type : Observational
Actual Enrollment : 2953748 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Use of Hydrochlorothiazide and the Risk of Skin Cancer
Actual Study Start Date : May 27, 2019
Actual Primary Completion Date : March 5, 2021
Actual Study Completion Date : March 5, 2021


Group/Cohort Intervention/treatment
Hydrochlorothiazide
Patients who received a new prescription for hydrochlorothiazide (alone or in combination with non-ACE inhibitor antihypertensive drugs) at cohort entry, and did not have a previous prescription for any antihypertensive drug any time before cohort entry.
Drug: Hydrochlorothiazide
Exposure to hydrochlorothiazide will be defined as a prescription for hydrochlorothiazide alone or in combination with non-ACE inhibitor antihypertensive drugs at cohort entry date.
Other Name: ATC C03AA03

Angiotensin-converting enzyme (ACE) inhibitors
Patients who received a new prescription for an ACE inhibitor (alone or in combination with non-hydrochlorothiazide antihypertensive drugs) at cohort entry, and did not have a previous prescription for any antihypertensive drug any time before cohort entry.
Drug: Angiotensin-converting enzyme (ACE) inhibitors
Exposure to ACE inhibitors will be defined as a prescription for an ACE inhibitor alone or in combination with non-hydrochlorothiazide antihypertensive drugs at cohort entry date.
Other Name: ATC C09A, C09B




Primary Outcome Measures :
  1. Non-melanoma skin cancer [ Time Frame: Patients will be followed starting 366 days after study cohort entry until an incident diagnosis of non-melanoma skin cancer, censoring or for up to 275 months, whichever occurs first. ]
    Incident non-melanoma skin cancer events will be identified using either cancer registry information (where available), or defined using an algorithm adapted from Chan et al., 2016. An event will be defined by the presence of a diagnosis code for non-melanoma skin cancer (ICD-9: 173.x; ICD-10: C44.x) plus a procedure code in hospital or physician claims data.

  2. Melanoma skin cancer [ Time Frame: Patients will be followed starting 366 days after study cohort entry until an incident diagnosis of melanoma skin cancer, censoring or for up to 275 months, whichever occurs first. ]
    Incident melanoma skin cancer events will be identified using either cancer registry information (where available), or defined using an algorithm. An event will be defined by the presence of a diagnosis code for malignant melanoma (ICD-9: 172.x; ICD-10: C43.x) plus a procedure code in hospital or physician claims data.



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
In each jurisdiction, the investigators will assemble a study cohort that includes all patients aged 40 years or older newly-treated with hydrochlorothiazide or an ACE inhibitor between April 1, 1995 and March 31, 2018 (or the latest date of data availability at each site). The date of study cohort entry will be defined by the dispensation date of the newly prescribed hydrochlorothiazide or ACE inhibitor.
Criteria

Inclusion Criteria:

  • Patients aged 40 years or older (or 66 years or older in Alberta, Nova Scotia and Ontario) newly-treated with hydrochlorothiazide or an ACE inhibitor between April 1, 1995 and March 31, 2018 (or the latest date of data availability at each site)

Exclusion Criteria:

  • Patients with less than one year of health coverage before cohort entry
  • Patients with a previous prescription of any antihypertensive drug at any time before cohort entry
  • Patients with a diagnosis of any type of skin cancer (non-melanoma and melanoma) at any time before cohort entry
  • Patients with a diagnosis of HIV at any time before cohort entry
  • Patients with a history of solid organ transplant at any time before cohort entry
  • Patients with less than one year of follow-up after cohort entry

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04334824


Locations
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Canada, Quebec
Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital
Montreal, Quebec, Canada, H3T1E2
Sponsors and Collaborators
Canadian Network for Observational Drug Effect Studies, CNODES
Drug Safety and Effectiveness Network, Canada
Canadian Institutes of Health Research (CIHR)
Investigators
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Principal Investigator: Laurent Azoulay, PhD Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital
Additional Information:
Publications:
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Responsible Party: Canadian Network for Observational Drug Effect Studies, CNODES
ClinicalTrials.gov Identifier: NCT04334824    
Other Study ID Numbers: Q19-05
First Posted: April 6, 2020    Key Record Dates
Last Update Posted: March 9, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Canadian Network for Observational Drug Effect Studies, CNODES:
Non-melanoma Skin Cancer
Melanoma
Hydrochlorothiazide
Hypertension
Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Hypertension
Vascular Diseases
Cardiovascular Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Hydrochlorothiazide
Angiotensin-Converting Enzyme Inhibitors
Antihypertensive Agents
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Protease Inhibitors
Enzyme Inhibitors