Hydrochlorothiazide and Risk of Skin Cancer

June 28, 2023 updated by: Canadian Network for Observational Drug Effect Studies, CNODES

Use of Hydrochlorothiazide and the Risk of Skin Cancer

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Actual)

2953748

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Montreal, Quebec, Canada, H3T1E2
        • Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years and older (Adult, Older Adult)

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

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 Names:
  • 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 Names:
  • ATC C09A, C09B

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.
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.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Canadian Network for Observational Drug Effect Studies, CNODES

Collaborators

Canadian Institutes of Health Research (CIHR)
Drug Safety and Effectiveness Network, Canada

Investigators

  • Principal Investigator: Laurent Azoulay, PhD, Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 27, 2019

Primary Completion (Actual)

March 5, 2021

Study Completion (Actual)

March 5, 2021

Study Registration Dates

First Submitted

April 2, 2020

First Submitted That Met QC Criteria

April 2, 2020

First Posted (Actual)

April 6, 2020

Study Record Updates

Last Update Posted (Actual)

June 29, 2023

Last Update Submitted That Met QC Criteria

June 28, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Q19-05

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Melanoma

Clinical Trials on Hydrochlorothiazide

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Japan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe