High Potency Statins and Acute Kidney Injury

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ClinicalTrials.gov Identifier: NCT02518516

Recruitment Status : Completed

First Posted : August 7, 2015

Last Update Posted : March 14, 2016

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

Study Description

Brief Summary:

Statins are a class of cholesterol lowering medications that are prescribed for the prevention and treatment of cardiovascular disease. The purpose of this study is to determine if there is an excess risk of acute kidney injury (AKI) with high potency statins compared to low potency statins.

The investigators will carry out separate population based cohort studies using administrative health care databases in nine jurisdictions in Canada, the US, and the UK. Cohorts will be defined by the initiation of a statin, with follow-up until hospitalization for AKI. Analyses will be done separately for groups of patients with and without chronic kidney disease. The results from the separate sites will be combined in a meta-analysis to provide an overall assessment of the risk of AKI in new statin users.

Condition or disease	Intervention/treatment
Hypercholesterolemia	Drug: Rosuvastatin (≥10 mg) Drug: Atorvastatin (≥20 mg) Drug: Simvastatin (≥40 mg) Drug: Fluvastatin Drug: Pravastatin Drug: Lovastatin Drug: Atorvastatin (<20mg) Drug: Simvastatin (<40 mg)

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Detailed Description:

The study objective is to determine whether the use of high potency statins, compared with the use of low potency statins, is associated with an increased risk of acute kidney injury (AKI) in routine clinical practice. The investigators will use a common-protocol approach to conduct retrospective cohort studies using health care data from nine jurisdictions (the Canadian provinces of Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec, and Saskatchewan, as well as the United States (US) MarketScan and the United Kingdom (UK) Clinical Practice Research Datalink [CPRD]). The Canadian provincial databases contain information on physician billing, diagnoses and procedures from hospital discharge abstracts, and dispensations for prescription drugs at a population level. The CPRD is a clinical database that is representative of the UK population and contains the records for patients seen at over 680 general practitioner practices in the UK; these data will be linked to the Hospital Episode Statistics (HES) database, which contains in-hospital diagnosis and procedure data.

Study population

In each jurisdiction, the investigators will assemble a study cohort that includes all patients with a new prescription for a statin, including simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin, from the earliest availability of data at each site to the last date of available data. The date of study cohort entry is defined by the prescription date of the newly-prescribed statin.

For the purpose of this study, two separate cohorts will be created based on the presence or absence of a history of chronic kidney disease at any time prior to and including the date of study cohort entry. Chronic kidney disease is defined as patients who have 1 hospitalization or 1 physician claim 3 years prior to study cohort entry with any of the following diagnoses and corresponding diagnostic codes: chronic or unspecified renal failure (ICD-9: 585, 586; ICD-10: N18, N19), hypertensive renal disease (ICD-9: 403.x1, 404.x2, 404.x3; ICD-10: I12.0, I13.1), nephritis and nephropathy (ICD-9: 582, 583; ICD-10: N03, N05), renal sclerosis or disorder from impaired renal function (ICD-9: 587, 588; ICD-10: S00-T98). Patients in each cohort will be followed from the date of study cohort entry until an event (defined below) or censoring due to death, departure from the database, 24 months after initiation of statin treatment, a dispensing for cerivastatin, or the end of the study period (31 March 2010 or the last date of data availability at that site), whichever occurs first. Data from Alberta, Ontario, and Nova Scotia will be restricted to patients aged 65 years and older as prescription data are not available for younger patients.

Case-control selection

The cohorts defined above will be analyzed using a nested case-control analysis, where cases are defined as a hospitalization for AKI. Risk set sampling will be used to randomly select up to 10 controls for each case, matched on sex, age (± one year; however, if no controls are available, within five years), cohort entry (± 90 days), and duration of follow-up.

Exposure assessment

The exposure categories will be separated by statin potency (high vs. low dose), and the duration of current and past exposure. For all cases and controls, exposure will be defined hierarchically; more specifically, patients who receive both a high and low potency statin within the same exposure category will be classified as high potency statin users. Current use of a high potency statin will be defined by the last prescription for a high dose statin within the 60 days prior to the index date.

Current users will be further classified into three mutually exclusive durations of current exposure (≤120, 121-365, and 366-730 days). Past exposure will be defined as a new prescription for a statin at least 120 days prior to the index date.

Statistical analyses

All analyses will be conducted separately among patients with and without a history of chronic kidney disease. Conditional logistic regression will be used to estimate the odds ratios and corresponding 95% confidence intervals (CIs) of the association of hospitalization for AKI, comparing current and past use of high potency statins to low potency statins. This is considered the primary analysis. Several sensitivity analyses will be performed to assess the robustness of study results and address some of the study limitations.

High dimensional propensity scores will be estimated for all patients in the cohorts using logistic regression. Fixed cohort analyses will also be conducted on the cohorts in each jurisdiction, where the statin exposure category will be defined by the initial prescription at cohort entry. Finally, all site-specific estimates will be meta-analyzed using fixed or random-effects models with inverse variance weighting. The amount of between-site heterogeneity will be estimated using the I square statistic.

Study Design

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Study Type :	Observational
Actual Enrollment :	2067639 participants
Observational Model:	Cohort
Time Perspective:	Retrospective
Official Title:	Use of High Potency Statins and Rates of Admission for Acute Kidney Injury: Multicenter, Retrospective Observational Analysis of Administrative Databases
Study Start Date :	January 2011
Actual Primary Completion Date :	January 2013
Actual Study Completion Date :	January 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cholesterol Cholesterol Levels: What You Need to Know Cholesterol Medicines Statins

Genetic and Rare Diseases Information Center resources: Acute Graft Versus Host Disease

U.S. FDA Resources

Groups and Cohorts

Group/Cohort	Intervention/treatment
High potency statin users Exposure will be defined as a new prescription for a high dose statin (rosuvastatin, high doses of atorvastatin, and high doses of simvastatin between 1 January 1997 and 30 of April 2008, or 1 year after the beginning of data availability.	Drug: Rosuvastatin (≥10 mg) Current cumulative exposure to high dose rosuvastatin (ATC C10AA07) will be defined as a prescription for ≥10 mg of rosuvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to high dose rosuvastatin (ATC C10AA07) will be defined as a prescription for ≥10 mg of rosuvastatin dispensed >120 days of the index date (i.e. no exposure within 120 days of the index date). Drug: Atorvastatin (≥20 mg) Current cumulative exposure to high dose atorvastatin (ATC C10AA05) will be defined as a prescription for ≥20 mg of atorvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to high dose atorvastatin (ATC C10AA05) will be defined as a prescription for ≥20 mg of atorvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date). Drug: Simvastatin (≥40 mg) Current cumulative exposure to high dose simvastatin (ATC C10AA01) will be defined as a prescription for ≥40 mg simvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to high dose simvastatin (ATC C10AA01) will be defined as a prescription for ≥40 mg simvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).
Low potency statin users Exposure will be defined as a new prescription for a low dose statin (all doses of fluvastatin, all doses of pravastatin, all doses of lovastatin; low doses of atorvastatin and simvastatin) between 1 January 1997 and 30 of April 2008, or 1 year after the beginning of data availability.	Drug: Fluvastatin Current cumulative exposure to fluvastatin (ATC C10AA04) will be defined as a prescription for any dose of fluvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to fluvastatin (ATC C10AA04) will be defined as a prescription for any dose of fluvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date). Drug: Pravastatin Current cumulative exposure to pravastatin (ATC C10AA03) will be defined as a prescription for any dose of pravastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to pravastatin will be defined as a prescription for any dose of pravastatin (ATC C10AA03) dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date). Drug: Lovastatin Current cumulative exposure to lovastatin (ATC C10AA02) will be defined as a prescription for any dose of lovastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to lovastatin will be defined as a prescription for any dose of lovastatin (ATC C10AA02) dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date). Drug: Atorvastatin (<20mg) Current cumulative exposure to low dose atorvastatin (ATC C10AA05) will be defined as a prescription for <20 mg of atorvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to low dose atorvastatin (ATC C10AA05) will be defined as a prescription for <20 mg of atorvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date). Drug: Simvastatin (<40 mg) Current cumulative exposure to low dose simvastatin (ATC C10AA01) will be defined as a prescription for <40 mg simvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days). Past exposure to low dose simvastatin (ATC C10AA01) will be defined as a prescription for <40 mg simvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Group/Cohort

Intervention/treatment

High potency statin users

Exposure will be defined as a new prescription for a high dose statin (rosuvastatin, high doses of atorvastatin, and high doses of simvastatin between 1 January 1997 and 30 of April 2008, or 1 year after the beginning of data availability.

Drug: Rosuvastatin (≥10 mg)

Current cumulative exposure to high dose rosuvastatin (ATC C10AA07) will be defined as a prescription for ≥10 mg of rosuvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to high dose rosuvastatin (ATC C10AA07) will be defined as a prescription for ≥10 mg of rosuvastatin dispensed >120 days of the index date (i.e. no exposure within 120 days of the index date).

Drug: Atorvastatin (≥20 mg)

Current cumulative exposure to high dose atorvastatin (ATC C10AA05) will be defined as a prescription for ≥20 mg of atorvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to high dose atorvastatin (ATC C10AA05) will be defined as a prescription for ≥20 mg of atorvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Drug: Simvastatin (≥40 mg)

Current cumulative exposure to high dose simvastatin (ATC C10AA01) will be defined as a prescription for ≥40 mg simvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to high dose simvastatin (ATC C10AA01) will be defined as a prescription for ≥40 mg simvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Low potency statin users

Exposure will be defined as a new prescription for a low dose statin (all doses of fluvastatin, all doses of pravastatin, all doses of lovastatin; low doses of atorvastatin and simvastatin) between 1 January 1997 and 30 of April 2008, or 1 year after the beginning of data availability.

Drug: Fluvastatin

Current cumulative exposure to fluvastatin (ATC C10AA04) will be defined as a prescription for any dose of fluvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to fluvastatin (ATC C10AA04) will be defined as a prescription for any dose of fluvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Drug: Pravastatin

Current cumulative exposure to pravastatin (ATC C10AA03) will be defined as a prescription for any dose of pravastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to pravastatin will be defined as a prescription for any dose of pravastatin (ATC C10AA03) dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Drug: Lovastatin

Current cumulative exposure to lovastatin (ATC C10AA02) will be defined as a prescription for any dose of lovastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to lovastatin will be defined as a prescription for any dose of lovastatin (ATC C10AA02) dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Drug: Atorvastatin (<20mg)

Current cumulative exposure to low dose atorvastatin (ATC C10AA05) will be defined as a prescription for <20 mg of atorvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to low dose atorvastatin (ATC C10AA05) will be defined as a prescription for <20 mg of atorvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Drug: Simvastatin (<40 mg)

Current cumulative exposure to low dose simvastatin (ATC C10AA01) will be defined as a prescription for <40 mg simvastatin dispensed prior to the index date in one of the following exposure duration categories (≤120 days, 121-365 days, or 366-730 days).

Past exposure to low dose simvastatin (ATC C10AA01) will be defined as a prescription for <40 mg simvastatin dispensed >120 days prior to the index date (i.e. no exposure within 120 days of the index date).

Outcome Measures

Primary Outcome Measures :

Number of patients hospitalized for acute kidney injury [ Time Frame: Patients will be followed from the date of study cohort entry until either hospitalization for acute kidney injury or censoring (whichever occurs first), or will be assessed for up to 24 months. ]
Patients hospitalized for acute kidney injury (including but not limited to hypertensive renal disease with renal failure, chronic glomerulonephiritis, and renal sclerosis) with any of the following diagnostic codes: ICD-9 584, 584.5, 584.6, 584.7, 584.8, or 584.9; ICD-10 N17, N17.0, N17.1, N17.2, N17.8, or N17.9.

Eligibility Criteria

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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 with a new prescription for a statin, including simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin between 1 January 1997 (or one year after the beginning of data availability) and 30 April 2008. The date of study cohort entry is defined by the prescription date of the newly-prescribed statin. Two separate cohorts will be created based on the presence or absence of a history of chronic kidney disease.

Criteria

Inclusion Criteria:

Patients with a new prescription for a statin from the earliest availability of data at each site to the last date of availability of data +365 days
Patients who are at least 40 years of age at cohort entry
Patients with at least one year of history in the database

Exclusion Criteria:

Patients under the age of 40 (<66 in jurisdictions with drug data for seniors only)
Patients with less than one year of history in the database
Patients who received any cholesterol lowering drugs (including fibrates, niacin and ezetimibe) or underwent dialysis or a kidney transplant in the previous year

Contacts and Locations

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): NCT02518516

Locations

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Canada, British Columbia
Dept. of Anesthesiology, Pharmacology & Therapeutics (APT), University of British Columbia
Vancouver, British Columbia, Canada, V6T 1Z3

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:	Colin Dormuth, M.Sc., Sc.D.	Departments of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver,BC

More Information

Additional Information:

This organization's website describing general functions, other CNODES projects, and investigator profiles. This link exits the ClinicalTrials.gov site

This link exits the ClinicalTrials.gov site

Publications of Results:

Dormuth CR, Hemmelgarn BR, Paterson JM, James MT, Teare GF, Raymond CB, Lafrance JP, Levy A, Garg AX, Ernst P; Canadian Network for Observational Drug Effect Studies. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ. 2013 Mar 18;346:f880. doi: 10.1136/bmj.f880.

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Responsible Party:	Canadian Network for Observational Drug Effect Studies, CNODES
ClinicalTrials.gov Identifier:	NCT02518516
Other Study ID Numbers:	CNODES_Demo_1
First Posted:	August 7, 2015 Key Record Dates
Last Update Posted:	March 14, 2016
Last Verified:	August 2015

Keywords provided by Canadian Network for Observational Drug Effect Studies, CNODES:


Statins, HMG-CoA Acute kidney injury Kidney diseases Renal failure

Additional relevant MeSH terms:

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Acute Kidney Injury Hypercholesterolemia Hyperlipidemias Dyslipidemias Lipid Metabolism Disorders Metabolic Diseases Renal Insufficiency Kidney Diseases Urologic Diseases Atorvastatin Rosuvastatin Calcium Simvastatin	Pravastatin Lovastatin L 647318 Dihydromevinolin Anticholesteremic Agents Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Enzyme Inhibitors

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