Statin Discontinuation in Advanced Illness

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01415934
• Collaborator: National Institute of Nursing Research (NINR) (NIH)
• Enrollment: 381
• Locations: 15
• Arms: 2
• Actual Duration (Months): 25.4
• Patients Per Site: 25.4
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if there is a difference in survival rate at 60 days after enrollment between patients with advanced life-limiting illness for whom statins are discontinued vs. for patients with advanced life-limiting illness who are maintained on the medication. Secondary outcomes of this study will determine the effects of medication cessation on overall survival, important cardiovascular events, quality of life (QOL), symptoms, performance status, polypharmacy issues, satisfaction with care, and costs.

Condition or Disease	Intervention/Treatment	Phase
Palliative Medicine; Cardiovascular Disease	Other: discontinue statins	N/A

Detailed Description

Currently, over 80% of the population is expected to die of chronic life-limiting illnesses, predominant among which are the various manifestations of cardiovascular disease, cancer, dementia, and chronic lung disease. Patients with high cholesterol and those potentially at risk for atherosclerotic heart disease and stroke are often treated preventively with HMG Co-A reductase inhibitors (a.k.a., statins). Clinical trial evidence supports the use of statins for patients with hyperlipidemia and established ischemic heart disease to reduce risk of future cardiovascular events and mortality, and to reduce risk of future cardiovascular events in patients with multiple cardiac risk factors. Beneficial outcomes are evident in these trials after 3-6 years of treatment. Hence, statins are among the most prescribed medications in the world. In the United States, over 25% of Medicare beneficiaries take a statin medication. Statin medications are frequently continued until the patient can no longer eat or swallow at the end of life, because there are no evidence-based guidelines regarding when or how to discontinue medications for co-morbidities. The risks and costs vs. benefits of statins for palliative care patients, for whom prognosis is limited, remains a genuine clinical uncertainty. Meanwhile, medications for symptoms and other concerns accumulate as illness progresses, and therefore polypharmacy and compounding medication side effects are troublesome problems in the setting of advanced life-limiting illness. While multiple studies have demonstrated the benefit of long-term preventive statin use for patients at cardiovascular risk, other studies have supported the discontinuation of medications (specifically statins) in end-stage disease. A rational approach to medication discontinuation, specifically statin discontinuation, therefore has the potential to reduce patient burden, polypharmacy, and side effects, while also preserving healthcare resources for more beneficial interventions.

This study is a multi-site randomized controlled trial of discontinuing vs. continuing statin medications in patients with advanced life-limiting illness. Eligible participants are adults with advanced life-limiting illness with an estimated prognosis of 1-6 months who are on statins for primary or secondary prevention of cardiovascular events. The primary outcome is survival rate at 60 days; secondary outcomes address cardiovascular events, polypharmacy, medication adverse effects, quality of life (QOL), and measures of the patient's health-related experience. The primary hypothesis is that discontinuing statins will not influence survival. Secondary hypotheses are that discontinuation of statins will not adversely affect cardiovascular events or overall QOL, but will improve statin-related symptoms and decrease polypharmacy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 381 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Health Services Research
• Official Title: Multisite Randomized Controlled Trial of Continuing vs. Discontinuing Statins
• Actual Study Start Date: Jun 3, 2011
• Actual Primary Completion Date: Jul 15, 2013
• Actual Study Completion Date: Jul 15, 2013

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Continue Statins Participant will continue on statins as per usual
Experimental: Discontinue statins Participant will stop taking their statin drugs	Other: discontinue statins; patients will be randomized to either continue taking statins or discontinue.

Outcome Measures

Primary Outcome Measures

1. Proportion of Deaths Within 60 Days of Enrollment. [Within 60 days of Subject Enrollment]

   To determine, among patients with life-limiting illness, if there is a difference in the proportion who die within 60 days after enrollment between patients for whom statins are discontinued vs. patients who are maintained on the medication.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• age >18 years old;

• have an advanced life-limiting illness;

• have a life expectancy of >1 month, AND patient exhibits declining functional status, defined as a reduction in Australia-modified Karnofsky Performance Status (AKPS)22 score to <80% in the previous 3 months;

• be on a statin medication for primary or secondary prevention of cardiovascular disease for ≥3 months;

• have adequately intact cognitive status to provide informed consent and complete the baseline assessment, as evidenced by a Short Portable Mental Status Questionnaire (SPMSQ)23 score of ≥6;

• provide informed consent; and,

• speak and read English at or above a grade 5 level (per patient or caregiver report).

Exclusion Criteria:

• primary treating physician/care provider estimates their life expectancy as < 1 month;

• under the care of a primary treating physician/primary care provider who is unwilling to have the patient enrolled;

• not consenting;

• having known active cardiovascular disease or sufficient risk of active cardiovascular disease to require ongoing therapy with statin drugs, in the opinion of the treating physician; OR,

• exhibiting obvious symptoms of myositis, known liver function test (LFT) abnormalities of >2.5x the upper limit of normal (ULN), known creatine kinase (CK) abnormalities of

2.5x ULN, or other contraindications to continuing statins, in the opinion of the treating physician.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama, Birmingham	Birmingham	Alabama	United States	35294
2	San Diego Hospice and the Institute for Palliative Medicine	San Diego	California	United States	92103
3	University of Colorado, Denver	Denver	Colorado	United States	80217
4	Kaiser Permanente	Denver	Colorado	United States	80231
5	Northwestern University	Chicago	Illinois	United States	60611
6	Mayo Clinic	Rochester	Minnesota	United States	55905
7	Washington University	Saint Louis	Missouri	United States	63110
8	Beth Israel Medical Center	New York	New York	United States	10003
9	Mount Sinai School of Medicine	New York	New York	United States	10029
10	University of North Carolina, Chapel Hill	Chapel Hill	North Carolina	United States	27599
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Four Seasons Hospice and Palliative Care	Flat Rock	North Carolina	United States	28731
13	Hospice of Western Reserve	Cleveland	Ohio	United States	44106
14	Capital Caring	Falls Church	Virginia	United States	22042
15	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• University of Colorado, Denver
• National Institute of Nursing Research (NINR)

Investigators

• Principal Investigator: Amy Abernethy, MD, Duke University
• Principal Investigator: Jean Kutner, MD, University of Colorado, Denver

Study Documents (Full-Text)

None provided.

More Information

Publications

• Hochman MJ, Kamal AH, Wolf SP, Samsa GP, Currow DC, Abernethy AP, LeBlanc TW. Anticholinergic Drug Burden in Noncancer Versus Cancer Patients Near the End of Life. J Pain Symptom Manage. 2016 Nov;52(5):737-743.e3. doi: 10.1016/j.jpainsymman.2016.03.020. Epub 2016 Sep 20. Erratum in: J Pain Symptom Manage. 2019 May;57(5):e9-e10.
• McNeil MJ, Kamal AH, Kutner JS, Ritchie CS, Abernethy AP. The Burden of Polypharmacy in Patients Near the End of Life. J Pain Symptom Manage. 2016 Feb;51(2):178-83.e2. doi: 10.1016/j.jpainsymman.2015.09.003. Epub 2015 Sep 30.
• Portz JD, Kutner JS, Blatchford PJ, Ritchie CS. High Symptom Burden and Low Functional Status in the Setting of Multimorbidity. J Am Geriatr Soc. 2017 Oct;65(10):2285-2289. doi: 10.1111/jgs.15045. Epub 2017 Aug 30. Erratum in: J Am Geriatr Soc. 2019 Jul;67(7):1536-1537.
• Tjia J, Kutner JS, Ritchie CS, Blatchford PJ, Bennett Kendrick RE, Prince-Paul M, Somers TJ, McPherson ML, Sloan JA, Abernethy AP, Furuno JP. Perceptions of Statin Discontinuation among Patients with Life-Limiting Illness. J Palliat Med. 2017 Oct;20(10):1098-1103. doi: 10.1089/jpm.2016.0489. Epub 2017 May 18. Erratum in: J Palliat Med. 2019 Mar;22(3):351.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01415934
• Other Study ID Numbers: 11-0314; UC4NR012584
• First Posted: Aug 12, 2011
• Last Update Posted: Sep 21, 2018
• Last Verified: Aug 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Cardiovascular Diseases

Study Results

Participant Flow

Arm/Group Title	Continue Statins	Discontinue Statins
Arm/Group Description	Participant will continue on statins as per usual	Participant will stop taking their statin drugs discontinue statins: patients will be randomized to either continue taking statins or discontinue.
Period Title: Overall Study
STARTED	192	189
COMPLETED	189	182
NOT COMPLETED	3	7

Baseline Characteristics

Arm/Group Title	Continue Statins	Discontinue Statins	Total
Arm/Group Description	Patients in the continuation group continued to receive statins.	Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group.	Total of all reporting groups
Overall Participants	192	189	381
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	38 19.8%	35 18.5%	73 19.2%
>=65 years	154 80.2%	154 81.5%	308 80.8%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.5 (11.5)	74.8 (11.7)	74.1 (11.6)
Sex: Female, Male (Count of Participants)
Female	80 41.7%	91 48.1%	171 44.9%
Male	112 58.3%	98 51.9%	210 55.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 5.2%	6 3.2%	16 4.2%
Not Hispanic or Latino	182 94.8%	183 96.8%	365 95.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 0.5%	0 0%	1 0.3%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	1 0.3%
Black or African American	22 11.5%	32 16.9%	54 14.2%
White	162 84.4%	153 81%	315 82.7%
More than one race	1 0.5%	1 0.5%	2 0.5%
Unknown or Not Reported	5 2.6%	3 1.6%	8 2.1%
Region of Enrollment (participants) [Number]
United States	192 100%	189 100%	381 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Deaths Within 60 Days of Enrollment.
Description	To determine, among patients with life-limiting illness, if there is a difference in the proportion who die within 60 days after enrollment between patients for whom statins are discontinued vs. patients who are maintained on the medication.
Time Frame	Within 60 days of Subject Enrollment

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	Continue Statins	Discontinue Statins
Arm/Group Description	Patients in the continuation group continued to receive statins.	Statin therapy was withdrawn from eligible patients who were randomized to the discontinuation group.
Measure Participants	192	189
Number (90% Confidence Interval) [proportion of deaths]	0.203	0.238

Adverse Events

Time Frame	12 months
Arm/Group Title	Continue Statins		Discontinue Statins
Arm/Group Description	Participant will continue on statins as per usual		Participant will stop taking their statin drugs discontinue statins: patients will be randomized to either continue taking statins or discontinue.
All Cause Mortality
	Continue Statins		Discontinue Statins
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/192 (20.3%)		45/189 (23.8%)
Serious Adverse Events
	Continue Statins		Discontinue Statins
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/192 (2.1%)		6/189 (3.2%)
Cardiac disorders
Chest Pain	1/192 (0.5%)	1	0/189 (0%)	0
Low Blood Pressure	0/192 (0%)	0	1/189 (0.5%)	1
Gastrointestinal disorders
Bowel Obstruction	2/192 (1%)	2	0/189 (0%)	0
Rectal Bleed	1/192 (0.5%)	1	0/189 (0%)	0
General disorders
Dehydration	1/192 (0.5%)	1	0/189 (0%)	0
Edema	0/192 (0%)	0	1/189 (0.5%)	1
Shortness of Breath	0/192 (0%)	0	3/189 (1.6%)	3
Fever	1/192 (0.5%)	1	0/189 (0%)	0
Pain	0/192 (0%)	0	1/189 (0.5%)	1
Musculoskeletal and connective tissue disorders
Hip Fracture	1/192 (0.5%)	1	0/189 (0%)	0
Psychiatric disorders
Suicidal Ideation and severe depression	0/192 (0%)	0	1/189 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Bronchitis	1/192 (0.5%)	1	0/189 (0%)	0
Pulmonary Embolus	0/192 (0%)	0	1/189 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Continue Statins		Discontinue Statins
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/192 (2.1%)		7/189 (3.7%)
Blood and lymphatic system disorders
Sepsis	1/192 (0.5%)	1	0/189 (0%)	0
Cardiac disorders
Hypotension	1/192 (0.5%)	1	0/189 (0%)	0
Ear and labyrinth disorders
Rehospitalization	0/192 (0%)	0	1/189 (0.5%)	1
General disorders
Fall	1/192 (0.5%)	1	6/189 (3.2%)	6
Fever	1/192 (0.5%)	1	0/189 (0%)	0
Headache	1/192 (0.5%)	1	0/189 (0%)	0
Nervous system disorders
Encephalpathy	1/192 (0.5%)	1	0/189 (0%)	0
Psychiatric disorders
Psychological Distress	0/192 (0%)	0	1/189 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Shortness of Breath	1/192 (0.5%)	1	2/189 (1.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.