There are many guidelines on when to start drug treatment, but surprisingly few guidelines on how and when to stop drugs. For example, there are currently no clear guidelines on when to stop preventive medications such as statins in patients in palliative cancer care. According to previous studies, these drugs are often deprescribed far too late in the process, often close to death. This can lead to unwanted side effects, such as muscle weakness, increased fatigue, and also contribute to unnecessary drug costs and unnecessary environmental impact.

In the STATIC I study the safety and effects of early deprescribing of statins in palliative cancer care is explored. The primary aim of the STATIC study is to study the change in LDL-levels (mmol/L) after statin termination. The secondary outcomes includes change in levels of other steroids (cholesterol, HDL, Q10, 25-hydroxyvitamin D, lanosterol), change in muscle strength, cardiovascular events, fatigue and quality of life after statin deprescribing. STATIC I is a pilot study to optimize the design for the randomized study STATIC II.

The study aim at including 40 patients with advanced cancer within specialized palliative care with an expected survival time >1 month to <1 year (surprise question 1 year). At start of the study statins are deprescribed and the patients are followed for 12 weeks. Data collection is performed at baseline, 2, 4, 8 and 12 weeks. A control group (n=40) comprising patients with advanced cancer and no ongoing statin treatment, are included from the same specialized palliative care units. The control group is followed for 12 weeks regarding muscle strength and symptom burden.

The current studies can provide important and valuable knowledge on the safety and effects of early describing.

STATIC - statin termination in cancer

Purpose and Aims To reduce overtreatment of statins in palliative cancer care. To this end, a prospective pilot study in patients with advanced cancer to evaluate effects and safety of deprescribing statins is performed.

Hypotheses

Statin treatment might do more harm than good in patients with advanced cancer with a limited life expectancy (less than 1 year) and should be discontinued earlier in the disease trajectory than is standard practice today.

Background Palliative Care and deprescribing Palliative medicine aims at providing relief from symptoms in incurable diseases and at maintaining functions and a high quality of life (QoL), i.e. "to live every day until you die". In medical treatment in palliative care, side effects should be minimized and should not outweigh possible beneficial effects.

Prescription of drugs often follows clear guidelines. However, there are few or no guidelines for when drugs should be discontinued, i.e. deprescribed. At the end of life, many medications can be directly harmful. As an example, the patient's life expectancy may be shorter than the time required for preventive medications to have an effect and the patients will only get side effects without any benefits (1). Such overtreatment can lead to unnecessary adverse effects and contribute to unnecessary costs. In addition, a large burden of tablets is often troublesome for patients.

Today, there are very few prospective studies performed on deprescribing. However, there is one randomized trial on deprescribing statins (2). This study showed that early deprescribing of statins (the last year before death) was associated with improved QoL among patients with early statin deprescription and no increased risk of cardiovascular events (2). However, due to a large drop-out rate, the primary aim of this study could not be full-filled, i.e. to study the safety of discontinuation. Moreover, in that study no cholesterol levels were measured.

There might be an overmedication of statins in patients in palliative cancer care and probably these drugs often can be deprescribed earlier. In previous retrospective studies, described below, it is shown that statins are often deprescribed very late in the disease trajectory.

Statins Statins lower blood cholesterol levels by inhibiting the endogenous synthesis of cholesterol in the liver by inhibiting the enzyme HMG CoA reductase, the rate-regulating enzyme in steroid synthesis. During statin treatment, total-cholesterol and LDL-cholesterol decreases, while HDL (the "good" cholesterol) increases. Statins have been shown to be effective drugs in reducing cardiovascular events and death (3). The most common side effects of statin treatment are muscle weakness, muscle pain and muscle fatigue (4).

Cholesterol levels in the blood are affected both by the endogenous synthesis in the liver (that is inhibited by statins) but also by diet. The best way to measure the effect of statins on HMG-CoA reductase is to measure the levels of lanosterol in the circulation, which levels are directly affected by the activity of HMG-CoA reductase (5). Statins also reduce the synthesis of several other steroid metabolites, including ubuiquinone (Q10) (4). Q10 is an essential antioxidant in the electron. In unpublished data we could show that low levels of Q10 in the circulation are associated with more fatigue in elderly and less muscle strength (Dahlen et al, unpublished data). Sex-hormones are also steroids, but their synthesis is not significantly affected by statins according to previous studies in healthy subjects. However, if statins affect the synthesis of sex-hormones in severely ill patients is not known.

In a recently performed Delfi study (6), the consensus was very high for discontinuation of statins if life expectancy is shorter than 6 months, both for primary prevention purposes and for secondary prevention if no cardiovascular event has occurred in the last 12 months. In contrast, an increased risk of cardiovascular events has been noted when discontinuing statins in the elderly who are not at the end of life (7). Thus, it is not clear when statins should be discontinued and at which time point the treatment in fact does more harm than good.

There are two previously published retrospective studies on statin discontinuation in patients with advanced cancer in palliative care (8, 9). In both studies, it is demonstrated that there was a sex difference, where statin treatment was usually discontinued earlier in women than in men. Generally, statins were also deprescribed late in the disease trajectory in men, in average 1.5 months before death (9). In both studies, there was no increased incidence of cardiovascular events after statin discontinuation - which is in concordance with the randomized study from Kutner et al (2).

Project plan STATIC I - STAtin Termination In Cancer, study I - a pilot study of statin termination in patients with advanced cancer Aim: To conduct a pilot study with early deprescribing of statin treatment in palliative care (STATIC I), which can serve as a basis for optimizing the design for a future randomized trial (STATIC II).

Primary endpoint: Change in LDL levels (mmol/L) after deprescribing.

Secondary endpoints:

(The 4 questionnaires EORTC-QLQ-C15-PAL, TSQM-9, ESAS and EQ-5D-5L are described on the next page.)

• Change in cholesterol (mmol/L) after statin termination.
• Change in HDL levels (mmol/L) after statin termination.
• Occurance of cardiovascular events after statin termination.
• Change in lanosterol (nmol/L) statin termination.
• Change in Q10 (ng/ml) statin termination.
• Changes in levels of testosteron (nmol/L) statin termination.
• Change in 25-hydroxyvitamin D (nmol/L) statin termination.
• Change in fatigue measured with the ESAS. Change over time and compared with control group.
• Change in muscle strength measured by hand grip, and compared with change control group
• Change in QoL measured with EORTC QLQ-C15-PAL (score 0-100)

Additional data collected:

• Perceived satisfaction with medication as measured by TSQM-9
• Change in health status and health economy measured with EQ-5D-5L
• Change in symtomburden after statin termination measured with ESAS (0-10)
• Changes in blood pressure after statin termination
• Qualitative analysis of semi-structured interviews to find out more about the participants' experiences and thoughts of participating in the study.

Study design: Prospective pilot study. This study will form the basis of a larger randomized study described in project 2: "STATIC II".

The study ends with participants being invited to semi-structured interviews to find out more about the participants' experiences of participating in the STATIC I study, their experiences of deprescription of statins and the different questionnaires.

Intervention: Discontinuation of statin treatment at the start of the study. Study period: 12 weeks Participants: Patients with advanced cancer in the palliative stage, who have an expected survival of a maximum of 1 year but at least 1 month and who are admitted to an Advanced medical home care (ASIH) unit at Stockholms Sjukhem or ASIH Stockholm Södra. These units have 300 and 400 patients admitted (700 patients in total), which forms the basis for recruitment. Palliative patients admitted to ASIH have a median remaining survival time of less than 4-5 months.

Inclusion criteria intervention group: ≥ 18 years, "No"-answer to the "surprise question" 1 year: Would you be surprised if this patient died in the next year? (this is a common and validated prognostic tool in palliative care), treatment with statins ≥ 3 months for primary or secondary prevention before study inclusion Inclusion criteria control group: ≥ 18 years, "No"-answer to the "surprise question" 1 year: Would you be surprised if this patient died in the next year? (this is a common and validated prognostic tool in palliative care), no ongoing statin treatment Exclusion criteria: Cognitive impairment, does not understand the Swedish language, known homozygous or double heterozygous familial hypercholesterolemia, active cardiovascular disease or sufficient risk of active cardiovascular disease that requires ongoing medication with statins (assessed by a specialist in cardiology), myositis symptoms, other contraindications to continuing statins.

Data collection: At inclusion, data on age, gender, BMI, smoking, main diagnosis, medications and comorbidities are collected. Information on statin treatment (drugs, dose, for how long) intervention group). Clinical examination with blood pressure (BP), heart auscultation, lung auscultation.

At inclusion and after 2, 4, 8 and 12 weeks intervention group:

• Blood samples are taken and analyzed for blood status, CRP, Krea, eGFR, CK, Na, K, Alb, S-total cholesterol, HDL, LDL, lanosterol, Q10, sex-hormones and liver status.
• Measurement of muscle strength measured by hand grip.
• Blood pressure and Performance status measured with ECOG.

At inclusion and after 2, 4, 8 and 12 weeks control group:

• Measurement of muscle strength measured by hand grip.
• Performance status measured with ECOG.

At 2, 4, 8 and 12 weeks (intervention): Adverse events such as hospitalization, emergency hospital visit, new cardiovascular event, pulmonary embolism, deep vein thrombosis, invasive procedure for cardiovascular event

Four questionnaires are collected on all occasions to assess 1) quality of life 2) symptom burden, 3) health economics and 4) satisfaction with drug treatment:

• EORTC QLQ C15 PAL - Quality of Life Questionnaire-15-Palliative is a 15-question questionnaire developed to measure health-related QoL in palliative cancer patients.
• ESAS (Edmonton Symptom Assessment System) supplemented with muscle pain and muscle weakness. A questionnaire with 10 questions where patients rate their symptoms from 0-10 and has been used in oncology for over 20 years.
• EQ-5D-5L - a questionnaire that measures the general health status of patients within five dimensions. Used to calculate health economics.
• TSQM-9 - an instrument to study patients' satisfaction with medication in three different domains: effectiveness, convenience and satisfaction with the current medication.

In control group: Adverse events such as hospitalization, emergency hospital visit, new cardiovascular event, pulmonary embolism, deep vein thrombosis, invasive procedure for cardiovascular event and only ESAS, muscle strenght.

Number of patients: Intervention group n=40; control group n= max 40. No power calculation is done as this is a pilot study.

Safety follow-up: A specialist in cardiology, Cardiology Department, Södersjukhuset in Stockholm, is part of the study team. The specialist is consulted to determine if it is safe for a patient to participate in the study if there are concerns. He is also consulted whether statins need to be restarted in the following scenario: 1) In primary prevention: If LDL cholesterol rises to above 5.3 mmol/L; 2) In secondary prevention if LDL cholesterol rises by >50% if LDL cholesterol > 1.4 at baseline or if it rises by >100% if LDL cholesterol < 1.4 at baseline or 3). If the study physician for another reason wishes to consult the specialist for a discussion about reinstating statin treatment.

Risk analysis: According to previous studies, discontinuing statins in this patient group does not lead to more cardiovascular events and can even lead to a better quality of life (2, 8, 9). However, an increased risk of cardiovascular events has been noted when statins are discontinued in the elderly who are not at the end of life (7). Through careful follow-up and close contact with the cardiology clinic at Södersjukhuset, patients at risk will be identified at an early stage. Patients admitted to ASIH also have a median remaining life expectancy of less than 4-5 months. Thus, the majority of participants include will be in the final stages of life.

Ethic approval: Dnr: 2025-00458-01. Approved January 21th, 2025. Timeline: Study start September 2025, last patient out December 2026.

References

1. Holmes HM, Hayley DC, Alexander GC, Sachs GA. Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006;166(6):605-9.
2. Kutner JS, Blatchford PJ, Taylor DH, Jr., Ritchie CS, Bull JH, Fairclough DL, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med. 2015;175(5):691-700.
3. Group SSSS. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-9.
4. Skilving I, Acimovic J, Rane A, Ovesjo ML, Bjorkhem-Bergman L. Statin-induced Myopathy and Ubiquinone Levels in Serum - Results from a Prospective, Observational Study. Basic Clin Pharmacol Toxicol. 2015;117(2):133-6.
5. Reihnér E, Rudling M, Ståhlberg D, Berglund L, Ewerth S, Björkhem I, et al. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med. 1990;323(4):224-8.
6. Elsten E, Pot IE, Geijteman ECT, Hedman C, van der Heide A, van der Kuy PHM, et al. Recommendations for Deprescribing of Medication in the Last Phase of Life: An International Delphi Study. J Pain Symptom Manage. 2024.
7. Thomas C, Ellison H, Taffet GE. Deprescribing statins, considerations for informed decision making. J Am Geriatr Soc. 2023;71(8):2685-9.
8. Bergstrom H, Brånvall E, Helde-Frankling M, Björkhem-Bergman L. Differences in discontinuation of statin treatment in women and men with advanced cancer disease. Biol Sex Differ. 2018;9(1):47.
9. Frisk G, Bergström H, Helde Frankling M, Björkhem-Bergman L. Sex-Differences in Discontinuation of Statin Treatment in Cancer Patients the Year before Death. Pharmaceuticals (Basel). 2021;14(4).

Inclusion Criteria intervention arm:

• ≥ 18 years,
• "No"-answer to the "surprise question" 1 year: Would you be surprised if this patient died in the next year? (this is a common and validated prognostic tool in palliative care)
• advanced cancer
• ongoing palliative care at the the unit study units
• treatment with statins ≥ 3 months for primary or secondary prevention before study inclusion

Inclusion Criteria control-group:

• Same as above but no statin treamnet

Exclusion Criteria:h

• Cognitive impairment
• Does not understand the Swedish language
• Known homozygous or double heterozygous familial hypercholesterolemia
• Active cardiovascular disease or sufficient risk of active cardiovascular disease that requires ongoing medication with statins (assessed by a specialist in cardiology)
• myositis symptoms
• Other contraindications to deprescribe statins.

According to Swedish law, individual patient data is not allowed for sharing.