Discontinuation of Statins in Routine Care Settings: A Cohort Study

As shown by Zhang at al. discontinuation of statins in routine care settings is common.1 Liver test abnormalities and perceived adverse effects are frequently reasons for discontinuation. Yet, sometimes statin therapy is the best treatment option for hyperlipidemia in patients with liver test abnormalities and prior statin-associated adverse effects.

A 63-year old woman was diagnosed at age 50 with severe hyperlipidemia; her cholesterol levels were 400-500 mg/dl. Her parents, three sisters and one brother all had hyperlipidemia; her father died at age 54 from a myocardial infarction, her mother had survived two cerebral vascular accidents and her brother had already had two myocardial infarctions, the first one at age 46. Initially she received atorvastatin but due to markedly abnormal liver tests atorvastatin was discontinued 4 years ago by her physicians. Autoimmune hepatitis was diagnosed and treated with prednisone. Review of her liver disease suggested an overlap syndrome of autoimmune and cholestatic hepatitis; therefore ursodeoxycholic acid was added to treat the cholestatic component of her liver disease. Her liver tests improved but her cholesterol level remained unchanged. Atorvastatin was restarted but the patient experienced diffuse muscle discomfort in arms and legs and therefore stopped the medication; liver tests remained mildly elevated. The patient was adamant and refused to take any further statins.

Given the degree of hyperlipidemia and the family history an N-of-1 trial was proposed to the patient; she agreed.2 Four bottles each containing 28 capsules, two with placebo and two with simvastatin 10 mg, were given in random order to the patient; both patient and physician were blinded to the content. The patient maintained a notebook of symptoms and every four weeks liver and lipid tests were obtained; only the physician was allowed to see the results. After 4 months treatment was unblinded and showed that liver tests remained unchanged, that cholesterol levels had decreased markedly on treatment and that symptoms were unrelated to treatment and worst when on placebo. Given these results the patient agreed to restart simvastatin with gradual dose increase until a normal cholesterol level was achieved; at the same time her liver tests gradually normalized. She has remained on treatment now for 10 years without any evidence of cardiovascular disease or progression of her liver disease.

This case shows that statins can be reintroduced in patients with known liver disease, liver test abnormalities and prior statin-associated adverse effects. An N-of-1 trial in these patients can convince patient as well as physicians of the feasibility, safety and benefit of statin therapy.2

REFERENCES

1. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med 2013;158:526-34.

2. Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT. The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann Intern Med 1990;112:293-9.

We read with great interest the article by Zhang and colleagues (1), which concludes that statin-related adverse events are tolerable and that patients should be rechallenged with statins. Drawing conclusions such as these from observational studies may be limited, as the safety, efficacy and the effects of withdrawing statins were not considered in this setting.

While statin rechallenge may well be justified for some patients, this may not be appropriate for patients in whom there is limited evidence on statin efficacy and well documented risk of harm such as older patients (2). In people aged over 75 years, the role of statins in primary prevention of cardiovascular disease is unclear, and there is limited evidence that statins are effective as secondary prevention (2, 3). In contrast, a strong body of evidence from well-designed observational studies suggests that statins are associated with adverse effects in older people (2). Indeed, younger patients may also experience statin-related side effects. Recent randomized trial conducted in younger patients suggests that compared to placebo, statin use is associated with a loss in energy and worsening exertional fatigue over six months (4). Therefore, for clinicians, it would be beneficial to know whether the occurrence of statin-related adverse events differs across age groups, as well as gender and clinical characteristics. It is interesting that the authors did not consider these factors, commonly investigated in studies of this type.

Finally, there are benefits to stopping statins. A recent pilot statin withdrawal study showed that statin reduction is feasible, safe and is associated with improvements in cognitive function in patients with Alzheimer’s disease (5). Improvements in cognition, measured using the Mini Mental State Examination (MMSE) scores with statin discontinuation were observed. More importantly, rechallenge with statins was associated with a significant decrease in MMSE scores of 1.9 (p<0.007). Rechallenging patients with statins may not be always necessary, particularly for those patients in whom there is limited randomized clinical trial evidence of benefit, and well documented observational evidence of harm.

References

1.Zhang H, Plutzky J, Skentzos S, Morrison F, Mar P, Shubina M, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158(7):526-34.

2.Hilmer SN, Gnjidic D. Statins in older adults. Aust Prescr. 2013; In press.

3.Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews. 2013:Issue 1. Art. No.: CD004816.

4. Golomb BA, Evans MA, Dimsdale JE, White HL. Effects of Statins on Energy and Fatigue With Exertion: Results From a Randomized Controlled Trial. Arch Intern Med. 2012:1-2.

5. Padala KP, Padala PR, McNeilly DP, Geske JA, Sullivan DH, Potter JF. The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer's dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother. 2012;10(5):296-302.

In their recent report, “Discontinuation of Statins in Routine Care Settings: A Cohort Study,” Zhang, et al, describe the frequency and nature of statin discontinuation at two large academic medical centers (1). The observed discontinuation rate was quite high, with over 50% of patients stopping the drug at some point during the 8-year study period. The paper and accompanying editorial suggest that this is a problem to be systematically resolved (2). However, discontinuation of statin medications may be appropriate in certain settings. A growing literature points towards the potentially problematic nature of statin use, such as increased symptomatic side effects and contribution to polypharmacy, in the setting of advanced or serious comorbid illness. There is a strong aggregate history of clinical trials to study the incremental benefit of adding new preventative medications; we need a similar approach to understanding if and when to discontinue those same medications. In a recent study evaluating its impact, thoughtful discontinuation of medications in the setting of advanced illness and multimorbidity was associated with global improvement in health (3).

The question of whether to continue or discontinue statin medications in the hospice and palliative care setting has been actively debated, acknowledging that statins may pose more risk than benefit since longer-term gains are less likely to be realized near the end of life. There is wide variation in practice; true clinical equipoise exists. In response, the National Institute of Nursing Research (NINR)-funded Palliative Care Research Cooperative (PCRC) Group is conducting a randomized controlled trial of statin discontinuation in advanced illness; accrual recently completed (4). This is the first of a planned series of studies to understand the safety and timing of intentional medication discontinuation in the setting of advanced illness – a question that needs as much careful attention as medication initiation.

REFERENCES:

1. Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Annals of internal medicine. Apr 2 2013;158(7):526-534.

2. Grundy SM. Statin discontinuation and intolerance: the challenge of lifelong therapy. Annals of internal medicine. Apr 2 2013;158(7):562-563.

3. Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy. Arch Intern Med. Oct 11 2010;170(18):1648-1654.

4. LeBlanc TW, Kutner JS, Ko D, Wheeler JL, Bull J, Abernethy AP. Developing the evidence base for palliative care: formation of the palliative care research cooperative and its first trial. Hospital practice. Aug 2010;38(5):137-143.

Disclosures: TW LeBlanc - no relevant disclosures; JS Kutner - Grants: NIH (NINR, NCI), AHRQ, ACS; Advisory Board: Medical Editor, Informed Medical Decisions Foundation; CS Ritchie - Research Funding: NIH/NIA, NIH/NINR, Retirement Research Foundation, Commonwealth Fund, Stephen D. Bechtel Foundation; Author: UptoDate; Consultant <$5K annual in past 1 year - University of Utah; Secretary, American Academy of Hospice & Palliative Medicine; AP Abernethy - Current Industry-funded clinical research: Biovex, DARA, Helsinn, MiCo and Pfizer; Pending industry-funded clinical research (in contracting): Eli Lilly, Genentech, Dendreon, BMS; Prior industry-funded research (since 2011): Alexion and Amgen; Consultant <$5K annual in past 2 years –Novartis (2011), Pfizer (2012); Corporate Board of Directors – Advoset (education company, including contracts from Novartis), Orange Leaf Associates LLC (IT development company); Paid role – President, American Academy of Hospice and Palliative Medicine

We agree with Dr. Gnjidic et al. that the balance of risks and benefits of treatment with statins must be carefully weighed in every patient, and might differ between subgroups of patients. To provide further guidance on treatment of dyslipidemia in older individuals, we examined statin discontinuation in patients older than 75 years of age at study entry. There were 19,185 (9.3%) patients older than 75 years out of the total of 107,835 patients included in our study. Among these patients, statin-related events were documented for 2,955 (15.4%) patients. Of these, 1,747 (59.1%) had statins discontinued at least temporarily and 910 (52.1%) were rechallenged with a statin over the subsequent 12 months. Similarly to the overall cohort, overwhelming majority (823 / 90.4%) of patients who were rechallenged were still taking a statin 12 months after the original statin-related event. In conjunction with dedicated clinical trials and meta-analyses that demonstrated improvements in cardiovascular outcomes and mortality in older patients^1,2 , these data provide reassurance that older patients can both benefit from and tolerate statins.

Many clinicians, including the authors, have experienced first-hand the difficulty of ascertaining the exact etiology of symptoms experienced by patients taking statins. While epidemiological data can illuminate the health of populations, the decisions on whether or not to treat someone with a statin have to be made at the individual patient level. In the most difficult situations a carefully designed N-of-1 experiment like the one described by Dr. de Groen can be invaluable in allowing to discern between common non-specific symptoms and an adverse reaction to a medication in a high-risk patient.

As correctly pointed out by Dr. LeBlanc et al., patients with a high load of non-cardiovascular comorbidities can present a particularly difficult dilemma to a clinician who needs to balance the risks of adverse reactions and drug-drug interactions stemming from polypharmacy against benefits that could be curtailed by shorter life expectancy. We are looking forward to the results of the trial the authors are conducting to help provide evidence-based guidance in these complicated clinical situations.

1.         Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. Nov 23 2002;360(9346):1623-1630.

2.         Cholesterol Treatment Trialists' Ctt C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. May 16 2012.