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Managing comorbidities in patients at the end of life
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     1 Southern Adelaide Palliative Services, Repatriation General Hospital, 700 Goodwood Road, Daw Park, South Australia 5041, Australia, 2 Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Division of Medical Oncology, 3 Division of General Medicine, Repatriation General Hospital, 4 Flinders University, Adelaide, Australia Department of Palliative and Supportive Services

    Correspondence to: D C Currow david.currow@rgh.sa.gov.au

    Chronic conditions require careful management in patients who develop a life limiting illness. Doctors need to consider both the physical and psychological effects of treatment

    Introduction

    Life limiting illnesses include advanced cancer, end stage organ failure, neurodegenerative disease, and AIDS. Common conditions that need active management at the end of life include hypertension, atrial fibrillation, hypercholesterolaemia, thromboembolic disease, dementia, osteoporosis, diabetes mellitus, and arrhythmia. Patients may also be taking hormone replacement therapy, immunosuppressive therapy after transplantation, or drugs to prevent opportunistic infections in people who are immunocompromised. Both the life limiting illness and comorbidity change clinically over time and therefore need regular review. What is the best way to minimise the increasing risks of long term drugs as a person's body changes with advancing life limiting illness and the known risks of polypharmacy as additional drugs are introduced to control symptoms?2

    Key considerations

    The pharmacokinetics and pharmacodynamics of drugs can change unpredictably in patients at the end of life. These changes will often heighten the effects of the drug. For example, the net effect of an antihypertensive drug may be much greater as death approaches. This is complicated by the fact that patients are often given drugs to control symptoms as the life limiting illness progresses. Polypharmacy increases the risk of drug interactions causing morbidity and potentially premature death. The risk of a serious adverse drug interaction is greater than 80% when more than seven drugs are taken.3 4

    Withdrawing long term drugs for comorbidities without considering the natural course of the illness can lead to serious problems. Rebound hypertension and tachycardia may occur when and adrenergic blockers are withdrawn. An increase in viral load has been reported in people with AIDS when antiretroviral therapy is stopped.5

    Pathophysiology of death

    The natural course of the life limiting illness and comorbidity affects clinical treatment. Most importantly, how does this disease behave with and without intervention? How does the disease usually progress over time? How likely is it that the course of either the life limiting illness or the comorbidity is now being influenced by the current interventions? What is the likelihood of an acute deterioration in the chronic comorbidity if treatment is reduced or withdrawn?

    Prognostication is important in the decisions about management of chronic comorbidity because it frames time and influences how we respond to data on number needed to treat. For example, median and 1 or 5 year survival figures give an indication of the behaviour of the illness. Studies of doctors treating patients with life limiting illness show that clinicians inconsistently predict the absolute life expectancy but are quite accurate at predicting the remaining time in days, weeks, or months.8 The rates of change in level of function and systemic measures (weight loss, anorexia, and fatigue) are good indices of the future disease trajectory if no reversible causes are evident.

    Measure of benefit

    The therapeutic aim of treating comorbidities has to be clear to decide how aggressively to treat them. Very few people take long term drugs for primary prevention (no disease present). Many people are treated for secondary prevention (disease present but no symptoms). Tertiary prevention minimises the effect of a disease that is causing symptoms.10 Tertiary prevention tends to have a lower number needed to treat than primary prevention for the same clinical condition. For example, in diabetes, the number needed to treat with tight glycaemic control to prevent nephropathy over five years is 83. To limit the progression of asymptomatic, established nephropathy, it is 48.11 Tight glycaemic control increases the risk of adverse effects such as hypoglycaemia, and that can be reflected in the number needed to harm. About one in three people treated with tight glycaemic control will develop life threatening hypoglycaemia in five years.12 13 Similar data can be derived for other long term conditions such as hypertension.14-18 Drugs prescribed for tertiary prevention of a disease are likely to be continued further into the course of the life limiting illness than those prescribed for secondary prevention of the same disease (figure).

    Factors influencing the likelihood of continuing treatment for medical comorbidities in patients with life limiting illness, and examples of conditions in each category

    Psychological concerns

    Every clinician is responsible for the quality use of medications. In the face of life limiting illness, the combination of drugs for symptom control and long term comorbidities creates specific challenges for which little guidance exists. Decisions to adjust drugs should be taken actively as whole body changes occur in life limiting illness, rather than in response to adverse effects. Patients require ongoing clinical assessments that incorporate an understanding of pharmacokinetics, pharmacodynamics, pathophysiology, prognosis, number needed to treat, and the aims of treatment within the context of patient choices and best clinical practice (see bmj.com). Research is needed to explore the psychological effect of changing long term drugs or redefining long term care goals. We also need to develop a way of standardising number needed to treat over time, incorporating the non-linear aspects of this measure, to allow comparisons between the benefits and burdens of treatment for chronic conditions in patients with life limiting illness.

    Summary points

    Managing comorbid conditions in patients with life limiting illness requires active review to balance the problem of diminishing benefits with increasing side effects

    Weight loss and other systemic changes reduce the need for many long term drugs or alter their metabolism

    Some long term drugs should be continued until death while others should be ceased as systemic changes occur

    Data on number needed to treat can be used to inform decisions about stopping long term treatments

    As prognosis worsens for a given condition, number needed to treat increases

    Illustrative clinical scenarios are presented on bmj.com

    Contributors and sources: DCC and APA are currently leading a national project looking at the evidence base for clinical practice in palliative care. Their clinical practice includes people from a wide range of clinical backgrounds at the end of life(caresearch.com.au). CM is a general physician, much of whose practice deals with chronic complex illness. JS is a registrar doing advanced training in palliative medicine. DCC and APA were responsible for the conception and design of this article. CM and JS contributed to drafting the article and revising it critically. DCC is the guarantor.

    Competing interests: None declared.

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