What appetite stimulants other than megestrol acetate (Megace) are appropriate for an older adult with cardiovascular risk factors who cannot tolerate Megace?

Appetite Stimulants for Older Adults with Cardiovascular Risk Factors

For older adults with cardiovascular risk factors who cannot tolerate megestrol acetate, mirtazapine (7.5-15 mg at bedtime) is the preferred first-line alternative, particularly if concurrent depression or sleep disturbance is present, followed by short-term dexamethasone (2-8 mg/day) for patients with limited life expectancy. 1, 2, 3

Primary Alternative: Mirtazapine

Mirtazapine is the safest choice for older adults with cardiovascular comorbidities because it avoids the thromboembolic and mortality risks associated with megestrol acetate while addressing common concurrent conditions. 2, 4

Dosing and Administration

• Start at 7.5 mg at bedtime and titrate up to a maximum of 30 mg based on response 4
• Bedtime dosing capitalizes on sedating properties to improve sleep while stimulating appetite 4
• Allow 4-8 weeks for a full therapeutic trial before declaring treatment failure 4

Expected Outcomes

• Retrospective data in elderly patients shows mean weight gain of 1.9 kg at 3 months and 2.1 kg at 6 months, with approximately 80% experiencing some weight gain 2, 4
• Simultaneously addresses depression, insomnia, and appetite loss—common comorbidities in this population 1, 4

Safety Profile

• No thromboembolic risk, making it superior to megestrol acetate for patients with cardiovascular disease 2
• Generally well-tolerated with beneficial side effects (sedation, appetite stimulation) 4
• Requires gradual discontinuation over 10-14 days to limit withdrawal symptoms 4

Secondary Alternative: Dexamethasone

For patients with very limited life expectancy (weeks to a few months), dexamethasone 2-8 mg/day offers rapid appetite stimulation with lower cost but significant toxicity concerns limit duration of use. 1, 2, 3

When to Choose Dexamethasone

• Life expectancy measured in weeks to months rather than months to years 2
• Need for rapid onset of action (faster than megestrol acetate or mirtazapine) 2, 3
• Cost is a significant concern (substantially cheaper than megestrol acetate) 2

Critical Limitations

• Restrict use to 1-3 weeks maximum due to cumulative toxicity 2
• Side effects include muscle wasting, insulin resistance, hyperglycemia, increased infection risk, and immunosuppression 1, 2
• In one trial, 36% of patients discontinued dexamethasone due to toxicity versus 25% on megestrol acetate (p=0.03) 2

Third-Line Option: Olanzapine

Olanzapine 5 mg/day can be considered for patients with concurrent nausea or vomiting, though evidence is more limited. 2, 3

• Improved appetite scores from 1-2 to 6-8 on a 0-10 scale (p<0.001) in advanced cancer patients 2
• When combined with megestrol acetate in one study, 85% achieved weight gain versus 41% with megestrol alone, though this requires further validation 2
• Particularly useful when nausea compounds poor appetite 3

Agents to Avoid in This Population

Dronabinol (Cannabinoids)

Do not use dronabinol in older adults with cardiovascular risk factors due to hemodynamic instability risks. 5

• FDA labeling specifically warns of hypotension, hypertension, syncope, and tachycardia, especially after initiation or dose increases 5
• Elderly patients, especially those with cardiac disorders or dementia, have increased risk of blood pressure changes and falls 5
• Meta-analysis shows cannabinoids are inferior to megestrol acetate for appetite stimulation 2
• Limited evidence in hospitalized adults shows no significant benefit 6, 7

Cyproheptadine

• Insufficient evidence of benefit for cachexia in adults 1
• Adverse effects reported in available trials 1
• Should only be used in clinical trial settings 1

Critical Contraindications and Precautions

Why Megestrol Acetate is Inappropriate

The question specifically addresses patients who cannot tolerate megestrol acetate, likely due to:

• Thromboembolic risk: 1.84 times higher than placebo (RR 1.84; 95% CI 1.07-3.18), with approximately 1 in 6 patients developing DVT or pulmonary embolism 2
• Increased mortality: 1.42 times higher than placebo (RR 1.42), with 1 in 23 patients dying from treatment-related complications 2
• Edema occurs with RR 1.36 2
• Weight gain is primarily adipose tissue, not lean muscle mass 2

Special Population: Dementia Patients

If the patient has dementia without concurrent depression, do not use any pharmacological appetite stimulants. 3, 4

• Clinical Nutrition guidelines state with 89% consensus that appetite stimulants are NOT recommended for persons with dementia due to limited evidence and potential risks outweighing uncertain benefits 3, 4
• Focus instead on non-pharmacological approaches: feeding assistance, emotional support during meals, social dining environments, and preferred foods 3

Non-Pharmacological Strategies to Implement Concurrently

Regardless of which medication is chosen, optimize these evidence-based interventions first: 3

• Medication review: Temporarily discontinue non-essential medications contributing to anorexia (e.g., iron supplements, excessive pre-meal medications) 4
• Social interventions: Encourage shared meals with family or other patients to improve intake 4
• Dietary modifications: Offer smaller, frequent meals with favorite foods; provide energy-dense options to maximize nutrition without increasing volume 3, 4
• Oral nutritional supplements when dietary intake falls to 50-75% of usual intake 3
• Protein-enriched foods and drinks to preserve lean body mass 3

Monitoring and Reassessment Algorithm

Initial 12 Weeks

• Assess response at weeks 1,2,4,8, and 12 4
• Monitor for adverse effects, particularly sedation (mirtazapine) or hyperglycemia (dexamethasone) 1, 4
• Document weight changes, meal intake percentage, and subjective appetite improvement 6

Long-Term Management (Mirtazapine)

• After 9 months of treatment, consider dose reduction to reassess need for continued medication 4
• Regularly reassess benefit versus harm, as goals of care may change with disease progression 1, 4

When to Stop

• If approaching end of life, focus on comfort and quality of life rather than nutritional goals; overly aggressive interventions can increase suffering 4
• No response after adequate trial period (4-8 weeks for mirtazapine, 1-3 weeks for dexamethasone) 2, 4

Common Pitfalls to Avoid

1. Do not use megestrol acetate in patients with cardiovascular risk factors without thoroughly discussing the 1.84-fold increased thromboembolic risk and 1.42-fold increased mortality risk 2

2. Do not prescribe dexamethasone for more than 1-3 weeks due to cumulative toxicity including muscle wasting and immunosuppression 2

3. Do not use dronabinol in elderly patients with cardiac disease due to FDA warnings about hemodynamic instability and increased fall risk 5

4. Do not prescribe appetite stimulants to dementia patients without depression—the evidence shows no consistent benefit and potential harm 3, 4

5. Do not expect lean muscle mass gain from any of these agents; weight gain is predominantly adipose tissue 2

6. Do not forget to address reversible causes of anorexia (medication side effects, depression, poor dentition, swallowing difficulties) before or concurrent with pharmacotherapy 4