A 65-year-old man presents with a 2-month history of generalized weakness, dizziness, and blurred vision. His symptoms began gradually and have been progressing over the last few weeks, so that they now affect his ability to perform normal daily activities.

He has lost 20 lb and has become anorectic. He has no fever, night sweats, headache, cough, hemoptysis, or dyspnea. He has no history of abdominal pain, changes in bowel habits, nausea, vomiting, or urinary symptoms. He was admitted 6 weeks ago for the same symptoms; he was treated for hypotension and received intravenous (IV) fluids and electrolyte supplements for dehydration.

He has a history of hypertension, stroke, vascular dementia, and atrial fibrillation. He is taking warfarin (Coumadin), extended-release diltiazem (Cardizem), simvastatin (Zocor), and donepezil (Aricept). He underwent right hemicolectomy 5 years ago for a large tubular adenoma with high-grade dysplasia in the cecum.

Initial laboratory values are as follows:

• White blood cell count 7.4 × 10⁹/L (reference range 4.5–11.0), with a normal differential
• Mild anemia, with a hemoglobin of 116 g/L (140–175)
• Activated partial thromboplastin time 59.9 sec (23.0–32.4)
• Serum sodium 135 mmol/L (136–142)
• Serum potassium 4.6 mmol/L (3.5–5.0)
• Aspartate aminotransferase 58 U/L (10–30)
• Alanine aminotransferase 16 U/L (10–40)
• Alkaline phosphatase 328 U/L (30–120)
• Urea, creatinine, and corrected calcium are normal.

Electrocardiography shows atrial fibrillation with low-voltage QRS complexes. Chest radiography is normal. A stool test is negative for occult blood. A workup for sepsis is negative.

Q: Which is the appropriate test at this point to determine the cause of the hypotension?

• Serum parathyroid-hormone-related protein
• Baseline serum cortisol, plasma adrenocorticotropic hormone (ACTH) levels, and an ACTH stimulation test with cosyntropin (Cortrosyn)
• Serum thyrotropin level
• Aspiration biopsy of subcutaneous fat with Congo red and immunostaining
• Late-night salivary cortisol

A: The correct next step is to measure baseline serum cortisol, to test ACTH levels, and to order an ACTH stimulation test with cosyntropin.

Primary adrenocortical insufficiency should be considered in patients with metastatic malignancy who present with peripheral vascular collapse, particularly when it is associated with cutaneous hyperpigmentation, chronic malaise, fatigue, weakness, anorexia, weight loss, hypoglycemia, and electrolyte disturbances such as hyponatremia and hyperkalemia.

Checking the baseline serum cortisol and ACTH levels and cosyntropin stimulation testing are vital steps in making an early diagnosis of primary adrenocortical insufficiency. Inappropriately low serum cortisol is highly suggestive of primary adrenal insufficiency, especially if accompanied by simultaneous elevation of the plasma ACTH level. The result of the ACTH stimulation test with cosyntropin is often confirmatory.

Measuring the serum parathyroid-hormone-related protein level is not indicated, since the patient has a normal corrected calcium. Patients with ectopic Cushing syndrome may present with weight loss due to underlying malignancy, but the presence of hypotension and a lack of hypokalemia makes such a diagnosis unlikely, and, therefore, measurement of late-night salivary cortisol is not the best answer. Amyloidosis, hypothyroidism, or hyperthyroidism are unlikely to have this patient’s presentation.

RESULTS OF FURTHER EVALUATION

Our patient’s ACTH serum level was elevated, and an ACTH stimulation test with cosyntropin confirmed the diagnosis of primary adrenal insufficiency.

CT of the abdomen failed to demonstrate primary tumors, but both adrenal glands were enlarged, likely from metastasis (Figure 4). His hypotension responded to treatment with hydrocortisone and fludrocortisone, and his symptoms resolved. No further testing or therapy was directed to the primary occult malignancy, as it was considered advanced. The prognosis was discussed with the patient, and he deferred any further management and was discharged to hospice care. He died a few months later.

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Primary adrenocortical insufficiency is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens. In the United States, nearly 6 million people are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.¹

Primary adrenocortical insufficiency affects men and women equally. However, the idiopathic autoimmune form of adrenal insufficiency (Addison disease) is two to three times more common in women than in men.

If the condition is undiagnosed or ineffectively treated, the risk of significant morbidity and death is high. Symptoms and signs are nonspecific, and the onset is insidious.

Almost all patients with primary adrenal insufficiency have malaise, fatigue, anorexia, and weight loss. Vomiting, abdominal pain, and fever are more common during an adrenal crisis, when a patient with subclinical disease is subjected to major stress. Postural dizziness or syncope is a common result of volume depletion and hypotension.^2–4 It is commonly accompanied by hyponatremia and hyperkalemia.

Hyperpigmentation is the most characteristic physical finding and is caused by an ACTH-mediated increase in melanin content in the skin.^2,4,5 The resulting brown hyperpigmentation is most obvious in areas exposed to sunlight (face, neck, backs of hands), and in areas exposed to chronic friction or pressure, such as the elbows, knees, knuckles, waist, and shoulders (brassiere straps).⁴ Pigmentation is also prominent in the palmar creases, areolae, axillae, perineum, surgical scars, and umbilicus. Other patterns of hyperpigmentation are patchy pigmentation on the inner surface of lips, the buccal mucosa, under the tongue, and on the hard palate.^3,5 The hyperpigmentation begins to fade within several days and largely disappears after a few months of adequate glucocorticoid therapy.⁴

In the United States, 80% of cases of primary adrenocortical insufficiency are caused by autoimmune adrenal destruction. The remainder are caused by infectious diseases (eg, tuberculosis, fungal infection, cytomegalovirus infection, and Mycobacterium aviumintracellulare infection in the context of human immunodeficiency virus infection), by infiltration of the adrenal glands by metastatic cancer, by adrenal hemorrhage, or by drugs such as ketoconazole, fluconazole (Diflucan), metyrapone (Metopirone), mitotane (Lysodren), and etomidate (Amidate).^4,6

Adrenal metastatic disease

Infiltration of the adrenal glands by metastatic cancer is not uncommon, probably because of their rich sinusoidal blood supply, and the adrenals are the fourth most common site of metastasis. Common primary tumors are lung, breast, melanoma, gastric, esophageal, and colorectal cancers, while metastasis due to an undetermined primary tumor is the least common.⁷

Clinically evident adrenal insufficiency produced by metastatic carcinoma is uncommon because most of the adrenal cortex must be destroyed before hypofunction becomes evident.^7–9

Malignancy rarely presents first as adrenal insufficiency caused by metastatic infiltration.¹⁰

Hormonal therapy may significantly improve symptoms and quality of life in patients with metastatic adrenal insufficiency.^8,11

DIAGNOSIS AND MANAGEMENT

Once primary adrenal insufficiency is suspected, prompt diagnosis and treatment are essential. A low plasma cortisol level (< 3 μg/dL) at 8 am is highly suggestive of adrenal insufficiency if exposure to exogenous glucocorticoids has been excluded (including oral, inhaled, and injected),^12,13 especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). An 8 am cortisol concentration above 15 μg/dL makes adrenal insufficiency highly unlikely, but levels between 3 and 15 μg/dL are nondiagnostic and need to be further evaluated by an ACTH stimulation test with cosyntropin.^4,7

Imaging in primary adrenal insufficiency may be considered when the condition is not clearly autoimmune.¹⁴ Abdominal CT is the ideal imaging test for detecting abnormal adrenal glands. CT shows small, noncalcified adrenals in autoimmune Addison disease. It demonstrates enlarged adrenals in about 85% of cases caused by metastatic or granulomatous disease; and calcification is noted in cases of tuberculous adrenal disease.⁴

Management involves treating the underlying cause and starting hormone replacement therapy. Hormonal therapy consists of corticosteroids and mineralocorticoids; hydrocortisone is the drug of choice and is usually given with fludrocortisone acetate, which has a potent sodium-retaining effect. In the presence of a stressor (fever, surgery, severe illness), the dose of hydrocortisone should be doubled (> 50 mg hydrocortisone per day) for at least 3 to 5 days.^2,4

A 65-year-old man presents with a 2-month history of generalized weakness, dizziness, and blurred vision. His symptoms began gradually and have been progressing over the last few weeks, so that they now affect his ability to perform normal daily activities.

He has lost 20 lb and has become anorectic. He has no fever, night sweats, headache, cough, hemoptysis, or dyspnea. He has no history of abdominal pain, changes in bowel habits, nausea, vomiting, or urinary symptoms. He was admitted 6 weeks ago for the same symptoms; he was treated for hypotension and received intravenous (IV) fluids and electrolyte supplements for dehydration.

He has a history of hypertension, stroke, vascular dementia, and atrial fibrillation. He is taking warfarin (Coumadin), extended-release diltiazem (Cardizem), simvastatin (Zocor), and donepezil (Aricept). He underwent right hemicolectomy 5 years ago for a large tubular adenoma with high-grade dysplasia in the cecum.

Initial laboratory values are as follows:

• White blood cell count 7.4 × 10⁹/L (reference range 4.5–11.0), with a normal differential
• Mild anemia, with a hemoglobin of 116 g/L (140–175)
• Activated partial thromboplastin time 59.9 sec (23.0–32.4)
• Serum sodium 135 mmol/L (136–142)
• Serum potassium 4.6 mmol/L (3.5–5.0)
• Aspartate aminotransferase 58 U/L (10–30)
• Alanine aminotransferase 16 U/L (10–40)
• Alkaline phosphatase 328 U/L (30–120)
• Urea, creatinine, and corrected calcium are normal.

Electrocardiography shows atrial fibrillation with low-voltage QRS complexes. Chest radiography is normal. A stool test is negative for occult blood. A workup for sepsis is negative.

Q: Which is the appropriate test at this point to determine the cause of the hypotension?

• Serum parathyroid-hormone-related protein
• Baseline serum cortisol, plasma adrenocorticotropic hormone (ACTH) levels, and an ACTH stimulation test with cosyntropin (Cortrosyn)
• Serum thyrotropin level
• Aspiration biopsy of subcutaneous fat with Congo red and immunostaining
• Late-night salivary cortisol

A: The correct next step is to measure baseline serum cortisol, to test ACTH levels, and to order an ACTH stimulation test with cosyntropin.

Primary adrenocortical insufficiency should be considered in patients with metastatic malignancy who present with peripheral vascular collapse, particularly when it is associated with cutaneous hyperpigmentation, chronic malaise, fatigue, weakness, anorexia, weight loss, hypoglycemia, and electrolyte disturbances such as hyponatremia and hyperkalemia.

Checking the baseline serum cortisol and ACTH levels and cosyntropin stimulation testing are vital steps in making an early diagnosis of primary adrenocortical insufficiency. Inappropriately low serum cortisol is highly suggestive of primary adrenal insufficiency, especially if accompanied by simultaneous elevation of the plasma ACTH level. The result of the ACTH stimulation test with cosyntropin is often confirmatory.

Measuring the serum parathyroid-hormone-related protein level is not indicated, since the patient has a normal corrected calcium. Patients with ectopic Cushing syndrome may present with weight loss due to underlying malignancy, but the presence of hypotension and a lack of hypokalemia makes such a diagnosis unlikely, and, therefore, measurement of late-night salivary cortisol is not the best answer. Amyloidosis, hypothyroidism, or hyperthyroidism are unlikely to have this patient’s presentation.

RESULTS OF FURTHER EVALUATION

Our patient’s ACTH serum level was elevated, and an ACTH stimulation test with cosyntropin confirmed the diagnosis of primary adrenal insufficiency.

CT of the abdomen failed to demonstrate primary tumors, but both adrenal glands were enlarged, likely from metastasis (Figure 4). His hypotension responded to treatment with hydrocortisone and fludrocortisone, and his symptoms resolved. No further testing or therapy was directed to the primary occult malignancy, as it was considered advanced. The prognosis was discussed with the patient, and he deferred any further management and was discharged to hospice care. He died a few months later.

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Primary adrenocortical insufficiency is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens. In the United States, nearly 6 million people are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.¹

Primary adrenocortical insufficiency affects men and women equally. However, the idiopathic autoimmune form of adrenal insufficiency (Addison disease) is two to three times more common in women than in men.

If the condition is undiagnosed or ineffectively treated, the risk of significant morbidity and death is high. Symptoms and signs are nonspecific, and the onset is insidious.

Almost all patients with primary adrenal insufficiency have malaise, fatigue, anorexia, and weight loss. Vomiting, abdominal pain, and fever are more common during an adrenal crisis, when a patient with subclinical disease is subjected to major stress. Postural dizziness or syncope is a common result of volume depletion and hypotension.^2–4 It is commonly accompanied by hyponatremia and hyperkalemia.

Hyperpigmentation is the most characteristic physical finding and is caused by an ACTH-mediated increase in melanin content in the skin.^2,4,5 The resulting brown hyperpigmentation is most obvious in areas exposed to sunlight (face, neck, backs of hands), and in areas exposed to chronic friction or pressure, such as the elbows, knees, knuckles, waist, and shoulders (brassiere straps).⁴ Pigmentation is also prominent in the palmar creases, areolae, axillae, perineum, surgical scars, and umbilicus. Other patterns of hyperpigmentation are patchy pigmentation on the inner surface of lips, the buccal mucosa, under the tongue, and on the hard palate.^3,5 The hyperpigmentation begins to fade within several days and largely disappears after a few months of adequate glucocorticoid therapy.⁴

In the United States, 80% of cases of primary adrenocortical insufficiency are caused by autoimmune adrenal destruction. The remainder are caused by infectious diseases (eg, tuberculosis, fungal infection, cytomegalovirus infection, and Mycobacterium aviumintracellulare infection in the context of human immunodeficiency virus infection), by infiltration of the adrenal glands by metastatic cancer, by adrenal hemorrhage, or by drugs such as ketoconazole, fluconazole (Diflucan), metyrapone (Metopirone), mitotane (Lysodren), and etomidate (Amidate).^4,6

Adrenal metastatic disease

Infiltration of the adrenal glands by metastatic cancer is not uncommon, probably because of their rich sinusoidal blood supply, and the adrenals are the fourth most common site of metastasis. Common primary tumors are lung, breast, melanoma, gastric, esophageal, and colorectal cancers, while metastasis due to an undetermined primary tumor is the least common.⁷

Clinically evident adrenal insufficiency produced by metastatic carcinoma is uncommon because most of the adrenal cortex must be destroyed before hypofunction becomes evident.^7–9

Malignancy rarely presents first as adrenal insufficiency caused by metastatic infiltration.¹⁰

Hormonal therapy may significantly improve symptoms and quality of life in patients with metastatic adrenal insufficiency.^8,11

DIAGNOSIS AND MANAGEMENT

Once primary adrenal insufficiency is suspected, prompt diagnosis and treatment are essential. A low plasma cortisol level (< 3 μg/dL) at 8 am is highly suggestive of adrenal insufficiency if exposure to exogenous glucocorticoids has been excluded (including oral, inhaled, and injected),^12,13 especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). An 8 am cortisol concentration above 15 μg/dL makes adrenal insufficiency highly unlikely, but levels between 3 and 15 μg/dL are nondiagnostic and need to be further evaluated by an ACTH stimulation test with cosyntropin.^4,7

Imaging in primary adrenal insufficiency may be considered when the condition is not clearly autoimmune.¹⁴ Abdominal CT is the ideal imaging test for detecting abnormal adrenal glands. CT shows small, noncalcified adrenals in autoimmune Addison disease. It demonstrates enlarged adrenals in about 85% of cases caused by metastatic or granulomatous disease; and calcification is noted in cases of tuberculous adrenal disease.⁴

Management involves treating the underlying cause and starting hormone replacement therapy. Hormonal therapy consists of corticosteroids and mineralocorticoids; hydrocortisone is the drug of choice and is usually given with fludrocortisone acetate, which has a potent sodium-retaining effect. In the presence of a stressor (fever, surgery, severe illness), the dose of hydrocortisone should be doubled (> 50 mg hydrocortisone per day) for at least 3 to 5 days.^2,4

A 65-year-old man presents with a 2-month history of generalized weakness, dizziness, and blurred vision. His symptoms began gradually and have been progressing over the last few weeks, so that they now affect his ability to perform normal daily activities.

He has lost 20 lb and has become anorectic. He has no fever, night sweats, headache, cough, hemoptysis, or dyspnea. He has no history of abdominal pain, changes in bowel habits, nausea, vomiting, or urinary symptoms. He was admitted 6 weeks ago for the same symptoms; he was treated for hypotension and received intravenous (IV) fluids and electrolyte supplements for dehydration.

He has a history of hypertension, stroke, vascular dementia, and atrial fibrillation. He is taking warfarin (Coumadin), extended-release diltiazem (Cardizem), simvastatin (Zocor), and donepezil (Aricept). He underwent right hemicolectomy 5 years ago for a large tubular adenoma with high-grade dysplasia in the cecum.

Initial laboratory values are as follows:

• White blood cell count 7.4 × 10⁹/L (reference range 4.5–11.0), with a normal differential
• Mild anemia, with a hemoglobin of 116 g/L (140–175)
• Activated partial thromboplastin time 59.9 sec (23.0–32.4)
• Serum sodium 135 mmol/L (136–142)
• Serum potassium 4.6 mmol/L (3.5–5.0)
• Aspartate aminotransferase 58 U/L (10–30)
• Alanine aminotransferase 16 U/L (10–40)
• Alkaline phosphatase 328 U/L (30–120)
• Urea, creatinine, and corrected calcium are normal.

Electrocardiography shows atrial fibrillation with low-voltage QRS complexes. Chest radiography is normal. A stool test is negative for occult blood. A workup for sepsis is negative.

Q: Which is the appropriate test at this point to determine the cause of the hypotension?

• Serum parathyroid-hormone-related protein
• Baseline serum cortisol, plasma adrenocorticotropic hormone (ACTH) levels, and an ACTH stimulation test with cosyntropin (Cortrosyn)
• Serum thyrotropin level
• Aspiration biopsy of subcutaneous fat with Congo red and immunostaining
• Late-night salivary cortisol

A: The correct next step is to measure baseline serum cortisol, to test ACTH levels, and to order an ACTH stimulation test with cosyntropin.

Primary adrenocortical insufficiency should be considered in patients with metastatic malignancy who present with peripheral vascular collapse, particularly when it is associated with cutaneous hyperpigmentation, chronic malaise, fatigue, weakness, anorexia, weight loss, hypoglycemia, and electrolyte disturbances such as hyponatremia and hyperkalemia.

Checking the baseline serum cortisol and ACTH levels and cosyntropin stimulation testing are vital steps in making an early diagnosis of primary adrenocortical insufficiency. Inappropriately low serum cortisol is highly suggestive of primary adrenal insufficiency, especially if accompanied by simultaneous elevation of the plasma ACTH level. The result of the ACTH stimulation test with cosyntropin is often confirmatory.

Measuring the serum parathyroid-hormone-related protein level is not indicated, since the patient has a normal corrected calcium. Patients with ectopic Cushing syndrome may present with weight loss due to underlying malignancy, but the presence of hypotension and a lack of hypokalemia makes such a diagnosis unlikely, and, therefore, measurement of late-night salivary cortisol is not the best answer. Amyloidosis, hypothyroidism, or hyperthyroidism are unlikely to have this patient’s presentation.

RESULTS OF FURTHER EVALUATION

Our patient’s ACTH serum level was elevated, and an ACTH stimulation test with cosyntropin confirmed the diagnosis of primary adrenal insufficiency.

CT of the abdomen failed to demonstrate primary tumors, but both adrenal glands were enlarged, likely from metastasis (Figure 4). His hypotension responded to treatment with hydrocortisone and fludrocortisone, and his symptoms resolved. No further testing or therapy was directed to the primary occult malignancy, as it was considered advanced. The prognosis was discussed with the patient, and he deferred any further management and was discharged to hospice care. He died a few months later.

PRIMARY ADRENOCORTICAL INSUFFICIENCY

Primary adrenocortical insufficiency is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. It is characterized by chronic deficiency of cortisol, aldosterone, and adrenal androgens. In the United States, nearly 6 million people are considered to have undiagnosed adrenal insufficiency, which is clinically significant only during times of physiologic stress.¹

Primary adrenocortical insufficiency affects men and women equally. However, the idiopathic autoimmune form of adrenal insufficiency (Addison disease) is two to three times more common in women than in men.

If the condition is undiagnosed or ineffectively treated, the risk of significant morbidity and death is high. Symptoms and signs are nonspecific, and the onset is insidious.

Almost all patients with primary adrenal insufficiency have malaise, fatigue, anorexia, and weight loss. Vomiting, abdominal pain, and fever are more common during an adrenal crisis, when a patient with subclinical disease is subjected to major stress. Postural dizziness or syncope is a common result of volume depletion and hypotension.^2–4 It is commonly accompanied by hyponatremia and hyperkalemia.

Hyperpigmentation is the most characteristic physical finding and is caused by an ACTH-mediated increase in melanin content in the skin.^2,4,5 The resulting brown hyperpigmentation is most obvious in areas exposed to sunlight (face, neck, backs of hands), and in areas exposed to chronic friction or pressure, such as the elbows, knees, knuckles, waist, and shoulders (brassiere straps).⁴ Pigmentation is also prominent in the palmar creases, areolae, axillae, perineum, surgical scars, and umbilicus. Other patterns of hyperpigmentation are patchy pigmentation on the inner surface of lips, the buccal mucosa, under the tongue, and on the hard palate.^3,5 The hyperpigmentation begins to fade within several days and largely disappears after a few months of adequate glucocorticoid therapy.⁴

In the United States, 80% of cases of primary adrenocortical insufficiency are caused by autoimmune adrenal destruction. The remainder are caused by infectious diseases (eg, tuberculosis, fungal infection, cytomegalovirus infection, and Mycobacterium aviumintracellulare infection in the context of human immunodeficiency virus infection), by infiltration of the adrenal glands by metastatic cancer, by adrenal hemorrhage, or by drugs such as ketoconazole, fluconazole (Diflucan), metyrapone (Metopirone), mitotane (Lysodren), and etomidate (Amidate).^4,6

Adrenal metastatic disease

Infiltration of the adrenal glands by metastatic cancer is not uncommon, probably because of their rich sinusoidal blood supply, and the adrenals are the fourth most common site of metastasis. Common primary tumors are lung, breast, melanoma, gastric, esophageal, and colorectal cancers, while metastasis due to an undetermined primary tumor is the least common.⁷

Clinically evident adrenal insufficiency produced by metastatic carcinoma is uncommon because most of the adrenal cortex must be destroyed before hypofunction becomes evident.^7–9

Malignancy rarely presents first as adrenal insufficiency caused by metastatic infiltration.¹⁰

Hormonal therapy may significantly improve symptoms and quality of life in patients with metastatic adrenal insufficiency.^8,11

DIAGNOSIS AND MANAGEMENT

Once primary adrenal insufficiency is suspected, prompt diagnosis and treatment are essential. A low plasma cortisol level (< 3 μg/dL) at 8 am is highly suggestive of adrenal insufficiency if exposure to exogenous glucocorticoids has been excluded (including oral, inhaled, and injected),^12,13 especially if accompanied by simultaneous elevation of the plasma ACTH level (usually > 200 pg/mL). An 8 am cortisol concentration above 15 μg/dL makes adrenal insufficiency highly unlikely, but levels between 3 and 15 μg/dL are nondiagnostic and need to be further evaluated by an ACTH stimulation test with cosyntropin.^4,7

Imaging in primary adrenal insufficiency may be considered when the condition is not clearly autoimmune.¹⁴ Abdominal CT is the ideal imaging test for detecting abnormal adrenal glands. CT shows small, noncalcified adrenals in autoimmune Addison disease. It demonstrates enlarged adrenals in about 85% of cases caused by metastatic or granulomatous disease; and calcification is noted in cases of tuberculous adrenal disease.⁴

Management involves treating the underlying cause and starting hormone replacement therapy. Hormonal therapy consists of corticosteroids and mineralocorticoids; hydrocortisone is the drug of choice and is usually given with fludrocortisone acetate, which has a potent sodium-retaining effect. In the presence of a stressor (fever, surgery, severe illness), the dose of hydrocortisone should be doubled (> 50 mg hydrocortisone per day) for at least 3 to 5 days.^2,4

Screening seems to be such an easy concept: look for cancer before it is symptomatic, find it at an early stage, and treat it. We should be more able to cure cancer if it is found during screening, or at least to significantly prolong the patient’s survival by slowing the cancer’s growth and metastasis. But exactly which screening strategies save lives (and what level of efficacy is cost-effective and risk-acceptable to society and individuals) has turned out to be difficult to prove in clinical trials.

For screening to be efficacious, the test must be able to detect cancer at a stage at which early treatment makes a difference. Herein lie two challenges. A person with a cancer that grows so slowly that early treatment may not make a survival difference will not benefit from screening, and neither will someone with cancer that is so aggressive that early treatment will not significantly slow its malignant outcome. The first scenario is called “overdiagnosis”—a diagnosis made during screening that may not affect the prognosis but can lead to significant anxiety as well as additional testing and treatments, with associated costs. This has yet to be fully addressed in lung cancer screening using repeated CT imaging, but it has been discussed in breast and prostate screening.

Other challenges include how individual physicians will implement a successful lung screening program, which is more complex than yearly mammography, requiring consecutive yearly CT screening with tracking of specific results and incidental findings. How will screening be limited to appropriate patients, as dictated by trial results? Will CT review be as successful in the community as it was in trial centers of excellence? Since smoking (an act of personal choice) is the major risk factor that warrants screening, who should bear the cost?

Then there are potential unintended consequences. What if lung cancer screening makes current smokers more complacent about continuing to smoke? We must increase our educational efforts on smoking cessation, efforts that I sense are having a disappointingly limited impact on the younger generation.

Screening seems to be such an easy concept: look for cancer before it is symptomatic, find it at an early stage, and treat it. We should be more able to cure cancer if it is found during screening, or at least to significantly prolong the patient’s survival by slowing the cancer’s growth and metastasis. But exactly which screening strategies save lives (and what level of efficacy is cost-effective and risk-acceptable to society and individuals) has turned out to be difficult to prove in clinical trials.

For screening to be efficacious, the test must be able to detect cancer at a stage at which early treatment makes a difference. Herein lie two challenges. A person with a cancer that grows so slowly that early treatment may not make a survival difference will not benefit from screening, and neither will someone with cancer that is so aggressive that early treatment will not significantly slow its malignant outcome. The first scenario is called “overdiagnosis”—a diagnosis made during screening that may not affect the prognosis but can lead to significant anxiety as well as additional testing and treatments, with associated costs. This has yet to be fully addressed in lung cancer screening using repeated CT imaging, but it has been discussed in breast and prostate screening.

Other challenges include how individual physicians will implement a successful lung screening program, which is more complex than yearly mammography, requiring consecutive yearly CT screening with tracking of specific results and incidental findings. How will screening be limited to appropriate patients, as dictated by trial results? Will CT review be as successful in the community as it was in trial centers of excellence? Since smoking (an act of personal choice) is the major risk factor that warrants screening, who should bear the cost?

Then there are potential unintended consequences. What if lung cancer screening makes current smokers more complacent about continuing to smoke? We must increase our educational efforts on smoking cessation, efforts that I sense are having a disappointingly limited impact on the younger generation.

Screening seems to be such an easy concept: look for cancer before it is symptomatic, find it at an early stage, and treat it. We should be more able to cure cancer if it is found during screening, or at least to significantly prolong the patient’s survival by slowing the cancer’s growth and metastasis. But exactly which screening strategies save lives (and what level of efficacy is cost-effective and risk-acceptable to society and individuals) has turned out to be difficult to prove in clinical trials.

For screening to be efficacious, the test must be able to detect cancer at a stage at which early treatment makes a difference. Herein lie two challenges. A person with a cancer that grows so slowly that early treatment may not make a survival difference will not benefit from screening, and neither will someone with cancer that is so aggressive that early treatment will not significantly slow its malignant outcome. The first scenario is called “overdiagnosis”—a diagnosis made during screening that may not affect the prognosis but can lead to significant anxiety as well as additional testing and treatments, with associated costs. This has yet to be fully addressed in lung cancer screening using repeated CT imaging, but it has been discussed in breast and prostate screening.

Other challenges include how individual physicians will implement a successful lung screening program, which is more complex than yearly mammography, requiring consecutive yearly CT screening with tracking of specific results and incidental findings. How will screening be limited to appropriate patients, as dictated by trial results? Will CT review be as successful in the community as it was in trial centers of excellence? Since smoking (an act of personal choice) is the major risk factor that warrants screening, who should bear the cost?

Then there are potential unintended consequences. What if lung cancer screening makes current smokers more complacent about continuing to smoke? We must increase our educational efforts on smoking cessation, efforts that I sense are having a disappointingly limited impact on the younger generation.

A number of new studies and guidelines published over the last few years are changing the way we treat older patients. This article summarizes these recent developments in a variety of areas—from prevention of falls to targets for hypertension therapy—relevant to the treatment of geriatric patients.

A MULTICOMPONENT APPROACH TO PREVENTING FALS

The American Geriatrics Society and British Geriatrics Society’s 2010 Clinical Practice Guideline for Prevention of Falls in Older Persons¹ has added an important new element since the 2001 guideline: in addition to asking older patients about a fall, clinicians should also ask whether a gait or balance problem has developed.

A complete falls evaluation and multicomponent intervention is indicated for patients who in the past year or since the previous visit have had one fall with an injury or more than one fall, or for patients who report or have been diagnosed with a gait or balance problem. A falls risk assessment is not indicated for a patient with no gait or balance problem and who has had only one noninjurious fall in the previous year that did not require medical attention.

The multicomponent evaluation detailed in the guideline is very thorough and comprises more elements than can be done in a follow-up office visit. In addition to the relevant medical history, physical examination, and cognitive and functional assessment, the fall-risk evaluation includes a falls history, medication review, visual acuity testing, gait and balance assessment, postural and heart-rate evaluation, examination of the feet and footwear, and, if appropriate, a referral for home assessment of environmental hazards.

Intervention consists of many aspects

Of the interventions, exercise has the strongest correlation with falls prevention, and a prescription should include exercises for balance, gait, and strength. Tai chi is specifically recommended.

Medications should be reduced or withdrawn. The previous guideline recommended reducing medications for patients taking four or more medications, but the current guideline applies to everyone.

First cataract removal is associated with reducing the risk of falls.

Postural hypotension should be treated if present.

Vitamin D at 800 U per day is recommended for all elderly people at risk. For elderly people in long-term care, giving vitamin D for proven or suspected deficiency is by itself correlated with risk reduction.

Interventions that by themselves are not associated with risk reduction include education (eg, providing a handout on preventing falls) and having vision checked. For adults who are cognitively impaired, there is insufficient evidence that even the multicomponent intervention helps prevent falls.

CALCIUM AND VITAMIN D MAY NOT BE HARMLESS

Calcium supplements: A cause of heart attack?

Questions have arisen in recent studies about the potential risks of calcium supplementation.

A meta-analysis of 11 trials with nearly 12,000 participants found that the risk of myocardial infarction was significantly higher in people taking calcium supplementation (relative risk 1.27; 95% confidence interval [CI] 1.01–1.59, P = .038).² Patients were predominantly postmenopausal women and were followed for a mean of 4 years. The incidence of stroke and death were also higher in people who took calcium, but the differences did not reach statistical significance. The dosages were primarily 1,000 mg per day (range 600 mg to 2 g). Risk was independent of age, sex, and type of supplement.

The authors concluded (somewhat provocatively, because only the risk of myocardial infarction reached statistical significance) that if 1,000 people were treated with calcium supplementation for 5 years, 26 fractures would be prevented but 14 myocardial infarctions, 10 strokes, and 13 deaths would be caused.

Comments. These data suggest that physicians may wish to prescribe calcium to supplement (not replace) dietary calcium to help patients reach but not exceed current guidelines for total calcium intake for age and sex. They may also want to advise the patient to take the calcium supplement separately from medications, as indicated in Table 2.

Benefits of vitamin D may depend on dosing

Studies show that the risk of hip fracture can be reduced with modest daily vitamin D supplementation, up to 800 U daily, regardless of calcium intake.³ Some vitamin D dosing regimens, however, may also entail risk.

Sanders et al⁴ randomized women age 70 and older to receive an annual injection of a high dose of vitamin D (500,000 U) or placebo for 3 to 5 years. Women in the vitamin D group had 15% more falls and 25% more fractures than those in the placebo group. The once-yearly dose of 500,000 U equates to 1,370 U/day, which is not much higher than the recommended daily dosage. The median baseline serum level was 49 nmol/L and reached 120 nmol/L at 30 days in the treatment group, which was not in the toxic range.

Comments. This study cautions physicians against giving large doses of vitamin D at long intervals. Future studies should focus on long-term clinical outcomes of falls and fractures for dosing regimens currently in practice, such as 50,000 units weekly or monthly.

BISPHOSPHONATES AND NONTRAUMATIC THICK BONE FRACTURES

Bisphosphonates have been regarded as the best drugs for preventing hip fracture. But in 2010, the US Food and Drug Administration (FDA) issued a warning that bisphosphonates have been associated with “atypical” femoral fractures. The atypical fracture pattern is a clean break through the thick bone of the shaft that occurs after minimal or no trauma.⁵ This pattern contrasts with the splintering “typical” fracture in the proximal femur in osteoporotic bone, usually after a fall.

Another characteristic of the atypical fractures is a higher incidence of postoperative complications requiring revision surgery. In more than 14,000 women in secondary analyses of three large randomized bisphosphonate trials, 12 fractures in 10 patients were found that were classified as atypical, averaging to an incidence of 2.3 per 10,000 patient-years.⁶

A population-based, nested case-control study⁷ using Canadian pharmacy records evaluated more than 200,000 women at least 68 years old who received bisphosphonate therapy. Of these, 716 (0.35%) sustained an atypical femoral fracture and 9,723 (4.7%) had a typical osteoporotic femoral fracture. Comparing the duration of bisphosphonate use between the two groups, the authors found that the risk of an atypical fracture increased with years of usage (at 5 years or more, the adjusted odds ratio was 2.74, 95% CI 1.25–6.02), but the risk of a typical fracture decreased (at 5 years or more, the adjusted odds ratio was 0.76, 95% CI 0.63–0.93). The study suggests that for every 100 hip fractures that bisphosphonate therapy prevents, it causes one atypical hip fracture.

Comments. These studies have caused some experts to advocate periodic bisphosphonate “vacations,”⁸ but for how long remains an open question because the risk of a typical fracture will increase. It is possible that a biomarker can help establish the best course, but that has yet to be determined.

DENOSUMAB: A NEW DRUG FOR OSTEOPOROSIS WITH A BIG PRICE TAG

Denosumab (Prolia, Xgeva), a newly available injectable drug, is a monoclonal antibody member of the tumor necrosis factor super-family.⁹ It is FDA-approved for osteoporosis in postmenopausal women at a dosage of 60 mg every 6 months and for skeletal metastases from solid tumors (120 mg every 4 weeks). It is also being used off-label for skeletal protection in women taking aromatase inhibitors and for men with androgen deficiency.

This drug is expensive, costing $850 per 60-mg dose wholesale, and no data are yet available on its long-term effects.

Since the drug is not cleared via renal mechanisms, there is some hope that it can be used to treat osteoporosis in patients with advanced chronic kidney disease, since bisphosphonates are contraindicated in those with an estimated glomerular filtration rate (GFR) less than 30 to 35 mL/min. However, the major study of denosumab to date, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, had no patients with stage 5 chronic kidney disease (GFR < 15 mL/min/1.73 m² or on dialysis), and too few with stage 4 chronic kidney disease (GFR 15–29) to demonstrate either the safety or efficacy of denosumab in patients with advanced chronic kidney disease.¹⁰

HYPERTENSION TREATMENT

A secondary analysis of a recent large hypertension study confirmed the benefits of antihypertensive therapy in very old adults and suggested new targets for systolic and diastolic blood pressures.^11,12

The Systolic Hypertension in the Elderly Program (SHEP) trial,¹³ the Systolic Hypertension in Europe (Syst-Eur) trial,¹⁴ and the Hypertension in the Very Elderly Trial (HYVET)¹⁵ are the major, randomized, placebo-controlled antihypertensive trials in older adults. They all showed a reduction in the risk of stroke and cardiovascular events. The diuretic studies (SHEP and HYVET)^13,15 also showed a lower risk of heart failure and death.

Most recently, secondary analysis of the International Verapamil-Trandolapril (INVEST) study^11,12 showed that adults in the oldest groups (age 70–79 and 80 and older), experienced a greater risk of adverse cardiovascular outcomes if systolic blood pressure was lowered to below about 130 mm Hg. As diastolic blood pressure was lowered to about the 65–70 mm Hg range, all age groups in the study experienced an increased risk of cardiovascular events. These results confirm the findings of a secondary analysis of the SHEP trial,¹⁶ showing an increased risk of cardiovascular events when diastolic pressure was lowered to below approximately 65 mm Hg.

These studies have been incorporated into 75 pages of the 2011 Expert Consensus Document on Hypertension in the Elderly issued by the American College of Cardiology Foundation and the American Heart Association.¹⁷ In a nutshell, the guidelines suggest that older adults less than 80 years of age be treated comparably to middle-aged adults. However, for adults age 80 and older:

• A target for systolic blood pressure of 140 to 145 mm Hg “can be acceptable.”
• Initiating treatment with monotherapy (with a low-dose thiazide, calcium channel blocker, or renin-angiotensin-aldosterone system drug) is reasonable. A second drug may be added if needed.
• Patients should be monitored for “excessive” orthostasis.
• Systolic blood pressure lower than 130 mm Hg and diastolic blood pressure lower than 65 mm Hg should be avoided.

TRANSCATHETER AORTIC VALVE IMPLANTATION APPROVED BY THE FDA

An estimated 2% to 9% of the elderly have aortic stenosis. Aortic valve replacement reduces mortality rates and improves function in all age groups, including octogenarians. Those with asymptomatic aortic stenosis tend to decline very quickly once they develop heart failure, syncope, or angina. Aortic valve replacement has been shown to put people back on the course they were on before they became symptomatic.

Transcatheter self-expanding transaortic valve implantation was approved by the FDA in November 2011. The procedure does not require open surgery and involves angioplasty of the old valve, with the new valve being passed into place through a catheter and expanded. Access is either transfemoral or transapical.

Transaortic valve implantation has been rapidly adopted in Europe since 2002 without any randomized control trials. The Placement of Aortic Transcatheter Valves (PARTNER) trial¹⁸ in 2011 was the first randomized trial of this therapy. It was conducted at 25 centers, with nearly 700 patients with severe aortic stenosis randomized to undergo either transcatheter aortic valve replacement with a balloon-expandable valve (244 via the transfemoral and 104 via the transapical approach) or surgical replacement. The mean age of the patients was 84 years, and the Society of Thoracic Surgeons mean score was 12%, indicating high perioperative risk.

At 30 days after the procedure, the rates of death were 3.4% with transcatheter implantation and 6.5% with surgical replacement (P = .07). At 1 year, the rates were 24.2% and 26.8%, respectively (P = 0.44, and P = .001 for noninferiority). However, the rate of major stroke was higher in the transcatheter implantation group: 3.8% vs 2.1% in the surgical group (P = .20) at 1 month and 5.1% vs 2.4% (P = .07) at 1 year. Vascular complications were significantly more frequent in the transcatheter implantation group, and the new onset of atrial fibrillation and major bleeding were significantly higher in the surgical group.

Patients in the transcatheter implantation group had a significantly shorter length of stay in the intensive care unit and a shorter index hospitalization. At 30 days, the transcatheter group also had a significant improvement in New York Heart Association functional status and a better 6-minute walk performance, although at 1 year, these measures were similar between the two groups and were greatly improved over baseline. Quality of life, measured using the Kansas City Cardiomyopathy Questionnaire, was higher both at 6 months and at 1 year in the transcatheter implantation group compared with those who underwent the open surgical procedure.¹⁹

Comments. The higher risk of stroke with the transcatheter implantation procedure remains a concern. More evaluation is also needed with respect to function and cognition in the very elderly, and of efficacy and safety in higher- and lower-risk patients.

DEPRESSION CAN BE EFFECTIVELY TREATED WITH MEDICATION

Many placebo-controlled trials have demonstrated the effectiveness of treating depression with medications in elderly people who are cognitively intact and living in the community. A Cochrane Review²⁰ found that in placebo-controlled trials, the number needed to treat to produce one recovery with tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors was less than 10 for each of the drug classes.

Since the newer drugs appear to be safer and to have fewer adverse effects than the older drugs, more older adults have been treated with antidepressants, including patients with comorbidities such as dementia that were exclusion criteria in early studies. For example, the number of older adults treated with antidepressants has increased 25% since 1992; at the same time the number being referred for cognitive-based therapies has been reduced by 43%.²¹ Similar trends are apparent in elderly people in long-term care. In 1999, about one-third of people in long-term care were diagnosed with depression; in 2007 more than one-half were.²²

Treating depression is less effective when dementia is present

Up to half of adults age 85 and older living in the community may have dementia. In long-term care facilities, most residents likely have some cognitive impairment or are diagnosed with dementia. Many of these are also taking antidepressive agents.

A review of studies in the Medline and Cochrane registries found seven trials that treated 330 patients with antidepressants for combined depression and dementia. Efficacy was not confirmed.²³

After this study was published, Banerjee et al²⁴ treated 218 patients who had depression and dementia in nine centers in the United Kingdom. Patients received sertraline (Zoloft), mirtazapine (Remeron), or placebo. Reductions in depression scores at 13 weeks and at 39 weeks did not differ between the groups, and adverse events were more frequent in the treatment groups than in the placebo groups.

Comments. The poor performance of antidepressants in patients with dementia may be due to misdiagnosis, such as mistaking apathy for depression.²⁵ It is also possible that better criteria than we have now are needed to diagnose depression in patients with dementia, or that current outcome measures are not sensitive for depression when dementia is present.

It may also be unsafe to treat older adults long-term with antidepressive agents. For example, although selective serotonin reuptake inhibitors, the most commonly prescribed antidepressive agents, are considered safe, their side effects are numerous and include sexual dysfunction, bleeding (due to platelet dysfunction), hyponatremia, early weight loss, tremor (mostly with paroxetine [Paxil]), sedation, apathy (especially with high doses), loose stools (with sertraline), urinary incontinence, falls, bone loss, and QTc prolongation.

Citalopram: Maximum dosage in elderly

In August 2011, an FDA Safety Communication was issued for citalopram (Celexa), stating that the daily dose should not exceed 40 mg in the general population and should not exceed 20 mg in patients age 60 and older. The dose should also not exceed 20 mg for a patient at any age who has hepatic impairment, who is known to be a poor metabolizer of CYP 2C19, or who takes cimetidine (Tagamet), since that drug inhibits the metabolism of citalopram at the CYP 2C19 enzyme site.

Although the FDA warning specifically mentions only cimetidine, physicians may have concerns about other drugs that inhibit CYP 2C19, such as proton pump inhibitors (eg, omeprazole [Prilosec]) when taken concomitantly with citalopram. Also, escitalopram (Lexapro) and sertraline are quite similar to citalopram; although they were not mentioned in the FDA Safety Communication, higher doses of these drugs may put patients at similar risk.

ALZHEIMER DISEASE: NEED TO BETTER IDENTIFY PEOPLE AT RISK

The definition of dementia is essentially the presence of a cognitive problem that affects the ability to function. For people with Alzheimer disease, impairment of cognitive performance precedes functional decline. Those with a cognitive deficit who still function well have, by definition, mild cognitive impairment (MCI). Although MCI could be caused by a variety of vascular and other neurologic processes, the most common cause of MCI in the United States is Alzheimer disease.

Unfortunately, the population with MCI currently enrolled in clinical trials to reduce the risk of progression to Alzheimer disease is heterogeneous. Many study participants may never get dementia, and others may have had the pathology present for decades and are progressing rapidly. Imaging and biomarkers are emerging as good indicators that predict progression and could help to better define populations for clinical trials.²⁶

Studies now indicate that people with MCI that is ultimately due to Alzheimer disease are likely to have amyloid beta peptide 42 evident in the cerebrospinal fluid 10 to 20 years before symptoms arise. At the same time, amyloid is also likely to be evident in the brain with amyloid-imaging positron emission tomography (PET). Some time later, abnormalities in metabolism are also evident on fluorodeoxyglucose (FDG) PET, as are changes such as reduced hippocampal volume on magnetic resonance imaging (MRI).

The 1984 criteria for diagnosing MCI due to Alzheimer disease were recently revised to incorporate the evolving availability of biomarkers.^27,28 The diagnosis of MCI itself is still based on clinical ascertainment including history, physical examination, and cognitive testing. It requires diagnosis of a cognitive decline from a prior level but maintenance of activities of daily living with no or minimal assistance. This diagnosis is certainly challenging since it requires ascertainment of a prior level of function and corroboration, when feasible, with an informant. Blood tests and imaging, which are readily available, constitute an important part of the assessment.

Attributing the MCI to Alzheimer disease requires consistency of the disease course—a gradual decline in Alzheimer disease, rather than a stroke, head injury, neurologic disease such as Parkinson disease, or mixed causes.

Knowledge of genetic factors, such as the presence of a mutation in APP, PS1, or PS2, can be predictive with young patients. The presence of one or two 34 alleles in the apolipoprotein E (APOE) gene is the only genetic variant broadly accepted as increasing the risk for late-onset Alzheimer dementia, whereas the 32 allele decreases risk.

Refining the risk attribution to Alzheimer disease requires biomarkers, currently available only in research settings:

• High likelihood—amyloid beta peptide detected by PET or cerebrospinal fluid analysis and evidence of neuronal degeneration or injury (elevated tau in the cerebrospinal fluid, decreased FDG uptake on PET, and atrophy evident by structural MRI)
• Intermediate likelihood—presence of amyloid beta peptide or evidence of neuronal degeneration or injury
• Unlikely—biomarkers tested and negative
• No comment—biomarkers not tested or reporting is indeterminate.

Comments. There is significant potential for misunderstanding the new definition for MCI. Patients who are concerned about their memory may request biomarker testing in an effort to determine if they currently have or will acquire Alzheimer disease. Doctors may be tempted to refer patients for biomarker testing (via imaging or lumbar puncture) to “screen” for MCI or Alzheimer disease.

It should be emphasized that MCI itself is still a clinical diagnosis, with the challenges noted above of determining whether there has been a cognitive decline from a prior level of function but preservation of activities of daily living. The biomarkers are not proposed to diagnose MCI, but only to help identify the subset of MCI patients most likely to progress rapidly to Alzheimer disease.

At present, the best use of biomarker testing is to aid research by identifying high-risk people among those with MCI who enroll in prospective trials for testing interventions to reduce the progression of Alzheimer disease.

A number of new studies and guidelines published over the last few years are changing the way we treat older patients. This article summarizes these recent developments in a variety of areas—from prevention of falls to targets for hypertension therapy—relevant to the treatment of geriatric patients.

A MULTICOMPONENT APPROACH TO PREVENTING FALS

The American Geriatrics Society and British Geriatrics Society’s 2010 Clinical Practice Guideline for Prevention of Falls in Older Persons¹ has added an important new element since the 2001 guideline: in addition to asking older patients about a fall, clinicians should also ask whether a gait or balance problem has developed.

A complete falls evaluation and multicomponent intervention is indicated for patients who in the past year or since the previous visit have had one fall with an injury or more than one fall, or for patients who report or have been diagnosed with a gait or balance problem. A falls risk assessment is not indicated for a patient with no gait or balance problem and who has had only one noninjurious fall in the previous year that did not require medical attention.

The multicomponent evaluation detailed in the guideline is very thorough and comprises more elements than can be done in a follow-up office visit. In addition to the relevant medical history, physical examination, and cognitive and functional assessment, the fall-risk evaluation includes a falls history, medication review, visual acuity testing, gait and balance assessment, postural and heart-rate evaluation, examination of the feet and footwear, and, if appropriate, a referral for home assessment of environmental hazards.

Intervention consists of many aspects

Of the interventions, exercise has the strongest correlation with falls prevention, and a prescription should include exercises for balance, gait, and strength. Tai chi is specifically recommended.

Medications should be reduced or withdrawn. The previous guideline recommended reducing medications for patients taking four or more medications, but the current guideline applies to everyone.

First cataract removal is associated with reducing the risk of falls.

Postural hypotension should be treated if present.

Vitamin D at 800 U per day is recommended for all elderly people at risk. For elderly people in long-term care, giving vitamin D for proven or suspected deficiency is by itself correlated with risk reduction.

Interventions that by themselves are not associated with risk reduction include education (eg, providing a handout on preventing falls) and having vision checked. For adults who are cognitively impaired, there is insufficient evidence that even the multicomponent intervention helps prevent falls.

CALCIUM AND VITAMIN D MAY NOT BE HARMLESS

Calcium supplements: A cause of heart attack?

Questions have arisen in recent studies about the potential risks of calcium supplementation.

A meta-analysis of 11 trials with nearly 12,000 participants found that the risk of myocardial infarction was significantly higher in people taking calcium supplementation (relative risk 1.27; 95% confidence interval [CI] 1.01–1.59, P = .038).² Patients were predominantly postmenopausal women and were followed for a mean of 4 years. The incidence of stroke and death were also higher in people who took calcium, but the differences did not reach statistical significance. The dosages were primarily 1,000 mg per day (range 600 mg to 2 g). Risk was independent of age, sex, and type of supplement.

The authors concluded (somewhat provocatively, because only the risk of myocardial infarction reached statistical significance) that if 1,000 people were treated with calcium supplementation for 5 years, 26 fractures would be prevented but 14 myocardial infarctions, 10 strokes, and 13 deaths would be caused.

Comments. These data suggest that physicians may wish to prescribe calcium to supplement (not replace) dietary calcium to help patients reach but not exceed current guidelines for total calcium intake for age and sex. They may also want to advise the patient to take the calcium supplement separately from medications, as indicated in Table 2.

Benefits of vitamin D may depend on dosing

Studies show that the risk of hip fracture can be reduced with modest daily vitamin D supplementation, up to 800 U daily, regardless of calcium intake.³ Some vitamin D dosing regimens, however, may also entail risk.

Sanders et al⁴ randomized women age 70 and older to receive an annual injection of a high dose of vitamin D (500,000 U) or placebo for 3 to 5 years. Women in the vitamin D group had 15% more falls and 25% more fractures than those in the placebo group. The once-yearly dose of 500,000 U equates to 1,370 U/day, which is not much higher than the recommended daily dosage. The median baseline serum level was 49 nmol/L and reached 120 nmol/L at 30 days in the treatment group, which was not in the toxic range.

Comments. This study cautions physicians against giving large doses of vitamin D at long intervals. Future studies should focus on long-term clinical outcomes of falls and fractures for dosing regimens currently in practice, such as 50,000 units weekly or monthly.

BISPHOSPHONATES AND NONTRAUMATIC THICK BONE FRACTURES

Bisphosphonates have been regarded as the best drugs for preventing hip fracture. But in 2010, the US Food and Drug Administration (FDA) issued a warning that bisphosphonates have been associated with “atypical” femoral fractures. The atypical fracture pattern is a clean break through the thick bone of the shaft that occurs after minimal or no trauma.⁵ This pattern contrasts with the splintering “typical” fracture in the proximal femur in osteoporotic bone, usually after a fall.

Another characteristic of the atypical fractures is a higher incidence of postoperative complications requiring revision surgery. In more than 14,000 women in secondary analyses of three large randomized bisphosphonate trials, 12 fractures in 10 patients were found that were classified as atypical, averaging to an incidence of 2.3 per 10,000 patient-years.⁶

A population-based, nested case-control study⁷ using Canadian pharmacy records evaluated more than 200,000 women at least 68 years old who received bisphosphonate therapy. Of these, 716 (0.35%) sustained an atypical femoral fracture and 9,723 (4.7%) had a typical osteoporotic femoral fracture. Comparing the duration of bisphosphonate use between the two groups, the authors found that the risk of an atypical fracture increased with years of usage (at 5 years or more, the adjusted odds ratio was 2.74, 95% CI 1.25–6.02), but the risk of a typical fracture decreased (at 5 years or more, the adjusted odds ratio was 0.76, 95% CI 0.63–0.93). The study suggests that for every 100 hip fractures that bisphosphonate therapy prevents, it causes one atypical hip fracture.

Comments. These studies have caused some experts to advocate periodic bisphosphonate “vacations,”⁸ but for how long remains an open question because the risk of a typical fracture will increase. It is possible that a biomarker can help establish the best course, but that has yet to be determined.

DENOSUMAB: A NEW DRUG FOR OSTEOPOROSIS WITH A BIG PRICE TAG

Denosumab (Prolia, Xgeva), a newly available injectable drug, is a monoclonal antibody member of the tumor necrosis factor super-family.⁹ It is FDA-approved for osteoporosis in postmenopausal women at a dosage of 60 mg every 6 months and for skeletal metastases from solid tumors (120 mg every 4 weeks). It is also being used off-label for skeletal protection in women taking aromatase inhibitors and for men with androgen deficiency.

This drug is expensive, costing $850 per 60-mg dose wholesale, and no data are yet available on its long-term effects.

Since the drug is not cleared via renal mechanisms, there is some hope that it can be used to treat osteoporosis in patients with advanced chronic kidney disease, since bisphosphonates are contraindicated in those with an estimated glomerular filtration rate (GFR) less than 30 to 35 mL/min. However, the major study of denosumab to date, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, had no patients with stage 5 chronic kidney disease (GFR < 15 mL/min/1.73 m² or on dialysis), and too few with stage 4 chronic kidney disease (GFR 15–29) to demonstrate either the safety or efficacy of denosumab in patients with advanced chronic kidney disease.¹⁰

HYPERTENSION TREATMENT

A secondary analysis of a recent large hypertension study confirmed the benefits of antihypertensive therapy in very old adults and suggested new targets for systolic and diastolic blood pressures.^11,12

The Systolic Hypertension in the Elderly Program (SHEP) trial,¹³ the Systolic Hypertension in Europe (Syst-Eur) trial,¹⁴ and the Hypertension in the Very Elderly Trial (HYVET)¹⁵ are the major, randomized, placebo-controlled antihypertensive trials in older adults. They all showed a reduction in the risk of stroke and cardiovascular events. The diuretic studies (SHEP and HYVET)^13,15 also showed a lower risk of heart failure and death.

Most recently, secondary analysis of the International Verapamil-Trandolapril (INVEST) study^11,12 showed that adults in the oldest groups (age 70–79 and 80 and older), experienced a greater risk of adverse cardiovascular outcomes if systolic blood pressure was lowered to below about 130 mm Hg. As diastolic blood pressure was lowered to about the 65–70 mm Hg range, all age groups in the study experienced an increased risk of cardiovascular events. These results confirm the findings of a secondary analysis of the SHEP trial,¹⁶ showing an increased risk of cardiovascular events when diastolic pressure was lowered to below approximately 65 mm Hg.

These studies have been incorporated into 75 pages of the 2011 Expert Consensus Document on Hypertension in the Elderly issued by the American College of Cardiology Foundation and the American Heart Association.¹⁷ In a nutshell, the guidelines suggest that older adults less than 80 years of age be treated comparably to middle-aged adults. However, for adults age 80 and older:

• A target for systolic blood pressure of 140 to 145 mm Hg “can be acceptable.”
• Initiating treatment with monotherapy (with a low-dose thiazide, calcium channel blocker, or renin-angiotensin-aldosterone system drug) is reasonable. A second drug may be added if needed.
• Patients should be monitored for “excessive” orthostasis.
• Systolic blood pressure lower than 130 mm Hg and diastolic blood pressure lower than 65 mm Hg should be avoided.

TRANSCATHETER AORTIC VALVE IMPLANTATION APPROVED BY THE FDA

An estimated 2% to 9% of the elderly have aortic stenosis. Aortic valve replacement reduces mortality rates and improves function in all age groups, including octogenarians. Those with asymptomatic aortic stenosis tend to decline very quickly once they develop heart failure, syncope, or angina. Aortic valve replacement has been shown to put people back on the course they were on before they became symptomatic.

Transcatheter self-expanding transaortic valve implantation was approved by the FDA in November 2011. The procedure does not require open surgery and involves angioplasty of the old valve, with the new valve being passed into place through a catheter and expanded. Access is either transfemoral or transapical.

Transaortic valve implantation has been rapidly adopted in Europe since 2002 without any randomized control trials. The Placement of Aortic Transcatheter Valves (PARTNER) trial¹⁸ in 2011 was the first randomized trial of this therapy. It was conducted at 25 centers, with nearly 700 patients with severe aortic stenosis randomized to undergo either transcatheter aortic valve replacement with a balloon-expandable valve (244 via the transfemoral and 104 via the transapical approach) or surgical replacement. The mean age of the patients was 84 years, and the Society of Thoracic Surgeons mean score was 12%, indicating high perioperative risk.

At 30 days after the procedure, the rates of death were 3.4% with transcatheter implantation and 6.5% with surgical replacement (P = .07). At 1 year, the rates were 24.2% and 26.8%, respectively (P = 0.44, and P = .001 for noninferiority). However, the rate of major stroke was higher in the transcatheter implantation group: 3.8% vs 2.1% in the surgical group (P = .20) at 1 month and 5.1% vs 2.4% (P = .07) at 1 year. Vascular complications were significantly more frequent in the transcatheter implantation group, and the new onset of atrial fibrillation and major bleeding were significantly higher in the surgical group.

Patients in the transcatheter implantation group had a significantly shorter length of stay in the intensive care unit and a shorter index hospitalization. At 30 days, the transcatheter group also had a significant improvement in New York Heart Association functional status and a better 6-minute walk performance, although at 1 year, these measures were similar between the two groups and were greatly improved over baseline. Quality of life, measured using the Kansas City Cardiomyopathy Questionnaire, was higher both at 6 months and at 1 year in the transcatheter implantation group compared with those who underwent the open surgical procedure.¹⁹

Comments. The higher risk of stroke with the transcatheter implantation procedure remains a concern. More evaluation is also needed with respect to function and cognition in the very elderly, and of efficacy and safety in higher- and lower-risk patients.

DEPRESSION CAN BE EFFECTIVELY TREATED WITH MEDICATION

Many placebo-controlled trials have demonstrated the effectiveness of treating depression with medications in elderly people who are cognitively intact and living in the community. A Cochrane Review²⁰ found that in placebo-controlled trials, the number needed to treat to produce one recovery with tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors was less than 10 for each of the drug classes.

Since the newer drugs appear to be safer and to have fewer adverse effects than the older drugs, more older adults have been treated with antidepressants, including patients with comorbidities such as dementia that were exclusion criteria in early studies. For example, the number of older adults treated with antidepressants has increased 25% since 1992; at the same time the number being referred for cognitive-based therapies has been reduced by 43%.²¹ Similar trends are apparent in elderly people in long-term care. In 1999, about one-third of people in long-term care were diagnosed with depression; in 2007 more than one-half were.²²

Treating depression is less effective when dementia is present

Up to half of adults age 85 and older living in the community may have dementia. In long-term care facilities, most residents likely have some cognitive impairment or are diagnosed with dementia. Many of these are also taking antidepressive agents.

A review of studies in the Medline and Cochrane registries found seven trials that treated 330 patients with antidepressants for combined depression and dementia. Efficacy was not confirmed.²³

After this study was published, Banerjee et al²⁴ treated 218 patients who had depression and dementia in nine centers in the United Kingdom. Patients received sertraline (Zoloft), mirtazapine (Remeron), or placebo. Reductions in depression scores at 13 weeks and at 39 weeks did not differ between the groups, and adverse events were more frequent in the treatment groups than in the placebo groups.

Comments. The poor performance of antidepressants in patients with dementia may be due to misdiagnosis, such as mistaking apathy for depression.²⁵ It is also possible that better criteria than we have now are needed to diagnose depression in patients with dementia, or that current outcome measures are not sensitive for depression when dementia is present.

It may also be unsafe to treat older adults long-term with antidepressive agents. For example, although selective serotonin reuptake inhibitors, the most commonly prescribed antidepressive agents, are considered safe, their side effects are numerous and include sexual dysfunction, bleeding (due to platelet dysfunction), hyponatremia, early weight loss, tremor (mostly with paroxetine [Paxil]), sedation, apathy (especially with high doses), loose stools (with sertraline), urinary incontinence, falls, bone loss, and QTc prolongation.

Citalopram: Maximum dosage in elderly

In August 2011, an FDA Safety Communication was issued for citalopram (Celexa), stating that the daily dose should not exceed 40 mg in the general population and should not exceed 20 mg in patients age 60 and older. The dose should also not exceed 20 mg for a patient at any age who has hepatic impairment, who is known to be a poor metabolizer of CYP 2C19, or who takes cimetidine (Tagamet), since that drug inhibits the metabolism of citalopram at the CYP 2C19 enzyme site.

Although the FDA warning specifically mentions only cimetidine, physicians may have concerns about other drugs that inhibit CYP 2C19, such as proton pump inhibitors (eg, omeprazole [Prilosec]) when taken concomitantly with citalopram. Also, escitalopram (Lexapro) and sertraline are quite similar to citalopram; although they were not mentioned in the FDA Safety Communication, higher doses of these drugs may put patients at similar risk.

ALZHEIMER DISEASE: NEED TO BETTER IDENTIFY PEOPLE AT RISK

The definition of dementia is essentially the presence of a cognitive problem that affects the ability to function. For people with Alzheimer disease, impairment of cognitive performance precedes functional decline. Those with a cognitive deficit who still function well have, by definition, mild cognitive impairment (MCI). Although MCI could be caused by a variety of vascular and other neurologic processes, the most common cause of MCI in the United States is Alzheimer disease.

Unfortunately, the population with MCI currently enrolled in clinical trials to reduce the risk of progression to Alzheimer disease is heterogeneous. Many study participants may never get dementia, and others may have had the pathology present for decades and are progressing rapidly. Imaging and biomarkers are emerging as good indicators that predict progression and could help to better define populations for clinical trials.²⁶

Studies now indicate that people with MCI that is ultimately due to Alzheimer disease are likely to have amyloid beta peptide 42 evident in the cerebrospinal fluid 10 to 20 years before symptoms arise. At the same time, amyloid is also likely to be evident in the brain with amyloid-imaging positron emission tomography (PET). Some time later, abnormalities in metabolism are also evident on fluorodeoxyglucose (FDG) PET, as are changes such as reduced hippocampal volume on magnetic resonance imaging (MRI).

The 1984 criteria for diagnosing MCI due to Alzheimer disease were recently revised to incorporate the evolving availability of biomarkers.^27,28 The diagnosis of MCI itself is still based on clinical ascertainment including history, physical examination, and cognitive testing. It requires diagnosis of a cognitive decline from a prior level but maintenance of activities of daily living with no or minimal assistance. This diagnosis is certainly challenging since it requires ascertainment of a prior level of function and corroboration, when feasible, with an informant. Blood tests and imaging, which are readily available, constitute an important part of the assessment.

Attributing the MCI to Alzheimer disease requires consistency of the disease course—a gradual decline in Alzheimer disease, rather than a stroke, head injury, neurologic disease such as Parkinson disease, or mixed causes.

Knowledge of genetic factors, such as the presence of a mutation in APP, PS1, or PS2, can be predictive with young patients. The presence of one or two 34 alleles in the apolipoprotein E (APOE) gene is the only genetic variant broadly accepted as increasing the risk for late-onset Alzheimer dementia, whereas the 32 allele decreases risk.

Refining the risk attribution to Alzheimer disease requires biomarkers, currently available only in research settings:

• High likelihood—amyloid beta peptide detected by PET or cerebrospinal fluid analysis and evidence of neuronal degeneration or injury (elevated tau in the cerebrospinal fluid, decreased FDG uptake on PET, and atrophy evident by structural MRI)
• Intermediate likelihood—presence of amyloid beta peptide or evidence of neuronal degeneration or injury
• Unlikely—biomarkers tested and negative
• No comment—biomarkers not tested or reporting is indeterminate.

Comments. There is significant potential for misunderstanding the new definition for MCI. Patients who are concerned about their memory may request biomarker testing in an effort to determine if they currently have or will acquire Alzheimer disease. Doctors may be tempted to refer patients for biomarker testing (via imaging or lumbar puncture) to “screen” for MCI or Alzheimer disease.

It should be emphasized that MCI itself is still a clinical diagnosis, with the challenges noted above of determining whether there has been a cognitive decline from a prior level of function but preservation of activities of daily living. The biomarkers are not proposed to diagnose MCI, but only to help identify the subset of MCI patients most likely to progress rapidly to Alzheimer disease.

At present, the best use of biomarker testing is to aid research by identifying high-risk people among those with MCI who enroll in prospective trials for testing interventions to reduce the progression of Alzheimer disease.

A number of new studies and guidelines published over the last few years are changing the way we treat older patients. This article summarizes these recent developments in a variety of areas—from prevention of falls to targets for hypertension therapy—relevant to the treatment of geriatric patients.

A MULTICOMPONENT APPROACH TO PREVENTING FALS

The American Geriatrics Society and British Geriatrics Society’s 2010 Clinical Practice Guideline for Prevention of Falls in Older Persons¹ has added an important new element since the 2001 guideline: in addition to asking older patients about a fall, clinicians should also ask whether a gait or balance problem has developed.

A complete falls evaluation and multicomponent intervention is indicated for patients who in the past year or since the previous visit have had one fall with an injury or more than one fall, or for patients who report or have been diagnosed with a gait or balance problem. A falls risk assessment is not indicated for a patient with no gait or balance problem and who has had only one noninjurious fall in the previous year that did not require medical attention.

The multicomponent evaluation detailed in the guideline is very thorough and comprises more elements than can be done in a follow-up office visit. In addition to the relevant medical history, physical examination, and cognitive and functional assessment, the fall-risk evaluation includes a falls history, medication review, visual acuity testing, gait and balance assessment, postural and heart-rate evaluation, examination of the feet and footwear, and, if appropriate, a referral for home assessment of environmental hazards.

Intervention consists of many aspects

Of the interventions, exercise has the strongest correlation with falls prevention, and a prescription should include exercises for balance, gait, and strength. Tai chi is specifically recommended.

Medications should be reduced or withdrawn. The previous guideline recommended reducing medications for patients taking four or more medications, but the current guideline applies to everyone.

First cataract removal is associated with reducing the risk of falls.

Postural hypotension should be treated if present.

Vitamin D at 800 U per day is recommended for all elderly people at risk. For elderly people in long-term care, giving vitamin D for proven or suspected deficiency is by itself correlated with risk reduction.

Interventions that by themselves are not associated with risk reduction include education (eg, providing a handout on preventing falls) and having vision checked. For adults who are cognitively impaired, there is insufficient evidence that even the multicomponent intervention helps prevent falls.

CALCIUM AND VITAMIN D MAY NOT BE HARMLESS

Calcium supplements: A cause of heart attack?

Questions have arisen in recent studies about the potential risks of calcium supplementation.

A meta-analysis of 11 trials with nearly 12,000 participants found that the risk of myocardial infarction was significantly higher in people taking calcium supplementation (relative risk 1.27; 95% confidence interval [CI] 1.01–1.59, P = .038).² Patients were predominantly postmenopausal women and were followed for a mean of 4 years. The incidence of stroke and death were also higher in people who took calcium, but the differences did not reach statistical significance. The dosages were primarily 1,000 mg per day (range 600 mg to 2 g). Risk was independent of age, sex, and type of supplement.

The authors concluded (somewhat provocatively, because only the risk of myocardial infarction reached statistical significance) that if 1,000 people were treated with calcium supplementation for 5 years, 26 fractures would be prevented but 14 myocardial infarctions, 10 strokes, and 13 deaths would be caused.

Comments. These data suggest that physicians may wish to prescribe calcium to supplement (not replace) dietary calcium to help patients reach but not exceed current guidelines for total calcium intake for age and sex. They may also want to advise the patient to take the calcium supplement separately from medications, as indicated in Table 2.

Benefits of vitamin D may depend on dosing

Studies show that the risk of hip fracture can be reduced with modest daily vitamin D supplementation, up to 800 U daily, regardless of calcium intake.³ Some vitamin D dosing regimens, however, may also entail risk.

Sanders et al⁴ randomized women age 70 and older to receive an annual injection of a high dose of vitamin D (500,000 U) or placebo for 3 to 5 years. Women in the vitamin D group had 15% more falls and 25% more fractures than those in the placebo group. The once-yearly dose of 500,000 U equates to 1,370 U/day, which is not much higher than the recommended daily dosage. The median baseline serum level was 49 nmol/L and reached 120 nmol/L at 30 days in the treatment group, which was not in the toxic range.

Comments. This study cautions physicians against giving large doses of vitamin D at long intervals. Future studies should focus on long-term clinical outcomes of falls and fractures for dosing regimens currently in practice, such as 50,000 units weekly or monthly.

BISPHOSPHONATES AND NONTRAUMATIC THICK BONE FRACTURES

Bisphosphonates have been regarded as the best drugs for preventing hip fracture. But in 2010, the US Food and Drug Administration (FDA) issued a warning that bisphosphonates have been associated with “atypical” femoral fractures. The atypical fracture pattern is a clean break through the thick bone of the shaft that occurs after minimal or no trauma.⁵ This pattern contrasts with the splintering “typical” fracture in the proximal femur in osteoporotic bone, usually after a fall.

Another characteristic of the atypical fractures is a higher incidence of postoperative complications requiring revision surgery. In more than 14,000 women in secondary analyses of three large randomized bisphosphonate trials, 12 fractures in 10 patients were found that were classified as atypical, averaging to an incidence of 2.3 per 10,000 patient-years.⁶

A population-based, nested case-control study⁷ using Canadian pharmacy records evaluated more than 200,000 women at least 68 years old who received bisphosphonate therapy. Of these, 716 (0.35%) sustained an atypical femoral fracture and 9,723 (4.7%) had a typical osteoporotic femoral fracture. Comparing the duration of bisphosphonate use between the two groups, the authors found that the risk of an atypical fracture increased with years of usage (at 5 years or more, the adjusted odds ratio was 2.74, 95% CI 1.25–6.02), but the risk of a typical fracture decreased (at 5 years or more, the adjusted odds ratio was 0.76, 95% CI 0.63–0.93). The study suggests that for every 100 hip fractures that bisphosphonate therapy prevents, it causes one atypical hip fracture.

Comments. These studies have caused some experts to advocate periodic bisphosphonate “vacations,”⁸ but for how long remains an open question because the risk of a typical fracture will increase. It is possible that a biomarker can help establish the best course, but that has yet to be determined.

DENOSUMAB: A NEW DRUG FOR OSTEOPOROSIS WITH A BIG PRICE TAG

Denosumab (Prolia, Xgeva), a newly available injectable drug, is a monoclonal antibody member of the tumor necrosis factor super-family.⁹ It is FDA-approved for osteoporosis in postmenopausal women at a dosage of 60 mg every 6 months and for skeletal metastases from solid tumors (120 mg every 4 weeks). It is also being used off-label for skeletal protection in women taking aromatase inhibitors and for men with androgen deficiency.

This drug is expensive, costing $850 per 60-mg dose wholesale, and no data are yet available on its long-term effects.

Since the drug is not cleared via renal mechanisms, there is some hope that it can be used to treat osteoporosis in patients with advanced chronic kidney disease, since bisphosphonates are contraindicated in those with an estimated glomerular filtration rate (GFR) less than 30 to 35 mL/min. However, the major study of denosumab to date, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, had no patients with stage 5 chronic kidney disease (GFR < 15 mL/min/1.73 m² or on dialysis), and too few with stage 4 chronic kidney disease (GFR 15–29) to demonstrate either the safety or efficacy of denosumab in patients with advanced chronic kidney disease.¹⁰

HYPERTENSION TREATMENT

A secondary analysis of a recent large hypertension study confirmed the benefits of antihypertensive therapy in very old adults and suggested new targets for systolic and diastolic blood pressures.^11,12

The Systolic Hypertension in the Elderly Program (SHEP) trial,¹³ the Systolic Hypertension in Europe (Syst-Eur) trial,¹⁴ and the Hypertension in the Very Elderly Trial (HYVET)¹⁵ are the major, randomized, placebo-controlled antihypertensive trials in older adults. They all showed a reduction in the risk of stroke and cardiovascular events. The diuretic studies (SHEP and HYVET)^13,15 also showed a lower risk of heart failure and death.

Most recently, secondary analysis of the International Verapamil-Trandolapril (INVEST) study^11,12 showed that adults in the oldest groups (age 70–79 and 80 and older), experienced a greater risk of adverse cardiovascular outcomes if systolic blood pressure was lowered to below about 130 mm Hg. As diastolic blood pressure was lowered to about the 65–70 mm Hg range, all age groups in the study experienced an increased risk of cardiovascular events. These results confirm the findings of a secondary analysis of the SHEP trial,¹⁶ showing an increased risk of cardiovascular events when diastolic pressure was lowered to below approximately 65 mm Hg.

These studies have been incorporated into 75 pages of the 2011 Expert Consensus Document on Hypertension in the Elderly issued by the American College of Cardiology Foundation and the American Heart Association.¹⁷ In a nutshell, the guidelines suggest that older adults less than 80 years of age be treated comparably to middle-aged adults. However, for adults age 80 and older:

• A target for systolic blood pressure of 140 to 145 mm Hg “can be acceptable.”
• Initiating treatment with monotherapy (with a low-dose thiazide, calcium channel blocker, or renin-angiotensin-aldosterone system drug) is reasonable. A second drug may be added if needed.
• Patients should be monitored for “excessive” orthostasis.
• Systolic blood pressure lower than 130 mm Hg and diastolic blood pressure lower than 65 mm Hg should be avoided.

TRANSCATHETER AORTIC VALVE IMPLANTATION APPROVED BY THE FDA

An estimated 2% to 9% of the elderly have aortic stenosis. Aortic valve replacement reduces mortality rates and improves function in all age groups, including octogenarians. Those with asymptomatic aortic stenosis tend to decline very quickly once they develop heart failure, syncope, or angina. Aortic valve replacement has been shown to put people back on the course they were on before they became symptomatic.

Transcatheter self-expanding transaortic valve implantation was approved by the FDA in November 2011. The procedure does not require open surgery and involves angioplasty of the old valve, with the new valve being passed into place through a catheter and expanded. Access is either transfemoral or transapical.

Transaortic valve implantation has been rapidly adopted in Europe since 2002 without any randomized control trials. The Placement of Aortic Transcatheter Valves (PARTNER) trial¹⁸ in 2011 was the first randomized trial of this therapy. It was conducted at 25 centers, with nearly 700 patients with severe aortic stenosis randomized to undergo either transcatheter aortic valve replacement with a balloon-expandable valve (244 via the transfemoral and 104 via the transapical approach) or surgical replacement. The mean age of the patients was 84 years, and the Society of Thoracic Surgeons mean score was 12%, indicating high perioperative risk.

At 30 days after the procedure, the rates of death were 3.4% with transcatheter implantation and 6.5% with surgical replacement (P = .07). At 1 year, the rates were 24.2% and 26.8%, respectively (P = 0.44, and P = .001 for noninferiority). However, the rate of major stroke was higher in the transcatheter implantation group: 3.8% vs 2.1% in the surgical group (P = .20) at 1 month and 5.1% vs 2.4% (P = .07) at 1 year. Vascular complications were significantly more frequent in the transcatheter implantation group, and the new onset of atrial fibrillation and major bleeding were significantly higher in the surgical group.

Patients in the transcatheter implantation group had a significantly shorter length of stay in the intensive care unit and a shorter index hospitalization. At 30 days, the transcatheter group also had a significant improvement in New York Heart Association functional status and a better 6-minute walk performance, although at 1 year, these measures were similar between the two groups and were greatly improved over baseline. Quality of life, measured using the Kansas City Cardiomyopathy Questionnaire, was higher both at 6 months and at 1 year in the transcatheter implantation group compared with those who underwent the open surgical procedure.¹⁹

Comments. The higher risk of stroke with the transcatheter implantation procedure remains a concern. More evaluation is also needed with respect to function and cognition in the very elderly, and of efficacy and safety in higher- and lower-risk patients.

DEPRESSION CAN BE EFFECTIVELY TREATED WITH MEDICATION

Many placebo-controlled trials have demonstrated the effectiveness of treating depression with medications in elderly people who are cognitively intact and living in the community. A Cochrane Review²⁰ found that in placebo-controlled trials, the number needed to treat to produce one recovery with tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors was less than 10 for each of the drug classes.

Since the newer drugs appear to be safer and to have fewer adverse effects than the older drugs, more older adults have been treated with antidepressants, including patients with comorbidities such as dementia that were exclusion criteria in early studies. For example, the number of older adults treated with antidepressants has increased 25% since 1992; at the same time the number being referred for cognitive-based therapies has been reduced by 43%.²¹ Similar trends are apparent in elderly people in long-term care. In 1999, about one-third of people in long-term care were diagnosed with depression; in 2007 more than one-half were.²²

Treating depression is less effective when dementia is present

Up to half of adults age 85 and older living in the community may have dementia. In long-term care facilities, most residents likely have some cognitive impairment or are diagnosed with dementia. Many of these are also taking antidepressive agents.

A review of studies in the Medline and Cochrane registries found seven trials that treated 330 patients with antidepressants for combined depression and dementia. Efficacy was not confirmed.²³

After this study was published, Banerjee et al²⁴ treated 218 patients who had depression and dementia in nine centers in the United Kingdom. Patients received sertraline (Zoloft), mirtazapine (Remeron), or placebo. Reductions in depression scores at 13 weeks and at 39 weeks did not differ between the groups, and adverse events were more frequent in the treatment groups than in the placebo groups.

Comments. The poor performance of antidepressants in patients with dementia may be due to misdiagnosis, such as mistaking apathy for depression.²⁵ It is also possible that better criteria than we have now are needed to diagnose depression in patients with dementia, or that current outcome measures are not sensitive for depression when dementia is present.

It may also be unsafe to treat older adults long-term with antidepressive agents. For example, although selective serotonin reuptake inhibitors, the most commonly prescribed antidepressive agents, are considered safe, their side effects are numerous and include sexual dysfunction, bleeding (due to platelet dysfunction), hyponatremia, early weight loss, tremor (mostly with paroxetine [Paxil]), sedation, apathy (especially with high doses), loose stools (with sertraline), urinary incontinence, falls, bone loss, and QTc prolongation.

Citalopram: Maximum dosage in elderly

In August 2011, an FDA Safety Communication was issued for citalopram (Celexa), stating that the daily dose should not exceed 40 mg in the general population and should not exceed 20 mg in patients age 60 and older. The dose should also not exceed 20 mg for a patient at any age who has hepatic impairment, who is known to be a poor metabolizer of CYP 2C19, or who takes cimetidine (Tagamet), since that drug inhibits the metabolism of citalopram at the CYP 2C19 enzyme site.

Although the FDA warning specifically mentions only cimetidine, physicians may have concerns about other drugs that inhibit CYP 2C19, such as proton pump inhibitors (eg, omeprazole [Prilosec]) when taken concomitantly with citalopram. Also, escitalopram (Lexapro) and sertraline are quite similar to citalopram; although they were not mentioned in the FDA Safety Communication, higher doses of these drugs may put patients at similar risk.

ALZHEIMER DISEASE: NEED TO BETTER IDENTIFY PEOPLE AT RISK

The definition of dementia is essentially the presence of a cognitive problem that affects the ability to function. For people with Alzheimer disease, impairment of cognitive performance precedes functional decline. Those with a cognitive deficit who still function well have, by definition, mild cognitive impairment (MCI). Although MCI could be caused by a variety of vascular and other neurologic processes, the most common cause of MCI in the United States is Alzheimer disease.

Unfortunately, the population with MCI currently enrolled in clinical trials to reduce the risk of progression to Alzheimer disease is heterogeneous. Many study participants may never get dementia, and others may have had the pathology present for decades and are progressing rapidly. Imaging and biomarkers are emerging as good indicators that predict progression and could help to better define populations for clinical trials.²⁶

Studies now indicate that people with MCI that is ultimately due to Alzheimer disease are likely to have amyloid beta peptide 42 evident in the cerebrospinal fluid 10 to 20 years before symptoms arise. At the same time, amyloid is also likely to be evident in the brain with amyloid-imaging positron emission tomography (PET). Some time later, abnormalities in metabolism are also evident on fluorodeoxyglucose (FDG) PET, as are changes such as reduced hippocampal volume on magnetic resonance imaging (MRI).

The 1984 criteria for diagnosing MCI due to Alzheimer disease were recently revised to incorporate the evolving availability of biomarkers.^27,28 The diagnosis of MCI itself is still based on clinical ascertainment including history, physical examination, and cognitive testing. It requires diagnosis of a cognitive decline from a prior level but maintenance of activities of daily living with no or minimal assistance. This diagnosis is certainly challenging since it requires ascertainment of a prior level of function and corroboration, when feasible, with an informant. Blood tests and imaging, which are readily available, constitute an important part of the assessment.

Attributing the MCI to Alzheimer disease requires consistency of the disease course—a gradual decline in Alzheimer disease, rather than a stroke, head injury, neurologic disease such as Parkinson disease, or mixed causes.

Knowledge of genetic factors, such as the presence of a mutation in APP, PS1, or PS2, can be predictive with young patients. The presence of one or two 34 alleles in the apolipoprotein E (APOE) gene is the only genetic variant broadly accepted as increasing the risk for late-onset Alzheimer dementia, whereas the 32 allele decreases risk.

Refining the risk attribution to Alzheimer disease requires biomarkers, currently available only in research settings:

• High likelihood—amyloid beta peptide detected by PET or cerebrospinal fluid analysis and evidence of neuronal degeneration or injury (elevated tau in the cerebrospinal fluid, decreased FDG uptake on PET, and atrophy evident by structural MRI)
• Intermediate likelihood—presence of amyloid beta peptide or evidence of neuronal degeneration or injury
• Unlikely—biomarkers tested and negative
• No comment—biomarkers not tested or reporting is indeterminate.

Comments. There is significant potential for misunderstanding the new definition for MCI. Patients who are concerned about their memory may request biomarker testing in an effort to determine if they currently have or will acquire Alzheimer disease. Doctors may be tempted to refer patients for biomarker testing (via imaging or lumbar puncture) to “screen” for MCI or Alzheimer disease.

It should be emphasized that MCI itself is still a clinical diagnosis, with the challenges noted above of determining whether there has been a cognitive decline from a prior level of function but preservation of activities of daily living. The biomarkers are not proposed to diagnose MCI, but only to help identify the subset of MCI patients most likely to progress rapidly to Alzheimer disease.

At present, the best use of biomarker testing is to aid research by identifying high-risk people among those with MCI who enroll in prospective trials for testing interventions to reduce the progression of Alzheimer disease.

In 2011, two papers were published that will shape the way we think about lung cancer screening for years to come.

See related patient information sheet

While the ability to screen for lung cancer is a major positive change, it also raises many thorny questions, such as who should be screened, how often should they be screened, and how should we respond when a nodule is detected.

To answer some of these questions, we will outline how Cleveland Clinic has structured its lung cancer screening program, and the rationale we used for making pragmatic patient-care decisions within this program. We will conclude with our thoughts about the potential evolution of lung cancer screening programs.

THE 40-YEAR QUEST FOR EFFECTIVE LUNG CANCER SCREENING

Lung cancer kills more people in the United States than the next four most lethal types of cancer combined.³ It is curable if found early in its course. Unfortunately, most people who develop lung cancer feel no symptoms when it is early in its course, and therefore it is too often diagnosed at a late stage. Treatment for late-stage lung cancer is effective, but it is rarely curative.

Screening refers to testing people at risk of developing a disease before its symptoms or signs have appeared. The goal of screening is to reduce the disease-specific mortality rate. For this to happen, the disease must be detectable in a preclinical form, and treatment must be more successful when applied early. Ideally, the screening test should pose little risk to the patient, be sensitive for detecting the disease early in its course, give few false-positive results, be acceptable to the patient, and be relatively inexpensive to the health system.

Over the past 4 decades, a large volume of research has been done in the hope of proving that conventional radiography or CT could be an effective screening test for lung cancer.^4,5

Cohort studies (ie, in which all the patients were screened) of radiography or CT have shown a longer survival from the time of lung cancer diagnosis than would be expected without screening. These studies were not designed to prove a reduction in the lung cancer-specific mortality rate.

Controlled trials (in which half the patients received the screening and the other half did not) of chest radiography have been interpreted as not showing a reduction in lung cancer mortality rates, though debate about the interpretation of these trials persisted until this past year. Biases inherent in using duration of survival rather than the mortality rate as an end point have been suggested as the reason for the apparent benefit in survival without a reduction in the mortality rate.

Controlled trials of CT screening were started nearly a decade ago. Until 2011, the results of these trials were not mature enough to comment on.

THE PROSTATE, LUNG, COLORECTAL, AND OVARIAN TRIAL

The lung cancer screening portion of the PLCO trial aimed to determine the effect of screening chest radiography on lung cancer-specific mortality rates.¹

In this trial, 154,901 people were randomized to undergo either posteroanterior chest radiography every year for 4 years or usual care, ie, no lung cancer screening. Participants were men and women age 55 to 74 with no history of prostate, lung, colorectal, or ovarian cancer. They did not need to be a smoker to participate. Those who had never smoked and who were randomized to the screening group received only 3 years of testing. All were followed for 13 years or until the conclusion of the study (8 years after the final participant was enrolled). About half were women, and nearly two-thirds were age 55 through 64. Only 10% were current smokers, while a full 45% had never smoked.

Results. Adherence to screening in the screening group ranged from 79% to 86.6% over the years of screening, and 11% of the usual-care group was estimated to have undergone screening chest radiography.

Cumulative lung cancer incidence rates were 201 per 100,000 person-years in the screening group and 192 in the usual-care group.

In the screening group, there were a total of 1,696 lung cancers during the entire study. Of these, 307 (18%) were detected by screening, 198 (12%) were interval cancers (diagnosed during the screening period but not by the screening test), and the remainder were diagnosed after the screening period during the years of follow-up. In the screening group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also in the screening group, the cancers detected by screening were more likely to be stage I (50%) than those not detected by screening.

The cumulative number of deaths from lung cancer was slightly but not significantly lower in the screening group from years 4 through 11. However, by the end of follow-up, the number of lung cancer deaths was equal between the groups (1,213 in the screening group vs 1,230 in the usual-care group). The cumulative overall mortality rate was also similar between the groups. For the subgroup who would have qualified for the NLST (see below), the lung cancer mortality rate was statistically similar between the two groups.

Comments. The results of the PLCO screening trial will be interpreted as the final word in lung cancer screening with standard chest radiography. The conclusion is that annual screening with chest radiography does not reduce lung cancer mortality rates and thus should not be performed in this context.

THE NATIONAL LUNG SCREENING TRIAL

The NLST aimed to determine if screening with low-dose chest CT could reduce lung cancer mortality rates.²

This controlled trial enrolled 53,454 people, who were randomized to undergo either low-dose chest CT or posteroanterior chest radiography at baseline and then yearly for 2 years.

Participants were men and women age 55 to 74 with at least 30 pack-years of cigarette smoking. If they had quit smoking, they had to have quit within the past 15 years. All were followed until study conclusion (median 6.5 years, maximum 7.4). About 41% were women, and nearly three-quarters were age 55 through 64. More than 48% were current smokers, with the rest being former smokers.

Results. Adherence to screening was 95% in the CT group and 93% in the radiography group, with a 4.3% annual rate of CT outside the study during the screening phase.

Cumulative lung cancer incidence rates were 645 per 100,000 person-years in the CT group and 572 in the radiography group.

In the CT group there were a total of 1,060 lung cancers during the entire study. Of these, 649 (61%) were detected by screening, 44 (4%) were interval cancers, and the rest were diagnosed after the screening period during follow-up.

In the chest radiography group, there were a total of 941 lung cancers during the entire study. Of these, 279 (30%) were detected by screening, 137 (15%) were interval cancers, and the rest were diagnosed after the screening period. Within the CT group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also within the CT group, the cancers detected by screening were more likely to be stage I (63%) than those not detected by screening.

The cumulative number of deaths from lung cancer was 443 in the radiography group, but only 356 in the CT group—20.0% lower (P =.004). The cumulative overall mortality rate was 6.7% lower in the CT group (P = .02).

Comments. The results of the NLST provide the first evidence that lung cancer mortality rates can be reduced by screening. Though many questions remain, the conclusions of this study are that screening a well-defined high-risk group with low-dose CT reduces the rate of death from lung cancer.

REMAINING CHALLENGES

The NLST showed that lung cancer screening with low-dose CT can meet the most important criterion for a successful screening program, ie, a reduction in the disease-specific mortality rate. Many challenges remain in meeting the other criteria for a successful or ideal screening program (low risk, few false-positive results, acceptability to the patient, and affordability). The issues with low-dose CT-based screening that challenge these ideals are outlined in this section.

Lung nodules: Benign or malignant?

A meta-analysis of CT screening studies found that for every 1,000 people screened at baseline, 9 were found to have stage I non-small-cell lung cancer, 235 had false-positive nodules, and 4 underwent thoracotomy for benign lesions.⁶

The NLST results were similar. In this trial, only nodules that were 4 mm or greater in diameter were reported. Using these criteria, over 27% of all study participants were found to have a lung nodule on CT at baseline and at year 1. The rate fell to nearly 17% at year 2, as nodules present from baseline were not reported. Of all the lung nodules detected, only 3.6% were ultimately proven to represent lung cancer.²

Many issues with small lung nodules need to be considered. The nodules are difficult to find, with highly variable reporting even by expert radiologists.⁷ They are difficult to measure accurately and thus are difficult to assess for growth.⁸ Adjunctive imaging and nonsurgical biopsy have a low yield for small nodules.^9–11 Follow-up of these lung nodules includes additional imaging and nonsurgical and surgical biopsy procedures, adding expense to the program and risk to the patient. Finally, knowing that they have a lung nodule makes patients feel anxious and thus negatively affects their quality of life.^12,13

Radiation exposure: How great is the risk?

There is a great deal of concern about radiation exposure from medical imaging, as many people receive a substantial amount of radiation each year from medical testing.¹⁴ A single low-dose scan with chest CT delivers a whole-body effective dose of about 1.5 mSv—less than one-fifth of the radiation dose of a typical diagnostic CT scan.

Many have tried to estimate the consequences of radiation exposure from low-dose CT screening. All estimates are extrapolations from unrelated radiation exposures. The increase in risk of death ranged from 0.01% to a few percent,¹⁵ and the increase in cancers was as high as 1.8% over a 25-year screening period.¹⁶ In general, the risks are felt to be very low but not negligible.

Cost-effectiveness is unknown

The cost-effectiveness of lung cancer screening is also unknown. Many highly variable estimates have been published.^17–20 The studies have differed in the perspective taken, the costs of testing assumed, and the rounds of screening included. The most cost-effective estimates are in populations with the highest risk of cancer, in programs that achieve the greatest reduction in mortality rate, and in programs that lead to high rates of smoking cessation.

Screening in the real world as opposed to a clinical trial may involve different risks, benefits, and costs. Compliance with screening and with nodule management algorithms may be lower outside of a study. One study suggested that those at highest risk of developing lung cancer would be the least likely to enroll in a screening program and the least likely to accept curative-intent surgery for screening-detected cancer.²¹

We expect that the NLST data will be analyzed for cost-effectiveness. This should provide the most accurate estimates for the group that was studied.

WE SET OUT TO DESIGN A SCREENING PROGRAM

With the evidence supporting a reduction in the rate of lung cancer mortality, and knowing the remaining challenges, we set out to provide a lung cancer screening program within Cleveland Clinic. In the design of our program, we considered several questions, outlined below.

Who should be offered low-dose CT screening?

The results of the NLST led to a great deal of excitement about lung cancer screening in both the medical community and the general public. The positive side of this publicity is that lung cancer is receiving attention that may lead to support for further advances. The negative side is that many patients who may seek out lung cancer screening are not at high enough risk of lung cancer to clearly benefit from it.

In the NLST, a very high-risk cohort was studied, as defined by clinical variables (age 55 to 74, at least 30 pack-years of smoking, and if a former smoker, had quit within the past 15 years). In this high-risk group, 320 patients needed to be screened (with three yearly chest CT scans) for one life to be saved from lung cancer, and only 3.6% of all lung nodules found (4 mm or larger) were actually lung cancer. In a group at lower risk, the number that needed to be screened to save one life would be higher, and the percentage of lung nodules that truly were lung cancer would be lower. This would lead to higher risks and costs related to screening, without a proven benefit to members of the lower-risk group.

The risk of the NLST cohort developing lung cancer was approximately 0.6% per year. Lung cancer risk-prediction models have been developed and published. Up to 2011, the three most commonly used models had only moderate accuracy at predicting risk.^22–25 In 2011 a risk model based on the PLCO cohort was developed and published.²⁶ This model seemed to be more accurate but perhaps a bit harder to apply in practice.

We discussed whether using a validated risk predictor with a target of 0.6% per year (ie, the risk in the NLST trial) would be an adequate means of deciding on candidacy for lung cancer screening or if we should strictly adhere to the inclusion criteria of the NLST cohort. We feel that the NLST cohort is the only group with true evidence of benefit (a reduction in the lung cancer-specific mortality rate). Thus, for our program’s entry criteria, we decided to use the same clinical predictors used for entry in the NLST.

How will the right patients get scheduled for low-dose screening CT?

Patients who enter the lung cancer screening program from our health system will require a physician’s order.

We are fortunate to have an electronic medical record in place. We have created an order set within the electronic record for low-dose chest CT. The order will eventually be able to be entered as “CT lung screening w/o” (ie, without contrast).

For patients from outside of our health system who would like to enter the lung cancer screening program, the entry criteria will be the same (see above). We will ask for the name of the patient’s primary care practitioner. If the patient does not have one, a member of our Respiratory Institute will see and enroll the patient.

How often should patients be screened, and for how many years?

Unfortunately, questions about the frequency of screening and how many years it should continue remain unanswered.

In the NLST, a similar number of early-stage lung cancers were detected during each of the three screening rounds. In both the NLST and PLCO trials, differences in the mortality rate curves began to narrow during the observation period, when active screening was no longer occurring. Thus, it is possible that a longer duration of screening could lead to a further reduction in mortality rates. Others have questioned whether a similar benefit, with less cost and risk, could be obtained by screening every 2 years.

The large amount of data obtained from the NLST and other CT-based studies is being reviewed so that models can be developed to help answer these questions. For now, we suggest at least three yearly CT screenings, with the hope that we will have clearer answers to these questions over time.

How will low-dose CT be performed and interpreted?

The parameters for low-dose CT were very tightly controlled and monitored during the NLST. This quality-control effort, designed to improve consistency across sites and to minimize risk to patients, should be carried into lung cancer screening programs.

Our program will closely mimic the CT performance criteria used in the NLST (tube current-time product 40 mAs for all patients, field of view lungs only, lung kernel images 3 mm at 1.5-mm intervals, and soft-tissue kernel images 5 mm at 2.5-mm intervals).²⁷ In the initial phase of the program, all screening scans will be performed at Cleveland Clinic’s main imaging facility.

Small lung nodules remain quite challenging to detect and measure. To minimize variability in scan interpretation, the NLST readers were all expertly trained radiologists. Despite this, much variability was noted in the number of nodules detected, their measured size, and the follow-up recommendations. All of the screening CT images for our program will be interpreted by board-certified radiologists with expertise in chest imaging.

Other screening studies have included novel imaging assessment in their testing algorithms, particularly volumetric analysis of lung nodules.²⁸ These tools may prove to assist in nodule detection, measurement, and management over time. At this point, we do not think they have been studied and standardized enough to include them in a standard-of-care screening program. We hope that they will evolve to the point of clinical utility in the near future.

Lung cancer screening is not currently covered by most insurers, including Medicare, although one major insurer has recently started to cover it. We expect decisions on coverage from other insurers in the next 12 months. In the meantime, we offer a low-dose screening chest CT to our patients for $125, which includes the radiologist’s fee for interpreting the scan.

Smoking cessation

The NLST showed that low-dose CT screening can reduce lung cancer mortality rates by 20% in a high-risk group. A 50-year-old active smoker who quits smoking reduces his or her risk of dying of lung cancer by more than 50%.²⁹ Entry into a lung cancer screening program provides an opportunity for education and assistance with tobacco dependency.

At Cleveland Clinic, we have an active Tobacco Treatment Center within our Wellness Institute. All lung cancer screening participants who are identified as active smokers will be given a program brochure and will be offered a consult in the program.

Studies of CT-based screening have highlighted the tremendous number of lung nodules that are identified and the low likelihood of malignancy in those that are less than 1 cm in diameter. Many screening studies define a positive result as a lung nodule above a particular size. The NLST used 4 mm or greater as the cutoff. The lower the cutoff, the greater the number of nodules found, and the lower the overall likelihood of malignancy in the nodules.

Studies in which annual CT screening was the intervention are able to use size criteria in part because the study design ensures another CT will be performed 12 months later. Current nodule management guidelines suggest 12-month CT follow-up of incidentally discovered lung nodules, 4 mm or smaller, in at-risk patients.³⁰ In a screening program, particularly one for which the patient must pay, the 12-month screening CT cannot be guaranteed. This makes it more difficult to ignore the smallest nodules identified on CT screening. Given this, we will be reporting all lung nodules identified, regardless of size on the initial screening.

Most studies of CT screening have reported any new nodule identified in subsequent screening rounds regardless of size. Though it is intuitive that a new nodule would have a high likelihood of malignancy in a high-risk cohort, malignancy rates have been reported to be as low as 1% for new nodules. As with the initial round of screening, we will report all new lung nodules identified in subsequent screening rounds.

The recommendations for the evaluation of lung nodules, both within the report and at the lung nodule clinic, are in keeping with currently available guidelines, such as those from the Fleischner Society³⁰ and the American College of Chest Physicians.³¹ For incidentally discovered lung nodules in patients at high risk, the Fleischner Society recommendations are as follows³⁰:

• For nodules 4 mm or smaller, follow-up in 12 months; if no growth, then no further follow-up
• For nodules 4 to 6 mm, follow-up at 6 to 12 months, then 18 to 24 months if no growth
• For nodules 6 to 8 mm, follow-up at 3 to 6 months, then 9 to 12 months, then 24 months if no growth
• For nodules 8 mm or larger, follow-up at 3, 9, and 24 months, or positron emission tomography, or biopsy, or both.

If the nodule is large enough or is deemed to be of high enough risk, adjuvant testing with diagnostic imaging, guided bronchoscopy, transthoracic needle aspiration, or minimally invasive resection will be offered. All patients with nodules believed to require biopsy will be discussed at our multidisciplinary lung cancer tumor board before biopsy.

How do we make practitioners and patients aware of the program and its indications, risks, and benefits?

Education will be the key to having lung cancer screening adopted as the standard of care, to lung cancer screening being provided within a well-designed and capable system, and to ensuring that patients have realistic expectations about screening. Articles such as this and grand rounds presentations within our health system will help provide education to our colleagues. Broader marketing campaigns will be considered in the future once demand and system capabilities are clearly identified. A patient information brochure will be provided at the time of the screening test (see the patient information sheet that accompanies this article).

How do we help to advance best practice?

As excited as we are that low-dose CT-based lung cancer screening has been proven to reduce lung cancer mortality rates, it is clear that there is a lot of room to improve the programs that are developed based on current data.

Advances in our ability to accurately predict an individual’s risk of developing lung cancer will allow us to offer screening to those it is most likely to benefit.

Advances in smoking cessation and chemoprevention will help to minimize the number of lung cancers that develop.

Advances in our ability to determine the nature of lung nodules will allow us to accelerate treatment of very early lung cancer while minimizing additional testing on benign nodules; advances in our ability to treat localized and advanced disease will improve the outcome for those identified as having lung cancer.

To help move the science of screening forward, we will develop a screening program registry that can be populated from the order set and the templated report. The registry can be used to ensure appropriate patient care, while studying relevant epidemiologic, quality, and cost-related questions.

We hope to assess novel imaging software capable of assisting with the detection and characterization of lung nodules.

We have an active biomarker development program to assess the ability of breath and blood-based biomarkers to identify those at risk of developing lung cancer; to assist with the management of screening-detected lung nodules; to assist with the diagnosis of early stage lung cancer; and to characterize the nature of the cancers identified. Accurate biomarkers could lead to further decreases in mortality rates while reducing the risks and costs of a screening program.

We have strong surgical, medical, and radiation oncology programs, actively pursuing advances in minimally invasive resection procedures and ablative and targeted therapies.

ENTERING A NEW ERA

We are entering a new era of lung cancer screening. The NLST has shown that lung cancer morality rates can be reduced through low-dose CT screening in a high-risk population. Many challenges remain, such as managing the nodules that are discovered, determining if the program is cost-effective, and minimizing radiation exposure. These need to be considered when designing a lung cancer screening program. Advances over time will help us optimize the programs that are developed.

In 2011, two papers were published that will shape the way we think about lung cancer screening for years to come.

See related patient information sheet

While the ability to screen for lung cancer is a major positive change, it also raises many thorny questions, such as who should be screened, how often should they be screened, and how should we respond when a nodule is detected.

To answer some of these questions, we will outline how Cleveland Clinic has structured its lung cancer screening program, and the rationale we used for making pragmatic patient-care decisions within this program. We will conclude with our thoughts about the potential evolution of lung cancer screening programs.

THE 40-YEAR QUEST FOR EFFECTIVE LUNG CANCER SCREENING

Lung cancer kills more people in the United States than the next four most lethal types of cancer combined.³ It is curable if found early in its course. Unfortunately, most people who develop lung cancer feel no symptoms when it is early in its course, and therefore it is too often diagnosed at a late stage. Treatment for late-stage lung cancer is effective, but it is rarely curative.

Screening refers to testing people at risk of developing a disease before its symptoms or signs have appeared. The goal of screening is to reduce the disease-specific mortality rate. For this to happen, the disease must be detectable in a preclinical form, and treatment must be more successful when applied early. Ideally, the screening test should pose little risk to the patient, be sensitive for detecting the disease early in its course, give few false-positive results, be acceptable to the patient, and be relatively inexpensive to the health system.

Over the past 4 decades, a large volume of research has been done in the hope of proving that conventional radiography or CT could be an effective screening test for lung cancer.^4,5

Cohort studies (ie, in which all the patients were screened) of radiography or CT have shown a longer survival from the time of lung cancer diagnosis than would be expected without screening. These studies were not designed to prove a reduction in the lung cancer-specific mortality rate.

Controlled trials (in which half the patients received the screening and the other half did not) of chest radiography have been interpreted as not showing a reduction in lung cancer mortality rates, though debate about the interpretation of these trials persisted until this past year. Biases inherent in using duration of survival rather than the mortality rate as an end point have been suggested as the reason for the apparent benefit in survival without a reduction in the mortality rate.

Controlled trials of CT screening were started nearly a decade ago. Until 2011, the results of these trials were not mature enough to comment on.

THE PROSTATE, LUNG, COLORECTAL, AND OVARIAN TRIAL

The lung cancer screening portion of the PLCO trial aimed to determine the effect of screening chest radiography on lung cancer-specific mortality rates.¹

In this trial, 154,901 people were randomized to undergo either posteroanterior chest radiography every year for 4 years or usual care, ie, no lung cancer screening. Participants were men and women age 55 to 74 with no history of prostate, lung, colorectal, or ovarian cancer. They did not need to be a smoker to participate. Those who had never smoked and who were randomized to the screening group received only 3 years of testing. All were followed for 13 years or until the conclusion of the study (8 years after the final participant was enrolled). About half were women, and nearly two-thirds were age 55 through 64. Only 10% were current smokers, while a full 45% had never smoked.

Results. Adherence to screening in the screening group ranged from 79% to 86.6% over the years of screening, and 11% of the usual-care group was estimated to have undergone screening chest radiography.

Cumulative lung cancer incidence rates were 201 per 100,000 person-years in the screening group and 192 in the usual-care group.

In the screening group, there were a total of 1,696 lung cancers during the entire study. Of these, 307 (18%) were detected by screening, 198 (12%) were interval cancers (diagnosed during the screening period but not by the screening test), and the remainder were diagnosed after the screening period during the years of follow-up. In the screening group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also in the screening group, the cancers detected by screening were more likely to be stage I (50%) than those not detected by screening.

The cumulative number of deaths from lung cancer was slightly but not significantly lower in the screening group from years 4 through 11. However, by the end of follow-up, the number of lung cancer deaths was equal between the groups (1,213 in the screening group vs 1,230 in the usual-care group). The cumulative overall mortality rate was also similar between the groups. For the subgroup who would have qualified for the NLST (see below), the lung cancer mortality rate was statistically similar between the two groups.

Comments. The results of the PLCO screening trial will be interpreted as the final word in lung cancer screening with standard chest radiography. The conclusion is that annual screening with chest radiography does not reduce lung cancer mortality rates and thus should not be performed in this context.

THE NATIONAL LUNG SCREENING TRIAL

The NLST aimed to determine if screening with low-dose chest CT could reduce lung cancer mortality rates.²

This controlled trial enrolled 53,454 people, who were randomized to undergo either low-dose chest CT or posteroanterior chest radiography at baseline and then yearly for 2 years.

Participants were men and women age 55 to 74 with at least 30 pack-years of cigarette smoking. If they had quit smoking, they had to have quit within the past 15 years. All were followed until study conclusion (median 6.5 years, maximum 7.4). About 41% were women, and nearly three-quarters were age 55 through 64. More than 48% were current smokers, with the rest being former smokers.

Results. Adherence to screening was 95% in the CT group and 93% in the radiography group, with a 4.3% annual rate of CT outside the study during the screening phase.

Cumulative lung cancer incidence rates were 645 per 100,000 person-years in the CT group and 572 in the radiography group.

In the CT group there were a total of 1,060 lung cancers during the entire study. Of these, 649 (61%) were detected by screening, 44 (4%) were interval cancers, and the rest were diagnosed after the screening period during follow-up.

In the chest radiography group, there were a total of 941 lung cancers during the entire study. Of these, 279 (30%) were detected by screening, 137 (15%) were interval cancers, and the rest were diagnosed after the screening period. Within the CT group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also within the CT group, the cancers detected by screening were more likely to be stage I (63%) than those not detected by screening.

The cumulative number of deaths from lung cancer was 443 in the radiography group, but only 356 in the CT group—20.0% lower (P =.004). The cumulative overall mortality rate was 6.7% lower in the CT group (P = .02).

Comments. The results of the NLST provide the first evidence that lung cancer mortality rates can be reduced by screening. Though many questions remain, the conclusions of this study are that screening a well-defined high-risk group with low-dose CT reduces the rate of death from lung cancer.

REMAINING CHALLENGES

The NLST showed that lung cancer screening with low-dose CT can meet the most important criterion for a successful screening program, ie, a reduction in the disease-specific mortality rate. Many challenges remain in meeting the other criteria for a successful or ideal screening program (low risk, few false-positive results, acceptability to the patient, and affordability). The issues with low-dose CT-based screening that challenge these ideals are outlined in this section.

Lung nodules: Benign or malignant?

A meta-analysis of CT screening studies found that for every 1,000 people screened at baseline, 9 were found to have stage I non-small-cell lung cancer, 235 had false-positive nodules, and 4 underwent thoracotomy for benign lesions.⁶

The NLST results were similar. In this trial, only nodules that were 4 mm or greater in diameter were reported. Using these criteria, over 27% of all study participants were found to have a lung nodule on CT at baseline and at year 1. The rate fell to nearly 17% at year 2, as nodules present from baseline were not reported. Of all the lung nodules detected, only 3.6% were ultimately proven to represent lung cancer.²

Many issues with small lung nodules need to be considered. The nodules are difficult to find, with highly variable reporting even by expert radiologists.⁷ They are difficult to measure accurately and thus are difficult to assess for growth.⁸ Adjunctive imaging and nonsurgical biopsy have a low yield for small nodules.^9–11 Follow-up of these lung nodules includes additional imaging and nonsurgical and surgical biopsy procedures, adding expense to the program and risk to the patient. Finally, knowing that they have a lung nodule makes patients feel anxious and thus negatively affects their quality of life.^12,13

Radiation exposure: How great is the risk?

There is a great deal of concern about radiation exposure from medical imaging, as many people receive a substantial amount of radiation each year from medical testing.¹⁴ A single low-dose scan with chest CT delivers a whole-body effective dose of about 1.5 mSv—less than one-fifth of the radiation dose of a typical diagnostic CT scan.

Many have tried to estimate the consequences of radiation exposure from low-dose CT screening. All estimates are extrapolations from unrelated radiation exposures. The increase in risk of death ranged from 0.01% to a few percent,¹⁵ and the increase in cancers was as high as 1.8% over a 25-year screening period.¹⁶ In general, the risks are felt to be very low but not negligible.

Cost-effectiveness is unknown

The cost-effectiveness of lung cancer screening is also unknown. Many highly variable estimates have been published.^17–20 The studies have differed in the perspective taken, the costs of testing assumed, and the rounds of screening included. The most cost-effective estimates are in populations with the highest risk of cancer, in programs that achieve the greatest reduction in mortality rate, and in programs that lead to high rates of smoking cessation.

Screening in the real world as opposed to a clinical trial may involve different risks, benefits, and costs. Compliance with screening and with nodule management algorithms may be lower outside of a study. One study suggested that those at highest risk of developing lung cancer would be the least likely to enroll in a screening program and the least likely to accept curative-intent surgery for screening-detected cancer.²¹

We expect that the NLST data will be analyzed for cost-effectiveness. This should provide the most accurate estimates for the group that was studied.

WE SET OUT TO DESIGN A SCREENING PROGRAM

With the evidence supporting a reduction in the rate of lung cancer mortality, and knowing the remaining challenges, we set out to provide a lung cancer screening program within Cleveland Clinic. In the design of our program, we considered several questions, outlined below.

Who should be offered low-dose CT screening?

The results of the NLST led to a great deal of excitement about lung cancer screening in both the medical community and the general public. The positive side of this publicity is that lung cancer is receiving attention that may lead to support for further advances. The negative side is that many patients who may seek out lung cancer screening are not at high enough risk of lung cancer to clearly benefit from it.

In the NLST, a very high-risk cohort was studied, as defined by clinical variables (age 55 to 74, at least 30 pack-years of smoking, and if a former smoker, had quit within the past 15 years). In this high-risk group, 320 patients needed to be screened (with three yearly chest CT scans) for one life to be saved from lung cancer, and only 3.6% of all lung nodules found (4 mm or larger) were actually lung cancer. In a group at lower risk, the number that needed to be screened to save one life would be higher, and the percentage of lung nodules that truly were lung cancer would be lower. This would lead to higher risks and costs related to screening, without a proven benefit to members of the lower-risk group.

The risk of the NLST cohort developing lung cancer was approximately 0.6% per year. Lung cancer risk-prediction models have been developed and published. Up to 2011, the three most commonly used models had only moderate accuracy at predicting risk.^22–25 In 2011 a risk model based on the PLCO cohort was developed and published.²⁶ This model seemed to be more accurate but perhaps a bit harder to apply in practice.

We discussed whether using a validated risk predictor with a target of 0.6% per year (ie, the risk in the NLST trial) would be an adequate means of deciding on candidacy for lung cancer screening or if we should strictly adhere to the inclusion criteria of the NLST cohort. We feel that the NLST cohort is the only group with true evidence of benefit (a reduction in the lung cancer-specific mortality rate). Thus, for our program’s entry criteria, we decided to use the same clinical predictors used for entry in the NLST.

How will the right patients get scheduled for low-dose screening CT?

Patients who enter the lung cancer screening program from our health system will require a physician’s order.

We are fortunate to have an electronic medical record in place. We have created an order set within the electronic record for low-dose chest CT. The order will eventually be able to be entered as “CT lung screening w/o” (ie, without contrast).

For patients from outside of our health system who would like to enter the lung cancer screening program, the entry criteria will be the same (see above). We will ask for the name of the patient’s primary care practitioner. If the patient does not have one, a member of our Respiratory Institute will see and enroll the patient.

How often should patients be screened, and for how many years?

Unfortunately, questions about the frequency of screening and how many years it should continue remain unanswered.

In the NLST, a similar number of early-stage lung cancers were detected during each of the three screening rounds. In both the NLST and PLCO trials, differences in the mortality rate curves began to narrow during the observation period, when active screening was no longer occurring. Thus, it is possible that a longer duration of screening could lead to a further reduction in mortality rates. Others have questioned whether a similar benefit, with less cost and risk, could be obtained by screening every 2 years.

The large amount of data obtained from the NLST and other CT-based studies is being reviewed so that models can be developed to help answer these questions. For now, we suggest at least three yearly CT screenings, with the hope that we will have clearer answers to these questions over time.

How will low-dose CT be performed and interpreted?

The parameters for low-dose CT were very tightly controlled and monitored during the NLST. This quality-control effort, designed to improve consistency across sites and to minimize risk to patients, should be carried into lung cancer screening programs.

Our program will closely mimic the CT performance criteria used in the NLST (tube current-time product 40 mAs for all patients, field of view lungs only, lung kernel images 3 mm at 1.5-mm intervals, and soft-tissue kernel images 5 mm at 2.5-mm intervals).²⁷ In the initial phase of the program, all screening scans will be performed at Cleveland Clinic’s main imaging facility.

Small lung nodules remain quite challenging to detect and measure. To minimize variability in scan interpretation, the NLST readers were all expertly trained radiologists. Despite this, much variability was noted in the number of nodules detected, their measured size, and the follow-up recommendations. All of the screening CT images for our program will be interpreted by board-certified radiologists with expertise in chest imaging.

Other screening studies have included novel imaging assessment in their testing algorithms, particularly volumetric analysis of lung nodules.²⁸ These tools may prove to assist in nodule detection, measurement, and management over time. At this point, we do not think they have been studied and standardized enough to include them in a standard-of-care screening program. We hope that they will evolve to the point of clinical utility in the near future.

Lung cancer screening is not currently covered by most insurers, including Medicare, although one major insurer has recently started to cover it. We expect decisions on coverage from other insurers in the next 12 months. In the meantime, we offer a low-dose screening chest CT to our patients for $125, which includes the radiologist’s fee for interpreting the scan.

Smoking cessation

The NLST showed that low-dose CT screening can reduce lung cancer mortality rates by 20% in a high-risk group. A 50-year-old active smoker who quits smoking reduces his or her risk of dying of lung cancer by more than 50%.²⁹ Entry into a lung cancer screening program provides an opportunity for education and assistance with tobacco dependency.

At Cleveland Clinic, we have an active Tobacco Treatment Center within our Wellness Institute. All lung cancer screening participants who are identified as active smokers will be given a program brochure and will be offered a consult in the program.

Studies of CT-based screening have highlighted the tremendous number of lung nodules that are identified and the low likelihood of malignancy in those that are less than 1 cm in diameter. Many screening studies define a positive result as a lung nodule above a particular size. The NLST used 4 mm or greater as the cutoff. The lower the cutoff, the greater the number of nodules found, and the lower the overall likelihood of malignancy in the nodules.

Studies in which annual CT screening was the intervention are able to use size criteria in part because the study design ensures another CT will be performed 12 months later. Current nodule management guidelines suggest 12-month CT follow-up of incidentally discovered lung nodules, 4 mm or smaller, in at-risk patients.³⁰ In a screening program, particularly one for which the patient must pay, the 12-month screening CT cannot be guaranteed. This makes it more difficult to ignore the smallest nodules identified on CT screening. Given this, we will be reporting all lung nodules identified, regardless of size on the initial screening.

Most studies of CT screening have reported any new nodule identified in subsequent screening rounds regardless of size. Though it is intuitive that a new nodule would have a high likelihood of malignancy in a high-risk cohort, malignancy rates have been reported to be as low as 1% for new nodules. As with the initial round of screening, we will report all new lung nodules identified in subsequent screening rounds.

The recommendations for the evaluation of lung nodules, both within the report and at the lung nodule clinic, are in keeping with currently available guidelines, such as those from the Fleischner Society³⁰ and the American College of Chest Physicians.³¹ For incidentally discovered lung nodules in patients at high risk, the Fleischner Society recommendations are as follows³⁰:

• For nodules 4 mm or smaller, follow-up in 12 months; if no growth, then no further follow-up
• For nodules 4 to 6 mm, follow-up at 6 to 12 months, then 18 to 24 months if no growth
• For nodules 6 to 8 mm, follow-up at 3 to 6 months, then 9 to 12 months, then 24 months if no growth
• For nodules 8 mm or larger, follow-up at 3, 9, and 24 months, or positron emission tomography, or biopsy, or both.

If the nodule is large enough or is deemed to be of high enough risk, adjuvant testing with diagnostic imaging, guided bronchoscopy, transthoracic needle aspiration, or minimally invasive resection will be offered. All patients with nodules believed to require biopsy will be discussed at our multidisciplinary lung cancer tumor board before biopsy.

How do we make practitioners and patients aware of the program and its indications, risks, and benefits?

Education will be the key to having lung cancer screening adopted as the standard of care, to lung cancer screening being provided within a well-designed and capable system, and to ensuring that patients have realistic expectations about screening. Articles such as this and grand rounds presentations within our health system will help provide education to our colleagues. Broader marketing campaigns will be considered in the future once demand and system capabilities are clearly identified. A patient information brochure will be provided at the time of the screening test (see the patient information sheet that accompanies this article).

How do we help to advance best practice?

As excited as we are that low-dose CT-based lung cancer screening has been proven to reduce lung cancer mortality rates, it is clear that there is a lot of room to improve the programs that are developed based on current data.

Advances in our ability to accurately predict an individual’s risk of developing lung cancer will allow us to offer screening to those it is most likely to benefit.

Advances in smoking cessation and chemoprevention will help to minimize the number of lung cancers that develop.

Advances in our ability to determine the nature of lung nodules will allow us to accelerate treatment of very early lung cancer while minimizing additional testing on benign nodules; advances in our ability to treat localized and advanced disease will improve the outcome for those identified as having lung cancer.

To help move the science of screening forward, we will develop a screening program registry that can be populated from the order set and the templated report. The registry can be used to ensure appropriate patient care, while studying relevant epidemiologic, quality, and cost-related questions.

We hope to assess novel imaging software capable of assisting with the detection and characterization of lung nodules.

We have an active biomarker development program to assess the ability of breath and blood-based biomarkers to identify those at risk of developing lung cancer; to assist with the management of screening-detected lung nodules; to assist with the diagnosis of early stage lung cancer; and to characterize the nature of the cancers identified. Accurate biomarkers could lead to further decreases in mortality rates while reducing the risks and costs of a screening program.

We have strong surgical, medical, and radiation oncology programs, actively pursuing advances in minimally invasive resection procedures and ablative and targeted therapies.

ENTERING A NEW ERA

We are entering a new era of lung cancer screening. The NLST has shown that lung cancer morality rates can be reduced through low-dose CT screening in a high-risk population. Many challenges remain, such as managing the nodules that are discovered, determining if the program is cost-effective, and minimizing radiation exposure. These need to be considered when designing a lung cancer screening program. Advances over time will help us optimize the programs that are developed.

In 2011, two papers were published that will shape the way we think about lung cancer screening for years to come.

See related patient information sheet

While the ability to screen for lung cancer is a major positive change, it also raises many thorny questions, such as who should be screened, how often should they be screened, and how should we respond when a nodule is detected.

To answer some of these questions, we will outline how Cleveland Clinic has structured its lung cancer screening program, and the rationale we used for making pragmatic patient-care decisions within this program. We will conclude with our thoughts about the potential evolution of lung cancer screening programs.

THE 40-YEAR QUEST FOR EFFECTIVE LUNG CANCER SCREENING

Lung cancer kills more people in the United States than the next four most lethal types of cancer combined.³ It is curable if found early in its course. Unfortunately, most people who develop lung cancer feel no symptoms when it is early in its course, and therefore it is too often diagnosed at a late stage. Treatment for late-stage lung cancer is effective, but it is rarely curative.

Screening refers to testing people at risk of developing a disease before its symptoms or signs have appeared. The goal of screening is to reduce the disease-specific mortality rate. For this to happen, the disease must be detectable in a preclinical form, and treatment must be more successful when applied early. Ideally, the screening test should pose little risk to the patient, be sensitive for detecting the disease early in its course, give few false-positive results, be acceptable to the patient, and be relatively inexpensive to the health system.

Over the past 4 decades, a large volume of research has been done in the hope of proving that conventional radiography or CT could be an effective screening test for lung cancer.^4,5

Cohort studies (ie, in which all the patients were screened) of radiography or CT have shown a longer survival from the time of lung cancer diagnosis than would be expected without screening. These studies were not designed to prove a reduction in the lung cancer-specific mortality rate.

Controlled trials (in which half the patients received the screening and the other half did not) of chest radiography have been interpreted as not showing a reduction in lung cancer mortality rates, though debate about the interpretation of these trials persisted until this past year. Biases inherent in using duration of survival rather than the mortality rate as an end point have been suggested as the reason for the apparent benefit in survival without a reduction in the mortality rate.

Controlled trials of CT screening were started nearly a decade ago. Until 2011, the results of these trials were not mature enough to comment on.

THE PROSTATE, LUNG, COLORECTAL, AND OVARIAN TRIAL

The lung cancer screening portion of the PLCO trial aimed to determine the effect of screening chest radiography on lung cancer-specific mortality rates.¹

In this trial, 154,901 people were randomized to undergo either posteroanterior chest radiography every year for 4 years or usual care, ie, no lung cancer screening. Participants were men and women age 55 to 74 with no history of prostate, lung, colorectal, or ovarian cancer. They did not need to be a smoker to participate. Those who had never smoked and who were randomized to the screening group received only 3 years of testing. All were followed for 13 years or until the conclusion of the study (8 years after the final participant was enrolled). About half were women, and nearly two-thirds were age 55 through 64. Only 10% were current smokers, while a full 45% had never smoked.

Results. Adherence to screening in the screening group ranged from 79% to 86.6% over the years of screening, and 11% of the usual-care group was estimated to have undergone screening chest radiography.

Cumulative lung cancer incidence rates were 201 per 100,000 person-years in the screening group and 192 in the usual-care group.

In the screening group, there were a total of 1,696 lung cancers during the entire study. Of these, 307 (18%) were detected by screening, 198 (12%) were interval cancers (diagnosed during the screening period but not by the screening test), and the remainder were diagnosed after the screening period during the years of follow-up. In the screening group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also in the screening group, the cancers detected by screening were more likely to be stage I (50%) than those not detected by screening.

The cumulative number of deaths from lung cancer was slightly but not significantly lower in the screening group from years 4 through 11. However, by the end of follow-up, the number of lung cancer deaths was equal between the groups (1,213 in the screening group vs 1,230 in the usual-care group). The cumulative overall mortality rate was also similar between the groups. For the subgroup who would have qualified for the NLST (see below), the lung cancer mortality rate was statistically similar between the two groups.

Comments. The results of the PLCO screening trial will be interpreted as the final word in lung cancer screening with standard chest radiography. The conclusion is that annual screening with chest radiography does not reduce lung cancer mortality rates and thus should not be performed in this context.

THE NATIONAL LUNG SCREENING TRIAL

The NLST aimed to determine if screening with low-dose chest CT could reduce lung cancer mortality rates.²

This controlled trial enrolled 53,454 people, who were randomized to undergo either low-dose chest CT or posteroanterior chest radiography at baseline and then yearly for 2 years.

Participants were men and women age 55 to 74 with at least 30 pack-years of cigarette smoking. If they had quit smoking, they had to have quit within the past 15 years. All were followed until study conclusion (median 6.5 years, maximum 7.4). About 41% were women, and nearly three-quarters were age 55 through 64. More than 48% were current smokers, with the rest being former smokers.

Results. Adherence to screening was 95% in the CT group and 93% in the radiography group, with a 4.3% annual rate of CT outside the study during the screening phase.

Cumulative lung cancer incidence rates were 645 per 100,000 person-years in the CT group and 572 in the radiography group.

In the CT group there were a total of 1,060 lung cancers during the entire study. Of these, 649 (61%) were detected by screening, 44 (4%) were interval cancers, and the rest were diagnosed after the screening period during follow-up.

In the chest radiography group, there were a total of 941 lung cancers during the entire study. Of these, 279 (30%) were detected by screening, 137 (15%) were interval cancers, and the rest were diagnosed after the screening period. Within the CT group, the cancers detected by screening were more likely to be adenocarcinomas and less likely to be small-cell carcinomas than those not detected by screening. Also within the CT group, the cancers detected by screening were more likely to be stage I (63%) than those not detected by screening.

The cumulative number of deaths from lung cancer was 443 in the radiography group, but only 356 in the CT group—20.0% lower (P =.004). The cumulative overall mortality rate was 6.7% lower in the CT group (P = .02).

Comments. The results of the NLST provide the first evidence that lung cancer mortality rates can be reduced by screening. Though many questions remain, the conclusions of this study are that screening a well-defined high-risk group with low-dose CT reduces the rate of death from lung cancer.

REMAINING CHALLENGES

The NLST showed that lung cancer screening with low-dose CT can meet the most important criterion for a successful screening program, ie, a reduction in the disease-specific mortality rate. Many challenges remain in meeting the other criteria for a successful or ideal screening program (low risk, few false-positive results, acceptability to the patient, and affordability). The issues with low-dose CT-based screening that challenge these ideals are outlined in this section.

Lung nodules: Benign or malignant?

A meta-analysis of CT screening studies found that for every 1,000 people screened at baseline, 9 were found to have stage I non-small-cell lung cancer, 235 had false-positive nodules, and 4 underwent thoracotomy for benign lesions.⁶

The NLST results were similar. In this trial, only nodules that were 4 mm or greater in diameter were reported. Using these criteria, over 27% of all study participants were found to have a lung nodule on CT at baseline and at year 1. The rate fell to nearly 17% at year 2, as nodules present from baseline were not reported. Of all the lung nodules detected, only 3.6% were ultimately proven to represent lung cancer.²

Many issues with small lung nodules need to be considered. The nodules are difficult to find, with highly variable reporting even by expert radiologists.⁷ They are difficult to measure accurately and thus are difficult to assess for growth.⁸ Adjunctive imaging and nonsurgical biopsy have a low yield for small nodules.^9–11 Follow-up of these lung nodules includes additional imaging and nonsurgical and surgical biopsy procedures, adding expense to the program and risk to the patient. Finally, knowing that they have a lung nodule makes patients feel anxious and thus negatively affects their quality of life.^12,13

Radiation exposure: How great is the risk?

There is a great deal of concern about radiation exposure from medical imaging, as many people receive a substantial amount of radiation each year from medical testing.¹⁴ A single low-dose scan with chest CT delivers a whole-body effective dose of about 1.5 mSv—less than one-fifth of the radiation dose of a typical diagnostic CT scan.

Many have tried to estimate the consequences of radiation exposure from low-dose CT screening. All estimates are extrapolations from unrelated radiation exposures. The increase in risk of death ranged from 0.01% to a few percent,¹⁵ and the increase in cancers was as high as 1.8% over a 25-year screening period.¹⁶ In general, the risks are felt to be very low but not negligible.

Cost-effectiveness is unknown

The cost-effectiveness of lung cancer screening is also unknown. Many highly variable estimates have been published.^17–20 The studies have differed in the perspective taken, the costs of testing assumed, and the rounds of screening included. The most cost-effective estimates are in populations with the highest risk of cancer, in programs that achieve the greatest reduction in mortality rate, and in programs that lead to high rates of smoking cessation.

Screening in the real world as opposed to a clinical trial may involve different risks, benefits, and costs. Compliance with screening and with nodule management algorithms may be lower outside of a study. One study suggested that those at highest risk of developing lung cancer would be the least likely to enroll in a screening program and the least likely to accept curative-intent surgery for screening-detected cancer.²¹

We expect that the NLST data will be analyzed for cost-effectiveness. This should provide the most accurate estimates for the group that was studied.

WE SET OUT TO DESIGN A SCREENING PROGRAM

With the evidence supporting a reduction in the rate of lung cancer mortality, and knowing the remaining challenges, we set out to provide a lung cancer screening program within Cleveland Clinic. In the design of our program, we considered several questions, outlined below.

Who should be offered low-dose CT screening?

The results of the NLST led to a great deal of excitement about lung cancer screening in both the medical community and the general public. The positive side of this publicity is that lung cancer is receiving attention that may lead to support for further advances. The negative side is that many patients who may seek out lung cancer screening are not at high enough risk of lung cancer to clearly benefit from it.

In the NLST, a very high-risk cohort was studied, as defined by clinical variables (age 55 to 74, at least 30 pack-years of smoking, and if a former smoker, had quit within the past 15 years). In this high-risk group, 320 patients needed to be screened (with three yearly chest CT scans) for one life to be saved from lung cancer, and only 3.6% of all lung nodules found (4 mm or larger) were actually lung cancer. In a group at lower risk, the number that needed to be screened to save one life would be higher, and the percentage of lung nodules that truly were lung cancer would be lower. This would lead to higher risks and costs related to screening, without a proven benefit to members of the lower-risk group.

The risk of the NLST cohort developing lung cancer was approximately 0.6% per year. Lung cancer risk-prediction models have been developed and published. Up to 2011, the three most commonly used models had only moderate accuracy at predicting risk.^22–25 In 2011 a risk model based on the PLCO cohort was developed and published.²⁶ This model seemed to be more accurate but perhaps a bit harder to apply in practice.

We discussed whether using a validated risk predictor with a target of 0.6% per year (ie, the risk in the NLST trial) would be an adequate means of deciding on candidacy for lung cancer screening or if we should strictly adhere to the inclusion criteria of the NLST cohort. We feel that the NLST cohort is the only group with true evidence of benefit (a reduction in the lung cancer-specific mortality rate). Thus, for our program’s entry criteria, we decided to use the same clinical predictors used for entry in the NLST.

How will the right patients get scheduled for low-dose screening CT?

Patients who enter the lung cancer screening program from our health system will require a physician’s order.

We are fortunate to have an electronic medical record in place. We have created an order set within the electronic record for low-dose chest CT. The order will eventually be able to be entered as “CT lung screening w/o” (ie, without contrast).

For patients from outside of our health system who would like to enter the lung cancer screening program, the entry criteria will be the same (see above). We will ask for the name of the patient’s primary care practitioner. If the patient does not have one, a member of our Respiratory Institute will see and enroll the patient.

How often should patients be screened, and for how many years?

Unfortunately, questions about the frequency of screening and how many years it should continue remain unanswered.

In the NLST, a similar number of early-stage lung cancers were detected during each of the three screening rounds. In both the NLST and PLCO trials, differences in the mortality rate curves began to narrow during the observation period, when active screening was no longer occurring. Thus, it is possible that a longer duration of screening could lead to a further reduction in mortality rates. Others have questioned whether a similar benefit, with less cost and risk, could be obtained by screening every 2 years.

The large amount of data obtained from the NLST and other CT-based studies is being reviewed so that models can be developed to help answer these questions. For now, we suggest at least three yearly CT screenings, with the hope that we will have clearer answers to these questions over time.

How will low-dose CT be performed and interpreted?

The parameters for low-dose CT were very tightly controlled and monitored during the NLST. This quality-control effort, designed to improve consistency across sites and to minimize risk to patients, should be carried into lung cancer screening programs.

Our program will closely mimic the CT performance criteria used in the NLST (tube current-time product 40 mAs for all patients, field of view lungs only, lung kernel images 3 mm at 1.5-mm intervals, and soft-tissue kernel images 5 mm at 2.5-mm intervals).²⁷ In the initial phase of the program, all screening scans will be performed at Cleveland Clinic’s main imaging facility.

Small lung nodules remain quite challenging to detect and measure. To minimize variability in scan interpretation, the NLST readers were all expertly trained radiologists. Despite this, much variability was noted in the number of nodules detected, their measured size, and the follow-up recommendations. All of the screening CT images for our program will be interpreted by board-certified radiologists with expertise in chest imaging.

Other screening studies have included novel imaging assessment in their testing algorithms, particularly volumetric analysis of lung nodules.²⁸ These tools may prove to assist in nodule detection, measurement, and management over time. At this point, we do not think they have been studied and standardized enough to include them in a standard-of-care screening program. We hope that they will evolve to the point of clinical utility in the near future.

Lung cancer screening is not currently covered by most insurers, including Medicare, although one major insurer has recently started to cover it. We expect decisions on coverage from other insurers in the next 12 months. In the meantime, we offer a low-dose screening chest CT to our patients for $125, which includes the radiologist’s fee for interpreting the scan.

Smoking cessation

The NLST showed that low-dose CT screening can reduce lung cancer mortality rates by 20% in a high-risk group. A 50-year-old active smoker who quits smoking reduces his or her risk of dying of lung cancer by more than 50%.²⁹ Entry into a lung cancer screening program provides an opportunity for education and assistance with tobacco dependency.

At Cleveland Clinic, we have an active Tobacco Treatment Center within our Wellness Institute. All lung cancer screening participants who are identified as active smokers will be given a program brochure and will be offered a consult in the program.

Studies of CT-based screening have highlighted the tremendous number of lung nodules that are identified and the low likelihood of malignancy in those that are less than 1 cm in diameter. Many screening studies define a positive result as a lung nodule above a particular size. The NLST used 4 mm or greater as the cutoff. The lower the cutoff, the greater the number of nodules found, and the lower the overall likelihood of malignancy in the nodules.

Studies in which annual CT screening was the intervention are able to use size criteria in part because the study design ensures another CT will be performed 12 months later. Current nodule management guidelines suggest 12-month CT follow-up of incidentally discovered lung nodules, 4 mm or smaller, in at-risk patients.³⁰ In a screening program, particularly one for which the patient must pay, the 12-month screening CT cannot be guaranteed. This makes it more difficult to ignore the smallest nodules identified on CT screening. Given this, we will be reporting all lung nodules identified, regardless of size on the initial screening.

Most studies of CT screening have reported any new nodule identified in subsequent screening rounds regardless of size. Though it is intuitive that a new nodule would have a high likelihood of malignancy in a high-risk cohort, malignancy rates have been reported to be as low as 1% for new nodules. As with the initial round of screening, we will report all new lung nodules identified in subsequent screening rounds.

The recommendations for the evaluation of lung nodules, both within the report and at the lung nodule clinic, are in keeping with currently available guidelines, such as those from the Fleischner Society³⁰ and the American College of Chest Physicians.³¹ For incidentally discovered lung nodules in patients at high risk, the Fleischner Society recommendations are as follows³⁰:

• For nodules 4 mm or smaller, follow-up in 12 months; if no growth, then no further follow-up
• For nodules 4 to 6 mm, follow-up at 6 to 12 months, then 18 to 24 months if no growth
• For nodules 6 to 8 mm, follow-up at 3 to 6 months, then 9 to 12 months, then 24 months if no growth
• For nodules 8 mm or larger, follow-up at 3, 9, and 24 months, or positron emission tomography, or biopsy, or both.

If the nodule is large enough or is deemed to be of high enough risk, adjuvant testing with diagnostic imaging, guided bronchoscopy, transthoracic needle aspiration, or minimally invasive resection will be offered. All patients with nodules believed to require biopsy will be discussed at our multidisciplinary lung cancer tumor board before biopsy.

How do we make practitioners and patients aware of the program and its indications, risks, and benefits?

Education will be the key to having lung cancer screening adopted as the standard of care, to lung cancer screening being provided within a well-designed and capable system, and to ensuring that patients have realistic expectations about screening. Articles such as this and grand rounds presentations within our health system will help provide education to our colleagues. Broader marketing campaigns will be considered in the future once demand and system capabilities are clearly identified. A patient information brochure will be provided at the time of the screening test (see the patient information sheet that accompanies this article).

How do we help to advance best practice?

As excited as we are that low-dose CT-based lung cancer screening has been proven to reduce lung cancer mortality rates, it is clear that there is a lot of room to improve the programs that are developed based on current data.

Advances in our ability to accurately predict an individual’s risk of developing lung cancer will allow us to offer screening to those it is most likely to benefit.

Advances in smoking cessation and chemoprevention will help to minimize the number of lung cancers that develop.

Advances in our ability to determine the nature of lung nodules will allow us to accelerate treatment of very early lung cancer while minimizing additional testing on benign nodules; advances in our ability to treat localized and advanced disease will improve the outcome for those identified as having lung cancer.

To help move the science of screening forward, we will develop a screening program registry that can be populated from the order set and the templated report. The registry can be used to ensure appropriate patient care, while studying relevant epidemiologic, quality, and cost-related questions.

We hope to assess novel imaging software capable of assisting with the detection and characterization of lung nodules.

We have an active biomarker development program to assess the ability of breath and blood-based biomarkers to identify those at risk of developing lung cancer; to assist with the management of screening-detected lung nodules; to assist with the diagnosis of early stage lung cancer; and to characterize the nature of the cancers identified. Accurate biomarkers could lead to further decreases in mortality rates while reducing the risks and costs of a screening program.

We have strong surgical, medical, and radiation oncology programs, actively pursuing advances in minimally invasive resection procedures and ablative and targeted therapies.

ENTERING A NEW ERA

We are entering a new era of lung cancer screening. The NLST has shown that lung cancer morality rates can be reduced through low-dose CT screening in a high-risk population. Many challenges remain, such as managing the nodules that are discovered, determining if the program is cost-effective, and minimizing radiation exposure. These need to be considered when designing a lung cancer screening program. Advances over time will help us optimize the programs that are developed.

A 62-year-old black nursing home resident was transported to the hospital emergency department with fever of 102°F, new-onset atrial fibrillation (A-fib), and dementia. His medical history was significant for hypertension and multiple strokes.

His inpatient work-up for A-fib and dementia revealed a thyroid-stimulating hormone (TSH) level below 0.005 µIU/mL (normal range, 0.3 to 3.0 µIU/mL). Results of thyroid function testing (TFT) revealed a triiodothyronine (T3) level within normal range but a free thyroxine (T4) level of 2.9 ng/dL (normal range, 0.7 to 1.5 ng/dL) and a total T4 of 17.8 µg/dL (normal, 4.5 to 12.0 µg/dL). The abnormal TSH and T4 levels were considered suggestive of a thyrotoxic state, warranting an endocrinology consult. Cardiology was consulted regarding new-onset A-fib.

During history taking, the patient denied any shortness of breath, cough, palpitations, heat intolerance, anxiety, tremors, insomnia, dysphagia, diarrhea, dysuria, weight loss, or recent ingestion of iodine-containing medications or supplements.

On examination, the patient was febrile, with a blood pressure of 106/71 mm Hg; pulse, 74 beats/min; respiratory rate, 20 breaths/min; and O2 saturation, 98% to 99% on room air. ECG showed a normal sinus rhythm and a ventricular rate of 64 beats/min.

The patient's weight was 58.9 kg, and his height, 63" (BMI, 22.8). The patient had no skin changes, and his mucous membranes were slightly moist. The patient's head was atraumatic and normocephalic. His extraocular movements were intact, and his pupils were equal, round, and reactive to light, with nonicteric sclera. There was no proptosis or ophthalmoplegia. The patient's neck was supple, with no jugular venous distension, tracheal deviation, or thyromegaly.

The cardiovascular exam revealed an irregular heartbeat, and repeat ECG showed A-fib with a ventricular rate of 151 beats/min (see Figure 1). The patient's chest was clear, with no wheezing or rhonchi. The abdomen was soft and slightly obese, and bowel sounds were present. The neurologic examination revealed no hyperreflexia. The patient's mental status was altered at times and he was alert, awake, and oriented to others. His speech was slightly slow, and some left-sided weakness was noted.

As recommended during the endocrinology consult, the patient underwent an I-123 sodium iodide thyroid scan, which showed faint uptake at the base of the neck, slightly to the left of midline; and a 24-hour radioactive iodide uptake (RAIU), which measured 2.8% (normal range, 8% to 35%).

The patient's chest X-ray showed a right tracheal deviation not previously noted on physical examination (see Figure 2); the possible cause of a thyroid mass was considered. Subsequent ultrasonography of the thyroid revealed generally normal dimensions and parenchymal echogenicity. However, a large complex mass was detected, arising from the inferior pole of the thyroid and displacing the trachea toward the right (see Figure 3). According to the radiologist's notes, the mass contained both solid and cystic elements, scattered calcifications, and foci of flow on color Doppler. It measured about 6 cm in the largest (transverse) dimension. A 2.0-mm nodule was noted in the isthmus, slightly to the right of midline, consistent with multinodular goiter.

Following the cardiology consult, a diltiazem drip was initiated, but the patient was later optimized on flecainide for rhythm control and metoprolol for rate control. He was also initially anticoagulated using a heparin drip and bridged to warfarin, with target international normalized ratio (INR) between 2.0 and 3.0. Echocardiography revealed normal systolic function with ejection fraction of 55%, left ventricular hypertrophy, pulmonary artery systolic pressure of 35 mm Hg, and no pericardial effusions or valvular disease.

Regarding the patient's unexplained fever, results of chest imaging were negative for signs of pneumonia or atelectasis, which might have suggested a pulmonary cause. Urinalysis results were normal. Complete blood count showed no leukocytosis. The patient's fever subsided within 48 hours.

The differential diagnosis included Graves' disease, toxic multinodular goiter, Jod-Basedow syndrome, and subacute thyroiditis.

Graves' disease, an autoimmune disease with an unknown trigger, is the most common cause of hyperthyroidism. In affected patients, the thyroid gland overproduces thyroid hormones, leading to thyrotoxicosis. Thyrotoxicosis can result in multiple clinical signs and symptoms, including Graves' ophthalmopathy, pretibial myxedema, and goiter; TFT results typically include elevated T3 and T4 and low TSH.^1-5 In the case patient (who had no history of thyroid disease, nor clinical signs or symptoms of Graves' disease), low uptake of iodine on thyroid scan precluded this diagnosis.

Toxic multinodular goiter, the second most common cause of hyperthyroidism, can be responsible for A-fib, tachycardia, and congestive heart failure.^6,7 Iodine deficiency causes enlargement of the thyroid gland, where numerous nodules can develop, as seen in the case patient. These nodules can function independently, sometimes producing excess thyroid hormone; this leads to hyperplasia of the thyroid gland, resulting in a nontoxic multinodular goiter. From this goiter, a toxic multinodular goiter can emerge insidiously. However, in this condition, RAIU typically exceeds 30%; in the case patient, low 24-hour RAIU (2.8%) and the absence of functioning nodules on scanning made it possible to rule out this diagnosis.

Jod-Basedow syndrome refers to hyperthyroidism that develops as a result of administration of iodide, either as a dietary supplement or as IV contrast medium, or as an adverse effect of the antiarrhythmic drug amiodarone. This phenomenon is usually seen in a patient with endemic goiter.^8-11 The relatively limited nature of the case patient's goiter and absence of a precipitating exposure to iodine made this diagnosis highly unlikely.

Subacute thyroiditis is a condition to which the patient's abnormal TFT results could reasonably be attributed. The patient had a substernal multinodular goiter that could not be palpated on physical examination, but it was visualized in the extended lower neck during thyroid scintigraphy.³ RAIU was minimal—a typical finding in this disorder,⁶ as TSH is suppressed by leakage of the excessive amounts of thyroid hormone. A tentative diagnosis of subacute thyroiditis was made.

As subacute thyroiditis is a self-limiting disorder, the patient was not started on any medications for hyperthyroidism but was advised to follow up with his primary care provider or an endocrinologist for repeat TFT and for fine-needle aspiration biopsy of the large thyroid nodule (a complex mass, containing cystic elements and calcifications, with a potential for malignancy) to rule out thyroid cancer.

Repeat ECG before discharge showed normal sinus rhythm with a ventricular rate of 74 beats/min. The patient was alert, awake, and oriented at discharge. He was continued on flecainide, metoprolol, and warfarin and advised to follow up with his primary care provider regarding his target INR.

DISCUSSION
The incidence of subacute thyroiditis, according to findings reported in 2003 from the Rochester Epidemiology Project in Olmsted County, Minnesota,¹² is 12.1 cases per 100,000/year, with a higher incidence in women than men. It is most common in young adults and decreases with advancing age. Coxsackie virus, adenovirus, mumps, echovirus, influenza, and Epstein-Barr virus have been implicated in the disorder.^12,13

Subacute thyroiditis is associated with a triphasic clinical course of hyperthyroidism, then hypothyroidism, then a return to normal thyroid function—as was seen in the case patient. Onset of subacute thyroiditis has been associated with recent viral infection, which may serve as a precipitant. The cause of this patient's high fever was never identified; thus, the etiology may have been viral.

The initial high thyroid hormone levels result from inflammation of thyroid tissue and release of preformed thyroid hormone into the circulation.⁶ At this point, TSH is suppressed and patients have very low RAIU, as was true in the case patient.

The condition is self-limiting and does not require treatment in the majority of patients, as TFT results return to normal levels within about two months.⁶ Patients can appear extremely ill due to thyrotoxicosis from subacute thyroiditis, but this usually lasts no longer than six to eight weeks.³ Subacute thyroiditis can be associated with atrial arrhythmia or heart failure.^14,15

PATIENT OUTCOME
New-onset A-fib was attributed to the patient's thyrotoxicosis, which in turn was caused by subacute thyroiditis. He had a multinodular goiter, although he had not received any iodine supplements or IV contrast. As in most cases of subacute thyroiditis, no precipitating event was identified. However, given this patient's residence in a nursing facility and presentation with a high fever with no identifiable cause, a viral etiology for his subacute thyroiditis is possible.⁶

The patient's dementia may have been secondary to acute thyrotoxicosis, as his mental state improved during the hospital stay. His vitamin B12, folate, and A1C levels were within normal range. CT of the head showed multiple chronic infarcts and cerebral atrophy, and MRI of the brain indicated microvascular ischemic disease.

The patient was readmitted one month later for an episode of near-syncope (which, it was concluded, was a vasovagal episode). At that time, his TSH was found normal at 1.350 µIU/mL. Flecainide and metoprolol were discontinued; he was started on diltiazem for continued rate and rhythm control (as recommended by cardiology) and continued on warfarin.

CONCLUSION
In this case, subacute thyroiditis was most likely caused by a viral infection that led to destruction of the normal thyroid follicles and release of their preformed thyroid hormone into the circulation; this in turn led to sudden-onset A-fib. The diagnosis of subacute thyroiditis was suggested based on the abnormalities seen in this patient's TFT results, coupled with the suppressed RAIU—a typical finding in this disease.

Because subacute thyroiditis is a self-limiting condition, there is no role for antithyroid medication. Instead, treatment should be focused on relieving the patient's symptoms, such as ß-blockade or calcium channel blockers for tachycardia and corticosteroids or NSAIDs for neck pain.

REFERENCES
1. Weetman AP. Graves' disease. N Engl J Med. 2000;343(17):1236-1248.

2. Delgado Hurtado JJ, Pineda M. Images in medicine: Graves' disease. N Engl J Med. 2011; 364(20):1955.

3. Al-Sharif AA, Abujbara MA, Chiacchio S, et al. Contribution of radioiodine uptake measurement and thyroid scintigraphy to the differential diagnosis of thyrotoxicosis. Hell J Nucl Med. 2010;13(2):132-137.

4. Buccelletti F, Carroccia A, Marsiliani D, et al. Utility of routine thyroid-stimulating hormone determination in new-onset atrial fibrillation in the ED. Am J Emerg Med. 2011;29(9):1158-1162.

5. Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011;364(6):542-550.

6. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17(3):456-520.

7. Erickson D, Gharib H, Li H, van Heerden JA. Treatment of patients with toxic multinodular goiter. Thyroid. 1998;8(4):277-282.

8. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med. 2005;118(7):706-714.

9. Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab. 2010;95(6):2529-2535.

10. El-Shirbiny AM, Stavrou SS, Dnistrian A, et al. Jod-Basedow syndrome following oral iodine and radioiodinated-antibody administration. J Nucl Med. 1997;38(11):1816-1817.

11. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid. 1998;8(1):83-100.

12. Fatourechi V, Aniszewski JP, Fatourechi GZ, et al. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab. 2003;88(5):2100-2105.

13. Golden SH, Robinson KA, Saldanha I, et al. Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009;94(6):1853-1878.

14. Volpé R. The management of subacute (DeQuervain's) thyroiditis. Thyroid. 1993;3(3):253-255.

15. Lee SL. Subacute thyroiditis (2009). http://emedicine.medscape.com/article/125648-overview. Accessed April 17, 2012.

A 62-year-old black nursing home resident was transported to the hospital emergency department with fever of 102°F, new-onset atrial fibrillation (A-fib), and dementia. His medical history was significant for hypertension and multiple strokes.

His inpatient work-up for A-fib and dementia revealed a thyroid-stimulating hormone (TSH) level below 0.005 µIU/mL (normal range, 0.3 to 3.0 µIU/mL). Results of thyroid function testing (TFT) revealed a triiodothyronine (T3) level within normal range but a free thyroxine (T4) level of 2.9 ng/dL (normal range, 0.7 to 1.5 ng/dL) and a total T4 of 17.8 µg/dL (normal, 4.5 to 12.0 µg/dL). The abnormal TSH and T4 levels were considered suggestive of a thyrotoxic state, warranting an endocrinology consult. Cardiology was consulted regarding new-onset A-fib.

During history taking, the patient denied any shortness of breath, cough, palpitations, heat intolerance, anxiety, tremors, insomnia, dysphagia, diarrhea, dysuria, weight loss, or recent ingestion of iodine-containing medications or supplements.

On examination, the patient was febrile, with a blood pressure of 106/71 mm Hg; pulse, 74 beats/min; respiratory rate, 20 breaths/min; and O2 saturation, 98% to 99% on room air. ECG showed a normal sinus rhythm and a ventricular rate of 64 beats/min.

The patient's weight was 58.9 kg, and his height, 63" (BMI, 22.8). The patient had no skin changes, and his mucous membranes were slightly moist. The patient's head was atraumatic and normocephalic. His extraocular movements were intact, and his pupils were equal, round, and reactive to light, with nonicteric sclera. There was no proptosis or ophthalmoplegia. The patient's neck was supple, with no jugular venous distension, tracheal deviation, or thyromegaly.

The cardiovascular exam revealed an irregular heartbeat, and repeat ECG showed A-fib with a ventricular rate of 151 beats/min (see Figure 1). The patient's chest was clear, with no wheezing or rhonchi. The abdomen was soft and slightly obese, and bowel sounds were present. The neurologic examination revealed no hyperreflexia. The patient's mental status was altered at times and he was alert, awake, and oriented to others. His speech was slightly slow, and some left-sided weakness was noted.

As recommended during the endocrinology consult, the patient underwent an I-123 sodium iodide thyroid scan, which showed faint uptake at the base of the neck, slightly to the left of midline; and a 24-hour radioactive iodide uptake (RAIU), which measured 2.8% (normal range, 8% to 35%).

The patient's chest X-ray showed a right tracheal deviation not previously noted on physical examination (see Figure 2); the possible cause of a thyroid mass was considered. Subsequent ultrasonography of the thyroid revealed generally normal dimensions and parenchymal echogenicity. However, a large complex mass was detected, arising from the inferior pole of the thyroid and displacing the trachea toward the right (see Figure 3). According to the radiologist's notes, the mass contained both solid and cystic elements, scattered calcifications, and foci of flow on color Doppler. It measured about 6 cm in the largest (transverse) dimension. A 2.0-mm nodule was noted in the isthmus, slightly to the right of midline, consistent with multinodular goiter.

Following the cardiology consult, a diltiazem drip was initiated, but the patient was later optimized on flecainide for rhythm control and metoprolol for rate control. He was also initially anticoagulated using a heparin drip and bridged to warfarin, with target international normalized ratio (INR) between 2.0 and 3.0. Echocardiography revealed normal systolic function with ejection fraction of 55%, left ventricular hypertrophy, pulmonary artery systolic pressure of 35 mm Hg, and no pericardial effusions or valvular disease.

Regarding the patient's unexplained fever, results of chest imaging were negative for signs of pneumonia or atelectasis, which might have suggested a pulmonary cause. Urinalysis results were normal. Complete blood count showed no leukocytosis. The patient's fever subsided within 48 hours.

The differential diagnosis included Graves' disease, toxic multinodular goiter, Jod-Basedow syndrome, and subacute thyroiditis.

Graves' disease, an autoimmune disease with an unknown trigger, is the most common cause of hyperthyroidism. In affected patients, the thyroid gland overproduces thyroid hormones, leading to thyrotoxicosis. Thyrotoxicosis can result in multiple clinical signs and symptoms, including Graves' ophthalmopathy, pretibial myxedema, and goiter; TFT results typically include elevated T3 and T4 and low TSH.^1-5 In the case patient (who had no history of thyroid disease, nor clinical signs or symptoms of Graves' disease), low uptake of iodine on thyroid scan precluded this diagnosis.

Toxic multinodular goiter, the second most common cause of hyperthyroidism, can be responsible for A-fib, tachycardia, and congestive heart failure.^6,7 Iodine deficiency causes enlargement of the thyroid gland, where numerous nodules can develop, as seen in the case patient. These nodules can function independently, sometimes producing excess thyroid hormone; this leads to hyperplasia of the thyroid gland, resulting in a nontoxic multinodular goiter. From this goiter, a toxic multinodular goiter can emerge insidiously. However, in this condition, RAIU typically exceeds 30%; in the case patient, low 24-hour RAIU (2.8%) and the absence of functioning nodules on scanning made it possible to rule out this diagnosis.

Jod-Basedow syndrome refers to hyperthyroidism that develops as a result of administration of iodide, either as a dietary supplement or as IV contrast medium, or as an adverse effect of the antiarrhythmic drug amiodarone. This phenomenon is usually seen in a patient with endemic goiter.^8-11 The relatively limited nature of the case patient's goiter and absence of a precipitating exposure to iodine made this diagnosis highly unlikely.

Subacute thyroiditis is a condition to which the patient's abnormal TFT results could reasonably be attributed. The patient had a substernal multinodular goiter that could not be palpated on physical examination, but it was visualized in the extended lower neck during thyroid scintigraphy.³ RAIU was minimal—a typical finding in this disorder,⁶ as TSH is suppressed by leakage of the excessive amounts of thyroid hormone. A tentative diagnosis of subacute thyroiditis was made.

As subacute thyroiditis is a self-limiting disorder, the patient was not started on any medications for hyperthyroidism but was advised to follow up with his primary care provider or an endocrinologist for repeat TFT and for fine-needle aspiration biopsy of the large thyroid nodule (a complex mass, containing cystic elements and calcifications, with a potential for malignancy) to rule out thyroid cancer.

Repeat ECG before discharge showed normal sinus rhythm with a ventricular rate of 74 beats/min. The patient was alert, awake, and oriented at discharge. He was continued on flecainide, metoprolol, and warfarin and advised to follow up with his primary care provider regarding his target INR.

DISCUSSION
The incidence of subacute thyroiditis, according to findings reported in 2003 from the Rochester Epidemiology Project in Olmsted County, Minnesota,¹² is 12.1 cases per 100,000/year, with a higher incidence in women than men. It is most common in young adults and decreases with advancing age. Coxsackie virus, adenovirus, mumps, echovirus, influenza, and Epstein-Barr virus have been implicated in the disorder.^12,13

Subacute thyroiditis is associated with a triphasic clinical course of hyperthyroidism, then hypothyroidism, then a return to normal thyroid function—as was seen in the case patient. Onset of subacute thyroiditis has been associated with recent viral infection, which may serve as a precipitant. The cause of this patient's high fever was never identified; thus, the etiology may have been viral.

The initial high thyroid hormone levels result from inflammation of thyroid tissue and release of preformed thyroid hormone into the circulation.⁶ At this point, TSH is suppressed and patients have very low RAIU, as was true in the case patient.

The condition is self-limiting and does not require treatment in the majority of patients, as TFT results return to normal levels within about two months.⁶ Patients can appear extremely ill due to thyrotoxicosis from subacute thyroiditis, but this usually lasts no longer than six to eight weeks.³ Subacute thyroiditis can be associated with atrial arrhythmia or heart failure.^14,15

PATIENT OUTCOME
New-onset A-fib was attributed to the patient's thyrotoxicosis, which in turn was caused by subacute thyroiditis. He had a multinodular goiter, although he had not received any iodine supplements or IV contrast. As in most cases of subacute thyroiditis, no precipitating event was identified. However, given this patient's residence in a nursing facility and presentation with a high fever with no identifiable cause, a viral etiology for his subacute thyroiditis is possible.⁶

The patient's dementia may have been secondary to acute thyrotoxicosis, as his mental state improved during the hospital stay. His vitamin B12, folate, and A1C levels were within normal range. CT of the head showed multiple chronic infarcts and cerebral atrophy, and MRI of the brain indicated microvascular ischemic disease.

The patient was readmitted one month later for an episode of near-syncope (which, it was concluded, was a vasovagal episode). At that time, his TSH was found normal at 1.350 µIU/mL. Flecainide and metoprolol were discontinued; he was started on diltiazem for continued rate and rhythm control (as recommended by cardiology) and continued on warfarin.

CONCLUSION
In this case, subacute thyroiditis was most likely caused by a viral infection that led to destruction of the normal thyroid follicles and release of their preformed thyroid hormone into the circulation; this in turn led to sudden-onset A-fib. The diagnosis of subacute thyroiditis was suggested based on the abnormalities seen in this patient's TFT results, coupled with the suppressed RAIU—a typical finding in this disease.

Because subacute thyroiditis is a self-limiting condition, there is no role for antithyroid medication. Instead, treatment should be focused on relieving the patient's symptoms, such as ß-blockade or calcium channel blockers for tachycardia and corticosteroids or NSAIDs for neck pain.

REFERENCES
1. Weetman AP. Graves' disease. N Engl J Med. 2000;343(17):1236-1248.

2. Delgado Hurtado JJ, Pineda M. Images in medicine: Graves' disease. N Engl J Med. 2011; 364(20):1955.

3. Al-Sharif AA, Abujbara MA, Chiacchio S, et al. Contribution of radioiodine uptake measurement and thyroid scintigraphy to the differential diagnosis of thyrotoxicosis. Hell J Nucl Med. 2010;13(2):132-137.

4. Buccelletti F, Carroccia A, Marsiliani D, et al. Utility of routine thyroid-stimulating hormone determination in new-onset atrial fibrillation in the ED. Am J Emerg Med. 2011;29(9):1158-1162.

5. Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011;364(6):542-550.

6. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17(3):456-520.

7. Erickson D, Gharib H, Li H, van Heerden JA. Treatment of patients with toxic multinodular goiter. Thyroid. 1998;8(4):277-282.

8. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med. 2005;118(7):706-714.

9. Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab. 2010;95(6):2529-2535.

10. El-Shirbiny AM, Stavrou SS, Dnistrian A, et al. Jod-Basedow syndrome following oral iodine and radioiodinated-antibody administration. J Nucl Med. 1997;38(11):1816-1817.

11. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid. 1998;8(1):83-100.

12. Fatourechi V, Aniszewski JP, Fatourechi GZ, et al. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab. 2003;88(5):2100-2105.

13. Golden SH, Robinson KA, Saldanha I, et al. Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009;94(6):1853-1878.

14. Volpé R. The management of subacute (DeQuervain's) thyroiditis. Thyroid. 1993;3(3):253-255.

15. Lee SL. Subacute thyroiditis (2009). http://emedicine.medscape.com/article/125648-overview. Accessed April 17, 2012.

A 62-year-old black nursing home resident was transported to the hospital emergency department with fever of 102°F, new-onset atrial fibrillation (A-fib), and dementia. His medical history was significant for hypertension and multiple strokes.

His inpatient work-up for A-fib and dementia revealed a thyroid-stimulating hormone (TSH) level below 0.005 µIU/mL (normal range, 0.3 to 3.0 µIU/mL). Results of thyroid function testing (TFT) revealed a triiodothyronine (T3) level within normal range but a free thyroxine (T4) level of 2.9 ng/dL (normal range, 0.7 to 1.5 ng/dL) and a total T4 of 17.8 µg/dL (normal, 4.5 to 12.0 µg/dL). The abnormal TSH and T4 levels were considered suggestive of a thyrotoxic state, warranting an endocrinology consult. Cardiology was consulted regarding new-onset A-fib.

During history taking, the patient denied any shortness of breath, cough, palpitations, heat intolerance, anxiety, tremors, insomnia, dysphagia, diarrhea, dysuria, weight loss, or recent ingestion of iodine-containing medications or supplements.

On examination, the patient was febrile, with a blood pressure of 106/71 mm Hg; pulse, 74 beats/min; respiratory rate, 20 breaths/min; and O2 saturation, 98% to 99% on room air. ECG showed a normal sinus rhythm and a ventricular rate of 64 beats/min.

The patient's weight was 58.9 kg, and his height, 63" (BMI, 22.8). The patient had no skin changes, and his mucous membranes were slightly moist. The patient's head was atraumatic and normocephalic. His extraocular movements were intact, and his pupils were equal, round, and reactive to light, with nonicteric sclera. There was no proptosis or ophthalmoplegia. The patient's neck was supple, with no jugular venous distension, tracheal deviation, or thyromegaly.

The cardiovascular exam revealed an irregular heartbeat, and repeat ECG showed A-fib with a ventricular rate of 151 beats/min (see Figure 1). The patient's chest was clear, with no wheezing or rhonchi. The abdomen was soft and slightly obese, and bowel sounds were present. The neurologic examination revealed no hyperreflexia. The patient's mental status was altered at times and he was alert, awake, and oriented to others. His speech was slightly slow, and some left-sided weakness was noted.

As recommended during the endocrinology consult, the patient underwent an I-123 sodium iodide thyroid scan, which showed faint uptake at the base of the neck, slightly to the left of midline; and a 24-hour radioactive iodide uptake (RAIU), which measured 2.8% (normal range, 8% to 35%).

The patient's chest X-ray showed a right tracheal deviation not previously noted on physical examination (see Figure 2); the possible cause of a thyroid mass was considered. Subsequent ultrasonography of the thyroid revealed generally normal dimensions and parenchymal echogenicity. However, a large complex mass was detected, arising from the inferior pole of the thyroid and displacing the trachea toward the right (see Figure 3). According to the radiologist's notes, the mass contained both solid and cystic elements, scattered calcifications, and foci of flow on color Doppler. It measured about 6 cm in the largest (transverse) dimension. A 2.0-mm nodule was noted in the isthmus, slightly to the right of midline, consistent with multinodular goiter.

Following the cardiology consult, a diltiazem drip was initiated, but the patient was later optimized on flecainide for rhythm control and metoprolol for rate control. He was also initially anticoagulated using a heparin drip and bridged to warfarin, with target international normalized ratio (INR) between 2.0 and 3.0. Echocardiography revealed normal systolic function with ejection fraction of 55%, left ventricular hypertrophy, pulmonary artery systolic pressure of 35 mm Hg, and no pericardial effusions or valvular disease.

Regarding the patient's unexplained fever, results of chest imaging were negative for signs of pneumonia or atelectasis, which might have suggested a pulmonary cause. Urinalysis results were normal. Complete blood count showed no leukocytosis. The patient's fever subsided within 48 hours.

The differential diagnosis included Graves' disease, toxic multinodular goiter, Jod-Basedow syndrome, and subacute thyroiditis.

Graves' disease, an autoimmune disease with an unknown trigger, is the most common cause of hyperthyroidism. In affected patients, the thyroid gland overproduces thyroid hormones, leading to thyrotoxicosis. Thyrotoxicosis can result in multiple clinical signs and symptoms, including Graves' ophthalmopathy, pretibial myxedema, and goiter; TFT results typically include elevated T3 and T4 and low TSH.^1-5 In the case patient (who had no history of thyroid disease, nor clinical signs or symptoms of Graves' disease), low uptake of iodine on thyroid scan precluded this diagnosis.

Toxic multinodular goiter, the second most common cause of hyperthyroidism, can be responsible for A-fib, tachycardia, and congestive heart failure.^6,7 Iodine deficiency causes enlargement of the thyroid gland, where numerous nodules can develop, as seen in the case patient. These nodules can function independently, sometimes producing excess thyroid hormone; this leads to hyperplasia of the thyroid gland, resulting in a nontoxic multinodular goiter. From this goiter, a toxic multinodular goiter can emerge insidiously. However, in this condition, RAIU typically exceeds 30%; in the case patient, low 24-hour RAIU (2.8%) and the absence of functioning nodules on scanning made it possible to rule out this diagnosis.

Jod-Basedow syndrome refers to hyperthyroidism that develops as a result of administration of iodide, either as a dietary supplement or as IV contrast medium, or as an adverse effect of the antiarrhythmic drug amiodarone. This phenomenon is usually seen in a patient with endemic goiter.^8-11 The relatively limited nature of the case patient's goiter and absence of a precipitating exposure to iodine made this diagnosis highly unlikely.

Subacute thyroiditis is a condition to which the patient's abnormal TFT results could reasonably be attributed. The patient had a substernal multinodular goiter that could not be palpated on physical examination, but it was visualized in the extended lower neck during thyroid scintigraphy.³ RAIU was minimal—a typical finding in this disorder,⁶ as TSH is suppressed by leakage of the excessive amounts of thyroid hormone. A tentative diagnosis of subacute thyroiditis was made.

As subacute thyroiditis is a self-limiting disorder, the patient was not started on any medications for hyperthyroidism but was advised to follow up with his primary care provider or an endocrinologist for repeat TFT and for fine-needle aspiration biopsy of the large thyroid nodule (a complex mass, containing cystic elements and calcifications, with a potential for malignancy) to rule out thyroid cancer.

Repeat ECG before discharge showed normal sinus rhythm with a ventricular rate of 74 beats/min. The patient was alert, awake, and oriented at discharge. He was continued on flecainide, metoprolol, and warfarin and advised to follow up with his primary care provider regarding his target INR.

DISCUSSION
The incidence of subacute thyroiditis, according to findings reported in 2003 from the Rochester Epidemiology Project in Olmsted County, Minnesota,¹² is 12.1 cases per 100,000/year, with a higher incidence in women than men. It is most common in young adults and decreases with advancing age. Coxsackie virus, adenovirus, mumps, echovirus, influenza, and Epstein-Barr virus have been implicated in the disorder.^12,13

Subacute thyroiditis is associated with a triphasic clinical course of hyperthyroidism, then hypothyroidism, then a return to normal thyroid function—as was seen in the case patient. Onset of subacute thyroiditis has been associated with recent viral infection, which may serve as a precipitant. The cause of this patient's high fever was never identified; thus, the etiology may have been viral.

The initial high thyroid hormone levels result from inflammation of thyroid tissue and release of preformed thyroid hormone into the circulation.⁶ At this point, TSH is suppressed and patients have very low RAIU, as was true in the case patient.

The condition is self-limiting and does not require treatment in the majority of patients, as TFT results return to normal levels within about two months.⁶ Patients can appear extremely ill due to thyrotoxicosis from subacute thyroiditis, but this usually lasts no longer than six to eight weeks.³ Subacute thyroiditis can be associated with atrial arrhythmia or heart failure.^14,15

PATIENT OUTCOME
New-onset A-fib was attributed to the patient's thyrotoxicosis, which in turn was caused by subacute thyroiditis. He had a multinodular goiter, although he had not received any iodine supplements or IV contrast. As in most cases of subacute thyroiditis, no precipitating event was identified. However, given this patient's residence in a nursing facility and presentation with a high fever with no identifiable cause, a viral etiology for his subacute thyroiditis is possible.⁶

The patient's dementia may have been secondary to acute thyrotoxicosis, as his mental state improved during the hospital stay. His vitamin B12, folate, and A1C levels were within normal range. CT of the head showed multiple chronic infarcts and cerebral atrophy, and MRI of the brain indicated microvascular ischemic disease.

The patient was readmitted one month later for an episode of near-syncope (which, it was concluded, was a vasovagal episode). At that time, his TSH was found normal at 1.350 µIU/mL. Flecainide and metoprolol were discontinued; he was started on diltiazem for continued rate and rhythm control (as recommended by cardiology) and continued on warfarin.

CONCLUSION
In this case, subacute thyroiditis was most likely caused by a viral infection that led to destruction of the normal thyroid follicles and release of their preformed thyroid hormone into the circulation; this in turn led to sudden-onset A-fib. The diagnosis of subacute thyroiditis was suggested based on the abnormalities seen in this patient's TFT results, coupled with the suppressed RAIU—a typical finding in this disease.

Because subacute thyroiditis is a self-limiting condition, there is no role for antithyroid medication. Instead, treatment should be focused on relieving the patient's symptoms, such as ß-blockade or calcium channel blockers for tachycardia and corticosteroids or NSAIDs for neck pain.

REFERENCES
1. Weetman AP. Graves' disease. N Engl J Med. 2000;343(17):1236-1248.

2. Delgado Hurtado JJ, Pineda M. Images in medicine: Graves' disease. N Engl J Med. 2011; 364(20):1955.

3. Al-Sharif AA, Abujbara MA, Chiacchio S, et al. Contribution of radioiodine uptake measurement and thyroid scintigraphy to the differential diagnosis of thyrotoxicosis. Hell J Nucl Med. 2010;13(2):132-137.

4. Buccelletti F, Carroccia A, Marsiliani D, et al. Utility of routine thyroid-stimulating hormone determination in new-onset atrial fibrillation in the ED. Am J Emerg Med. 2011;29(9):1158-1162.

5. Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011;364(6):542-550.

6. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17(3):456-520.

7. Erickson D, Gharib H, Li H, van Heerden JA. Treatment of patients with toxic multinodular goiter. Thyroid. 1998;8(4):277-282.

8. Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med. 2005;118(7):706-714.

9. Bogazzi F, Bartalena L, Martino E. Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab. 2010;95(6):2529-2535.

10. El-Shirbiny AM, Stavrou SS, Dnistrian A, et al. Jod-Basedow syndrome following oral iodine and radioiodinated-antibody administration. J Nucl Med. 1997;38(11):1816-1817.

11. Stanbury JB, Ermans AE, Bourdoux P, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid. 1998;8(1):83-100.

12. Fatourechi V, Aniszewski JP, Fatourechi GZ, et al. Clinical features and outcome of subacute thyroiditis in an incidence cohort: Olmsted County, Minnesota, study. J Clin Endocrinol Metab. 2003;88(5):2100-2105.

13. Golden SH, Robinson KA, Saldanha I, et al. Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009;94(6):1853-1878.

14. Volpé R. The management of subacute (DeQuervain's) thyroiditis. Thyroid. 1993;3(3):253-255.

15. Lee SL. Subacute thyroiditis (2009). http://emedicine.medscape.com/article/125648-overview. Accessed April 17, 2012.

As physicians, we are always trying to keep up with the latest techniques and technology to provide the best possible care for our patients. However, history shows us that many of the “newest and greatest” devices have poorly understood, or maybe even, unknown consequences. You may remember the excitement over the Gortex ligament augmenta­tion device (LAD) for ACL reconstruction in the 1970’s or the thermal cap­sular shrinkage “heat probe” of the 1990’s. The orthopedic annals are littered with groundbreaking technologies that proved to be, at best, merely failures,or, at worst, dangerous to the patients we are trying to heal.

We are now in a time of rapidly changing technology and information overload, clogged with access to reams of information through our PDAs and the internet. Patients learn about new techniques and technology not from their physician, but from advertisements in the media or online. This dissemination of information without any real “filter” to verify accuracy and safety has heightened the burden on us, as surgeons, to be up to speed and critical of every “better mousetrap.” Patients may request or even demand a certain technique based on limited study of online discussions, chat rooms, or non–peer reviewed data. It is our obligation to “first, do no harm” even if the patient demands it.

How can we possibly provide the best for our patients and keep up with technol­ogy that may prove to be “the holy grail”? We must rely on well planned, peer-reviewed research studies that clearly analyze not only the positive results, but also the potential complications of new technology. In this month’s issue, E. Carlos Rodríguez-Merchán MD, PhD, (‘‘The Treatment of Cartilage Defects in the Knee Joint: Microfracture, Mosaicplasty, and Autologous Chondrocyte Implantation,’’click here) reviews the treatment of cartilage defects in the knee joint: comparing microfracture, mosaicplasty, and autologous chondrocyte implantation (ACI). However, he concludes that good level I evidence is lacking to show significant difference between any of the 3 commonly performed techniques. Does this mean that all of the procedures result in equal outcomes? No. Does this mean that we should abandon the more costly procedures, such as ACI? No. What Dr. Rodríguez-Merchán does is highlight the need for carefully designed level I studies to define the real outcomes, indications, and complications of our new technologies.

What is the holy grail in orthopedics? I would argue that the ability to take an easily obtained and prepared stem cell line and use the appropriate growth factors and chemical signals to cause the cells to differentiate into different tissue types (eg, bone, cartilage, ligament, etc.) rep­resents this holy grail. Think about all of the potential uses for this technology and it is easy to see the whole field of orthopedic surgery being transformed during my lifetime. Imagine being able to grow new cartilage or ligament tissue and direct the body’s response to these new tissues. However, with these pos­sibilities also come enormous risk.

One significant unpredicted outcome or inappropriate application could lead to huge consequences, terrible com­plications, bad publicity, and loss of patient-physician trust. Just imagine the late night television commercials and billboards advertising for the local law firm that “you may be entitled to com­pensation.” Or just imagine the uncer­tainty injected into the physician-patient relationship, “you aren’t going to put one of those recalled parts in me are you?” You may have followed the recent controversy over “pink slime,” the “lean, finely textured beef” added to processed hamburger patties. Although used for decades, the recent media coverage of beef filler has severely affected the pub­lic’s trust in the food industry. Can you imagine how a similar public relations nightmare over failed technology could affect the orthopedic industry?

I have often been guilty of complain­ing about the arduous task of getting new technology approved though the regulatory bodies in the United States, compared with the perceived progres­sive nature of the process in Europe. I do believe that we should have a streamlined process for some new tech­nology that may save lives, especially chemotherapy medications. However, a more diligent, and thorough process must be applied to new technology used for elective procedures, as in most orthopedic applications. Unfortunately, until sufficient safety data and good outcomes research is completed and analyzed, we must temper the enthusi­asm of doctors and patients alike.

Author's Disclosure Statement. The author reports no actual or poten­tial conflict of interest in relation to this article.

As physicians, we are always trying to keep up with the latest techniques and technology to provide the best possible care for our patients. However, history shows us that many of the “newest and greatest” devices have poorly understood, or maybe even, unknown consequences. You may remember the excitement over the Gortex ligament augmenta­tion device (LAD) for ACL reconstruction in the 1970’s or the thermal cap­sular shrinkage “heat probe” of the 1990’s. The orthopedic annals are littered with groundbreaking technologies that proved to be, at best, merely failures,or, at worst, dangerous to the patients we are trying to heal.

We are now in a time of rapidly changing technology and information overload, clogged with access to reams of information through our PDAs and the internet. Patients learn about new techniques and technology not from their physician, but from advertisements in the media or online. This dissemination of information without any real “filter” to verify accuracy and safety has heightened the burden on us, as surgeons, to be up to speed and critical of every “better mousetrap.” Patients may request or even demand a certain technique based on limited study of online discussions, chat rooms, or non–peer reviewed data. It is our obligation to “first, do no harm” even if the patient demands it.

How can we possibly provide the best for our patients and keep up with technol­ogy that may prove to be “the holy grail”? We must rely on well planned, peer-reviewed research studies that clearly analyze not only the positive results, but also the potential complications of new technology. In this month’s issue, E. Carlos Rodríguez-Merchán MD, PhD, (‘‘The Treatment of Cartilage Defects in the Knee Joint: Microfracture, Mosaicplasty, and Autologous Chondrocyte Implantation,’’click here) reviews the treatment of cartilage defects in the knee joint: comparing microfracture, mosaicplasty, and autologous chondrocyte implantation (ACI). However, he concludes that good level I evidence is lacking to show significant difference between any of the 3 commonly performed techniques. Does this mean that all of the procedures result in equal outcomes? No. Does this mean that we should abandon the more costly procedures, such as ACI? No. What Dr. Rodríguez-Merchán does is highlight the need for carefully designed level I studies to define the real outcomes, indications, and complications of our new technologies.

What is the holy grail in orthopedics? I would argue that the ability to take an easily obtained and prepared stem cell line and use the appropriate growth factors and chemical signals to cause the cells to differentiate into different tissue types (eg, bone, cartilage, ligament, etc.) rep­resents this holy grail. Think about all of the potential uses for this technology and it is easy to see the whole field of orthopedic surgery being transformed during my lifetime. Imagine being able to grow new cartilage or ligament tissue and direct the body’s response to these new tissues. However, with these pos­sibilities also come enormous risk.

One significant unpredicted outcome or inappropriate application could lead to huge consequences, terrible com­plications, bad publicity, and loss of patient-physician trust. Just imagine the late night television commercials and billboards advertising for the local law firm that “you may be entitled to com­pensation.” Or just imagine the uncer­tainty injected into the physician-patient relationship, “you aren’t going to put one of those recalled parts in me are you?” You may have followed the recent controversy over “pink slime,” the “lean, finely textured beef” added to processed hamburger patties. Although used for decades, the recent media coverage of beef filler has severely affected the pub­lic’s trust in the food industry. Can you imagine how a similar public relations nightmare over failed technology could affect the orthopedic industry?

I have often been guilty of complain­ing about the arduous task of getting new technology approved though the regulatory bodies in the United States, compared with the perceived progres­sive nature of the process in Europe. I do believe that we should have a streamlined process for some new tech­nology that may save lives, especially chemotherapy medications. However, a more diligent, and thorough process must be applied to new technology used for elective procedures, as in most orthopedic applications. Unfortunately, until sufficient safety data and good outcomes research is completed and analyzed, we must temper the enthusi­asm of doctors and patients alike.

Author's Disclosure Statement. The author reports no actual or poten­tial conflict of interest in relation to this article.

As physicians, we are always trying to keep up with the latest techniques and technology to provide the best possible care for our patients. However, history shows us that many of the “newest and greatest” devices have poorly understood, or maybe even, unknown consequences. You may remember the excitement over the Gortex ligament augmenta­tion device (LAD) for ACL reconstruction in the 1970’s or the thermal cap­sular shrinkage “heat probe” of the 1990’s. The orthopedic annals are littered with groundbreaking technologies that proved to be, at best, merely failures,or, at worst, dangerous to the patients we are trying to heal.

We are now in a time of rapidly changing technology and information overload, clogged with access to reams of information through our PDAs and the internet. Patients learn about new techniques and technology not from their physician, but from advertisements in the media or online. This dissemination of information without any real “filter” to verify accuracy and safety has heightened the burden on us, as surgeons, to be up to speed and critical of every “better mousetrap.” Patients may request or even demand a certain technique based on limited study of online discussions, chat rooms, or non–peer reviewed data. It is our obligation to “first, do no harm” even if the patient demands it.

How can we possibly provide the best for our patients and keep up with technol­ogy that may prove to be “the holy grail”? We must rely on well planned, peer-reviewed research studies that clearly analyze not only the positive results, but also the potential complications of new technology. In this month’s issue, E. Carlos Rodríguez-Merchán MD, PhD, (‘‘The Treatment of Cartilage Defects in the Knee Joint: Microfracture, Mosaicplasty, and Autologous Chondrocyte Implantation,’’click here) reviews the treatment of cartilage defects in the knee joint: comparing microfracture, mosaicplasty, and autologous chondrocyte implantation (ACI). However, he concludes that good level I evidence is lacking to show significant difference between any of the 3 commonly performed techniques. Does this mean that all of the procedures result in equal outcomes? No. Does this mean that we should abandon the more costly procedures, such as ACI? No. What Dr. Rodríguez-Merchán does is highlight the need for carefully designed level I studies to define the real outcomes, indications, and complications of our new technologies.

What is the holy grail in orthopedics? I would argue that the ability to take an easily obtained and prepared stem cell line and use the appropriate growth factors and chemical signals to cause the cells to differentiate into different tissue types (eg, bone, cartilage, ligament, etc.) rep­resents this holy grail. Think about all of the potential uses for this technology and it is easy to see the whole field of orthopedic surgery being transformed during my lifetime. Imagine being able to grow new cartilage or ligament tissue and direct the body’s response to these new tissues. However, with these pos­sibilities also come enormous risk.

One significant unpredicted outcome or inappropriate application could lead to huge consequences, terrible com­plications, bad publicity, and loss of patient-physician trust. Just imagine the late night television commercials and billboards advertising for the local law firm that “you may be entitled to com­pensation.” Or just imagine the uncer­tainty injected into the physician-patient relationship, “you aren’t going to put one of those recalled parts in me are you?” You may have followed the recent controversy over “pink slime,” the “lean, finely textured beef” added to processed hamburger patties. Although used for decades, the recent media coverage of beef filler has severely affected the pub­lic’s trust in the food industry. Can you imagine how a similar public relations nightmare over failed technology could affect the orthopedic industry?

I have often been guilty of complain­ing about the arduous task of getting new technology approved though the regulatory bodies in the United States, compared with the perceived progres­sive nature of the process in Europe. I do believe that we should have a streamlined process for some new tech­nology that may save lives, especially chemotherapy medications. However, a more diligent, and thorough process must be applied to new technology used for elective procedures, as in most orthopedic applications. Unfortunately, until sufficient safety data and good outcomes research is completed and analyzed, we must temper the enthusi­asm of doctors and patients alike.

Author's Disclosure Statement. The author reports no actual or poten­tial conflict of interest in relation to this article.