A 65-year-old woman was recently diagnosed with osteoporosis after a screening bone mineral density test. She has hypertension (treated with lisinopril), and she had an episode of passing a kidney stone 10 years ago. A 24-hour urine study reveals an elevated urinary calcium level.

What should the physician keep in mind in managing this patient?

IDIOPATHIC HYPERCALCIURIA

Many potential causes of secondary hypercalciuria must be ruled out before deciding that a patient has idiopathic hypercalciuria, which was first noted as a distinct entity by Albright et al in 1953.¹ Causes of secondary hypercalciuria include primary hyperparathyroidism, hyperthyroidism, Paget disease, myeloma, malignancy, immobility, accelerated osteoporosis, sarcoidosis, renal tubular acidosis, and drug-induced urinary calcium loss such as that seen with loop diuretics.

Idiopathic hypercalciuria is identified by the following:

• Persistent hypercalciuria despite normal or restricted calcium intake^2,3
• Normal levels of parathyroid hormone (PTH), phosphorus, and 1,25-dihydroxy-vitamin D (the active form of vitamin D, also called calcitriol) in the presence of hypercalciuria; serum calcium levels are also normal.

An alias for idiopathic hypercalciuria is “fasting hypercalciuria,” as increased urinary calcium persists and sometimes worsens while fasting or on a low-calcium diet, with increased bone turnover, reduced bone density, and normal serum PTH levels.^4,5

Mineral loss from bone predominates in idiopathic hypercalciuria, but there is also a minor component of intestinal hyperabsorption of calcium and reduced renal calcium reabsorption.⁶ Distinguishing among intestinal hyperabsorptive hypercalciuria, renal leak hypercalciuria, and idiopathic or fasting hypercalciuria can be difficult and subtle. It has been argued that differentiating among hypercalciuric subtypes (hyperabsorptive, renal leak, idiopathic) is not useful; in general clinical practice, it is impractical to collect multiple 24-hour urine samples in the setting of controlled high- vs low-calcium diets.

COMPLICATIONS OF IDIOPATHIC HYPERCALCIURIA

Calcium is an important component in many physiologic processes, including coagulation, cell membrane transfer, hormone release, neuromuscular activation, and myocardial contraction. A sophisticated system of hormonally mediated interactions normally maintains stable extracellular calcium levels. Calcium is vital for bone strength, but the bones are the body’s calcium “bank,” and withdrawals from this bank are made at the expense of bone strength and integrity.

Renal stones

Patients with idiopathic hypercalciuria have a high incidence of renal stones. Conversely, 40% to 50% of patients with recurrent kidney stones have evidence of idiopathic hypercalciuria, the most common metabolic abnormality in “stone-formers.”^7,8 Further, 35% to 40% of first- and second-degree relatives of stone-formers who have idiopathic hypercalciuria also have the condition.⁹ In the general population without kidney stones and without first-degree relatives with stones, the prevalence is approximately 5% to 10%.^10,11

Bone loss

People with idiopathic hypercalciuria have lower bone density and a higher incidence of fracture than their normocalciuric peers. This relationship has been observed in both sexes and all ages. Idiopathic hypercalciuria has been noted in 10% to 19% of otherwise healthy men with low bone mass, in postmenopausal women with osteoporosis,^10–12 and in up to 40% of postmenopausal women with osteoporotic fractures and no history of kidney stones.¹³

LABORATORY DEFINITION

Urinary calcium excretion

Heaney et al¹⁴ measured 24-hour urinary calcium excretion in a group of early postmenopausal women, whom he divided into 3 groups by dietary calcium intake:

• Low intake (< 500 mg/day)
• Moderate intake (500–1,000 mg/day)
• High intake (> 1,000 mg/day).

In the women who were estrogen-deprived (ie, postmenopausal and not on estrogen replacement therapy), the 95% probability ranges for urinary calcium excretion were:

• 32–252 mg/day (0.51–4.06 mg/kg/day) with low calcium intake
• 36–286 mg/day (0.57–4.52 mg/kg/day) with moderate calcium intake
• 45–357 mg/day (0.69–5.47 mg/kg/day) with high calcium intake.

For estrogen-replete women (perimenopausal or postmenopausal on estrogen replacement), using the same categories of dietary calcium intake, calcium excretion was:

• 39–194 mg/day (0.65–3.23 mg/kg/day) with low calcium intake
• 54–269 mg/day (0.77–3.84 mg/kg/day) with moderate calcium intake
• 66–237 mg/day (0.98–4.89 mg/kg/day) with high calcium intake.

In the estrogen-deprived group, urinary calcium excretion increased by only 55 mg/day per 1,000-mg increase in dietary intake, though there was individual variability. These data suggest that hypercalciuria should be defined as:

• Greater than 250 mg/day (> 4.1 mg/kg/day) in estrogen-replete women
• Greater than 300 mg/day (> 5.0 mg/kg/day) in estrogen-deprived women.

Urinary calcium-to-creatinine ratio

Use of a spot urinary calcium-to-creatinine ratio has been advocated as an alternative to the more labor-intensive 24-hour urine collection.¹⁵ However, the spot urine calcium-creatinine ratio correlates poorly with 24-hour urine criteria for hypercalciuria whether by absolute, weight-based, or menopausal and calcium-adjusted definitions.

Importantly, spot urine measurements show poor sensitivity and specificity for hypercalciuria. Spot urine samples underestimate the 24-hour urinary calcium (Bland-Altman bias –71 mg/24 hours), and postprandial sampling overestimates it (Bland-Altman bias +61 mg/24 hours).¹⁵

The pathophysiology of idiopathic hypercalciuria has been difficult to establish.

Increased sensitivity to vitamin D? In the hyperabsorbing population, activated vitamin D levels are often robust, but a few studies of rats with hyperabsorbing, hyperexcreting physiology have shown normal calcitriol levels, suggesting an increased sensitivity to the actions of 1,25-dihydroxyvitamin D.¹⁶

Another study found that hypercalciuric stone-forming rats have more 1,25-dihydroxyvitamin D receptors than do controls.¹⁷

These changes have not been demonstrated in patients with idiopathic hypercalciuria.

High sodium intake has been proposed as the cause of idiopathic hypercalciuria. High sodium intake leads to increased urinary sodium excretion, and the increased tubular sodium load can decrease tubular calcium reabsorption, possibly favoring a reduction in bone mineral density over time.^18–20

In healthy people, urine calcium excretion increases by about 0.6 mmol/day (20–40 mg/day) for each 100-mmol (2,300 mg) increment in daily sodium ingestion.^21,22 But high sodium intake is seldom the principal cause of idiopathic hypercalciuria.

High protein intake, often observed in patients with nephrolithiasis, increases dietary acid load, stimulating release of calcium from bone and inhibiting renal reabsorption of calcium.^23,24 Increasing dietary protein from 0.5 to 2.0 mg/kg/day can double the urinary calcium output.²⁵

In mice, induction of metabolic acidosis, thought to mimic a high-protein diet, inhibits osteoblastic alkaline phosphatase activity while stimulating prostaglandin E2 production.²⁶ This in turn increases osteoblastic expression of receptor activator for nuclear factor kappa b (RANK) ligand, thereby potentially contributing to osteoclastogenesis and osteoclast activity.²⁶

Decreasing dietary protein decreases the recurrence of nephrolithiasis in established stone-formers.²⁷ Still, urine calcium levels are higher in those with idiopathic hypercalciuria than in normal controls at comparable levels of acid excretion, so while protein ingestion could potentially exacerbate the hypercalciuria, it is unlikely to be the sole cause.

Renal calcium leak? The frequent finding of low to low-normal PTH levels in patients with idiopathic hypercalciuria contradicts the potential etiologic mechanism of renal calcium “leak.” In idiopathic hypercalciuria, the PTH response to an oral calcium load is abnormal. If given an oral calcium load, the PTH level should decline if this were due to renal leak, but in the setting of idiopathic hypercalciuria, no clinically meaningful change in PTH occurs. This lack of response of PTH to oral calcium load has been seen in both rat and human studies. Patients also excrete normal to high amounts of urine calcium after prolonged fasting or a low-calcium diet. Low-calcium diets do not induce hyperparathyroidism in these patients, and so the source of the elevated calcium in the urine must be primarily from bone. Increased levels of 1,25-dihydroxyvitamin D in patients with idiopathic hypercalciuria have been noted.^28,29

Whether the cytokine milieu also contributes to the calcitriol levels is unclear, but the high or high-normal plasma level of 1,25-dihydroxyvitamin D may be the reason that the PTH is unperturbed.

IMPACT ON BONE HEALTH

Nephrolithiasis is strongly linked to fracture risk.

The bone mineral density of trabecular bone is more affected by calcium excretion than that of cortical bone.^18,20,30 However, lumbar spine bone mineral density has not been consistently found to be lower in patients with hyperabsorptive hypercalciuria. Rather, bone mineral density is correlated inversely with urine calcium excretion in men and women who form stones, but not in patients without nephrolithiasis.

In children

In children, idiopathic hypercalciuria is well known to be linked to osteopenia. This is an important group to study, as adult idiopathic hypercalciuria often begins in childhood. However, the trajectory of bone loss vs gain in children is fraught with variables such as growth, puberty, and body mass index, making this a difficult group from which to extrapolate conclusions to adults.

In men

There is more information on the relationship between hypercalciuria and osteoporosis in men than in women.

In 1998, Melton et al³¹ published the findings of a 25-year population-based cohort study of 624 patients, 442 (71%) of whom were men, referred for new-onset urolithiasis. The incidence of vertebral fracture was 4 times higher in this group than in patients without stone disease, but there was no difference in the rate of hip, forearm, or nonvertebral fractures. This is consistent with earlier data that report a loss of predominantly cancellous bone associated with urolithiasis.

National Health and Nutrition Examination Survey III data in 2001 focused on a potential relationship between kidney stones and bone mineral density or prevalent spine or wrist fracture.³² More than 14,000 people had hip bone mineral density measurements, of whom 793 (477 men, 316 women) had kidney stones. Men with previous nephrolithiasis had lower femoral neck bone mineral density than those without. Men with kidney stones were also more likely to report prevalent wrist and spine fractures. In women, no difference was noted between those with or without stone disease with respect to femoral neck bone mineral density or fracture incidence.

Cauley et al³³ also evaluated a relationship between kidney stones and bone mineral density in the Osteoporotic Fractures in Men (MrOS) study. Of approximately 6,000 men, 13.2% reported a history of kidney stones. These men had lower spine and total hip bone mineral density than controls who had not had kidney stones, and the difference persisted after adjusting for age, race, weight, and other variables. However, further data from this cohort revealed that so few men with osteoporosis had hypercalciuria that its routine measurement was not recommended.³⁴

The relationship between idiopathic hypercalciuria and fractures has been more difficult to establish in women.

Sowers et al³⁵ performed an observational study of 1,309 women ages 20 to 92 with a history of nephrolithiasis. No association was noted between stone disease and reduced bone mineral density in the femoral neck, lumbar spine, or radius.

These epidemiologic studies did not include the cause of the kidney stones (eg, whether or not there was associated hypercalciuria or primary hyperparathyroidism), and typically a diagnosis of idiopathic hypercalciuria was not established.

The difference in association between low bone mineral density or fracture with nephrolithiasis between men and women is not well understood, but the most consistent hypothesis is that the influence of hypoestrogenemia in women is much stronger than that of the hypercalciuria.²⁰

Does the degree of hypercalciuria influence the amount of bone loss?

A few trials have tried to determine whether the amount of calcium in the urine influences the magnitude of bone loss.

In 2003, Asplin et al³⁶ reported that bone mineral density Z-scores differed significantly by urinary calcium excretion, but only in stone-formers. In patients without stone disease, there was no difference in Z-scores according to the absolute value of hypercalciuria. This may be due to a self-selection bias in which stone-formers avoid calcium in the diet and those without stone disease do not.

Three studies looking solely at men with idiopathic hypercalciuria also did not detect a significant difference in bone mineral loss according to degree of hypercalciuria.^20,30,37

A POLYGENIC DISORDER?

The potential contribution of genetic changes to the development of idiopathic hypercalciuria has been studied. While there is an increased risk of idiopathic hypercalciuria in first-degree relatives of patients with nephrolithiasis, most experts believe that idiopathic hypercalciuria is likely a polygenic disorder.^9,38

EVALUATION AND TREATMENT

The 2014 revised version of the National Osteoporosis Foundation’s “Clinician’s guide to prevention and treatment of osteoporosis”³⁹ noted that hypercalciuria is a risk factor that contributes to the development of osteoporosis and possibly osteoporotic fractures, and that consideration should be given to evaluating for hypercalciuria, but only in selected cases. In patients with kidney stones, the link between hypercalciuria and bone loss and fracture is recognized and should be explored in both women and men at risk of osteoporosis, as 45% to 50% of patients who form calcium stones have hypercalciuria.

Patients with kidney stones who have low bone mass and idiopathic hypercalciuria should increase their daily fluid intake, follow a low-salt and low-animal-protein diet, and take thiazide diuretics to reduce the incidence of further calcium stones. Whether this approach also improves bone mass and strength and reduces the risk of fractures within this cohort requires further study.

Dietary interventions

Don’t restrict calcium intake. Despite the connection between hypercalciuria and nephrolithiasis, restriction of dietary calcium to prevent relapse of nephrolithiasis is a risk factor for negative calcium balance and bone demineralization. Observational studies and prospective clinical trials have demonstrated an increased risk of stone formation with low calcium intake.^27,30 Nevertheless, this practice seems logical to many patients with kidney stones, and this process may independently contribute to lower bone mineral density.

A low-sodium, low-animal-protein diet is beneficial. Though increased intake of sodium or protein is not the main cause of idiopathic hypercalciuria, pharmacologic therapy, especially with thiazide diuretics, is more likely to be successful in the setting of a low-sodium, low-protein diet.

Borghi et al²⁷ studied 2 diets in men with nephrolithiasis and idiopathic hypercalciuria: a low-calcium diet and a low-salt, low-animal-protein, normal-calcium diet. Men on the latter diet experienced a greater reduction in urinary calcium excretion than those on the low-calcium diet.

Breslau et al⁴⁰ found that urinary calcium excretion fell by 50% in 15 people when they switched from an animal-based to a plant-based protein diet.

Thiazide diuretics

Several epidemiologic and randomized studies^41–45 found that thiazide therapy decreased the likelihood of hip fracture in postmenopausal women, men, and premenopausal women. Doses ranged from 12.5 to 50 mg of hydrochlorothiazide. Bone density increased in the radius, total body, total hip, and lumbar spine. One prospective trial noted that fracture risk declined with longer duration of thiazide use, with the largest reduction in those who used thiazides for 8 or more years.⁴⁶

Thiazides have anticalciuric actions.⁴⁷ In addition, they have positive effects on osteoblastic cell proliferation and activity, inhibiting osteocalcin expression by osteoblasts, thereby possibly improving bone formation and mineralization.⁴⁸ The effects of thiazides on bone was reviewed by Sakhaee et al.⁴⁹

However, fewer studies have looked at thiazides in patients with idiopathic hypercalciuria.

García-Nieto et al⁵⁰ looked retrospectively at 22 children (average age 11.7) with idiopathic hypercalciuria and osteopenia who had received thiazides (19 received chlorthalidone 25 mg daily, and 3 received hydrochlorothiazide 25 mg daily) for an average of 2.4 years, and at 32 similar patients who had not received thiazides. Twelve (55%) of the patients receiving thiazides had an improvement in bone mineral density Z-scores, compared with 23 (72%) of the controls. This finding is confounded by growth that occurred during the study, and both groups demonstrated a significantly increased body mass index and bone mineral apparent density at the end of the trial.

Bushinsky and Favus⁵¹ evaluated whether chlorthalidone improved bone quality or structure in rats that were genetically prone to hypercalciuric stones. These rats are uniformly stone-formers, and while they have components of calcium hyperabsorption, they also demonstrate renal hyperexcretion (leak) and enhanced bone mineral resorption.⁵¹ When fed a high-calcium diet, they maintain a reduction in bone mineral density and bone strength. Study rats were given chlorthalidone 4 to 5 mg/kg/day. After 18 weeks of therapy, significant improvements were observed in trabecular thickness and connectivity as well as increased vertebral compressive strength.⁵² No difference in cortical bone was noted.

No randomized, blinded, placebo-controlled trial has yet been done to study the impact of thiazides on bone mineral density or fracture risk in patients with idiopathic hypercalciuria.

In practice, many physicians choose chlorthali­done over hydrochlorothiazide because of chlorthalidone’s longer half-life. Combinations of a thiazide diuretic and potassium-sparing medications are also employed, such as hydrochlorothiazide plus either triamterene or spironolactone to reduce the number of pills the patient has to take.

When prescribing thiazide diuretics, one should also consider prescribing potassium citrate, as this agent not only prevents hypokalemia but also increases urinary citrate excretion, which can help to inhibit crystallization of calcium salts.⁶

In a longitudinal study of 28 patients with hypercalciuria,⁵³ combined therapy with a thiazide or indapamide and potassium citrate over a mean of 7 years increased bone density of the lumbar spine by 7.1% and of the femoral neck by 4.1%, compared with treatment in age- and sex-matched normocalcemic peers. In the same study, daily urinary calcium excretion decreased and urinary pH and citrate levels increased; urinary saturation of calcium oxalate decreased by 46%, and stone formation was decreased.

Another trial evaluated 120 patients with idiopathic calcium nephrolithiasis, half of whom were given potassium citrate. Those given potassium citrate experienced an increase in distal radius bone mineral density over 2 years.⁵⁴ It is theorized that alkalinization may decrease bone turnover in these patients.

Bisphosphonates

As one of the proposed main mechanisms of bone loss in idiopathic hypercalciuria is direct bone resorption, a potential target for therapy is the osteoclast, which bisphosphonates inhibit.

Ruml et al⁵⁵ studied the impact of alendronate vs placebo in 16 normal men undergoing 3 weeks of strict bedrest. Compared with the placebo group, those who received alendronate had significantly lower 24-hour urine calcium excretion and higher levels of PTH and 1,25-dihydroxyvitamin D.

Weisinger et al⁵⁶ evaluated the effects of alendronate 10 mg daily in 10 patients who had stone disease with documented idiopathic hypercalciuria and also in 8 normocalciuric patients without stone disease. Alendronate resulted in a sustained reduction of calcium in the urine in the patients with idiopathic hypercalciuria but not in the normocalciuric patients.

Data are somewhat scant as to the effect of bisphosphonates on bone health in the setting of idiopathic hypercalciuria,^57,58 and therapy with bisphosphonates is not recommended in patients with idiopathic hypercalciuria outside the realm of postmenopausal osteoporosis or other indications for bisphosphonates approved by the US Food and Drug Administration (FDA).

Calcimimetics

Calcium-sensing receptors are found not only in parathyroid tissue but also in the intestines and kidneys. Locally, elevated plasma calcium in the kidney causes activation of the calcium-sensing receptor, diminishing further calcium reabsorption.⁵⁹ Agents that increase the sensitivity of the calcium-sensing receptors are classified as calcimimetics.

Cinacalcet is a calcimimetic approved by the FDA for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, for the treatment of hypercalcemia in patients with parathyroid carcinoma, and for patients with primary hyperpara­thyroidism who are unable to undergo parathyroidectomy. In an uncontrolled 5-year study of cinacalcet in patients with primary hyperparathyroidism, there was no significant change in bone density.⁶⁰

Anti-inflammatory drugs

The role of cytokines in stimulating bone resorption in idiopathic hypercalciuria has led to the investigation of several anti-inflammatory drugs (eg, diclofenac, indomethacin) as potential treatments, but studies have been limited in number and scope.^61,62

Omega-3 fatty acids

Omega-3 fatty acids are thought to alter prostaglandin metabolism and to potentially reduce stone formation.⁶³

A retrospective study of 29 patients with stone disease found that, combined with dietary counseling, omega-3 fatty acids could potentially reduce urinary calcium and oxalate excretion and increase urinary citrate in hypercalciuric stone-formers.⁶⁴

A review of published randomized controlled trials of omega-3 fatty acids in skeletal health discovered that 4 studies found positive effects on bone mineral density or bone turnover markers, whereas 5 studies reported no differences. All trials were small, and none evaluated fracture outcome.⁶⁵

A 65-year-old woman was recently diagnosed with osteoporosis after a screening bone mineral density test. She has hypertension (treated with lisinopril), and she had an episode of passing a kidney stone 10 years ago. A 24-hour urine study reveals an elevated urinary calcium level.

What should the physician keep in mind in managing this patient?

IDIOPATHIC HYPERCALCIURIA

Many potential causes of secondary hypercalciuria must be ruled out before deciding that a patient has idiopathic hypercalciuria, which was first noted as a distinct entity by Albright et al in 1953.¹ Causes of secondary hypercalciuria include primary hyperparathyroidism, hyperthyroidism, Paget disease, myeloma, malignancy, immobility, accelerated osteoporosis, sarcoidosis, renal tubular acidosis, and drug-induced urinary calcium loss such as that seen with loop diuretics.

Idiopathic hypercalciuria is identified by the following:

• Persistent hypercalciuria despite normal or restricted calcium intake^2,3
• Normal levels of parathyroid hormone (PTH), phosphorus, and 1,25-dihydroxy-vitamin D (the active form of vitamin D, also called calcitriol) in the presence of hypercalciuria; serum calcium levels are also normal.

An alias for idiopathic hypercalciuria is “fasting hypercalciuria,” as increased urinary calcium persists and sometimes worsens while fasting or on a low-calcium diet, with increased bone turnover, reduced bone density, and normal serum PTH levels.^4,5

Mineral loss from bone predominates in idiopathic hypercalciuria, but there is also a minor component of intestinal hyperabsorption of calcium and reduced renal calcium reabsorption.⁶ Distinguishing among intestinal hyperabsorptive hypercalciuria, renal leak hypercalciuria, and idiopathic or fasting hypercalciuria can be difficult and subtle. It has been argued that differentiating among hypercalciuric subtypes (hyperabsorptive, renal leak, idiopathic) is not useful; in general clinical practice, it is impractical to collect multiple 24-hour urine samples in the setting of controlled high- vs low-calcium diets.

COMPLICATIONS OF IDIOPATHIC HYPERCALCIURIA

Calcium is an important component in many physiologic processes, including coagulation, cell membrane transfer, hormone release, neuromuscular activation, and myocardial contraction. A sophisticated system of hormonally mediated interactions normally maintains stable extracellular calcium levels. Calcium is vital for bone strength, but the bones are the body’s calcium “bank,” and withdrawals from this bank are made at the expense of bone strength and integrity.

Renal stones

Patients with idiopathic hypercalciuria have a high incidence of renal stones. Conversely, 40% to 50% of patients with recurrent kidney stones have evidence of idiopathic hypercalciuria, the most common metabolic abnormality in “stone-formers.”^7,8 Further, 35% to 40% of first- and second-degree relatives of stone-formers who have idiopathic hypercalciuria also have the condition.⁹ In the general population without kidney stones and without first-degree relatives with stones, the prevalence is approximately 5% to 10%.^10,11

Bone loss

People with idiopathic hypercalciuria have lower bone density and a higher incidence of fracture than their normocalciuric peers. This relationship has been observed in both sexes and all ages. Idiopathic hypercalciuria has been noted in 10% to 19% of otherwise healthy men with low bone mass, in postmenopausal women with osteoporosis,^10–12 and in up to 40% of postmenopausal women with osteoporotic fractures and no history of kidney stones.¹³

LABORATORY DEFINITION

Urinary calcium excretion

Heaney et al¹⁴ measured 24-hour urinary calcium excretion in a group of early postmenopausal women, whom he divided into 3 groups by dietary calcium intake:

• Low intake (< 500 mg/day)
• Moderate intake (500–1,000 mg/day)
• High intake (> 1,000 mg/day).

In the women who were estrogen-deprived (ie, postmenopausal and not on estrogen replacement therapy), the 95% probability ranges for urinary calcium excretion were:

• 32–252 mg/day (0.51–4.06 mg/kg/day) with low calcium intake
• 36–286 mg/day (0.57–4.52 mg/kg/day) with moderate calcium intake
• 45–357 mg/day (0.69–5.47 mg/kg/day) with high calcium intake.

For estrogen-replete women (perimenopausal or postmenopausal on estrogen replacement), using the same categories of dietary calcium intake, calcium excretion was:

• 39–194 mg/day (0.65–3.23 mg/kg/day) with low calcium intake
• 54–269 mg/day (0.77–3.84 mg/kg/day) with moderate calcium intake
• 66–237 mg/day (0.98–4.89 mg/kg/day) with high calcium intake.

In the estrogen-deprived group, urinary calcium excretion increased by only 55 mg/day per 1,000-mg increase in dietary intake, though there was individual variability. These data suggest that hypercalciuria should be defined as:

• Greater than 250 mg/day (> 4.1 mg/kg/day) in estrogen-replete women
• Greater than 300 mg/day (> 5.0 mg/kg/day) in estrogen-deprived women.

Urinary calcium-to-creatinine ratio

Use of a spot urinary calcium-to-creatinine ratio has been advocated as an alternative to the more labor-intensive 24-hour urine collection.¹⁵ However, the spot urine calcium-creatinine ratio correlates poorly with 24-hour urine criteria for hypercalciuria whether by absolute, weight-based, or menopausal and calcium-adjusted definitions.

Importantly, spot urine measurements show poor sensitivity and specificity for hypercalciuria. Spot urine samples underestimate the 24-hour urinary calcium (Bland-Altman bias –71 mg/24 hours), and postprandial sampling overestimates it (Bland-Altman bias +61 mg/24 hours).¹⁵

The pathophysiology of idiopathic hypercalciuria has been difficult to establish.

Increased sensitivity to vitamin D? In the hyperabsorbing population, activated vitamin D levels are often robust, but a few studies of rats with hyperabsorbing, hyperexcreting physiology have shown normal calcitriol levels, suggesting an increased sensitivity to the actions of 1,25-dihydroxyvitamin D.¹⁶

Another study found that hypercalciuric stone-forming rats have more 1,25-dihydroxyvitamin D receptors than do controls.¹⁷

These changes have not been demonstrated in patients with idiopathic hypercalciuria.

High sodium intake has been proposed as the cause of idiopathic hypercalciuria. High sodium intake leads to increased urinary sodium excretion, and the increased tubular sodium load can decrease tubular calcium reabsorption, possibly favoring a reduction in bone mineral density over time.^18–20

In healthy people, urine calcium excretion increases by about 0.6 mmol/day (20–40 mg/day) for each 100-mmol (2,300 mg) increment in daily sodium ingestion.^21,22 But high sodium intake is seldom the principal cause of idiopathic hypercalciuria.

High protein intake, often observed in patients with nephrolithiasis, increases dietary acid load, stimulating release of calcium from bone and inhibiting renal reabsorption of calcium.^23,24 Increasing dietary protein from 0.5 to 2.0 mg/kg/day can double the urinary calcium output.²⁵

In mice, induction of metabolic acidosis, thought to mimic a high-protein diet, inhibits osteoblastic alkaline phosphatase activity while stimulating prostaglandin E2 production.²⁶ This in turn increases osteoblastic expression of receptor activator for nuclear factor kappa b (RANK) ligand, thereby potentially contributing to osteoclastogenesis and osteoclast activity.²⁶

Decreasing dietary protein decreases the recurrence of nephrolithiasis in established stone-formers.²⁷ Still, urine calcium levels are higher in those with idiopathic hypercalciuria than in normal controls at comparable levels of acid excretion, so while protein ingestion could potentially exacerbate the hypercalciuria, it is unlikely to be the sole cause.

Renal calcium leak? The frequent finding of low to low-normal PTH levels in patients with idiopathic hypercalciuria contradicts the potential etiologic mechanism of renal calcium “leak.” In idiopathic hypercalciuria, the PTH response to an oral calcium load is abnormal. If given an oral calcium load, the PTH level should decline if this were due to renal leak, but in the setting of idiopathic hypercalciuria, no clinically meaningful change in PTH occurs. This lack of response of PTH to oral calcium load has been seen in both rat and human studies. Patients also excrete normal to high amounts of urine calcium after prolonged fasting or a low-calcium diet. Low-calcium diets do not induce hyperparathyroidism in these patients, and so the source of the elevated calcium in the urine must be primarily from bone. Increased levels of 1,25-dihydroxyvitamin D in patients with idiopathic hypercalciuria have been noted.^28,29

Whether the cytokine milieu also contributes to the calcitriol levels is unclear, but the high or high-normal plasma level of 1,25-dihydroxyvitamin D may be the reason that the PTH is unperturbed.

IMPACT ON BONE HEALTH

Nephrolithiasis is strongly linked to fracture risk.

The bone mineral density of trabecular bone is more affected by calcium excretion than that of cortical bone.^18,20,30 However, lumbar spine bone mineral density has not been consistently found to be lower in patients with hyperabsorptive hypercalciuria. Rather, bone mineral density is correlated inversely with urine calcium excretion in men and women who form stones, but not in patients without nephrolithiasis.

In children

In children, idiopathic hypercalciuria is well known to be linked to osteopenia. This is an important group to study, as adult idiopathic hypercalciuria often begins in childhood. However, the trajectory of bone loss vs gain in children is fraught with variables such as growth, puberty, and body mass index, making this a difficult group from which to extrapolate conclusions to adults.

In men

There is more information on the relationship between hypercalciuria and osteoporosis in men than in women.

In 1998, Melton et al³¹ published the findings of a 25-year population-based cohort study of 624 patients, 442 (71%) of whom were men, referred for new-onset urolithiasis. The incidence of vertebral fracture was 4 times higher in this group than in patients without stone disease, but there was no difference in the rate of hip, forearm, or nonvertebral fractures. This is consistent with earlier data that report a loss of predominantly cancellous bone associated with urolithiasis.

National Health and Nutrition Examination Survey III data in 2001 focused on a potential relationship between kidney stones and bone mineral density or prevalent spine or wrist fracture.³² More than 14,000 people had hip bone mineral density measurements, of whom 793 (477 men, 316 women) had kidney stones. Men with previous nephrolithiasis had lower femoral neck bone mineral density than those without. Men with kidney stones were also more likely to report prevalent wrist and spine fractures. In women, no difference was noted between those with or without stone disease with respect to femoral neck bone mineral density or fracture incidence.

Cauley et al³³ also evaluated a relationship between kidney stones and bone mineral density in the Osteoporotic Fractures in Men (MrOS) study. Of approximately 6,000 men, 13.2% reported a history of kidney stones. These men had lower spine and total hip bone mineral density than controls who had not had kidney stones, and the difference persisted after adjusting for age, race, weight, and other variables. However, further data from this cohort revealed that so few men with osteoporosis had hypercalciuria that its routine measurement was not recommended.³⁴

The relationship between idiopathic hypercalciuria and fractures has been more difficult to establish in women.

Sowers et al³⁵ performed an observational study of 1,309 women ages 20 to 92 with a history of nephrolithiasis. No association was noted between stone disease and reduced bone mineral density in the femoral neck, lumbar spine, or radius.

These epidemiologic studies did not include the cause of the kidney stones (eg, whether or not there was associated hypercalciuria or primary hyperparathyroidism), and typically a diagnosis of idiopathic hypercalciuria was not established.

The difference in association between low bone mineral density or fracture with nephrolithiasis between men and women is not well understood, but the most consistent hypothesis is that the influence of hypoestrogenemia in women is much stronger than that of the hypercalciuria.²⁰

Does the degree of hypercalciuria influence the amount of bone loss?

A few trials have tried to determine whether the amount of calcium in the urine influences the magnitude of bone loss.

In 2003, Asplin et al³⁶ reported that bone mineral density Z-scores differed significantly by urinary calcium excretion, but only in stone-formers. In patients without stone disease, there was no difference in Z-scores according to the absolute value of hypercalciuria. This may be due to a self-selection bias in which stone-formers avoid calcium in the diet and those without stone disease do not.

Three studies looking solely at men with idiopathic hypercalciuria also did not detect a significant difference in bone mineral loss according to degree of hypercalciuria.^20,30,37

A POLYGENIC DISORDER?

The potential contribution of genetic changes to the development of idiopathic hypercalciuria has been studied. While there is an increased risk of idiopathic hypercalciuria in first-degree relatives of patients with nephrolithiasis, most experts believe that idiopathic hypercalciuria is likely a polygenic disorder.^9,38

EVALUATION AND TREATMENT

The 2014 revised version of the National Osteoporosis Foundation’s “Clinician’s guide to prevention and treatment of osteoporosis”³⁹ noted that hypercalciuria is a risk factor that contributes to the development of osteoporosis and possibly osteoporotic fractures, and that consideration should be given to evaluating for hypercalciuria, but only in selected cases. In patients with kidney stones, the link between hypercalciuria and bone loss and fracture is recognized and should be explored in both women and men at risk of osteoporosis, as 45% to 50% of patients who form calcium stones have hypercalciuria.

Patients with kidney stones who have low bone mass and idiopathic hypercalciuria should increase their daily fluid intake, follow a low-salt and low-animal-protein diet, and take thiazide diuretics to reduce the incidence of further calcium stones. Whether this approach also improves bone mass and strength and reduces the risk of fractures within this cohort requires further study.

Dietary interventions

Don’t restrict calcium intake. Despite the connection between hypercalciuria and nephrolithiasis, restriction of dietary calcium to prevent relapse of nephrolithiasis is a risk factor for negative calcium balance and bone demineralization. Observational studies and prospective clinical trials have demonstrated an increased risk of stone formation with low calcium intake.^27,30 Nevertheless, this practice seems logical to many patients with kidney stones, and this process may independently contribute to lower bone mineral density.

A low-sodium, low-animal-protein diet is beneficial. Though increased intake of sodium or protein is not the main cause of idiopathic hypercalciuria, pharmacologic therapy, especially with thiazide diuretics, is more likely to be successful in the setting of a low-sodium, low-protein diet.

Borghi et al²⁷ studied 2 diets in men with nephrolithiasis and idiopathic hypercalciuria: a low-calcium diet and a low-salt, low-animal-protein, normal-calcium diet. Men on the latter diet experienced a greater reduction in urinary calcium excretion than those on the low-calcium diet.

Breslau et al⁴⁰ found that urinary calcium excretion fell by 50% in 15 people when they switched from an animal-based to a plant-based protein diet.

Thiazide diuretics

Several epidemiologic and randomized studies^41–45 found that thiazide therapy decreased the likelihood of hip fracture in postmenopausal women, men, and premenopausal women. Doses ranged from 12.5 to 50 mg of hydrochlorothiazide. Bone density increased in the radius, total body, total hip, and lumbar spine. One prospective trial noted that fracture risk declined with longer duration of thiazide use, with the largest reduction in those who used thiazides for 8 or more years.⁴⁶

Thiazides have anticalciuric actions.⁴⁷ In addition, they have positive effects on osteoblastic cell proliferation and activity, inhibiting osteocalcin expression by osteoblasts, thereby possibly improving bone formation and mineralization.⁴⁸ The effects of thiazides on bone was reviewed by Sakhaee et al.⁴⁹

However, fewer studies have looked at thiazides in patients with idiopathic hypercalciuria.

García-Nieto et al⁵⁰ looked retrospectively at 22 children (average age 11.7) with idiopathic hypercalciuria and osteopenia who had received thiazides (19 received chlorthalidone 25 mg daily, and 3 received hydrochlorothiazide 25 mg daily) for an average of 2.4 years, and at 32 similar patients who had not received thiazides. Twelve (55%) of the patients receiving thiazides had an improvement in bone mineral density Z-scores, compared with 23 (72%) of the controls. This finding is confounded by growth that occurred during the study, and both groups demonstrated a significantly increased body mass index and bone mineral apparent density at the end of the trial.

Bushinsky and Favus⁵¹ evaluated whether chlorthalidone improved bone quality or structure in rats that were genetically prone to hypercalciuric stones. These rats are uniformly stone-formers, and while they have components of calcium hyperabsorption, they also demonstrate renal hyperexcretion (leak) and enhanced bone mineral resorption.⁵¹ When fed a high-calcium diet, they maintain a reduction in bone mineral density and bone strength. Study rats were given chlorthalidone 4 to 5 mg/kg/day. After 18 weeks of therapy, significant improvements were observed in trabecular thickness and connectivity as well as increased vertebral compressive strength.⁵² No difference in cortical bone was noted.

No randomized, blinded, placebo-controlled trial has yet been done to study the impact of thiazides on bone mineral density or fracture risk in patients with idiopathic hypercalciuria.

In practice, many physicians choose chlorthali­done over hydrochlorothiazide because of chlorthalidone’s longer half-life. Combinations of a thiazide diuretic and potassium-sparing medications are also employed, such as hydrochlorothiazide plus either triamterene or spironolactone to reduce the number of pills the patient has to take.

When prescribing thiazide diuretics, one should also consider prescribing potassium citrate, as this agent not only prevents hypokalemia but also increases urinary citrate excretion, which can help to inhibit crystallization of calcium salts.⁶

In a longitudinal study of 28 patients with hypercalciuria,⁵³ combined therapy with a thiazide or indapamide and potassium citrate over a mean of 7 years increased bone density of the lumbar spine by 7.1% and of the femoral neck by 4.1%, compared with treatment in age- and sex-matched normocalcemic peers. In the same study, daily urinary calcium excretion decreased and urinary pH and citrate levels increased; urinary saturation of calcium oxalate decreased by 46%, and stone formation was decreased.

Another trial evaluated 120 patients with idiopathic calcium nephrolithiasis, half of whom were given potassium citrate. Those given potassium citrate experienced an increase in distal radius bone mineral density over 2 years.⁵⁴ It is theorized that alkalinization may decrease bone turnover in these patients.

Bisphosphonates

As one of the proposed main mechanisms of bone loss in idiopathic hypercalciuria is direct bone resorption, a potential target for therapy is the osteoclast, which bisphosphonates inhibit.

Ruml et al⁵⁵ studied the impact of alendronate vs placebo in 16 normal men undergoing 3 weeks of strict bedrest. Compared with the placebo group, those who received alendronate had significantly lower 24-hour urine calcium excretion and higher levels of PTH and 1,25-dihydroxyvitamin D.

Weisinger et al⁵⁶ evaluated the effects of alendronate 10 mg daily in 10 patients who had stone disease with documented idiopathic hypercalciuria and also in 8 normocalciuric patients without stone disease. Alendronate resulted in a sustained reduction of calcium in the urine in the patients with idiopathic hypercalciuria but not in the normocalciuric patients.

Data are somewhat scant as to the effect of bisphosphonates on bone health in the setting of idiopathic hypercalciuria,^57,58 and therapy with bisphosphonates is not recommended in patients with idiopathic hypercalciuria outside the realm of postmenopausal osteoporosis or other indications for bisphosphonates approved by the US Food and Drug Administration (FDA).

Calcimimetics

Calcium-sensing receptors are found not only in parathyroid tissue but also in the intestines and kidneys. Locally, elevated plasma calcium in the kidney causes activation of the calcium-sensing receptor, diminishing further calcium reabsorption.⁵⁹ Agents that increase the sensitivity of the calcium-sensing receptors are classified as calcimimetics.

Cinacalcet is a calcimimetic approved by the FDA for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, for the treatment of hypercalcemia in patients with parathyroid carcinoma, and for patients with primary hyperpara­thyroidism who are unable to undergo parathyroidectomy. In an uncontrolled 5-year study of cinacalcet in patients with primary hyperparathyroidism, there was no significant change in bone density.⁶⁰

Anti-inflammatory drugs

The role of cytokines in stimulating bone resorption in idiopathic hypercalciuria has led to the investigation of several anti-inflammatory drugs (eg, diclofenac, indomethacin) as potential treatments, but studies have been limited in number and scope.^61,62

Omega-3 fatty acids

Omega-3 fatty acids are thought to alter prostaglandin metabolism and to potentially reduce stone formation.⁶³

A retrospective study of 29 patients with stone disease found that, combined with dietary counseling, omega-3 fatty acids could potentially reduce urinary calcium and oxalate excretion and increase urinary citrate in hypercalciuric stone-formers.⁶⁴

A review of published randomized controlled trials of omega-3 fatty acids in skeletal health discovered that 4 studies found positive effects on bone mineral density or bone turnover markers, whereas 5 studies reported no differences. All trials were small, and none evaluated fracture outcome.⁶⁵

A 65-year-old woman was recently diagnosed with osteoporosis after a screening bone mineral density test. She has hypertension (treated with lisinopril), and she had an episode of passing a kidney stone 10 years ago. A 24-hour urine study reveals an elevated urinary calcium level.

What should the physician keep in mind in managing this patient?

IDIOPATHIC HYPERCALCIURIA

Many potential causes of secondary hypercalciuria must be ruled out before deciding that a patient has idiopathic hypercalciuria, which was first noted as a distinct entity by Albright et al in 1953.¹ Causes of secondary hypercalciuria include primary hyperparathyroidism, hyperthyroidism, Paget disease, myeloma, malignancy, immobility, accelerated osteoporosis, sarcoidosis, renal tubular acidosis, and drug-induced urinary calcium loss such as that seen with loop diuretics.

Idiopathic hypercalciuria is identified by the following:

• Persistent hypercalciuria despite normal or restricted calcium intake^2,3
• Normal levels of parathyroid hormone (PTH), phosphorus, and 1,25-dihydroxy-vitamin D (the active form of vitamin D, also called calcitriol) in the presence of hypercalciuria; serum calcium levels are also normal.

An alias for idiopathic hypercalciuria is “fasting hypercalciuria,” as increased urinary calcium persists and sometimes worsens while fasting or on a low-calcium diet, with increased bone turnover, reduced bone density, and normal serum PTH levels.^4,5

Mineral loss from bone predominates in idiopathic hypercalciuria, but there is also a minor component of intestinal hyperabsorption of calcium and reduced renal calcium reabsorption.⁶ Distinguishing among intestinal hyperabsorptive hypercalciuria, renal leak hypercalciuria, and idiopathic or fasting hypercalciuria can be difficult and subtle. It has been argued that differentiating among hypercalciuric subtypes (hyperabsorptive, renal leak, idiopathic) is not useful; in general clinical practice, it is impractical to collect multiple 24-hour urine samples in the setting of controlled high- vs low-calcium diets.

COMPLICATIONS OF IDIOPATHIC HYPERCALCIURIA

Calcium is an important component in many physiologic processes, including coagulation, cell membrane transfer, hormone release, neuromuscular activation, and myocardial contraction. A sophisticated system of hormonally mediated interactions normally maintains stable extracellular calcium levels. Calcium is vital for bone strength, but the bones are the body’s calcium “bank,” and withdrawals from this bank are made at the expense of bone strength and integrity.

Renal stones

Patients with idiopathic hypercalciuria have a high incidence of renal stones. Conversely, 40% to 50% of patients with recurrent kidney stones have evidence of idiopathic hypercalciuria, the most common metabolic abnormality in “stone-formers.”^7,8 Further, 35% to 40% of first- and second-degree relatives of stone-formers who have idiopathic hypercalciuria also have the condition.⁹ In the general population without kidney stones and without first-degree relatives with stones, the prevalence is approximately 5% to 10%.^10,11

Bone loss

People with idiopathic hypercalciuria have lower bone density and a higher incidence of fracture than their normocalciuric peers. This relationship has been observed in both sexes and all ages. Idiopathic hypercalciuria has been noted in 10% to 19% of otherwise healthy men with low bone mass, in postmenopausal women with osteoporosis,^10–12 and in up to 40% of postmenopausal women with osteoporotic fractures and no history of kidney stones.¹³

LABORATORY DEFINITION

Urinary calcium excretion

Heaney et al¹⁴ measured 24-hour urinary calcium excretion in a group of early postmenopausal women, whom he divided into 3 groups by dietary calcium intake:

• Low intake (< 500 mg/day)
• Moderate intake (500–1,000 mg/day)
• High intake (> 1,000 mg/day).

In the women who were estrogen-deprived (ie, postmenopausal and not on estrogen replacement therapy), the 95% probability ranges for urinary calcium excretion were:

• 32–252 mg/day (0.51–4.06 mg/kg/day) with low calcium intake
• 36–286 mg/day (0.57–4.52 mg/kg/day) with moderate calcium intake
• 45–357 mg/day (0.69–5.47 mg/kg/day) with high calcium intake.

For estrogen-replete women (perimenopausal or postmenopausal on estrogen replacement), using the same categories of dietary calcium intake, calcium excretion was:

• 39–194 mg/day (0.65–3.23 mg/kg/day) with low calcium intake
• 54–269 mg/day (0.77–3.84 mg/kg/day) with moderate calcium intake
• 66–237 mg/day (0.98–4.89 mg/kg/day) with high calcium intake.

In the estrogen-deprived group, urinary calcium excretion increased by only 55 mg/day per 1,000-mg increase in dietary intake, though there was individual variability. These data suggest that hypercalciuria should be defined as:

• Greater than 250 mg/day (> 4.1 mg/kg/day) in estrogen-replete women
• Greater than 300 mg/day (> 5.0 mg/kg/day) in estrogen-deprived women.

Urinary calcium-to-creatinine ratio

Use of a spot urinary calcium-to-creatinine ratio has been advocated as an alternative to the more labor-intensive 24-hour urine collection.¹⁵ However, the spot urine calcium-creatinine ratio correlates poorly with 24-hour urine criteria for hypercalciuria whether by absolute, weight-based, or menopausal and calcium-adjusted definitions.

Importantly, spot urine measurements show poor sensitivity and specificity for hypercalciuria. Spot urine samples underestimate the 24-hour urinary calcium (Bland-Altman bias –71 mg/24 hours), and postprandial sampling overestimates it (Bland-Altman bias +61 mg/24 hours).¹⁵

The pathophysiology of idiopathic hypercalciuria has been difficult to establish.

Increased sensitivity to vitamin D? In the hyperabsorbing population, activated vitamin D levels are often robust, but a few studies of rats with hyperabsorbing, hyperexcreting physiology have shown normal calcitriol levels, suggesting an increased sensitivity to the actions of 1,25-dihydroxyvitamin D.¹⁶

Another study found that hypercalciuric stone-forming rats have more 1,25-dihydroxyvitamin D receptors than do controls.¹⁷

These changes have not been demonstrated in patients with idiopathic hypercalciuria.

High sodium intake has been proposed as the cause of idiopathic hypercalciuria. High sodium intake leads to increased urinary sodium excretion, and the increased tubular sodium load can decrease tubular calcium reabsorption, possibly favoring a reduction in bone mineral density over time.^18–20

In healthy people, urine calcium excretion increases by about 0.6 mmol/day (20–40 mg/day) for each 100-mmol (2,300 mg) increment in daily sodium ingestion.^21,22 But high sodium intake is seldom the principal cause of idiopathic hypercalciuria.

High protein intake, often observed in patients with nephrolithiasis, increases dietary acid load, stimulating release of calcium from bone and inhibiting renal reabsorption of calcium.^23,24 Increasing dietary protein from 0.5 to 2.0 mg/kg/day can double the urinary calcium output.²⁵

In mice, induction of metabolic acidosis, thought to mimic a high-protein diet, inhibits osteoblastic alkaline phosphatase activity while stimulating prostaglandin E2 production.²⁶ This in turn increases osteoblastic expression of receptor activator for nuclear factor kappa b (RANK) ligand, thereby potentially contributing to osteoclastogenesis and osteoclast activity.²⁶

Decreasing dietary protein decreases the recurrence of nephrolithiasis in established stone-formers.²⁷ Still, urine calcium levels are higher in those with idiopathic hypercalciuria than in normal controls at comparable levels of acid excretion, so while protein ingestion could potentially exacerbate the hypercalciuria, it is unlikely to be the sole cause.

Renal calcium leak? The frequent finding of low to low-normal PTH levels in patients with idiopathic hypercalciuria contradicts the potential etiologic mechanism of renal calcium “leak.” In idiopathic hypercalciuria, the PTH response to an oral calcium load is abnormal. If given an oral calcium load, the PTH level should decline if this were due to renal leak, but in the setting of idiopathic hypercalciuria, no clinically meaningful change in PTH occurs. This lack of response of PTH to oral calcium load has been seen in both rat and human studies. Patients also excrete normal to high amounts of urine calcium after prolonged fasting or a low-calcium diet. Low-calcium diets do not induce hyperparathyroidism in these patients, and so the source of the elevated calcium in the urine must be primarily from bone. Increased levels of 1,25-dihydroxyvitamin D in patients with idiopathic hypercalciuria have been noted.^28,29

Whether the cytokine milieu also contributes to the calcitriol levels is unclear, but the high or high-normal plasma level of 1,25-dihydroxyvitamin D may be the reason that the PTH is unperturbed.

IMPACT ON BONE HEALTH

Nephrolithiasis is strongly linked to fracture risk.

The bone mineral density of trabecular bone is more affected by calcium excretion than that of cortical bone.^18,20,30 However, lumbar spine bone mineral density has not been consistently found to be lower in patients with hyperabsorptive hypercalciuria. Rather, bone mineral density is correlated inversely with urine calcium excretion in men and women who form stones, but not in patients without nephrolithiasis.

In children

In children, idiopathic hypercalciuria is well known to be linked to osteopenia. This is an important group to study, as adult idiopathic hypercalciuria often begins in childhood. However, the trajectory of bone loss vs gain in children is fraught with variables such as growth, puberty, and body mass index, making this a difficult group from which to extrapolate conclusions to adults.

In men

There is more information on the relationship between hypercalciuria and osteoporosis in men than in women.

In 1998, Melton et al³¹ published the findings of a 25-year population-based cohort study of 624 patients, 442 (71%) of whom were men, referred for new-onset urolithiasis. The incidence of vertebral fracture was 4 times higher in this group than in patients without stone disease, but there was no difference in the rate of hip, forearm, or nonvertebral fractures. This is consistent with earlier data that report a loss of predominantly cancellous bone associated with urolithiasis.

National Health and Nutrition Examination Survey III data in 2001 focused on a potential relationship between kidney stones and bone mineral density or prevalent spine or wrist fracture.³² More than 14,000 people had hip bone mineral density measurements, of whom 793 (477 men, 316 women) had kidney stones. Men with previous nephrolithiasis had lower femoral neck bone mineral density than those without. Men with kidney stones were also more likely to report prevalent wrist and spine fractures. In women, no difference was noted between those with or without stone disease with respect to femoral neck bone mineral density or fracture incidence.

Cauley et al³³ also evaluated a relationship between kidney stones and bone mineral density in the Osteoporotic Fractures in Men (MrOS) study. Of approximately 6,000 men, 13.2% reported a history of kidney stones. These men had lower spine and total hip bone mineral density than controls who had not had kidney stones, and the difference persisted after adjusting for age, race, weight, and other variables. However, further data from this cohort revealed that so few men with osteoporosis had hypercalciuria that its routine measurement was not recommended.³⁴

The relationship between idiopathic hypercalciuria and fractures has been more difficult to establish in women.

Sowers et al³⁵ performed an observational study of 1,309 women ages 20 to 92 with a history of nephrolithiasis. No association was noted between stone disease and reduced bone mineral density in the femoral neck, lumbar spine, or radius.

These epidemiologic studies did not include the cause of the kidney stones (eg, whether or not there was associated hypercalciuria or primary hyperparathyroidism), and typically a diagnosis of idiopathic hypercalciuria was not established.

The difference in association between low bone mineral density or fracture with nephrolithiasis between men and women is not well understood, but the most consistent hypothesis is that the influence of hypoestrogenemia in women is much stronger than that of the hypercalciuria.²⁰

Does the degree of hypercalciuria influence the amount of bone loss?

A few trials have tried to determine whether the amount of calcium in the urine influences the magnitude of bone loss.

In 2003, Asplin et al³⁶ reported that bone mineral density Z-scores differed significantly by urinary calcium excretion, but only in stone-formers. In patients without stone disease, there was no difference in Z-scores according to the absolute value of hypercalciuria. This may be due to a self-selection bias in which stone-formers avoid calcium in the diet and those without stone disease do not.

Three studies looking solely at men with idiopathic hypercalciuria also did not detect a significant difference in bone mineral loss according to degree of hypercalciuria.^20,30,37

A POLYGENIC DISORDER?

The potential contribution of genetic changes to the development of idiopathic hypercalciuria has been studied. While there is an increased risk of idiopathic hypercalciuria in first-degree relatives of patients with nephrolithiasis, most experts believe that idiopathic hypercalciuria is likely a polygenic disorder.^9,38

EVALUATION AND TREATMENT

The 2014 revised version of the National Osteoporosis Foundation’s “Clinician’s guide to prevention and treatment of osteoporosis”³⁹ noted that hypercalciuria is a risk factor that contributes to the development of osteoporosis and possibly osteoporotic fractures, and that consideration should be given to evaluating for hypercalciuria, but only in selected cases. In patients with kidney stones, the link between hypercalciuria and bone loss and fracture is recognized and should be explored in both women and men at risk of osteoporosis, as 45% to 50% of patients who form calcium stones have hypercalciuria.

Patients with kidney stones who have low bone mass and idiopathic hypercalciuria should increase their daily fluid intake, follow a low-salt and low-animal-protein diet, and take thiazide diuretics to reduce the incidence of further calcium stones. Whether this approach also improves bone mass and strength and reduces the risk of fractures within this cohort requires further study.

Dietary interventions

Don’t restrict calcium intake. Despite the connection between hypercalciuria and nephrolithiasis, restriction of dietary calcium to prevent relapse of nephrolithiasis is a risk factor for negative calcium balance and bone demineralization. Observational studies and prospective clinical trials have demonstrated an increased risk of stone formation with low calcium intake.^27,30 Nevertheless, this practice seems logical to many patients with kidney stones, and this process may independently contribute to lower bone mineral density.

A low-sodium, low-animal-protein diet is beneficial. Though increased intake of sodium or protein is not the main cause of idiopathic hypercalciuria, pharmacologic therapy, especially with thiazide diuretics, is more likely to be successful in the setting of a low-sodium, low-protein diet.

Borghi et al²⁷ studied 2 diets in men with nephrolithiasis and idiopathic hypercalciuria: a low-calcium diet and a low-salt, low-animal-protein, normal-calcium diet. Men on the latter diet experienced a greater reduction in urinary calcium excretion than those on the low-calcium diet.

Breslau et al⁴⁰ found that urinary calcium excretion fell by 50% in 15 people when they switched from an animal-based to a plant-based protein diet.

Thiazide diuretics

Several epidemiologic and randomized studies^41–45 found that thiazide therapy decreased the likelihood of hip fracture in postmenopausal women, men, and premenopausal women. Doses ranged from 12.5 to 50 mg of hydrochlorothiazide. Bone density increased in the radius, total body, total hip, and lumbar spine. One prospective trial noted that fracture risk declined with longer duration of thiazide use, with the largest reduction in those who used thiazides for 8 or more years.⁴⁶

Thiazides have anticalciuric actions.⁴⁷ In addition, they have positive effects on osteoblastic cell proliferation and activity, inhibiting osteocalcin expression by osteoblasts, thereby possibly improving bone formation and mineralization.⁴⁸ The effects of thiazides on bone was reviewed by Sakhaee et al.⁴⁹

However, fewer studies have looked at thiazides in patients with idiopathic hypercalciuria.

García-Nieto et al⁵⁰ looked retrospectively at 22 children (average age 11.7) with idiopathic hypercalciuria and osteopenia who had received thiazides (19 received chlorthalidone 25 mg daily, and 3 received hydrochlorothiazide 25 mg daily) for an average of 2.4 years, and at 32 similar patients who had not received thiazides. Twelve (55%) of the patients receiving thiazides had an improvement in bone mineral density Z-scores, compared with 23 (72%) of the controls. This finding is confounded by growth that occurred during the study, and both groups demonstrated a significantly increased body mass index and bone mineral apparent density at the end of the trial.

Bushinsky and Favus⁵¹ evaluated whether chlorthalidone improved bone quality or structure in rats that were genetically prone to hypercalciuric stones. These rats are uniformly stone-formers, and while they have components of calcium hyperabsorption, they also demonstrate renal hyperexcretion (leak) and enhanced bone mineral resorption.⁵¹ When fed a high-calcium diet, they maintain a reduction in bone mineral density and bone strength. Study rats were given chlorthalidone 4 to 5 mg/kg/day. After 18 weeks of therapy, significant improvements were observed in trabecular thickness and connectivity as well as increased vertebral compressive strength.⁵² No difference in cortical bone was noted.

No randomized, blinded, placebo-controlled trial has yet been done to study the impact of thiazides on bone mineral density or fracture risk in patients with idiopathic hypercalciuria.

In practice, many physicians choose chlorthali­done over hydrochlorothiazide because of chlorthalidone’s longer half-life. Combinations of a thiazide diuretic and potassium-sparing medications are also employed, such as hydrochlorothiazide plus either triamterene or spironolactone to reduce the number of pills the patient has to take.

When prescribing thiazide diuretics, one should also consider prescribing potassium citrate, as this agent not only prevents hypokalemia but also increases urinary citrate excretion, which can help to inhibit crystallization of calcium salts.⁶

In a longitudinal study of 28 patients with hypercalciuria,⁵³ combined therapy with a thiazide or indapamide and potassium citrate over a mean of 7 years increased bone density of the lumbar spine by 7.1% and of the femoral neck by 4.1%, compared with treatment in age- and sex-matched normocalcemic peers. In the same study, daily urinary calcium excretion decreased and urinary pH and citrate levels increased; urinary saturation of calcium oxalate decreased by 46%, and stone formation was decreased.

Another trial evaluated 120 patients with idiopathic calcium nephrolithiasis, half of whom were given potassium citrate. Those given potassium citrate experienced an increase in distal radius bone mineral density over 2 years.⁵⁴ It is theorized that alkalinization may decrease bone turnover in these patients.

Bisphosphonates

As one of the proposed main mechanisms of bone loss in idiopathic hypercalciuria is direct bone resorption, a potential target for therapy is the osteoclast, which bisphosphonates inhibit.

Ruml et al⁵⁵ studied the impact of alendronate vs placebo in 16 normal men undergoing 3 weeks of strict bedrest. Compared with the placebo group, those who received alendronate had significantly lower 24-hour urine calcium excretion and higher levels of PTH and 1,25-dihydroxyvitamin D.

Weisinger et al⁵⁶ evaluated the effects of alendronate 10 mg daily in 10 patients who had stone disease with documented idiopathic hypercalciuria and also in 8 normocalciuric patients without stone disease. Alendronate resulted in a sustained reduction of calcium in the urine in the patients with idiopathic hypercalciuria but not in the normocalciuric patients.

Data are somewhat scant as to the effect of bisphosphonates on bone health in the setting of idiopathic hypercalciuria,^57,58 and therapy with bisphosphonates is not recommended in patients with idiopathic hypercalciuria outside the realm of postmenopausal osteoporosis or other indications for bisphosphonates approved by the US Food and Drug Administration (FDA).

Calcimimetics

Calcium-sensing receptors are found not only in parathyroid tissue but also in the intestines and kidneys. Locally, elevated plasma calcium in the kidney causes activation of the calcium-sensing receptor, diminishing further calcium reabsorption.⁵⁹ Agents that increase the sensitivity of the calcium-sensing receptors are classified as calcimimetics.

Cinacalcet is a calcimimetic approved by the FDA for treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, for the treatment of hypercalcemia in patients with parathyroid carcinoma, and for patients with primary hyperpara­thyroidism who are unable to undergo parathyroidectomy. In an uncontrolled 5-year study of cinacalcet in patients with primary hyperparathyroidism, there was no significant change in bone density.⁶⁰

Anti-inflammatory drugs

The role of cytokines in stimulating bone resorption in idiopathic hypercalciuria has led to the investigation of several anti-inflammatory drugs (eg, diclofenac, indomethacin) as potential treatments, but studies have been limited in number and scope.^61,62

Omega-3 fatty acids

Omega-3 fatty acids are thought to alter prostaglandin metabolism and to potentially reduce stone formation.⁶³

A retrospective study of 29 patients with stone disease found that, combined with dietary counseling, omega-3 fatty acids could potentially reduce urinary calcium and oxalate excretion and increase urinary citrate in hypercalciuric stone-formers.⁶⁴

A review of published randomized controlled trials of omega-3 fatty acids in skeletal health discovered that 4 studies found positive effects on bone mineral density or bone turnover markers, whereas 5 studies reported no differences. All trials were small, and none evaluated fracture outcome.⁶⁵

For patients age 16 and older with advanced chronic kidney disease (CKD), including those undergoing hemodialysis, we recommend a higher dose of hepatitis B virus (HBV) vaccine, more doses, or both. Vaccination with a higher dose may improve the immune response. The hepatitis B surface antibody (anti-HBs) titer should be monitored 1 to 2 months after completion of the vaccination schedule and annually thereafter, with a target titer of 10 IU/mL or greater. For patients who do not develop a protective antibody titer after completing the initial vaccination schedule, the vaccination schedule should be repeated.

RECOMMENDED DOSES AND SCHEDULES

Recommendation 1

Give higher vaccine doses, increase the number of doses, or both.

Recommendation 2

A 4-dose regimen may provide a better antibody response than a 3-dose regimen. (Note: This recommendation applies only to Engerix-B; 4 doses of Recombivax-HB would be an off-label use.)

Rationale. The US Centers for Disease Control and Prevention reported that after completion of a 3-dose vaccination schedule, the median proportion of patients developing a protective antibody response was 64% (range 34%–88%) vs a median of 86% (range 40%–98%) after a 4-dose schedule.³

Lacson et al⁵ compared antibody response rates after 3 doses of Recombivax-HB and after 4 doses of Engerix-B and found a better response rate with the 4-dose schedule. The rate of persistent protective anti-HBs titer after 1 year was 77% for Engerix-B vs 53% for Recombivax-HB.

Agarwal et al⁶ evaluated response rates in patients who had mild CKD (serum creatinine levels 1.5–3.0 mg/dL), moderate CKD (creatinine 3.0–6.0 mg/dL), and severe CKD (creatinine > 6.0 mg/dL). The seroconversion rates after 3 doses of 40-μg HBV vaccine were 87.5% in those with mild CKD, 66.6% in those with moderate CKD, and 35.7% in those with severe disease. After a fourth dose, rates improved significantly to 100%, 77%, and 36.4%, respectively.

Recommendation 3

In patients with CKD, vaccination should be done early, before they become dependent on hemodialysis.

Rationale. Patients with advanced CKD may have a lower seroconversion rate. Fraser et al⁷ found that after a 4-dose series, the seroprotection rate in adult prehemodialysis patients with serum creatinine levels of 4 mg/dL or less was 86%, compared with 37% in patients with serum creatinine levels above 4 mg/dL, of whom 88% were on hemodialysis.⁷

In a 2003 prospective cohort study by DaRoza et al,⁸ patients with higher levels of kidney function were more likely to respond to HBV vaccination, and the level of kidney function was found to be an independent predictor of seroconversion.⁸

A 2012 prospective study by Ghadiani et al⁹ compared seroconversion rates in patients with stage 3 or 4 CKD vs patients on hemodialysis, with medical staff as controls. The authors reported seroprotection rates of 26.1% in patients on hemodialysis, 55.2% in patients with stage 3 or 4 CKD, and 96.2% in controls. They concluded that vaccination is more likely to induce seroconversion in earlier stages of kidney disease.⁹

Testing after vaccination is recommended to determine response. Testing should be done 1 to 2 months after the last dose of the vaccination schedule.^1–3 Anti-HBs levels 10 IU/mL and greater are considered protective.¹⁰

Revaccination with a full vaccination series is recommended for patients who do not develop adequate levels of protective antibodies after completion of the vaccination schedule.² Reported response rates to revaccination have varied from 40% to 50% after 2 or 3 additional intramuscular  doses of 40 µg, to 64% after 4 additional intramuscular doses of 10 µg.³ Serologic testing should be repeated after the last dose of the vaccination series, as serologic testing after only 1 or 2 additional doses appears to be no more cost-effective.^2,3

To the best of our knowledge, no data exist to indicate that in nonresponders, further doses given after completion of 2 full vaccination schedules would induce an antibody response.

ANTIBODY PERSISTENCE AND BOOSTER DOSES

Antibody levels fall with time in patients on hemodialysis. Limited data suggest that in patients who respond to the primary vaccination series, antibodies remain detectable for 6 months in 80% to 100% (median 100%) of patients and for 12 months in 58% to 100% (median 70%) of patients.³ The need for booster doses should be assessed by annual monitoring.^2,11 Booster doses should be given when the anti-HBs titer declines to below 10 IU/mL. Limited data indicate that nearly all such patients would respond to a booster dose.³

OTHER WAYS TO IMPROVE VACCINE RESPONSE

Other strategies to improve vaccine response, such as the addition of adjuvants or immunostimulants, have shown variable success.¹² Intradermal HBV vaccination in patients on chronic hemodialysis has also been proposed. The efficacy of intradermal vaccination may be related to the dense network of immunologic dendritic cells within the dermis. After intradermal administration, the antigen is taken up by dendritic cells residing in the dermis, which mature and travel to the regional lymph node where further immunostimulation takes place.¹³

In a systematic review of four prospective trials with a total of 204 hemodialysis patients,¹³ a significantly higher proportion of patients achieved seroconversion with intradermal HBV vaccine administration than with intramuscular administration. The authors concluded that the intradermal route in primary nonresponders undergoing hemodialysis provides an effective alternative to the intramuscular route to protect against HBV infection in this highly susceptible population.

Additional well-designed, double-blinded, randomized trials are needed to establish clear guidelines on intradermal HBV vaccine dosing and vaccination schedules.

For patients age 16 and older with advanced chronic kidney disease (CKD), including those undergoing hemodialysis, we recommend a higher dose of hepatitis B virus (HBV) vaccine, more doses, or both. Vaccination with a higher dose may improve the immune response. The hepatitis B surface antibody (anti-HBs) titer should be monitored 1 to 2 months after completion of the vaccination schedule and annually thereafter, with a target titer of 10 IU/mL or greater. For patients who do not develop a protective antibody titer after completing the initial vaccination schedule, the vaccination schedule should be repeated.

RECOMMENDED DOSES AND SCHEDULES

Recommendation 1

Give higher vaccine doses, increase the number of doses, or both.

Recommendation 2

A 4-dose regimen may provide a better antibody response than a 3-dose regimen. (Note: This recommendation applies only to Engerix-B; 4 doses of Recombivax-HB would be an off-label use.)

Rationale. The US Centers for Disease Control and Prevention reported that after completion of a 3-dose vaccination schedule, the median proportion of patients developing a protective antibody response was 64% (range 34%–88%) vs a median of 86% (range 40%–98%) after a 4-dose schedule.³

Lacson et al⁵ compared antibody response rates after 3 doses of Recombivax-HB and after 4 doses of Engerix-B and found a better response rate with the 4-dose schedule. The rate of persistent protective anti-HBs titer after 1 year was 77% for Engerix-B vs 53% for Recombivax-HB.

Agarwal et al⁶ evaluated response rates in patients who had mild CKD (serum creatinine levels 1.5–3.0 mg/dL), moderate CKD (creatinine 3.0–6.0 mg/dL), and severe CKD (creatinine > 6.0 mg/dL). The seroconversion rates after 3 doses of 40-μg HBV vaccine were 87.5% in those with mild CKD, 66.6% in those with moderate CKD, and 35.7% in those with severe disease. After a fourth dose, rates improved significantly to 100%, 77%, and 36.4%, respectively.

Recommendation 3

In patients with CKD, vaccination should be done early, before they become dependent on hemodialysis.

Rationale. Patients with advanced CKD may have a lower seroconversion rate. Fraser et al⁷ found that after a 4-dose series, the seroprotection rate in adult prehemodialysis patients with serum creatinine levels of 4 mg/dL or less was 86%, compared with 37% in patients with serum creatinine levels above 4 mg/dL, of whom 88% were on hemodialysis.⁷

In a 2003 prospective cohort study by DaRoza et al,⁸ patients with higher levels of kidney function were more likely to respond to HBV vaccination, and the level of kidney function was found to be an independent predictor of seroconversion.⁸

A 2012 prospective study by Ghadiani et al⁹ compared seroconversion rates in patients with stage 3 or 4 CKD vs patients on hemodialysis, with medical staff as controls. The authors reported seroprotection rates of 26.1% in patients on hemodialysis, 55.2% in patients with stage 3 or 4 CKD, and 96.2% in controls. They concluded that vaccination is more likely to induce seroconversion in earlier stages of kidney disease.⁹

Testing after vaccination is recommended to determine response. Testing should be done 1 to 2 months after the last dose of the vaccination schedule.^1–3 Anti-HBs levels 10 IU/mL and greater are considered protective.¹⁰

Revaccination with a full vaccination series is recommended for patients who do not develop adequate levels of protective antibodies after completion of the vaccination schedule.² Reported response rates to revaccination have varied from 40% to 50% after 2 or 3 additional intramuscular  doses of 40 µg, to 64% after 4 additional intramuscular doses of 10 µg.³ Serologic testing should be repeated after the last dose of the vaccination series, as serologic testing after only 1 or 2 additional doses appears to be no more cost-effective.^2,3

To the best of our knowledge, no data exist to indicate that in nonresponders, further doses given after completion of 2 full vaccination schedules would induce an antibody response.

ANTIBODY PERSISTENCE AND BOOSTER DOSES

Antibody levels fall with time in patients on hemodialysis. Limited data suggest that in patients who respond to the primary vaccination series, antibodies remain detectable for 6 months in 80% to 100% (median 100%) of patients and for 12 months in 58% to 100% (median 70%) of patients.³ The need for booster doses should be assessed by annual monitoring.^2,11 Booster doses should be given when the anti-HBs titer declines to below 10 IU/mL. Limited data indicate that nearly all such patients would respond to a booster dose.³

OTHER WAYS TO IMPROVE VACCINE RESPONSE

Other strategies to improve vaccine response, such as the addition of adjuvants or immunostimulants, have shown variable success.¹² Intradermal HBV vaccination in patients on chronic hemodialysis has also been proposed. The efficacy of intradermal vaccination may be related to the dense network of immunologic dendritic cells within the dermis. After intradermal administration, the antigen is taken up by dendritic cells residing in the dermis, which mature and travel to the regional lymph node where further immunostimulation takes place.¹³

In a systematic review of four prospective trials with a total of 204 hemodialysis patients,¹³ a significantly higher proportion of patients achieved seroconversion with intradermal HBV vaccine administration than with intramuscular administration. The authors concluded that the intradermal route in primary nonresponders undergoing hemodialysis provides an effective alternative to the intramuscular route to protect against HBV infection in this highly susceptible population.

Additional well-designed, double-blinded, randomized trials are needed to establish clear guidelines on intradermal HBV vaccine dosing and vaccination schedules.

For patients age 16 and older with advanced chronic kidney disease (CKD), including those undergoing hemodialysis, we recommend a higher dose of hepatitis B virus (HBV) vaccine, more doses, or both. Vaccination with a higher dose may improve the immune response. The hepatitis B surface antibody (anti-HBs) titer should be monitored 1 to 2 months after completion of the vaccination schedule and annually thereafter, with a target titer of 10 IU/mL or greater. For patients who do not develop a protective antibody titer after completing the initial vaccination schedule, the vaccination schedule should be repeated.

RECOMMENDED DOSES AND SCHEDULES

Recommendation 1

Give higher vaccine doses, increase the number of doses, or both.

Recommendation 2

A 4-dose regimen may provide a better antibody response than a 3-dose regimen. (Note: This recommendation applies only to Engerix-B; 4 doses of Recombivax-HB would be an off-label use.)

Rationale. The US Centers for Disease Control and Prevention reported that after completion of a 3-dose vaccination schedule, the median proportion of patients developing a protective antibody response was 64% (range 34%–88%) vs a median of 86% (range 40%–98%) after a 4-dose schedule.³

Lacson et al⁵ compared antibody response rates after 3 doses of Recombivax-HB and after 4 doses of Engerix-B and found a better response rate with the 4-dose schedule. The rate of persistent protective anti-HBs titer after 1 year was 77% for Engerix-B vs 53% for Recombivax-HB.

Agarwal et al⁶ evaluated response rates in patients who had mild CKD (serum creatinine levels 1.5–3.0 mg/dL), moderate CKD (creatinine 3.0–6.0 mg/dL), and severe CKD (creatinine > 6.0 mg/dL). The seroconversion rates after 3 doses of 40-μg HBV vaccine were 87.5% in those with mild CKD, 66.6% in those with moderate CKD, and 35.7% in those with severe disease. After a fourth dose, rates improved significantly to 100%, 77%, and 36.4%, respectively.

Recommendation 3

In patients with CKD, vaccination should be done early, before they become dependent on hemodialysis.

Rationale. Patients with advanced CKD may have a lower seroconversion rate. Fraser et al⁷ found that after a 4-dose series, the seroprotection rate in adult prehemodialysis patients with serum creatinine levels of 4 mg/dL or less was 86%, compared with 37% in patients with serum creatinine levels above 4 mg/dL, of whom 88% were on hemodialysis.⁷

In a 2003 prospective cohort study by DaRoza et al,⁸ patients with higher levels of kidney function were more likely to respond to HBV vaccination, and the level of kidney function was found to be an independent predictor of seroconversion.⁸

A 2012 prospective study by Ghadiani et al⁹ compared seroconversion rates in patients with stage 3 or 4 CKD vs patients on hemodialysis, with medical staff as controls. The authors reported seroprotection rates of 26.1% in patients on hemodialysis, 55.2% in patients with stage 3 or 4 CKD, and 96.2% in controls. They concluded that vaccination is more likely to induce seroconversion in earlier stages of kidney disease.⁹

Testing after vaccination is recommended to determine response. Testing should be done 1 to 2 months after the last dose of the vaccination schedule.^1–3 Anti-HBs levels 10 IU/mL and greater are considered protective.¹⁰

Revaccination with a full vaccination series is recommended for patients who do not develop adequate levels of protective antibodies after completion of the vaccination schedule.² Reported response rates to revaccination have varied from 40% to 50% after 2 or 3 additional intramuscular  doses of 40 µg, to 64% after 4 additional intramuscular doses of 10 µg.³ Serologic testing should be repeated after the last dose of the vaccination series, as serologic testing after only 1 or 2 additional doses appears to be no more cost-effective.^2,3

To the best of our knowledge, no data exist to indicate that in nonresponders, further doses given after completion of 2 full vaccination schedules would induce an antibody response.

ANTIBODY PERSISTENCE AND BOOSTER DOSES

Antibody levels fall with time in patients on hemodialysis. Limited data suggest that in patients who respond to the primary vaccination series, antibodies remain detectable for 6 months in 80% to 100% (median 100%) of patients and for 12 months in 58% to 100% (median 70%) of patients.³ The need for booster doses should be assessed by annual monitoring.^2,11 Booster doses should be given when the anti-HBs titer declines to below 10 IU/mL. Limited data indicate that nearly all such patients would respond to a booster dose.³

OTHER WAYS TO IMPROVE VACCINE RESPONSE

Other strategies to improve vaccine response, such as the addition of adjuvants or immunostimulants, have shown variable success.¹² Intradermal HBV vaccination in patients on chronic hemodialysis has also been proposed. The efficacy of intradermal vaccination may be related to the dense network of immunologic dendritic cells within the dermis. After intradermal administration, the antigen is taken up by dendritic cells residing in the dermis, which mature and travel to the regional lymph node where further immunostimulation takes place.¹³

In a systematic review of four prospective trials with a total of 204 hemodialysis patients,¹³ a significantly higher proportion of patients achieved seroconversion with intradermal HBV vaccine administration than with intramuscular administration. The authors concluded that the intradermal route in primary nonresponders undergoing hemodialysis provides an effective alternative to the intramuscular route to protect against HBV infection in this highly susceptible population.

Additional well-designed, double-blinded, randomized trials are needed to establish clear guidelines on intradermal HBV vaccine dosing and vaccination schedules.

Although rare, inadvertent placement of a pacemaker or defibrillator lead in the left ventricle can have serious consequences, including arterial thromboembolism and aortic or mitral valve damage or infection.^1–4

This article discusses situations in which lead malpositioning is likely to occur, how to prevent it, how to detect and correct it immediately, and how to manage cases discovered long after implantation.

RARE, BUT LIKELY UNDERREPORTED

In 2011, Rodriguez et al¹ reviewed 56 reported cases in which an endocardial lead had been mistakenly placed in the left ventricle. A few more cases have been reported since then, but some cases are not reported, so how often this occurs is unknown.

A large single-center retrospective study² reported a 3.4% incidence of inadvertent lead placement in the left side of the heart, including the cardiac veins.

HOW LEADS CAN END UP IN THE WRONG PLACE

Risk factors for lead malpositioning include abnormal thoracic anatomy, underlying congenital heart disease, and operator inexperience.²

Normally, in single- and double-lead systems, leads are inserted into a cephalic, subclavian, or axillary vein and advanced into the right atrium, right ventricle, or both. However, pacing, sensing, and defibrillation leads have inadvertently been placed in the left ventricular endocardium and even on the epicardial surface.

Leads can end up inside the left ventricle by passing through an unrecognized atrial septal defect, patent foramen ovale, or ventricular septal defect, or by perforating the interventricular septum. Another route into the left ventricle is by gaining vascular access through the axillary or subclavian artery and advancing the lead retrograde across the aortic valve.

Epicardial lead placement may result from perforating the right ventricle⁵ or inadvertent positioning within the main coronary sinus or in a cardiac vein.

PREVENTION IS THE BEST MANAGEMENT

The best way to manage lead malpositioning is to prevent it in the first place.

Make sure you are in a vein, not an artery! If you are working from the patient’s left side, you should see the guidewire cross the midline on fluoroscopy. Working from either the left or the right side, you can ensure that the guidewire is in the venous system by advancing it into the inferior vena cava and then all the way below the diaphragm (best seen on anteroposterior views). These observations help avoid lead placement in the left ventricle by an inadvertent retrograde aortic approach.

Suspect that you are taking the wrong route to the heart (ie, through the arterial system) if, in the anteroposterior view, the guidewire bends as it approaches the left spinal border. This sign suggests that you are going backwards through the ascending aorta and bumping up against the aortic cusps. Occasionally, the wire may pass through the aortic valve without resistance and bending. Additional advancement toward the left chest wall will make contact with the left ventricular endocardium and may result in ventricular ectopy. Placement in the left ventricle is best seen in the left anterior oblique projection; the lead will cross the spine or its distal end will point toward the spine in progressive projections from farther to the left.

Make sure you are in the right ventricle. Even if you have gone through the venous system, you are not home free. Advancing the lead into the right ventricular outflow tract (best seen in the right anterior oblique projection) is a key step in avoiding lead misplacement. In the right ventricular outflow tract, the lead tip should move freely; if it does not, it may be in the coronary sinus or middle cardiac vein. 

If a lead passes through a patent foramen ovale or septal defect to the left atrium, a left anterior oblique view should also demonstrate movement toward or beyond the spine. If the lead passes beyond the left heart border, a position in a pulmonary vein is possible. This is often associated with loss of a recordable intracardiac electrogram. A position in a right pulmonary vein is possible but very, very unlikely. If a lead passes through a patent foramen ovale or septal defect to the left ventricle, it will point toward the spine in left anterior oblique projections. (See “Postoperative detection by chest radiography.”)

Ventricular paced QRS complexes should show a left bundle branch pattern on electrocardiography (ECG), not a right bundle branch pattern (more about this below). However, when inserting a pacemaker, the sterile field includes the front of the chest and therefore lead V₁ is usually omitted, depriving the operator of valuable information.

Fortunately, operators may fluoroscopically view leads intended for the right ventricle in left anterior oblique projections. We recommend beginning at 40° left anterior oblique. In this view, septally positioned right ventricular leads may appear to abut the spine. A right ventricular position is confirmed in a steeper left anterior oblique projection, where the lead should be seen to be away from the spine.⁴

Careful evaluation of the 12-lead electrocardiogram during ventricular pacing is important for confirming correct lead placement. If ventricular pacing is absent, eg, if the device fires only if the natural heart rate drops below a set number and the heart happens to be firing on its own when you happen to be looking at it, programming the device to pace the right ventricle 10 beats per minute faster than the intrinsic heart rate usually suffices. Temporarily disabling atrial pacing and cardiac venous pacing in biventricular devices facilitates interpretation of the paced QRS complex.

Bundle branch block patterns

The typical morphology for paced events originating from the right ventricle has a left bundle branch block pattern, ie, a dominant S wave in leads V₁ and V₂.  Nevertheless, many patients with a safely placed lead in the right ventricle can also demonstrate right bundle branch morphology during pacing,⁶ ie, a dominant R wave in leads V₁ and V₂.

Reprinted from reference 6 with permission.

Klein et al⁷ reported on 8 patients who had features of right bundle branch block in leads V₁ and V₂ and noted that placing these leads 1 interspace lower eliminated the right bundle branch block appearance. The utility of this maneuver is demonstrated in Figure 1.

Almehairi et al⁸ demonstrated transition to a left bundle branch block-like pattern in V₁ in 14 of 26 patients after leads V₁ and V₂ were moved to the fifth intercostal space. Moving these leads to the sixth intercostal space produced a left bundle branch block-like pattern in all the remaining patients. Additional study is needed to validate this precordial mapping technique.⁹

Reprinted from reference 6 and reference 14 with permission.

Although the Coman and Trohman algorithm suggests that a frontal plane axis of −90° to –180° is specific for left ventricular pacing,⁶ other reports have identified this axis in the presence of true right ventricular pacing.^6,9–12 Therefore, Barold and Giudici⁹ argue that a frontal plane axis in the right superior quadrant has limited diagnostic value.

POSTOPERATIVE DETECTION BY CHEST RADIOGRAPHY

Adapted with permission from references 14 and 15.

A lead in the left ventricle may be a subtle finding on an anteroposterior or posteroanterior chest radiograph. The definitive view is the lateral projection, which is also true during intraoperative fluoroscopy.^13–15 The tip of a malpositioned left-ventricular lead is characteristically seen farther posterior (toward the spine) in the cardiac silhouette on the lateral view (Figure 3).² If the lead is properly positioned, the general direction of the middle to distal portion should be away from the spine.

ECHOCARDIOGRAPHY TO CONFIRM

Echocardiograms adapted with permission from reference 16; medical illustration by Joseph Pangrace.

Two-dimensional echocardiography can help to confirm left ventricular placement via an atrial septal defect, patent foramen ovale, or perforation of the interventricular septum.^16,17

Three-dimensional echocardiography can facilitate cardiac venous lead placement and assess the impact of right ventricular lead placement on tricuspid valve function.^18,19 In one case report, 3-dimensional echocardiography provided a definitive diagnosis of interventricular septal perforation when findings on computed tomography (CT) were indeterminate.²⁰

CT AND MRI: LIMITED ROLES

When echocardiographic findings are equivocal, CT can help diagnose lead perforation. Electrocardiogram-triggered cardiac CT can help visualize lead positions and potential lead perforation. Unfortunately, the precise location of the lead tip (and the diagnosis) can be missed due to streaking (“star”) artifacts and acoustic shadowing from the metallic lead.^21–26 Because of these limitations, as well as radiation exposure and high costs, CT should be used sparingly, if at all, for diagnosing lead malposition.

Technological advances and the increasing use of magnetic resonance imaging (MRI) in clinical practice have led to the development of “MRI-conditional” cardiac implantable electronic devices (ie, safe for undergoing MRI), as well as more lenient regulation of MRI in patients with nonconditional devices.^27,28 Although the widely held opinion that patients with a pacemaker or implantable cardioverter defibrillator are not eligible to undergo MRI has largely been abandoned, it seems unlikely that cardiac MRI will become a pivotal tool in assessing lead malposition.

Inadvertent left ventricular lead placement provides a nidus for thrombus formation. When inadvertent left ventricular lead malposition is identified acutely, correction of the lead position should be performed immediately by an experienced electrophysiologist.

Treatment of left ventricular lead misplacement discovered late after implantation includes lead removal or chronic anticoagulation with warfarin to prevent thromboemboli.

Long-term anticoagulation

No thromboembolic events have been reported² in patients with lead malposition who take warfarin and maintain an international normalized ratio of 2.5 to 3.5.

Antiplatelet agents are not enough by themselves.¹⁶

The use of direct oral anticoagulants has not been explored in this setting. Use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications compared with warfarin.²⁹ Based on these results and an overall lack of evidence, we do not recommend substituting a direct oral anticoagulant for warfarin in the setting of malpositioned left ventricular leads.

Late percutaneous removal

Late lead removal is most appropriate if cardiac surgery is planned for other reasons. Although percutaneous extraction of a malpositioned left ventricular lead was first described over 25 years ago,¹³ the safety of this procedure remains uncertain.

Kosmidou et al¹⁷ reported two cases of percutaneous removal of inadvertent transarterial leads employing standard interventional cardiology methods for cerebral embolic protection. Distal embolic filter wires were deployed in the left and right internal carotid arteries. A covered stent was deployed at the arterial entry site simultaneously with lead removal, providing immediate and effective hemostasis. Similar protection should be considered during transvenous access and extraction via an atrial septal or patent foramen ovale.

Nevertheless, not even transesophageal echocardiography can reliably exclude adhered thrombi, and the risk of embolization of fibrous adhesions or thrombi has been cited as a pivotal contraindication to percutaneous lead extraction regardless of modality.¹⁶

Although rare, inadvertent placement of a pacemaker or defibrillator lead in the left ventricle can have serious consequences, including arterial thromboembolism and aortic or mitral valve damage or infection.^1–4

This article discusses situations in which lead malpositioning is likely to occur, how to prevent it, how to detect and correct it immediately, and how to manage cases discovered long after implantation.

RARE, BUT LIKELY UNDERREPORTED

In 2011, Rodriguez et al¹ reviewed 56 reported cases in which an endocardial lead had been mistakenly placed in the left ventricle. A few more cases have been reported since then, but some cases are not reported, so how often this occurs is unknown.

A large single-center retrospective study² reported a 3.4% incidence of inadvertent lead placement in the left side of the heart, including the cardiac veins.

HOW LEADS CAN END UP IN THE WRONG PLACE

Risk factors for lead malpositioning include abnormal thoracic anatomy, underlying congenital heart disease, and operator inexperience.²

Normally, in single- and double-lead systems, leads are inserted into a cephalic, subclavian, or axillary vein and advanced into the right atrium, right ventricle, or both. However, pacing, sensing, and defibrillation leads have inadvertently been placed in the left ventricular endocardium and even on the epicardial surface.

Leads can end up inside the left ventricle by passing through an unrecognized atrial septal defect, patent foramen ovale, or ventricular septal defect, or by perforating the interventricular septum. Another route into the left ventricle is by gaining vascular access through the axillary or subclavian artery and advancing the lead retrograde across the aortic valve.

Epicardial lead placement may result from perforating the right ventricle⁵ or inadvertent positioning within the main coronary sinus or in a cardiac vein.

PREVENTION IS THE BEST MANAGEMENT

The best way to manage lead malpositioning is to prevent it in the first place.

Make sure you are in a vein, not an artery! If you are working from the patient’s left side, you should see the guidewire cross the midline on fluoroscopy. Working from either the left or the right side, you can ensure that the guidewire is in the venous system by advancing it into the inferior vena cava and then all the way below the diaphragm (best seen on anteroposterior views). These observations help avoid lead placement in the left ventricle by an inadvertent retrograde aortic approach.

Suspect that you are taking the wrong route to the heart (ie, through the arterial system) if, in the anteroposterior view, the guidewire bends as it approaches the left spinal border. This sign suggests that you are going backwards through the ascending aorta and bumping up against the aortic cusps. Occasionally, the wire may pass through the aortic valve without resistance and bending. Additional advancement toward the left chest wall will make contact with the left ventricular endocardium and may result in ventricular ectopy. Placement in the left ventricle is best seen in the left anterior oblique projection; the lead will cross the spine or its distal end will point toward the spine in progressive projections from farther to the left.

Make sure you are in the right ventricle. Even if you have gone through the venous system, you are not home free. Advancing the lead into the right ventricular outflow tract (best seen in the right anterior oblique projection) is a key step in avoiding lead misplacement. In the right ventricular outflow tract, the lead tip should move freely; if it does not, it may be in the coronary sinus or middle cardiac vein. 

If a lead passes through a patent foramen ovale or septal defect to the left atrium, a left anterior oblique view should also demonstrate movement toward or beyond the spine. If the lead passes beyond the left heart border, a position in a pulmonary vein is possible. This is often associated with loss of a recordable intracardiac electrogram. A position in a right pulmonary vein is possible but very, very unlikely. If a lead passes through a patent foramen ovale or septal defect to the left ventricle, it will point toward the spine in left anterior oblique projections. (See “Postoperative detection by chest radiography.”)

Ventricular paced QRS complexes should show a left bundle branch pattern on electrocardiography (ECG), not a right bundle branch pattern (more about this below). However, when inserting a pacemaker, the sterile field includes the front of the chest and therefore lead V₁ is usually omitted, depriving the operator of valuable information.

Fortunately, operators may fluoroscopically view leads intended for the right ventricle in left anterior oblique projections. We recommend beginning at 40° left anterior oblique. In this view, septally positioned right ventricular leads may appear to abut the spine. A right ventricular position is confirmed in a steeper left anterior oblique projection, where the lead should be seen to be away from the spine.⁴

Careful evaluation of the 12-lead electrocardiogram during ventricular pacing is important for confirming correct lead placement. If ventricular pacing is absent, eg, if the device fires only if the natural heart rate drops below a set number and the heart happens to be firing on its own when you happen to be looking at it, programming the device to pace the right ventricle 10 beats per minute faster than the intrinsic heart rate usually suffices. Temporarily disabling atrial pacing and cardiac venous pacing in biventricular devices facilitates interpretation of the paced QRS complex.

Bundle branch block patterns

The typical morphology for paced events originating from the right ventricle has a left bundle branch block pattern, ie, a dominant S wave in leads V₁ and V₂.  Nevertheless, many patients with a safely placed lead in the right ventricle can also demonstrate right bundle branch morphology during pacing,⁶ ie, a dominant R wave in leads V₁ and V₂.

Reprinted from reference 6 with permission.

Klein et al⁷ reported on 8 patients who had features of right bundle branch block in leads V₁ and V₂ and noted that placing these leads 1 interspace lower eliminated the right bundle branch block appearance. The utility of this maneuver is demonstrated in Figure 1.

Almehairi et al⁸ demonstrated transition to a left bundle branch block-like pattern in V₁ in 14 of 26 patients after leads V₁ and V₂ were moved to the fifth intercostal space. Moving these leads to the sixth intercostal space produced a left bundle branch block-like pattern in all the remaining patients. Additional study is needed to validate this precordial mapping technique.⁹

Reprinted from reference 6 and reference 14 with permission.

Although the Coman and Trohman algorithm suggests that a frontal plane axis of −90° to –180° is specific for left ventricular pacing,⁶ other reports have identified this axis in the presence of true right ventricular pacing.^6,9–12 Therefore, Barold and Giudici⁹ argue that a frontal plane axis in the right superior quadrant has limited diagnostic value.

POSTOPERATIVE DETECTION BY CHEST RADIOGRAPHY

Adapted with permission from references 14 and 15.

A lead in the left ventricle may be a subtle finding on an anteroposterior or posteroanterior chest radiograph. The definitive view is the lateral projection, which is also true during intraoperative fluoroscopy.^13–15 The tip of a malpositioned left-ventricular lead is characteristically seen farther posterior (toward the spine) in the cardiac silhouette on the lateral view (Figure 3).² If the lead is properly positioned, the general direction of the middle to distal portion should be away from the spine.

ECHOCARDIOGRAPHY TO CONFIRM

Echocardiograms adapted with permission from reference 16; medical illustration by Joseph Pangrace.

Two-dimensional echocardiography can help to confirm left ventricular placement via an atrial septal defect, patent foramen ovale, or perforation of the interventricular septum.^16,17

Three-dimensional echocardiography can facilitate cardiac venous lead placement and assess the impact of right ventricular lead placement on tricuspid valve function.^18,19 In one case report, 3-dimensional echocardiography provided a definitive diagnosis of interventricular septal perforation when findings on computed tomography (CT) were indeterminate.²⁰

CT AND MRI: LIMITED ROLES

When echocardiographic findings are equivocal, CT can help diagnose lead perforation. Electrocardiogram-triggered cardiac CT can help visualize lead positions and potential lead perforation. Unfortunately, the precise location of the lead tip (and the diagnosis) can be missed due to streaking (“star”) artifacts and acoustic shadowing from the metallic lead.^21–26 Because of these limitations, as well as radiation exposure and high costs, CT should be used sparingly, if at all, for diagnosing lead malposition.

Technological advances and the increasing use of magnetic resonance imaging (MRI) in clinical practice have led to the development of “MRI-conditional” cardiac implantable electronic devices (ie, safe for undergoing MRI), as well as more lenient regulation of MRI in patients with nonconditional devices.^27,28 Although the widely held opinion that patients with a pacemaker or implantable cardioverter defibrillator are not eligible to undergo MRI has largely been abandoned, it seems unlikely that cardiac MRI will become a pivotal tool in assessing lead malposition.

Inadvertent left ventricular lead placement provides a nidus for thrombus formation. When inadvertent left ventricular lead malposition is identified acutely, correction of the lead position should be performed immediately by an experienced electrophysiologist.

Treatment of left ventricular lead misplacement discovered late after implantation includes lead removal or chronic anticoagulation with warfarin to prevent thromboemboli.

Long-term anticoagulation

No thromboembolic events have been reported² in patients with lead malposition who take warfarin and maintain an international normalized ratio of 2.5 to 3.5.

Antiplatelet agents are not enough by themselves.¹⁶

The use of direct oral anticoagulants has not been explored in this setting. Use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications compared with warfarin.²⁹ Based on these results and an overall lack of evidence, we do not recommend substituting a direct oral anticoagulant for warfarin in the setting of malpositioned left ventricular leads.

Late percutaneous removal

Late lead removal is most appropriate if cardiac surgery is planned for other reasons. Although percutaneous extraction of a malpositioned left ventricular lead was first described over 25 years ago,¹³ the safety of this procedure remains uncertain.

Kosmidou et al¹⁷ reported two cases of percutaneous removal of inadvertent transarterial leads employing standard interventional cardiology methods for cerebral embolic protection. Distal embolic filter wires were deployed in the left and right internal carotid arteries. A covered stent was deployed at the arterial entry site simultaneously with lead removal, providing immediate and effective hemostasis. Similar protection should be considered during transvenous access and extraction via an atrial septal or patent foramen ovale.

Nevertheless, not even transesophageal echocardiography can reliably exclude adhered thrombi, and the risk of embolization of fibrous adhesions or thrombi has been cited as a pivotal contraindication to percutaneous lead extraction regardless of modality.¹⁶

Although rare, inadvertent placement of a pacemaker or defibrillator lead in the left ventricle can have serious consequences, including arterial thromboembolism and aortic or mitral valve damage or infection.^1–4

This article discusses situations in which lead malpositioning is likely to occur, how to prevent it, how to detect and correct it immediately, and how to manage cases discovered long after implantation.

RARE, BUT LIKELY UNDERREPORTED

In 2011, Rodriguez et al¹ reviewed 56 reported cases in which an endocardial lead had been mistakenly placed in the left ventricle. A few more cases have been reported since then, but some cases are not reported, so how often this occurs is unknown.

A large single-center retrospective study² reported a 3.4% incidence of inadvertent lead placement in the left side of the heart, including the cardiac veins.

HOW LEADS CAN END UP IN THE WRONG PLACE

Risk factors for lead malpositioning include abnormal thoracic anatomy, underlying congenital heart disease, and operator inexperience.²

Normally, in single- and double-lead systems, leads are inserted into a cephalic, subclavian, or axillary vein and advanced into the right atrium, right ventricle, or both. However, pacing, sensing, and defibrillation leads have inadvertently been placed in the left ventricular endocardium and even on the epicardial surface.

Leads can end up inside the left ventricle by passing through an unrecognized atrial septal defect, patent foramen ovale, or ventricular septal defect, or by perforating the interventricular septum. Another route into the left ventricle is by gaining vascular access through the axillary or subclavian artery and advancing the lead retrograde across the aortic valve.

Epicardial lead placement may result from perforating the right ventricle⁵ or inadvertent positioning within the main coronary sinus or in a cardiac vein.

PREVENTION IS THE BEST MANAGEMENT

The best way to manage lead malpositioning is to prevent it in the first place.

Make sure you are in a vein, not an artery! If you are working from the patient’s left side, you should see the guidewire cross the midline on fluoroscopy. Working from either the left or the right side, you can ensure that the guidewire is in the venous system by advancing it into the inferior vena cava and then all the way below the diaphragm (best seen on anteroposterior views). These observations help avoid lead placement in the left ventricle by an inadvertent retrograde aortic approach.

Suspect that you are taking the wrong route to the heart (ie, through the arterial system) if, in the anteroposterior view, the guidewire bends as it approaches the left spinal border. This sign suggests that you are going backwards through the ascending aorta and bumping up against the aortic cusps. Occasionally, the wire may pass through the aortic valve without resistance and bending. Additional advancement toward the left chest wall will make contact with the left ventricular endocardium and may result in ventricular ectopy. Placement in the left ventricle is best seen in the left anterior oblique projection; the lead will cross the spine or its distal end will point toward the spine in progressive projections from farther to the left.

Make sure you are in the right ventricle. Even if you have gone through the venous system, you are not home free. Advancing the lead into the right ventricular outflow tract (best seen in the right anterior oblique projection) is a key step in avoiding lead misplacement. In the right ventricular outflow tract, the lead tip should move freely; if it does not, it may be in the coronary sinus or middle cardiac vein. 

If a lead passes through a patent foramen ovale or septal defect to the left atrium, a left anterior oblique view should also demonstrate movement toward or beyond the spine. If the lead passes beyond the left heart border, a position in a pulmonary vein is possible. This is often associated with loss of a recordable intracardiac electrogram. A position in a right pulmonary vein is possible but very, very unlikely. If a lead passes through a patent foramen ovale or septal defect to the left ventricle, it will point toward the spine in left anterior oblique projections. (See “Postoperative detection by chest radiography.”)

Ventricular paced QRS complexes should show a left bundle branch pattern on electrocardiography (ECG), not a right bundle branch pattern (more about this below). However, when inserting a pacemaker, the sterile field includes the front of the chest and therefore lead V₁ is usually omitted, depriving the operator of valuable information.

Fortunately, operators may fluoroscopically view leads intended for the right ventricle in left anterior oblique projections. We recommend beginning at 40° left anterior oblique. In this view, septally positioned right ventricular leads may appear to abut the spine. A right ventricular position is confirmed in a steeper left anterior oblique projection, where the lead should be seen to be away from the spine.⁴

Careful evaluation of the 12-lead electrocardiogram during ventricular pacing is important for confirming correct lead placement. If ventricular pacing is absent, eg, if the device fires only if the natural heart rate drops below a set number and the heart happens to be firing on its own when you happen to be looking at it, programming the device to pace the right ventricle 10 beats per minute faster than the intrinsic heart rate usually suffices. Temporarily disabling atrial pacing and cardiac venous pacing in biventricular devices facilitates interpretation of the paced QRS complex.

Bundle branch block patterns

The typical morphology for paced events originating from the right ventricle has a left bundle branch block pattern, ie, a dominant S wave in leads V₁ and V₂.  Nevertheless, many patients with a safely placed lead in the right ventricle can also demonstrate right bundle branch morphology during pacing,⁶ ie, a dominant R wave in leads V₁ and V₂.

Reprinted from reference 6 with permission.

Klein et al⁷ reported on 8 patients who had features of right bundle branch block in leads V₁ and V₂ and noted that placing these leads 1 interspace lower eliminated the right bundle branch block appearance. The utility of this maneuver is demonstrated in Figure 1.

Almehairi et al⁸ demonstrated transition to a left bundle branch block-like pattern in V₁ in 14 of 26 patients after leads V₁ and V₂ were moved to the fifth intercostal space. Moving these leads to the sixth intercostal space produced a left bundle branch block-like pattern in all the remaining patients. Additional study is needed to validate this precordial mapping technique.⁹

Reprinted from reference 6 and reference 14 with permission.

Although the Coman and Trohman algorithm suggests that a frontal plane axis of −90° to –180° is specific for left ventricular pacing,⁶ other reports have identified this axis in the presence of true right ventricular pacing.^6,9–12 Therefore, Barold and Giudici⁹ argue that a frontal plane axis in the right superior quadrant has limited diagnostic value.

POSTOPERATIVE DETECTION BY CHEST RADIOGRAPHY

Adapted with permission from references 14 and 15.

A lead in the left ventricle may be a subtle finding on an anteroposterior or posteroanterior chest radiograph. The definitive view is the lateral projection, which is also true during intraoperative fluoroscopy.^13–15 The tip of a malpositioned left-ventricular lead is characteristically seen farther posterior (toward the spine) in the cardiac silhouette on the lateral view (Figure 3).² If the lead is properly positioned, the general direction of the middle to distal portion should be away from the spine.

ECHOCARDIOGRAPHY TO CONFIRM

Echocardiograms adapted with permission from reference 16; medical illustration by Joseph Pangrace.

Two-dimensional echocardiography can help to confirm left ventricular placement via an atrial septal defect, patent foramen ovale, or perforation of the interventricular septum.^16,17

Three-dimensional echocardiography can facilitate cardiac venous lead placement and assess the impact of right ventricular lead placement on tricuspid valve function.^18,19 In one case report, 3-dimensional echocardiography provided a definitive diagnosis of interventricular septal perforation when findings on computed tomography (CT) were indeterminate.²⁰

CT AND MRI: LIMITED ROLES

When echocardiographic findings are equivocal, CT can help diagnose lead perforation. Electrocardiogram-triggered cardiac CT can help visualize lead positions and potential lead perforation. Unfortunately, the precise location of the lead tip (and the diagnosis) can be missed due to streaking (“star”) artifacts and acoustic shadowing from the metallic lead.^21–26 Because of these limitations, as well as radiation exposure and high costs, CT should be used sparingly, if at all, for diagnosing lead malposition.

Technological advances and the increasing use of magnetic resonance imaging (MRI) in clinical practice have led to the development of “MRI-conditional” cardiac implantable electronic devices (ie, safe for undergoing MRI), as well as more lenient regulation of MRI in patients with nonconditional devices.^27,28 Although the widely held opinion that patients with a pacemaker or implantable cardioverter defibrillator are not eligible to undergo MRI has largely been abandoned, it seems unlikely that cardiac MRI will become a pivotal tool in assessing lead malposition.

Inadvertent left ventricular lead placement provides a nidus for thrombus formation. When inadvertent left ventricular lead malposition is identified acutely, correction of the lead position should be performed immediately by an experienced electrophysiologist.

Treatment of left ventricular lead misplacement discovered late after implantation includes lead removal or chronic anticoagulation with warfarin to prevent thromboemboli.

Long-term anticoagulation

No thromboembolic events have been reported² in patients with lead malposition who take warfarin and maintain an international normalized ratio of 2.5 to 3.5.

Antiplatelet agents are not enough by themselves.¹⁶

The use of direct oral anticoagulants has not been explored in this setting. Use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications compared with warfarin.²⁹ Based on these results and an overall lack of evidence, we do not recommend substituting a direct oral anticoagulant for warfarin in the setting of malpositioned left ventricular leads.

Late percutaneous removal

Late lead removal is most appropriate if cardiac surgery is planned for other reasons. Although percutaneous extraction of a malpositioned left ventricular lead was first described over 25 years ago,¹³ the safety of this procedure remains uncertain.

Kosmidou et al¹⁷ reported two cases of percutaneous removal of inadvertent transarterial leads employing standard interventional cardiology methods for cerebral embolic protection. Distal embolic filter wires were deployed in the left and right internal carotid arteries. A covered stent was deployed at the arterial entry site simultaneously with lead removal, providing immediate and effective hemostasis. Similar protection should be considered during transvenous access and extraction via an atrial septal or patent foramen ovale.

Nevertheless, not even transesophageal echocardiography can reliably exclude adhered thrombi, and the risk of embolization of fibrous adhesions or thrombi has been cited as a pivotal contraindication to percutaneous lead extraction regardless of modality.¹⁶

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Dr. Cosgrove took the leadership reins of the Clinic in 2004, the same year Dr. Mihaljevic joined the Department of Cardiothoracic Surgery. Under Dr. Cosgrove’s leadership the Clinic has grown in size, scope of practice, and international impact. His support of education has contributed enormously to the maturation of the Cleveland Clinic Lerner College of Medicine, the continued successes of our sizeable postgraduate education training program, and many other activities including our CME Center and the Cleveland Clinic Journal of Medicine. His willingness to recognize and continue to subsidize the Journal as an educational vehicle, with no direct marketing intent, has permitted the Journal to thrive in the international medical education space as a leading purveyor of sound, practical, evidence-based medical information. I speak for our editorial staff, authors, and readers when I say, “Thank you, Toby, for your support, trust, and belief in our educational mission.”

Dr. Mihaljevic is also a notable cardiothoracic surgeon, widely recognized for his skills and expertise in innovative minimally invasive and robotic-assisted cardiac valve surgery. He has returned to our Cleveland campus after several years as CEO of Cleveland Clinic Abu Dhabi. We welcome him back in his new role.

As Cleveland Clinic leadership undergoes an expected smooth transition, healthcare in the United States seems perpetually stuck trying to balance the response to a plethora of scientific and clinical advances, the rapid technologic changes in healthcare delivery systems, the cost-profit distribution within and external to expanding healthcare systems, and divergent social and political pressures. Advances in molecular medicine are changing the diagnosis and therapy of cancers and inflammatory diseases. Personalized precision medicine is evolving from the abstract to the tangible. Surgical advances on a true macro scale are leading to deliverable, effective treatments of the metabolic manifestations of diabetes, while microscopic, intravascular, and minimally invasive approaches are transforming the management of patients with structural and infiltrative disease. Understanding of the microbiome may well lead to better management of cardiovascular and inflammatory diseases. There have been advances in tissue scaffolding as well as gene and cell replacement techniques that may soon transform the therapy of several diseases. These advances provide cause for intellectual and clinical enthusiasm.

And yet, the environment in which we live and practice is increasingly divided and divisive socially and politically. Medicine has lost much of its luster. Burnout and early retirement are adversely affecting the physician workforce. The current model of financial support for medical education in the United States is being reevaluated, without a clear effective alternative. Costs of healthcare are rising at unsustainable rates, and swathes of our vulnerable, elderly, and young middle-class population are faced with serious challenges in getting and maintaining medical care because it is inaccessible and unaffordable. Even for patients of comfortable financial means, acquiring health insurance is not an activity for the weak of heart (and that weakness might be interpreted in the future as a pre-existing condition).

Who will pay for the exciting innovations I noted above, and who will deliver them? As reimbursement is shrinking, the time demands for physician electronic charting and communications with insurance companies are increasing. More physicians are employed and controlled by healthcare systems. How many will have the time and updated knowledge to discuss the appropriateness and clinical implications of these therapies between the phone calls begging for insurance company approval of coverage and payment?

As corporate taxes appear on the brink of being reduced, we can hope that this corporate financial benefit will translate to reduced drug and device costs and more affordable insurance for our more vulnerable populations. But this is not certain.

I have concerns as to how clinical science and healthcare delivery can move forward in an environment in which federal directives now prohibit our most respected federal research agencies from using such terms as “vulnerable” (populations) and “evidence-based” to justify their proposals for budgetary support for their ongoing work in population disease health and disease management.¹ Even a short time spent in the hallways or emergency rooms of any of our safety-net hospitals reveals the strain that acute and chronic illness is imposing on the social fabric of families, society, and the often underfunded infrastructure of this aspect of our healthcare system. Who will be in the position to empathetically and objectively assess the value of translating these ongoing efforts in discovery to implementation?

Basic stem cell and genetic research is also under ongoing scrutiny. There remains legitimate fear that ultimate policy decisions will not be made by fully informed scientists and ethicists. The ongoing “dialogue” in the United States around climate change and global warming does not give me confidence that our current government policy-makers are up to the task of objectively dealing with these more nuanced and emotionally charged issues, particularly while avoiding the expression of any evidence-based rationales.

In 2016, the world lost the iconic musical poet Leonard Cohen. Hopefully, he got it right when he wrote:

Ring the bells that still can ring
Forget your perfect offering
There is a crack in everything
That’s how the light gets in
—“Anthem”; 1992

I and the rest of our editorial team wish you, our readers, a healthy and peaceful 2018. I am optimistic that we can all find or create at least some light.

Emergency departments are not primary care clinics, but some patients use them that way. This relatively small group of patients consumes a disproportionate share of healthcare at great cost, earning them the label of “high users.” Mostly poor and often burdened with mental illness and addiction, they are not necessarily sicker than other patients, and they do not enjoy better outcomes from the extra money spent on them. (Another subset of high users, those with end-stage chronic disease, is outside the scope of this review.)

Herein lies an opportunity. If—and this is a big if—we could manage their care in a systematic way instead of haphazardly, proactively instead of reactively, with continuity of care instead of episodically, and in a way that is convenient for the patient, we might be able to improve quality and save money.

A DISPROPORTIONATE SHARE OF COSTS

In the United States in 2012, the 5% of the population who were the highest users were responsible for 50% of healthcare costs.¹ The mean cost per person in this group was more than $43,000 annually. The top 1% of users accounted for nearly 23% of all expenditures, averaging nearly $98,000 per patient per year—10 times more than the average yearly cost per patient.

CARE IS OFTEN INAPPROPRIATE AND UNNECESSARY

In addition to being disproportionately expensive, the care that these patients receive is often inappropriate and unnecessary for the severity of their disease.

A 2007–2009 study² of 1,969 patients who had visited the emergency department 10 or more times in a year found they received more than twice as many computed tomography (CT) scans as a control group of infrequent users (< 3 visits/year). This occurred even though they were not as sick as infrequent users, based on significantly lower hospital admission rates (11.1% vs 17.9%; P < .001) and mortality rates (0.7% vs 1.5%; P < .002).²

This inverse relationship between emergency department use and illness severity was even more exaggerated at the upper extreme of the use curve. The highest users (> 29 visits to the emergency department in a year) had the lowest triage acuity and hospital admission rates but the highest number of CT scans. Charges per visit were lower among frequent users, but total charges rose steadily with increasing emergency department use, accounting for significantly more costs per year.²

We believe that one reason these patients receive more medical care than necessary is because their medical records are too large and complex for the average physician to distill effectively in a 20-minute physician-patient encounter. Physicians therefore simply order more tests, procedures, and admissions, which are often medically unnecessary and redundant.

WHAT DRIVES HIGH COST?

Mental illness and chemical dependence

Drug addiction, mental illness, and poverty frequently accompany (and influence) high-use behavior, particularly in patients without end-stage diseases.

Szekendi et al,³ in a study of 28,291 patients who had been admitted at least 5 times in a year in a Chicago health system, found that these high users were 2 to 3 times more likely to suffer from comorbid depression (40% vs 13%), psychosis (18% vs 5%), recreational drug dependence (20% vs 7%), and alcohol abuse (16% vs 7%) than non-high-use hospitalized patients.³

Mercer et al⁴ conducted a study at Duke University Medical Center, Durham, NC, aimed at reducing emergency department visits and hospital admissions among 24 of its highest users. They found that 23 (96%) were either addicted to drugs or mentally ill, and 20 (83%) suffered from chronic pain.⁴

Drug abuse among high users is becoming even more relevant as the opioid epidemic worsens. Given that most patients requiring high levels of care suffer from chronic pain and many of them develop an opioid addiction while treating their pain, physicians have a moral imperative to reduce the prevalence of drug abuse in this population.

Low socioeconomic status

Low socioeconomic status is an important factor among high users, as it is highly associated with greater disease severity, which usually increases cost without any guarantee of an associated increase in quality. Data suggest that patients of low socioeconomic status are twice as likely to require urgent emergency department visits, 4 times as likely to require admission to the hospital, and, importantly, about half as likely to use ambulatory care compared with patients of higher socioeconomic status.⁵ While this pattern of low-quality, high-cost spending in acute care settings reflects spending in the healthcare system at large, the pattern is greatly exaggerated among high users.

Lost to follow-up

Low socioeconomic status also complicates communication and follow-up. In a 2013 study, physician researchers in St. Paul, MN, documented attempts to interview 64 recently discharged high users. They could not reach 47 (73%) of them, for reasons largely attributable to low socioeconomic status, such as disconnected phone lines and changes in address.⁶

Clearly, the usual contact methods for follow-up care after discharge, such as phone calls and mailings, are unlikely to be effective in coordinating the outpatient care of these individuals.

Additionally, we must find ways of making primary care more convenient, gaining our patients’ trust, and finding ways to engage patients in follow-up without relying on traditional means of communication.

Do high users have medical insurance?

Surprisingly, most high users of the emergency department have health insurance. The Chicago health system study³ found that most (72.4%) of their high users had either Medicare or private health insurance, while 27.6% had either Medicaid or no insurance (compared with 21.6% in the general population). Other studies also found that most of the frequent emergency department users are insured,⁷ although the overall percentage who rely on publicly paid insurance is greater than in the population at large.

Many prefer acute care over primary care

Although one might think that high users go to the emergency department because they have nowhere else to go for care, a report published in 2013 by Kangovi et al⁵ suggests another reason—they prefer the emergency department.⁵ They interviewed 40 urban patients of low socioeconomic status who consistently cited the 24-hour, no-appointment-necessary structure of the emergency department as an advantage over primary care. The flexibility of emergency access to healthcare makes sense if one reflects on how difficult it is for even high-functioning individuals to schedule and keep medical appointments.

Specific reasons for preferring the emergency department included the following:

Affordability. Even if their insurance fully paid for visits to their primary care physicians, the primary care physician was likely to refer them to specialists, whose visits required a copay, and which required taking another day off of work. The emergency department is cheaper for the patient and it is a “one-stop shop.” Patients appreciated the emergency department guarantee of seeing a physician regardless of proof of insurance, a policy not guaranteed in primary care and specialist offices.

Accessibility. For those without a car, public transportation and even patient transportation services are inconvenient and unreliable, whereas emergency medical services will take you to the emergency department.

Accommodations. Although medical centers may tout their same-day appointments, often same-day appointments are all that they have—and you have no choice about the time. You have to call first thing in the morning and stay on hold for a long time, and then when you finally get through, all the same-day appointments are gone.

Availability. Patients said they often had a hard time getting timely medical advice from their primary care physicians. When they could get through to their primary care physicians on the phone, they would be told to go to the emergency department.

Acceptability. Men, especially, feel they need to be very sick indeed to seek medical care, so going to the emergency department is more acceptable.

Trust in the provider. For reasons that were not entirely clear, patients felt that acute care providers were more trustworthy, competent, and compassionate than primary care physicians.⁵

None of these reasons for using the emergency department has anything to do with disease severity, which supports the findings that high users of the emergency department were not as sick as their normal-use peers.²

QUALITY IMPROVEMENT AND COST-REDUCTION STRATEGIES

Efforts are being made to reduce the cost of healthcare for high users while improving the quality of their care. Promising strategies focus on coordinating care management, creating individualized patient care plans, and improving the components and instructions of discharge summaries.

Care management organizations

A care management organization (CMO) model has emerged as a strategy for quality improvement and cost reduction in the high-use population. In this model, social workers, health coaches, nurses, mid-level providers, and physicians collaborate on designing individualized care plans to meet the specific needs of patients.

Teams typically work in stepwise fashion, first identifying and engaging patients at high risk of poor outcomes and unnecessary care, often using sophisticated quantitative, risk-prediction tools. Then, they perform health assessments and identify potential interventions aimed at preventing expensive acute-care medical interventions. Third, they work with patients to rapidly identify and effectively respond to changes in their conditions and direct them to the most appropriate medical setting, typically primary or urgent care.

Effective models

In 1998, the Camden (NJ) Coalition of Healthcare Providers established a model for CMO care plans. Starting with the first 36 patients enrolled in the program, hospital admissions and emergency department visits were cut by 47% (from 62 to 37 per month), and collective hospital costs were cut by 56% (from $1.2 million to about $500,000 per month).⁸ It should be noted that this was a small, nonrandomized study and these preliminary numbers did not take into account the cost of outpatient physician visits or new medications. Thus, how much money this program actually saves is not clear.

Similar programs have had similar results. A nurse-led care coordination program in Doylestown, PA, showed an impressive 25% reduction in annual mortality and a 36% reduction in overall costs during a 10-year period.⁹

A program in Atlantic City, NJ, combined the typical CMO model with a primary care clinic to provide high users with unlimited access, while paying its providers in a capitation model (as opposed to fee for service). It achieved a 40% reduction in yearly emergency department visits and hospital admissions.⁸

Patient care plans

Individualized patient care plans for high users are among the most promising tools for reducing costs and improving quality in this group. They are low-cost and relatively easy to implement. The goal of these care plans is to provide practitioners with a concise care summary to help them make rational and consistent medical decisions.

Typically, a care plan is written by an interdisciplinary committee composed of physicians, nurses, and social workers. It is based on the patient’s pertinent medical and psychiatric history, which may include recent imaging results or other relevant diagnostic tests. It provides suggestions for managing complex chronic issues, such as drug abuse, that lead to high use of healthcare resources.

These care plans provide a rational and prespecified approach to workup and management, typically including a narcotic prescription protocol, regardless of the setting or the number of providers who see the patient. Practitioners guided by effective care plans are much more likely to effectively navigate a complex patient encounter as opposed to looking through extensive medical notes and hoping to find relevant information.

Effective models

Data show these plans can be effective. For example, Regions Hospital in St. Paul, MN, implemented patient care plans in 2010. During the first 4 months, hospital admissions in the first 94 patients were reduced by 67%.¹⁰

A study of high users at Duke University Medical Center reported similar results. One year after starting care plans, inpatient admissions had decreased by 50.5%, readmissions had decreased by 51.5%, and variable direct costs per admission were reduced by 35.8%. Paradoxically, emergency department visits went up, but this anomaly was driven by 134 visits incurred by a single dialysis patient. After removing this patient from the data, emergency department visits were relatively stable.⁴

Better discharge summaries

Although improving discharge summaries is not a novel concept, changing the summary from a historical document to a proactive discharge plan has the potential to prevent readmissions and promote a durable de-escalation in care acuity.

For example, when moving a patient to a subacute care facility, providing a concise summary of which treatments worked and which did not, a list of comorbidities, and a list of medications and strategies to consider, can help the next providers to better target their plan of care. Studies have shown that nearly half of discharge statements lack important information on treatments and tests.¹¹

Improvement can be as simple as encouraging practitioners to construct their summaries in an “if-then” format. Instead of noting for instance that “Mr. Smith was treated for pneumonia with antibiotics and discharged to a rehab facility,” the following would be more useful: “Family would like to see if Mr. Smith can get back to his functional baseline after his acute pneumonia. If he clinically does not do well over the next 1 to 2 weeks and has a poor quality of life, then family would like to pursue hospice.”

In addition to shifting the philosophy, we believe that providing timely discharge summaries is a fundamental, high-yield aspect of ensuring their effectiveness. As an example, patients being discharged to a skilled nursing facility should have a discharge summary completed and in hand before leaving the hospital.

Evidence suggests that timely writing of discharge summaries improves their quality. In a retrospective cohort study published in 2012, discharge summaries created more than 24 hours after discharge were less likely to include important plan-of-care components.¹²

FUTURE NEEDS

Randomized trials

Although initial results have been promising for the strategies outlined above, much of the apparent cost reduction of these interventions may be at least partially related to the study design as opposed to the interventions themselves.

For example, Hong et al¹³ examined 18 of the more promising CMOs that had reported initial cost savings. Of these, only 4 had conducted randomized controlled trials. When broken down further, the initial cost reduction reported by most of these randomized controlled trials was generated primarily by small subgroups.¹⁴

These results, however, do not necessarily reflect an inherent failure in the system. We contend that they merely demonstrate that CMOs and care plan administrators need to be more selective about whom they enroll, either by targeting patients at the extremes of the usage curve or by identifying patient characteristics and usage parameters amenable to cost reduction and quality improvement strategies.

Better social infrastructure

Although patient care plans and CMOs have been effective in managing high users, we believe that the most promising quality improvement and cost-reduction strategy involves redirecting much of the expensive healthcare spending to the social determinants of health (eg, homelessness, mental illness, low socioeconomic status).

Organization for Economic Co-operation and Development. Health at a Glance 2009: OECD Indicators. Paris, France: OECD Publishing; 2009.

Among developed countries, the United States has the highest healthcare spending and the lowest social service spending as a percentage of its gross domestic product (Figure 1).¹⁵ Although seemingly discouraging, these data can actually be interpreted as hopeful, as they support the notion that the inefficiencies of our current system are not part of an inescapable reality, but rather reflect a system that has evolved uniquely in this country.

Using the available social programs

Exemplifying this medical and social services balance is a high user who visited her local emergency department 450 times in 1 year for reasons primarily related to homelessness.¹⁶ Each time, the medical system (as it is currently designed to do) applied a short-term medical solution to this patient’s problems and discharged her home, ie, back to the street.

But this patient’s high use was really a manifestation of a deeper social issue: homelessness. When the medical staff eventually noted how much this lack of stable shelter was contributing to her pattern of use, she was referred to appropriate social resources and provided with the housing she needed. Her hospital visits decreased from 450 to 12 in the subsequent year, amounting to a huge cost reduction and a clear improvement in her quality of life.

Similar encouraging results have resulted when available social programs are applied to the high-use population at large, which is particularly reassuring given this population’s preponderance of low socioeconomic status, mental illness, and homelessness. (The prevalence of homelessness is roughly 20%, depending on the definition of a high user).

New York Medicaid, for example, has a housing program that provides stable shelter outside of acute care medical settings for patients at a rate as low as $50 per day, compared with area hospital costs that often exceed $2,200 daily.¹⁷ A similar program in Westchester County, NY, reported a 45.9% reduction in inpatient costs and a 15.4% reduction in emergency department visits among 61 of its highest users after 2 years of enrollment.¹⁷

Need to reform privacy laws

Although legally daunting, reform of the Health Insurance Portability and Accountability Act (HIPAA) and other privacy laws in favor of a more open model of information sharing, particularly for high-risk patients, holds great opportunity for quality improvement. For patients who obtain their care from several healthcare facilities, the documentation is often inscrutable. If some of the HIPAA regulations and other patient privacy laws were exchanged for rules more akin to the current model of narcotic prescription tracking, for example, physicians would be better equipped to provide safe, organized, and efficient medical care for high-use patients.

Need to reform the system

A fundamental flaw in our healthcare system, which is largely based on a fee-for-service model, is that it was not designed for patients who use the system at the highest frequency and greatest cost. Also, it does not account for the psychosocial factors that beset many high-use patients. As such, it is imperative for the safety of our patients as well as the viability of the healthcare system that we change our historical way of thinking and reform this system that provides high users with care that is high-cost, low-quality, and not patient-centered.

IMPROVING QUALITY, REDUCING COST

High users of emergency services are a medically and socially complex group, predominantly characterized by low socioeconomic status and high rates of mental illness and drug dependency. Despite their increased healthcare use, they do not have better outcomes even though they are not sicker. Improving those outcomes requires both medical and social efforts.

Among the effective medical efforts are strategies aimed at creating individualized patient care plans, using coordinated care teams, and improving discharge summaries. Addressing patients’ social factors, such as homelessness, is more difficult, but healthcare systems can help patients navigate the available social programs. These strategies are part of a comprehensive care plan that can help reduce the cost and improve the quality of healthcare for high users.

Emergency departments are not primary care clinics, but some patients use them that way. This relatively small group of patients consumes a disproportionate share of healthcare at great cost, earning them the label of “high users.” Mostly poor and often burdened with mental illness and addiction, they are not necessarily sicker than other patients, and they do not enjoy better outcomes from the extra money spent on them. (Another subset of high users, those with end-stage chronic disease, is outside the scope of this review.)

Herein lies an opportunity. If—and this is a big if—we could manage their care in a systematic way instead of haphazardly, proactively instead of reactively, with continuity of care instead of episodically, and in a way that is convenient for the patient, we might be able to improve quality and save money.

A DISPROPORTIONATE SHARE OF COSTS

In the United States in 2012, the 5% of the population who were the highest users were responsible for 50% of healthcare costs.¹ The mean cost per person in this group was more than $43,000 annually. The top 1% of users accounted for nearly 23% of all expenditures, averaging nearly $98,000 per patient per year—10 times more than the average yearly cost per patient.

CARE IS OFTEN INAPPROPRIATE AND UNNECESSARY

In addition to being disproportionately expensive, the care that these patients receive is often inappropriate and unnecessary for the severity of their disease.

A 2007–2009 study² of 1,969 patients who had visited the emergency department 10 or more times in a year found they received more than twice as many computed tomography (CT) scans as a control group of infrequent users (< 3 visits/year). This occurred even though they were not as sick as infrequent users, based on significantly lower hospital admission rates (11.1% vs 17.9%; P < .001) and mortality rates (0.7% vs 1.5%; P < .002).²

This inverse relationship between emergency department use and illness severity was even more exaggerated at the upper extreme of the use curve. The highest users (> 29 visits to the emergency department in a year) had the lowest triage acuity and hospital admission rates but the highest number of CT scans. Charges per visit were lower among frequent users, but total charges rose steadily with increasing emergency department use, accounting for significantly more costs per year.²

We believe that one reason these patients receive more medical care than necessary is because their medical records are too large and complex for the average physician to distill effectively in a 20-minute physician-patient encounter. Physicians therefore simply order more tests, procedures, and admissions, which are often medically unnecessary and redundant.

WHAT DRIVES HIGH COST?

Mental illness and chemical dependence

Drug addiction, mental illness, and poverty frequently accompany (and influence) high-use behavior, particularly in patients without end-stage diseases.

Szekendi et al,³ in a study of 28,291 patients who had been admitted at least 5 times in a year in a Chicago health system, found that these high users were 2 to 3 times more likely to suffer from comorbid depression (40% vs 13%), psychosis (18% vs 5%), recreational drug dependence (20% vs 7%), and alcohol abuse (16% vs 7%) than non-high-use hospitalized patients.³

Mercer et al⁴ conducted a study at Duke University Medical Center, Durham, NC, aimed at reducing emergency department visits and hospital admissions among 24 of its highest users. They found that 23 (96%) were either addicted to drugs or mentally ill, and 20 (83%) suffered from chronic pain.⁴

Drug abuse among high users is becoming even more relevant as the opioid epidemic worsens. Given that most patients requiring high levels of care suffer from chronic pain and many of them develop an opioid addiction while treating their pain, physicians have a moral imperative to reduce the prevalence of drug abuse in this population.

Low socioeconomic status

Low socioeconomic status is an important factor among high users, as it is highly associated with greater disease severity, which usually increases cost without any guarantee of an associated increase in quality. Data suggest that patients of low socioeconomic status are twice as likely to require urgent emergency department visits, 4 times as likely to require admission to the hospital, and, importantly, about half as likely to use ambulatory care compared with patients of higher socioeconomic status.⁵ While this pattern of low-quality, high-cost spending in acute care settings reflects spending in the healthcare system at large, the pattern is greatly exaggerated among high users.

Lost to follow-up

Low socioeconomic status also complicates communication and follow-up. In a 2013 study, physician researchers in St. Paul, MN, documented attempts to interview 64 recently discharged high users. They could not reach 47 (73%) of them, for reasons largely attributable to low socioeconomic status, such as disconnected phone lines and changes in address.⁶

Clearly, the usual contact methods for follow-up care after discharge, such as phone calls and mailings, are unlikely to be effective in coordinating the outpatient care of these individuals.

Additionally, we must find ways of making primary care more convenient, gaining our patients’ trust, and finding ways to engage patients in follow-up without relying on traditional means of communication.

Do high users have medical insurance?

Surprisingly, most high users of the emergency department have health insurance. The Chicago health system study³ found that most (72.4%) of their high users had either Medicare or private health insurance, while 27.6% had either Medicaid or no insurance (compared with 21.6% in the general population). Other studies also found that most of the frequent emergency department users are insured,⁷ although the overall percentage who rely on publicly paid insurance is greater than in the population at large.

Many prefer acute care over primary care

Although one might think that high users go to the emergency department because they have nowhere else to go for care, a report published in 2013 by Kangovi et al⁵ suggests another reason—they prefer the emergency department.⁵ They interviewed 40 urban patients of low socioeconomic status who consistently cited the 24-hour, no-appointment-necessary structure of the emergency department as an advantage over primary care. The flexibility of emergency access to healthcare makes sense if one reflects on how difficult it is for even high-functioning individuals to schedule and keep medical appointments.

Specific reasons for preferring the emergency department included the following:

Affordability. Even if their insurance fully paid for visits to their primary care physicians, the primary care physician was likely to refer them to specialists, whose visits required a copay, and which required taking another day off of work. The emergency department is cheaper for the patient and it is a “one-stop shop.” Patients appreciated the emergency department guarantee of seeing a physician regardless of proof of insurance, a policy not guaranteed in primary care and specialist offices.

Accessibility. For those without a car, public transportation and even patient transportation services are inconvenient and unreliable, whereas emergency medical services will take you to the emergency department.

Accommodations. Although medical centers may tout their same-day appointments, often same-day appointments are all that they have—and you have no choice about the time. You have to call first thing in the morning and stay on hold for a long time, and then when you finally get through, all the same-day appointments are gone.

Availability. Patients said they often had a hard time getting timely medical advice from their primary care physicians. When they could get through to their primary care physicians on the phone, they would be told to go to the emergency department.

Acceptability. Men, especially, feel they need to be very sick indeed to seek medical care, so going to the emergency department is more acceptable.

Trust in the provider. For reasons that were not entirely clear, patients felt that acute care providers were more trustworthy, competent, and compassionate than primary care physicians.⁵

None of these reasons for using the emergency department has anything to do with disease severity, which supports the findings that high users of the emergency department were not as sick as their normal-use peers.²

QUALITY IMPROVEMENT AND COST-REDUCTION STRATEGIES

Efforts are being made to reduce the cost of healthcare for high users while improving the quality of their care. Promising strategies focus on coordinating care management, creating individualized patient care plans, and improving the components and instructions of discharge summaries.

Care management organizations

A care management organization (CMO) model has emerged as a strategy for quality improvement and cost reduction in the high-use population. In this model, social workers, health coaches, nurses, mid-level providers, and physicians collaborate on designing individualized care plans to meet the specific needs of patients.

Teams typically work in stepwise fashion, first identifying and engaging patients at high risk of poor outcomes and unnecessary care, often using sophisticated quantitative, risk-prediction tools. Then, they perform health assessments and identify potential interventions aimed at preventing expensive acute-care medical interventions. Third, they work with patients to rapidly identify and effectively respond to changes in their conditions and direct them to the most appropriate medical setting, typically primary or urgent care.

Effective models

In 1998, the Camden (NJ) Coalition of Healthcare Providers established a model for CMO care plans. Starting with the first 36 patients enrolled in the program, hospital admissions and emergency department visits were cut by 47% (from 62 to 37 per month), and collective hospital costs were cut by 56% (from $1.2 million to about $500,000 per month).⁸ It should be noted that this was a small, nonrandomized study and these preliminary numbers did not take into account the cost of outpatient physician visits or new medications. Thus, how much money this program actually saves is not clear.

Similar programs have had similar results. A nurse-led care coordination program in Doylestown, PA, showed an impressive 25% reduction in annual mortality and a 36% reduction in overall costs during a 10-year period.⁹

A program in Atlantic City, NJ, combined the typical CMO model with a primary care clinic to provide high users with unlimited access, while paying its providers in a capitation model (as opposed to fee for service). It achieved a 40% reduction in yearly emergency department visits and hospital admissions.⁸

Patient care plans

Individualized patient care plans for high users are among the most promising tools for reducing costs and improving quality in this group. They are low-cost and relatively easy to implement. The goal of these care plans is to provide practitioners with a concise care summary to help them make rational and consistent medical decisions.

Typically, a care plan is written by an interdisciplinary committee composed of physicians, nurses, and social workers. It is based on the patient’s pertinent medical and psychiatric history, which may include recent imaging results or other relevant diagnostic tests. It provides suggestions for managing complex chronic issues, such as drug abuse, that lead to high use of healthcare resources.

These care plans provide a rational and prespecified approach to workup and management, typically including a narcotic prescription protocol, regardless of the setting or the number of providers who see the patient. Practitioners guided by effective care plans are much more likely to effectively navigate a complex patient encounter as opposed to looking through extensive medical notes and hoping to find relevant information.

Effective models

Data show these plans can be effective. For example, Regions Hospital in St. Paul, MN, implemented patient care plans in 2010. During the first 4 months, hospital admissions in the first 94 patients were reduced by 67%.¹⁰

A study of high users at Duke University Medical Center reported similar results. One year after starting care plans, inpatient admissions had decreased by 50.5%, readmissions had decreased by 51.5%, and variable direct costs per admission were reduced by 35.8%. Paradoxically, emergency department visits went up, but this anomaly was driven by 134 visits incurred by a single dialysis patient. After removing this patient from the data, emergency department visits were relatively stable.⁴

Better discharge summaries

Although improving discharge summaries is not a novel concept, changing the summary from a historical document to a proactive discharge plan has the potential to prevent readmissions and promote a durable de-escalation in care acuity.

For example, when moving a patient to a subacute care facility, providing a concise summary of which treatments worked and which did not, a list of comorbidities, and a list of medications and strategies to consider, can help the next providers to better target their plan of care. Studies have shown that nearly half of discharge statements lack important information on treatments and tests.¹¹

Improvement can be as simple as encouraging practitioners to construct their summaries in an “if-then” format. Instead of noting for instance that “Mr. Smith was treated for pneumonia with antibiotics and discharged to a rehab facility,” the following would be more useful: “Family would like to see if Mr. Smith can get back to his functional baseline after his acute pneumonia. If he clinically does not do well over the next 1 to 2 weeks and has a poor quality of life, then family would like to pursue hospice.”

In addition to shifting the philosophy, we believe that providing timely discharge summaries is a fundamental, high-yield aspect of ensuring their effectiveness. As an example, patients being discharged to a skilled nursing facility should have a discharge summary completed and in hand before leaving the hospital.

Evidence suggests that timely writing of discharge summaries improves their quality. In a retrospective cohort study published in 2012, discharge summaries created more than 24 hours after discharge were less likely to include important plan-of-care components.¹²

FUTURE NEEDS

Randomized trials

Although initial results have been promising for the strategies outlined above, much of the apparent cost reduction of these interventions may be at least partially related to the study design as opposed to the interventions themselves.

For example, Hong et al¹³ examined 18 of the more promising CMOs that had reported initial cost savings. Of these, only 4 had conducted randomized controlled trials. When broken down further, the initial cost reduction reported by most of these randomized controlled trials was generated primarily by small subgroups.¹⁴

These results, however, do not necessarily reflect an inherent failure in the system. We contend that they merely demonstrate that CMOs and care plan administrators need to be more selective about whom they enroll, either by targeting patients at the extremes of the usage curve or by identifying patient characteristics and usage parameters amenable to cost reduction and quality improvement strategies.

Better social infrastructure

Although patient care plans and CMOs have been effective in managing high users, we believe that the most promising quality improvement and cost-reduction strategy involves redirecting much of the expensive healthcare spending to the social determinants of health (eg, homelessness, mental illness, low socioeconomic status).

Organization for Economic Co-operation and Development. Health at a Glance 2009: OECD Indicators. Paris, France: OECD Publishing; 2009.

Among developed countries, the United States has the highest healthcare spending and the lowest social service spending as a percentage of its gross domestic product (Figure 1).¹⁵ Although seemingly discouraging, these data can actually be interpreted as hopeful, as they support the notion that the inefficiencies of our current system are not part of an inescapable reality, but rather reflect a system that has evolved uniquely in this country.

Using the available social programs

Exemplifying this medical and social services balance is a high user who visited her local emergency department 450 times in 1 year for reasons primarily related to homelessness.¹⁶ Each time, the medical system (as it is currently designed to do) applied a short-term medical solution to this patient’s problems and discharged her home, ie, back to the street.

But this patient’s high use was really a manifestation of a deeper social issue: homelessness. When the medical staff eventually noted how much this lack of stable shelter was contributing to her pattern of use, she was referred to appropriate social resources and provided with the housing she needed. Her hospital visits decreased from 450 to 12 in the subsequent year, amounting to a huge cost reduction and a clear improvement in her quality of life.

Similar encouraging results have resulted when available social programs are applied to the high-use population at large, which is particularly reassuring given this population’s preponderance of low socioeconomic status, mental illness, and homelessness. (The prevalence of homelessness is roughly 20%, depending on the definition of a high user).

New York Medicaid, for example, has a housing program that provides stable shelter outside of acute care medical settings for patients at a rate as low as $50 per day, compared with area hospital costs that often exceed $2,200 daily.¹⁷ A similar program in Westchester County, NY, reported a 45.9% reduction in inpatient costs and a 15.4% reduction in emergency department visits among 61 of its highest users after 2 years of enrollment.¹⁷

Need to reform privacy laws

Although legally daunting, reform of the Health Insurance Portability and Accountability Act (HIPAA) and other privacy laws in favor of a more open model of information sharing, particularly for high-risk patients, holds great opportunity for quality improvement. For patients who obtain their care from several healthcare facilities, the documentation is often inscrutable. If some of the HIPAA regulations and other patient privacy laws were exchanged for rules more akin to the current model of narcotic prescription tracking, for example, physicians would be better equipped to provide safe, organized, and efficient medical care for high-use patients.

Need to reform the system

A fundamental flaw in our healthcare system, which is largely based on a fee-for-service model, is that it was not designed for patients who use the system at the highest frequency and greatest cost. Also, it does not account for the psychosocial factors that beset many high-use patients. As such, it is imperative for the safety of our patients as well as the viability of the healthcare system that we change our historical way of thinking and reform this system that provides high users with care that is high-cost, low-quality, and not patient-centered.

IMPROVING QUALITY, REDUCING COST

High users of emergency services are a medically and socially complex group, predominantly characterized by low socioeconomic status and high rates of mental illness and drug dependency. Despite their increased healthcare use, they do not have better outcomes even though they are not sicker. Improving those outcomes requires both medical and social efforts.

Among the effective medical efforts are strategies aimed at creating individualized patient care plans, using coordinated care teams, and improving discharge summaries. Addressing patients’ social factors, such as homelessness, is more difficult, but healthcare systems can help patients navigate the available social programs. These strategies are part of a comprehensive care plan that can help reduce the cost and improve the quality of healthcare for high users.

Emergency departments are not primary care clinics, but some patients use them that way. This relatively small group of patients consumes a disproportionate share of healthcare at great cost, earning them the label of “high users.” Mostly poor and often burdened with mental illness and addiction, they are not necessarily sicker than other patients, and they do not enjoy better outcomes from the extra money spent on them. (Another subset of high users, those with end-stage chronic disease, is outside the scope of this review.)

Herein lies an opportunity. If—and this is a big if—we could manage their care in a systematic way instead of haphazardly, proactively instead of reactively, with continuity of care instead of episodically, and in a way that is convenient for the patient, we might be able to improve quality and save money.

A DISPROPORTIONATE SHARE OF COSTS

In the United States in 2012, the 5% of the population who were the highest users were responsible for 50% of healthcare costs.¹ The mean cost per person in this group was more than $43,000 annually. The top 1% of users accounted for nearly 23% of all expenditures, averaging nearly $98,000 per patient per year—10 times more than the average yearly cost per patient.

CARE IS OFTEN INAPPROPRIATE AND UNNECESSARY

In addition to being disproportionately expensive, the care that these patients receive is often inappropriate and unnecessary for the severity of their disease.

A 2007–2009 study² of 1,969 patients who had visited the emergency department 10 or more times in a year found they received more than twice as many computed tomography (CT) scans as a control group of infrequent users (< 3 visits/year). This occurred even though they were not as sick as infrequent users, based on significantly lower hospital admission rates (11.1% vs 17.9%; P < .001) and mortality rates (0.7% vs 1.5%; P < .002).²

This inverse relationship between emergency department use and illness severity was even more exaggerated at the upper extreme of the use curve. The highest users (> 29 visits to the emergency department in a year) had the lowest triage acuity and hospital admission rates but the highest number of CT scans. Charges per visit were lower among frequent users, but total charges rose steadily with increasing emergency department use, accounting for significantly more costs per year.²

We believe that one reason these patients receive more medical care than necessary is because their medical records are too large and complex for the average physician to distill effectively in a 20-minute physician-patient encounter. Physicians therefore simply order more tests, procedures, and admissions, which are often medically unnecessary and redundant.

WHAT DRIVES HIGH COST?

Mental illness and chemical dependence

Drug addiction, mental illness, and poverty frequently accompany (and influence) high-use behavior, particularly in patients without end-stage diseases.

Szekendi et al,³ in a study of 28,291 patients who had been admitted at least 5 times in a year in a Chicago health system, found that these high users were 2 to 3 times more likely to suffer from comorbid depression (40% vs 13%), psychosis (18% vs 5%), recreational drug dependence (20% vs 7%), and alcohol abuse (16% vs 7%) than non-high-use hospitalized patients.³

Mercer et al⁴ conducted a study at Duke University Medical Center, Durham, NC, aimed at reducing emergency department visits and hospital admissions among 24 of its highest users. They found that 23 (96%) were either addicted to drugs or mentally ill, and 20 (83%) suffered from chronic pain.⁴

Drug abuse among high users is becoming even more relevant as the opioid epidemic worsens. Given that most patients requiring high levels of care suffer from chronic pain and many of them develop an opioid addiction while treating their pain, physicians have a moral imperative to reduce the prevalence of drug abuse in this population.

Low socioeconomic status

Low socioeconomic status is an important factor among high users, as it is highly associated with greater disease severity, which usually increases cost without any guarantee of an associated increase in quality. Data suggest that patients of low socioeconomic status are twice as likely to require urgent emergency department visits, 4 times as likely to require admission to the hospital, and, importantly, about half as likely to use ambulatory care compared with patients of higher socioeconomic status.⁵ While this pattern of low-quality, high-cost spending in acute care settings reflects spending in the healthcare system at large, the pattern is greatly exaggerated among high users.

Lost to follow-up

Low socioeconomic status also complicates communication and follow-up. In a 2013 study, physician researchers in St. Paul, MN, documented attempts to interview 64 recently discharged high users. They could not reach 47 (73%) of them, for reasons largely attributable to low socioeconomic status, such as disconnected phone lines and changes in address.⁶

Clearly, the usual contact methods for follow-up care after discharge, such as phone calls and mailings, are unlikely to be effective in coordinating the outpatient care of these individuals.

Additionally, we must find ways of making primary care more convenient, gaining our patients’ trust, and finding ways to engage patients in follow-up without relying on traditional means of communication.

Do high users have medical insurance?

Surprisingly, most high users of the emergency department have health insurance. The Chicago health system study³ found that most (72.4%) of their high users had either Medicare or private health insurance, while 27.6% had either Medicaid or no insurance (compared with 21.6% in the general population). Other studies also found that most of the frequent emergency department users are insured,⁷ although the overall percentage who rely on publicly paid insurance is greater than in the population at large.

Many prefer acute care over primary care

Although one might think that high users go to the emergency department because they have nowhere else to go for care, a report published in 2013 by Kangovi et al⁵ suggests another reason—they prefer the emergency department.⁵ They interviewed 40 urban patients of low socioeconomic status who consistently cited the 24-hour, no-appointment-necessary structure of the emergency department as an advantage over primary care. The flexibility of emergency access to healthcare makes sense if one reflects on how difficult it is for even high-functioning individuals to schedule and keep medical appointments.

Specific reasons for preferring the emergency department included the following:

Affordability. Even if their insurance fully paid for visits to their primary care physicians, the primary care physician was likely to refer them to specialists, whose visits required a copay, and which required taking another day off of work. The emergency department is cheaper for the patient and it is a “one-stop shop.” Patients appreciated the emergency department guarantee of seeing a physician regardless of proof of insurance, a policy not guaranteed in primary care and specialist offices.

Accessibility. For those without a car, public transportation and even patient transportation services are inconvenient and unreliable, whereas emergency medical services will take you to the emergency department.

Accommodations. Although medical centers may tout their same-day appointments, often same-day appointments are all that they have—and you have no choice about the time. You have to call first thing in the morning and stay on hold for a long time, and then when you finally get through, all the same-day appointments are gone.

Availability. Patients said they often had a hard time getting timely medical advice from their primary care physicians. When they could get through to their primary care physicians on the phone, they would be told to go to the emergency department.

Acceptability. Men, especially, feel they need to be very sick indeed to seek medical care, so going to the emergency department is more acceptable.

Trust in the provider. For reasons that were not entirely clear, patients felt that acute care providers were more trustworthy, competent, and compassionate than primary care physicians.⁵

None of these reasons for using the emergency department has anything to do with disease severity, which supports the findings that high users of the emergency department were not as sick as their normal-use peers.²

QUALITY IMPROVEMENT AND COST-REDUCTION STRATEGIES

Efforts are being made to reduce the cost of healthcare for high users while improving the quality of their care. Promising strategies focus on coordinating care management, creating individualized patient care plans, and improving the components and instructions of discharge summaries.

Care management organizations

A care management organization (CMO) model has emerged as a strategy for quality improvement and cost reduction in the high-use population. In this model, social workers, health coaches, nurses, mid-level providers, and physicians collaborate on designing individualized care plans to meet the specific needs of patients.

Teams typically work in stepwise fashion, first identifying and engaging patients at high risk of poor outcomes and unnecessary care, often using sophisticated quantitative, risk-prediction tools. Then, they perform health assessments and identify potential interventions aimed at preventing expensive acute-care medical interventions. Third, they work with patients to rapidly identify and effectively respond to changes in their conditions and direct them to the most appropriate medical setting, typically primary or urgent care.

Effective models

In 1998, the Camden (NJ) Coalition of Healthcare Providers established a model for CMO care plans. Starting with the first 36 patients enrolled in the program, hospital admissions and emergency department visits were cut by 47% (from 62 to 37 per month), and collective hospital costs were cut by 56% (from $1.2 million to about $500,000 per month).⁸ It should be noted that this was a small, nonrandomized study and these preliminary numbers did not take into account the cost of outpatient physician visits or new medications. Thus, how much money this program actually saves is not clear.

Similar programs have had similar results. A nurse-led care coordination program in Doylestown, PA, showed an impressive 25% reduction in annual mortality and a 36% reduction in overall costs during a 10-year period.⁹

A program in Atlantic City, NJ, combined the typical CMO model with a primary care clinic to provide high users with unlimited access, while paying its providers in a capitation model (as opposed to fee for service). It achieved a 40% reduction in yearly emergency department visits and hospital admissions.⁸

Patient care plans

Individualized patient care plans for high users are among the most promising tools for reducing costs and improving quality in this group. They are low-cost and relatively easy to implement. The goal of these care plans is to provide practitioners with a concise care summary to help them make rational and consistent medical decisions.

Typically, a care plan is written by an interdisciplinary committee composed of physicians, nurses, and social workers. It is based on the patient’s pertinent medical and psychiatric history, which may include recent imaging results or other relevant diagnostic tests. It provides suggestions for managing complex chronic issues, such as drug abuse, that lead to high use of healthcare resources.

These care plans provide a rational and prespecified approach to workup and management, typically including a narcotic prescription protocol, regardless of the setting or the number of providers who see the patient. Practitioners guided by effective care plans are much more likely to effectively navigate a complex patient encounter as opposed to looking through extensive medical notes and hoping to find relevant information.

Effective models

Data show these plans can be effective. For example, Regions Hospital in St. Paul, MN, implemented patient care plans in 2010. During the first 4 months, hospital admissions in the first 94 patients were reduced by 67%.¹⁰

A study of high users at Duke University Medical Center reported similar results. One year after starting care plans, inpatient admissions had decreased by 50.5%, readmissions had decreased by 51.5%, and variable direct costs per admission were reduced by 35.8%. Paradoxically, emergency department visits went up, but this anomaly was driven by 134 visits incurred by a single dialysis patient. After removing this patient from the data, emergency department visits were relatively stable.⁴

Better discharge summaries

Although improving discharge summaries is not a novel concept, changing the summary from a historical document to a proactive discharge plan has the potential to prevent readmissions and promote a durable de-escalation in care acuity.

For example, when moving a patient to a subacute care facility, providing a concise summary of which treatments worked and which did not, a list of comorbidities, and a list of medications and strategies to consider, can help the next providers to better target their plan of care. Studies have shown that nearly half of discharge statements lack important information on treatments and tests.¹¹

Improvement can be as simple as encouraging practitioners to construct their summaries in an “if-then” format. Instead of noting for instance that “Mr. Smith was treated for pneumonia with antibiotics and discharged to a rehab facility,” the following would be more useful: “Family would like to see if Mr. Smith can get back to his functional baseline after his acute pneumonia. If he clinically does not do well over the next 1 to 2 weeks and has a poor quality of life, then family would like to pursue hospice.”

In addition to shifting the philosophy, we believe that providing timely discharge summaries is a fundamental, high-yield aspect of ensuring their effectiveness. As an example, patients being discharged to a skilled nursing facility should have a discharge summary completed and in hand before leaving the hospital.

Evidence suggests that timely writing of discharge summaries improves their quality. In a retrospective cohort study published in 2012, discharge summaries created more than 24 hours after discharge were less likely to include important plan-of-care components.¹²

FUTURE NEEDS

Randomized trials

Although initial results have been promising for the strategies outlined above, much of the apparent cost reduction of these interventions may be at least partially related to the study design as opposed to the interventions themselves.

For example, Hong et al¹³ examined 18 of the more promising CMOs that had reported initial cost savings. Of these, only 4 had conducted randomized controlled trials. When broken down further, the initial cost reduction reported by most of these randomized controlled trials was generated primarily by small subgroups.¹⁴

These results, however, do not necessarily reflect an inherent failure in the system. We contend that they merely demonstrate that CMOs and care plan administrators need to be more selective about whom they enroll, either by targeting patients at the extremes of the usage curve or by identifying patient characteristics and usage parameters amenable to cost reduction and quality improvement strategies.

Better social infrastructure

Although patient care plans and CMOs have been effective in managing high users, we believe that the most promising quality improvement and cost-reduction strategy involves redirecting much of the expensive healthcare spending to the social determinants of health (eg, homelessness, mental illness, low socioeconomic status).

Organization for Economic Co-operation and Development. Health at a Glance 2009: OECD Indicators. Paris, France: OECD Publishing; 2009.

Among developed countries, the United States has the highest healthcare spending and the lowest social service spending as a percentage of its gross domestic product (Figure 1).¹⁵ Although seemingly discouraging, these data can actually be interpreted as hopeful, as they support the notion that the inefficiencies of our current system are not part of an inescapable reality, but rather reflect a system that has evolved uniquely in this country.

Using the available social programs

Exemplifying this medical and social services balance is a high user who visited her local emergency department 450 times in 1 year for reasons primarily related to homelessness.¹⁶ Each time, the medical system (as it is currently designed to do) applied a short-term medical solution to this patient’s problems and discharged her home, ie, back to the street.

But this patient’s high use was really a manifestation of a deeper social issue: homelessness. When the medical staff eventually noted how much this lack of stable shelter was contributing to her pattern of use, she was referred to appropriate social resources and provided with the housing she needed. Her hospital visits decreased from 450 to 12 in the subsequent year, amounting to a huge cost reduction and a clear improvement in her quality of life.

Similar encouraging results have resulted when available social programs are applied to the high-use population at large, which is particularly reassuring given this population’s preponderance of low socioeconomic status, mental illness, and homelessness. (The prevalence of homelessness is roughly 20%, depending on the definition of a high user).

New York Medicaid, for example, has a housing program that provides stable shelter outside of acute care medical settings for patients at a rate as low as $50 per day, compared with area hospital costs that often exceed $2,200 daily.¹⁷ A similar program in Westchester County, NY, reported a 45.9% reduction in inpatient costs and a 15.4% reduction in emergency department visits among 61 of its highest users after 2 years of enrollment.¹⁷

Need to reform privacy laws

Although legally daunting, reform of the Health Insurance Portability and Accountability Act (HIPAA) and other privacy laws in favor of a more open model of information sharing, particularly for high-risk patients, holds great opportunity for quality improvement. For patients who obtain their care from several healthcare facilities, the documentation is often inscrutable. If some of the HIPAA regulations and other patient privacy laws were exchanged for rules more akin to the current model of narcotic prescription tracking, for example, physicians would be better equipped to provide safe, organized, and efficient medical care for high-use patients.

Need to reform the system

A fundamental flaw in our healthcare system, which is largely based on a fee-for-service model, is that it was not designed for patients who use the system at the highest frequency and greatest cost. Also, it does not account for the psychosocial factors that beset many high-use patients. As such, it is imperative for the safety of our patients as well as the viability of the healthcare system that we change our historical way of thinking and reform this system that provides high users with care that is high-cost, low-quality, and not patient-centered.

IMPROVING QUALITY, REDUCING COST

High users of emergency services are a medically and socially complex group, predominantly characterized by low socioeconomic status and high rates of mental illness and drug dependency. Despite their increased healthcare use, they do not have better outcomes even though they are not sicker. Improving those outcomes requires both medical and social efforts.

Among the effective medical efforts are strategies aimed at creating individualized patient care plans, using coordinated care teams, and improving discharge summaries. Addressing patients’ social factors, such as homelessness, is more difficult, but healthcare systems can help patients navigate the available social programs. These strategies are part of a comprehensive care plan that can help reduce the cost and improve the quality of healthcare for high users.

The retail price for a set of 768 prescription drugs rose by 6.4% in 2015, while the general inflation rate increased by just 0.1%, according to the AARP Public Policy Institute and the PRIME Institute at the University of Minnesota in Minneapolis.

One year, of course, does not make a trend, but how about 10 years? The average increase in the price of the “market basket” of 768 drugs widely used by older Americans has exceeded the rate of inflation every year since the AARP started tracking costs in 2004. This is “attributable entirely to drug price growth among brand name and specialty drugs, which more than offset often substantial price decreases among generic drugs,” Leigh Purvis of AARP and Stephen Schondelmeyer, PharmD, PhD, of the Prime Institute, said in an Rx Price Watch report.

[email protected]

The retail price for a set of 768 prescription drugs rose by 6.4% in 2015, while the general inflation rate increased by just 0.1%, according to the AARP Public Policy Institute and the PRIME Institute at the University of Minnesota in Minneapolis.

One year, of course, does not make a trend, but how about 10 years? The average increase in the price of the “market basket” of 768 drugs widely used by older Americans has exceeded the rate of inflation every year since the AARP started tracking costs in 2004. This is “attributable entirely to drug price growth among brand name and specialty drugs, which more than offset often substantial price decreases among generic drugs,” Leigh Purvis of AARP and Stephen Schondelmeyer, PharmD, PhD, of the Prime Institute, said in an Rx Price Watch report.

[email protected]

The retail price for a set of 768 prescription drugs rose by 6.4% in 2015, while the general inflation rate increased by just 0.1%, according to the AARP Public Policy Institute and the PRIME Institute at the University of Minnesota in Minneapolis.

One year, of course, does not make a trend, but how about 10 years? The average increase in the price of the “market basket” of 768 drugs widely used by older Americans has exceeded the rate of inflation every year since the AARP started tracking costs in 2004. This is “attributable entirely to drug price growth among brand name and specialty drugs, which more than offset often substantial price decreases among generic drugs,” Leigh Purvis of AARP and Stephen Schondelmeyer, PharmD, PhD, of the Prime Institute, said in an Rx Price Watch report.

[email protected]

SAN DIEGO – Over half of hospitalized, influenza-related deaths occurred within 30 days of discharge, according to a study presented at an annual scientific meeting on infectious diseases.

As physicians and pharmaceutical companies attempt to measure the burden of seasonal influenza, discharged patients are currently not considered as much as they should be, according to investigators.

Among 968 deceased patients studied, 444 (46%) died in hospital, while 524 (54%) died within 30 days of discharge.

Investigators conducted a retrospective study of 15,562 patients hospitalized for influenza-related cases between 2014 and 2015, as recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET), a database of the Centers for Disease Control and Prevention.

The majority of the studied patients were women (55%) and the majority were white.

Those who died were more likely to have been admitted to the hospital immediately after influenza onset, with 26% of those who died after discharge and 22% of those who died in hospital having been admitted the same day. In contrast, 13% of those who lived past 30 days were admitted immediately after onset.

A total of 46% of those who died after hospitalization had a length of stay longer than 1 week, compared to 15% of those who lived.

Among patients who died after discharge, 356 (68%) died within 2 weeks of discharge, with the highest number of deaths occurring within the first few days, according to presenter Craig McGowan of the Influenza Division of the CDC in Atlanta.

Age also seemed to be a possible mortality predictor, according to Mr. McGowan and his fellow investigators. “Those who died were more likely to be elderly, and those who died after discharge were even more likely to be 85 [years or older] than those who died during their influenza-related hospitalizations,” said Mr. McGowan, who added that patients aged 85 years and older made up more than half of those who died after discharge.

Patients who died in hospital were significantly more likely to have influenza listed as a cause of death. Overall, influenza-related and non–influenza-related respiratory issues were the two most common causes of death listed on death certificates of patients who died during hospitalization or within 14 days of discharge, while cardiovascular or other symptoms were listed for those who died between 15 and 30 days after discharge.

Admission and discharge locations among patients who did not die were almost 80% from a private residence to a private residence, while observations of those who died revealed a different pattern. “Those individuals who died after discharge were almost evenly split between admission from a nursing home or a private residence,” Mr. McGowan said. “Those who were admitted from the nursing home were almost exclusively discharged to either hospice care or back to a nursing home.”

Mr. McGowan noted rehospitalization to be a significant factor among those who died, with 34% of deaths occurring back in the hospital after initial discharge.

Influenza testing of studied patients was given at clinicians’ discretion, which may make the sample not generalizable to the overall influenza population, and the investigators included only bivariate associations, which means there were likely confounding effects that could not be accounted for.

Mr. McGowan and his fellow investigators plan to expand their research by determining underlying causes of death in these patients, to create more accurate estimates of influenza-associated mortality.

Mr. McGowan reported no relevant financial disclosures.

[email protected]

SOURCE: McGowan, C., et al., ID Week 2017, Abstract 951.

SAN DIEGO – Over half of hospitalized, influenza-related deaths occurred within 30 days of discharge, according to a study presented at an annual scientific meeting on infectious diseases.

As physicians and pharmaceutical companies attempt to measure the burden of seasonal influenza, discharged patients are currently not considered as much as they should be, according to investigators.

Among 968 deceased patients studied, 444 (46%) died in hospital, while 524 (54%) died within 30 days of discharge.

Investigators conducted a retrospective study of 15,562 patients hospitalized for influenza-related cases between 2014 and 2015, as recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET), a database of the Centers for Disease Control and Prevention.

The majority of the studied patients were women (55%) and the majority were white.

Those who died were more likely to have been admitted to the hospital immediately after influenza onset, with 26% of those who died after discharge and 22% of those who died in hospital having been admitted the same day. In contrast, 13% of those who lived past 30 days were admitted immediately after onset.

A total of 46% of those who died after hospitalization had a length of stay longer than 1 week, compared to 15% of those who lived.

Among patients who died after discharge, 356 (68%) died within 2 weeks of discharge, with the highest number of deaths occurring within the first few days, according to presenter Craig McGowan of the Influenza Division of the CDC in Atlanta.

Age also seemed to be a possible mortality predictor, according to Mr. McGowan and his fellow investigators. “Those who died were more likely to be elderly, and those who died after discharge were even more likely to be 85 [years or older] than those who died during their influenza-related hospitalizations,” said Mr. McGowan, who added that patients aged 85 years and older made up more than half of those who died after discharge.

Patients who died in hospital were significantly more likely to have influenza listed as a cause of death. Overall, influenza-related and non–influenza-related respiratory issues were the two most common causes of death listed on death certificates of patients who died during hospitalization or within 14 days of discharge, while cardiovascular or other symptoms were listed for those who died between 15 and 30 days after discharge.

Admission and discharge locations among patients who did not die were almost 80% from a private residence to a private residence, while observations of those who died revealed a different pattern. “Those individuals who died after discharge were almost evenly split between admission from a nursing home or a private residence,” Mr. McGowan said. “Those who were admitted from the nursing home were almost exclusively discharged to either hospice care or back to a nursing home.”

Mr. McGowan noted rehospitalization to be a significant factor among those who died, with 34% of deaths occurring back in the hospital after initial discharge.

Influenza testing of studied patients was given at clinicians’ discretion, which may make the sample not generalizable to the overall influenza population, and the investigators included only bivariate associations, which means there were likely confounding effects that could not be accounted for.

Mr. McGowan and his fellow investigators plan to expand their research by determining underlying causes of death in these patients, to create more accurate estimates of influenza-associated mortality.

Mr. McGowan reported no relevant financial disclosures.

[email protected]

SOURCE: McGowan, C., et al., ID Week 2017, Abstract 951.

SAN DIEGO – Over half of hospitalized, influenza-related deaths occurred within 30 days of discharge, according to a study presented at an annual scientific meeting on infectious diseases.

As physicians and pharmaceutical companies attempt to measure the burden of seasonal influenza, discharged patients are currently not considered as much as they should be, according to investigators.

Among 968 deceased patients studied, 444 (46%) died in hospital, while 524 (54%) died within 30 days of discharge.

Investigators conducted a retrospective study of 15,562 patients hospitalized for influenza-related cases between 2014 and 2015, as recorded in Influenza-Associated Hospitalizations Surveillance (FluSurv-NET), a database of the Centers for Disease Control and Prevention.

The majority of the studied patients were women (55%) and the majority were white.

Those who died were more likely to have been admitted to the hospital immediately after influenza onset, with 26% of those who died after discharge and 22% of those who died in hospital having been admitted the same day. In contrast, 13% of those who lived past 30 days were admitted immediately after onset.

A total of 46% of those who died after hospitalization had a length of stay longer than 1 week, compared to 15% of those who lived.

Among patients who died after discharge, 356 (68%) died within 2 weeks of discharge, with the highest number of deaths occurring within the first few days, according to presenter Craig McGowan of the Influenza Division of the CDC in Atlanta.

Age also seemed to be a possible mortality predictor, according to Mr. McGowan and his fellow investigators. “Those who died were more likely to be elderly, and those who died after discharge were even more likely to be 85 [years or older] than those who died during their influenza-related hospitalizations,” said Mr. McGowan, who added that patients aged 85 years and older made up more than half of those who died after discharge.

Patients who died in hospital were significantly more likely to have influenza listed as a cause of death. Overall, influenza-related and non–influenza-related respiratory issues were the two most common causes of death listed on death certificates of patients who died during hospitalization or within 14 days of discharge, while cardiovascular or other symptoms were listed for those who died between 15 and 30 days after discharge.

Admission and discharge locations among patients who did not die were almost 80% from a private residence to a private residence, while observations of those who died revealed a different pattern. “Those individuals who died after discharge were almost evenly split between admission from a nursing home or a private residence,” Mr. McGowan said. “Those who were admitted from the nursing home were almost exclusively discharged to either hospice care or back to a nursing home.”

Mr. McGowan noted rehospitalization to be a significant factor among those who died, with 34% of deaths occurring back in the hospital after initial discharge.

Influenza testing of studied patients was given at clinicians’ discretion, which may make the sample not generalizable to the overall influenza population, and the investigators included only bivariate associations, which means there were likely confounding effects that could not be accounted for.

Mr. McGowan and his fellow investigators plan to expand their research by determining underlying causes of death in these patients, to create more accurate estimates of influenza-associated mortality.

Mr. McGowan reported no relevant financial disclosures.

[email protected]

SOURCE: McGowan, C., et al., ID Week 2017, Abstract 951.

The risk for gastroesophageal reflux disease and cancer of the larynx, tonsils, and other areas of the upper aerodigestive tract was strongly associated in a longitudinal-based population study of the U.S. elderly population.

A total of 13,805 cases involving gastroesophageal reflux disease (GERD) and malignancies of the upper aerodigestive tract (UADT) and 13,805 GERD cases with no UADT from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER)-Medicare linked database in patients aged 66 years and older from 2003 through 2011 were examined. Only those who had no malignancy before they were diagnosed with GERD were included in the study, which was published in JAMA Otolaryngology–Head & Neck Surgery (doi: 10.1001/jamaoto.2017.2561.

Lead author Charles A. Riley, MD, of Tulane University in New Orleans, and his coauthors noted that previous studies had drawn conflicting conclusions about the link between GERD and UADT malignancies. To their knowledge, this is the first study to investigate UADT malignancies specifically in the elderly in the United States.

“The increased relative risk for laryngeal and pharyngeal cancers in this population suggests an opportunity for earlier detection and intervention,” Dr. Riley and his colleagues said.

For the study, they calculated the adjusted odds ratios (aOR) of cancer in six areas of the UADT in patients with GERD vs. patients who never had GERD: larynx (2.86), hypopharynx (2.54), oropharynx (2.47), tonsil (2.14), nasopharynx (2.04), and paranasal sinuses (1.40).

The study also evaluated the relative risk of malignancy with GERD and without GERD. “These data suggest that elderly patients with GERD in the United States are 3.47, 3.23, 2.88, and 2.37 times as likely as those without GERD to be diagnosed with laryngeal, hypopharyngeal, oropharyngeal and tonsillar cancers, respectively,” Dr. Riley and his associates wrote.

These findings may point to a need for a paradigm shift like that which led to the use of screening esophagogastroduodenoscopy for patients at risk of Barrett esophagus and esophageal cancer. “A similar screening platform may benefit those patients at higher risk for the development of malignancy of the UADT, though further research is necessary,” they said.

Dr. Riley and his coauthors reported having no financial disclosures.

Source: Riley C et al. JAMA Otolaryngol Head Neck Surg. 2017 Dec 21. doi: 10.1001/jamaoto.2017.2561.

The risk for gastroesophageal reflux disease and cancer of the larynx, tonsils, and other areas of the upper aerodigestive tract was strongly associated in a longitudinal-based population study of the U.S. elderly population.

A total of 13,805 cases involving gastroesophageal reflux disease (GERD) and malignancies of the upper aerodigestive tract (UADT) and 13,805 GERD cases with no UADT from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER)-Medicare linked database in patients aged 66 years and older from 2003 through 2011 were examined. Only those who had no malignancy before they were diagnosed with GERD were included in the study, which was published in JAMA Otolaryngology–Head & Neck Surgery (doi: 10.1001/jamaoto.2017.2561.

Lead author Charles A. Riley, MD, of Tulane University in New Orleans, and his coauthors noted that previous studies had drawn conflicting conclusions about the link between GERD and UADT malignancies. To their knowledge, this is the first study to investigate UADT malignancies specifically in the elderly in the United States.

“The increased relative risk for laryngeal and pharyngeal cancers in this population suggests an opportunity for earlier detection and intervention,” Dr. Riley and his colleagues said.

For the study, they calculated the adjusted odds ratios (aOR) of cancer in six areas of the UADT in patients with GERD vs. patients who never had GERD: larynx (2.86), hypopharynx (2.54), oropharynx (2.47), tonsil (2.14), nasopharynx (2.04), and paranasal sinuses (1.40).

The study also evaluated the relative risk of malignancy with GERD and without GERD. “These data suggest that elderly patients with GERD in the United States are 3.47, 3.23, 2.88, and 2.37 times as likely as those without GERD to be diagnosed with laryngeal, hypopharyngeal, oropharyngeal and tonsillar cancers, respectively,” Dr. Riley and his associates wrote.

These findings may point to a need for a paradigm shift like that which led to the use of screening esophagogastroduodenoscopy for patients at risk of Barrett esophagus and esophageal cancer. “A similar screening platform may benefit those patients at higher risk for the development of malignancy of the UADT, though further research is necessary,” they said.

Dr. Riley and his coauthors reported having no financial disclosures.

Source: Riley C et al. JAMA Otolaryngol Head Neck Surg. 2017 Dec 21. doi: 10.1001/jamaoto.2017.2561.

The risk for gastroesophageal reflux disease and cancer of the larynx, tonsils, and other areas of the upper aerodigestive tract was strongly associated in a longitudinal-based population study of the U.S. elderly population.

A total of 13,805 cases involving gastroesophageal reflux disease (GERD) and malignancies of the upper aerodigestive tract (UADT) and 13,805 GERD cases with no UADT from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER)-Medicare linked database in patients aged 66 years and older from 2003 through 2011 were examined. Only those who had no malignancy before they were diagnosed with GERD were included in the study, which was published in JAMA Otolaryngology–Head & Neck Surgery (doi: 10.1001/jamaoto.2017.2561.

Lead author Charles A. Riley, MD, of Tulane University in New Orleans, and his coauthors noted that previous studies had drawn conflicting conclusions about the link between GERD and UADT malignancies. To their knowledge, this is the first study to investigate UADT malignancies specifically in the elderly in the United States.

“The increased relative risk for laryngeal and pharyngeal cancers in this population suggests an opportunity for earlier detection and intervention,” Dr. Riley and his colleagues said.

For the study, they calculated the adjusted odds ratios (aOR) of cancer in six areas of the UADT in patients with GERD vs. patients who never had GERD: larynx (2.86), hypopharynx (2.54), oropharynx (2.47), tonsil (2.14), nasopharynx (2.04), and paranasal sinuses (1.40).

The study also evaluated the relative risk of malignancy with GERD and without GERD. “These data suggest that elderly patients with GERD in the United States are 3.47, 3.23, 2.88, and 2.37 times as likely as those without GERD to be diagnosed with laryngeal, hypopharyngeal, oropharyngeal and tonsillar cancers, respectively,” Dr. Riley and his associates wrote.

These findings may point to a need for a paradigm shift like that which led to the use of screening esophagogastroduodenoscopy for patients at risk of Barrett esophagus and esophageal cancer. “A similar screening platform may benefit those patients at higher risk for the development of malignancy of the UADT, though further research is necessary,” they said.

Dr. Riley and his coauthors reported having no financial disclosures.

Source: Riley C et al. JAMA Otolaryngol Head Neck Surg. 2017 Dec 21. doi: 10.1001/jamaoto.2017.2561.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their first, second and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

It truly has been a rewarding experience participating in a quality improvement project and I am excited to see what the future holds. Our project, “Reducing CAUTI with Noninvasive UC Alternatives and Measure-vention,” aimed to combat catheter associated urinary tract infections, with a three-pronged approach: by reducing UC placement, performing proper maintenance of IUC, and ensuring prompt removal of unnecessary UC.

Victor Ekuta is a third-year medical student at UC San Diego.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their first, second and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

It truly has been a rewarding experience participating in a quality improvement project and I am excited to see what the future holds. Our project, “Reducing CAUTI with Noninvasive UC Alternatives and Measure-vention,” aimed to combat catheter associated urinary tract infections, with a three-pronged approach: by reducing UC placement, performing proper maintenance of IUC, and ensuring prompt removal of unnecessary UC.

Victor Ekuta is a third-year medical student at UC San Diego.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-18 year, offering two options for students to receive funding and engage in scholarly work during their first, second and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

It truly has been a rewarding experience participating in a quality improvement project and I am excited to see what the future holds. Our project, “Reducing CAUTI with Noninvasive UC Alternatives and Measure-vention,” aimed to combat catheter associated urinary tract infections, with a three-pronged approach: by reducing UC placement, performing proper maintenance of IUC, and ensuring prompt removal of unnecessary UC.

Victor Ekuta is a third-year medical student at UC San Diego.

ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

Amy Karon/Frontline Medical News

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.

ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

Amy Karon/Frontline Medical News

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.

ATLANTA – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

Amy Karon/Frontline Medical News

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507; Roussel M et al. ASH 2017 Abstract 508.