Drug Therapy

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of the combination of ibrutinib plus rituximab in patients with previously untreated or recurrent and rituximab-sensitive Waldenström macroglobulinemia.

Design. International, randomized phase 3 trial.

Setting and participants. Patients from 45 sites in 9 countries were enrolled after receiving a centrally confirmed diagnosis of Waldenström macroglobulinemia that required treatment according to current guidelines.¹ Patients who were treatment-naive or had relapsed disease were eligible. Those with relapsed disease must have demonstrated response to rituximab in the past with a duration of response of at least 12 months. Patients who were rituximab resistant or those who received rituximab within the prior 12 months were excluded.

Intervention. Patients were randomized in a 1:1 fashion to receive oral ibrutinib 420 mg once daily or placebo. All patients received rituximab 375 mg/m² at weeks 1 to 4 and 17 to 20. Treatment was continued until disease progression or intolerable adverse effects developed. Patients were stratified according to International Prognostic Scoring System for Waldenström Macroglobulinemia (IPSS) score, number of prior therapies, and performance status. Those who received placebo were permitted to crossover to receive ibrutinib at the time of progression.

Main outcome measures. The primary outcome of this study was progression-free survival (PFS). Secondary endpoints included time to next treatment, overall survival (OS), response rate, sustained hematologic improvement, quality of life, and safety. MYD88 and CXCR4 mutational status were assessed on pre-treatment bone marrow specimens.

Results. 150 patients were randomized to receive ibrutinib-rituximab (75 patients) or placebo-rituximab (75 patients). The median age was 69 years, and approximately one-third of patients were over the age of 75 years; 45% were treatment-naive. Those with relapsed disease had received a median of 2 prior treatments, and 85% of these received prior rituximab. Baseline characteristics were well balanced between the 2 groups. Mutation data was available for 136 patients enrolled, and MYD88 L265P and CXCR4 WHIM mutations were found in 85% and 36%, respectively. Rituximab therapy was completed in 93% of patients in the ibrutinib group and 71% in the placebo group.

After a median follow up of 26.5 months, the 30-month PFS was 82% in the ibrutinib group and 28% in the placebo group (median not reached vs. 20.3 months; hazard ratio 0.20, 95% confidence interval [CI] 0.11-0.38). This translated into an 80% reduction in the risk of progression or death. Overall, there was a low rate of histologic transformation to diffuse large B-cell lymphoma in the study group (2 patients in ibrutinib arm and none in placebo arm). In the treatment-naive subgroup, at 24 months the PFS rate was 84% in the ibrutinib arm compared with 59% in the placebo arm. In those with recurrent disease, the 30-month PFS was 80% in the ibrutinib arm compared with 22% in the placebo arm. Analysis across different MYD88 and CXCR4 genotypes showed consistent rates of higher PFS with ibrutinib-rituximab (Table). In addition, 30-month PFS was higher with ibrutinib regardless of IPSS score.

The 30-month OS was 94% with ibrutinib and 92% with placebo. There were 30 patients in the placebo arm that crossed over to receive ibrutinib. As assessed by the independent review committee, response rates were significantly higher with ibrutinib-rituximab (overall response rate, 92% vs. 47%). The major response rate (complete response, very good partial response, or partial response) was higher in the ibrutinib arm (72% vs. 32%). Mutation status did not affect the response rate or quality of response. Among those with at least a partial response, the median duration of response was not reached in the ibrutinib group, as compared with a median duration of response of 21.2 months in the placebo group. Serum IgM response was greater and more rapid with ibrutinib compared to placebo. Furthermore, transient increases in serum IgM levels, or “IgM flare,” was seen less frequently with the addition of ibrutinib (8% vs. 47%). No patient receiving ibrutinib required plasmapheresis. Hemoglobin response was seen more frequently with ibrutinib (73% vs. 41%).

Grade 3 or higher adverse events (AE) were seen in 60% of patients in each group. Hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%) occurred more commonly in the ibrutinib group compared with placebo. Serious AEs were seen more frequently with ibrutinib compared to placebo (43% vs. 33%). Atrial fibrillation of any grade occurred in 15% of patients receiving ibrutinib; however, 27% of these patients had a history of atrial fibrillation prior to enrollment. Bleeding occurred more frequently with ibrutinib; however, the vast majority of these were grade 1 or grade 2. Major bleeding occurred in 3 patients in each arm. No fatal adverse events were noted in the ibrutinib group, while 3 patients in the placebo group experienced a fatal event. Discontinuation rates were similar in both arms (5% vs. 4%). Dose reduction of ibrutinib occurred in 13 patients.

Conclusion. The combination of ibrutinib and rituximab reduced the risk of disease progression by 80% compared with rituximab alone. This combination should be considered as a standard treatment option for patients with symptomatic Waldenström macroglobulinemia.

Commentary

Waldenström macroglobulinemia is a B-cell lymphoma characterized by infiltrating IgM producing clonal lymphoplasmacytic cells. Observation remains the preferred approach to asymptomatic patients; however, the presence of clinical symptoms including anemia, hyperviscosity, fatigue, or other constitutional symptoms should prompt initiation of therapy. Given the relative lack of large studies to define standard treatment strategies, rituximab monotherapy has frequently been used, with response rates of approximately 40% to 50%.^2,3 Complete responses to single-agent rituximab have not been reported. Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that has shown high response rates in the relapsed setting in previous studies. A study of single-agent ibrutinib in patients with relapsed disease showed overall and major response rates of 90% and 73%, respectively.⁴ The 2-year PFS was 69%. Additionally, such studies have suggested higher response rates in patients with mutated MYD88 genotype. This data led to the approval of ibrutinib for rituximab-refractory disease. In the treatment-naive setting, at least a minor response was seen in all patients (n = 30) in a small cohort treated with ibrutinib.⁵

In the reported trial, the combination of ibrutinib plus rituximab resulted in a more robust and durable response than single-agent rituximab, with significantly prolonged PFS. Of note, the response was similar for both treatment-naive and relapsed, rituximab-sensitive patients. Interestingly, a transient increase in serum IgM level was not seen in those treated with combination ibrutinib-rituximab. Improvements in PFS and response rates were independent of IPSS score. Previous studies have suggested that response to ibrutinib is related to MYD88 and CXCR4 mutational status. For example, in a phase 2 trial of ibrutinib in previously treated patients with symptomatic disease, major response rates for MYD88 L265P/CXCR WT, MYD88 L265P/CXCR4 WHIM, and MYD88 WT/CXCR4 WT groups were 91%, 62%, and 29%, respectively.⁴ In the current study, however, responses with ibrutinib-rituximab were seen across all genotypes at similar rates. Furthermore, PFS did not differ based on mutational status.

Similar rates of grade 3 or higher AEs were observed in each arm. Atrial fibrillation did occur in 15% of patients in the ibrutinib arm, but discontinuation rates were low. In addition, bleeding complications with ibrutinib have been increasingly recognized; however, in this cohort there did not seem to be an increased risk of major bleeding, with a vast majority of the bleeding events being grade 1 or grade 2.

Applications for Clinical Practice

The combination of ibrutinib plus rituximab represents a reasonable first-line treatment for patients with Waldenstrom macroglobulinemia. Importantly, mutational status does not appear to impact response rates and thus this combination can be considered irrespective of MYD88 status.

—Daniel Isaac, DO, MS

Many breast cancer survivors and women at high risk of breast cancer suffer from genitourinary syndrome of menopause (GSM), a term that encompasses any urinary, genital, or sexual dysfunction related to a hypoestrogenic state. Although GSM is usually caused by postmenopausal estrogen loss, it can also be caused by cancer treatments such as chemotherapy, radiation, and systemic endocrine therapy (eg, tamoxifen, aromatase inhibitors). These treatments can substantially decrease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality of life.

Managing GSM in these women poses a dilemma because systemic estrogen-containing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants and moisturizers provide only minimal benefit. Fortunately, there are hormonal options, including locally applied estrogen, intravaginal dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists (ospemifene and bazedoxifene).

Here, we review the clinical management of GSM in breast cancer survivors and women at high risk of breast cancer and the efficacy and safety of available treatments, including their impact on breast cancer risk.

DRYNESS, IRRITATION, ATROPHY

The term GSM describes vulvovaginal and genitourinary symptoms associated with estrogen loss after menopause. Common symptoms are vaginal dryness, dyspareunia, irritation of genital skin, and pruritus.

LOCAL ESTROGEN THERAPY

Systemic estrogen therapy is widely used and effective for GSM, but there are concerns that it could increase the risk of breast cancer. After the Women’s Health Initiative in 2002 showed higher rates of cardiovascular disease and breast cancer with systemic estrogen-progestin use,⁵ the use of this hormone therapy declined by approximately 80%.⁶ Since then, healthcare providers have turned to local (ie, vaginal) estrogen therapies to manage GSM. These therapies have several advantages over systemic hormone therapy:

• Lower risk of adverse effects on the breast and cardiovascular system
• Greater efficacy in treating GSM
• In general, no need for progesterone when low-dose local estrogen is given to a woman with a uterus.⁷

Is locally applied estrogen systemically absorbed?

Despite these advantages, concerns remain as to whether vaginal estrogen therapy has adverse consequences associated with systemic absorption, particularly from atrophic vaginal tissues.

Santen,⁸ in a 2015 review of 33 studies, concluded that systemic absorption from low-dose vaginal estrogen is minimal, which provides some rationale for using it to treat vulvovaginal atrophy in postmenopausal women. This finding also suggests that the US Food and Drug Administration (FDA) “black box” warning of possible toxicities with vaginal estrogen is likely overstated, given that serum estrogen levels remained within normal postmenopausal levels.

Nevertheless, many providers are apprehensive about prescribing vaginal estrogen in women with a history of breast cancer because the threshold for systemic estrogen levels associated with breast cancer recurrence has not been established.

ACOG statement. In 2016, a committee of the American College of Obstetricians and Gynecologists cited data showing that low-dose vaginal estrogens do not result in sustained serum estrogen levels exceeding the normal postmenopausal range, and that the use of vaginal estrogens does not increase the risk of cancer recurrence.⁹ However, they recommend caution with vaginal estrogen use, especially in women with a history of estrogen-dependent breast cancer, reserving it for patients with GSM symptoms nonresponsive to nonhormonal treatment and specifying that it be used in low doses.

Vaginal estrogen formulations

Several types of locally applied estrogens are available, each with different properties and affinity for estrogen receptors. These include conjugated estrogens, 17-beta estradiol, estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: creams, rings, and tablets (Table 2).

Vaginal creams. Two vaginal creams are available, one (Estrace) containing 17-beta estradiol and the other (Premarin) containing conjugated estrogens.

The FDA-approved dosage for 17-beta estradiol is 2 to 4 g/day for 1 or 2 weeks, then gradually reduced to half the dose for a similar time. Maintenance dosing is 1 g 1 to 3 times per week. However, the ACOG statement notes that the FDA-approved dosages are higher than those proven to be effective and currently used in clinical practice, eg, 0.5 g twice a week.⁹

The FDA-approved dosage of conjugated estrogen cream for moderate to severe dyspareunia is 0.5 g daily for 21 days, then off for 7 days, or 0.5 g twice a week.

Vaginal tablets. The vaginal tablet Vagifem and its generic equivalent Yuvafem contain 10 µg of estradiol hemihydrate. The FDA-approved dosage is 10 µg daily for 2 weeks, followed by 10 µg twice a week, inserted into the lower third of the vagina. This dosage is significantly lower than that of estrogen creams.

Vaginal insert. A newly approved vaginal insert (Imvexxy) contains estradiol 4 µg (the lowest dose of vaginal estradiol available) or 10 µg, in a coconut oil vehicle. Its indications are for moderate to severe dyspareunia due to menopause and atrophic vaginitis due to menopause. A study cited in its package insert (www.accessdata.fda.gov/drugsatfda_docs/label/2018/208564s000lbl.pdf) showed that, in patients who used this product, systemic absorption of estradiol remained within the postmenopausal range. Its effects on breast cancer have not yet been studied.

Vaginal rings. Two vaginal rings are marketed. One (Estring) contains 17-beta estradiol, and the other (Femring) contains estradiol acetate. Only the 17-beta estradiol ring delivers a low dose to vaginal tissues, releasing 7.5 µg/day for 90 days. The estradiol acetate ring releases 0.05 mg/day or 0.10 mg/day and is a systemic treatment meant to be used with a progestin, not for local therapy.

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.

Symptoms of GSM are common in breast cancer survivors, both pre- and postmenopausal, especially those treated with tamoxifen or an aromatase inhibitor. Estimates are that 60% of postmenopausal breast cancer survivors and 40% of premenopausal breast cancer survivors suffer from GSM.²⁶ Unfortunately, many women do not seek medical attention for their symptoms.

A variety of hormonal and nonhormonal options are available for these patients. We recommend an interdisciplinary approach to treatment, with the decision to use hormonal options made in collaboration with the patient’s oncologist and the patient herself, in an informed, shared decision-making process that takes into consideration the risks and possible benefits depending on the symptoms.

The first step in selecting a management plan for GSM symptoms in women with breast cancer is to conduct a thorough assessment to provide data for individualizing the care plan. The decision to use a hormonal option should be made in collaboration with a woman’s oncologist and should include an informed decision-making process during which the potential risks and benefits, including the breast cancer impact, are fully disclosed.

Alternatives to systemic estrogen

Vaginal estrogen is an effective and safe option to treat GSM in women with either estrogen receptor-negative or estrogen receptor-positive breast cancer. It often completely cures the symptoms without any noticeable increase in serum estrogen levels.

Vaginal DHEA therapy is a nonestrogen option shown to effectively treat GSM without increasing systemic levels of estrogen or testosterone. This profile makes vaginal DHEA therapy a particularly attractive treatment for symptoms of GSM in women at risk for breast cancer.

Use of an estrogen receptor agonist/antagonist in breast cancer survivors needs careful consideration. Ospemifene has antiestrogenic effects that make it a good option for women with bone loss and those at high risk for breast cancer, but it should not be used concurrently with tamoxifen or raloxifene. Additionally, ospemifene does not cause uterine hyperplasia, so it can be used in women with a uterus.

Although more study is needed, we do have options to improve the overall quality of life in breast cancer survivors with GSM.

Many breast cancer survivors and women at high risk of breast cancer suffer from genitourinary syndrome of menopause (GSM), a term that encompasses any urinary, genital, or sexual dysfunction related to a hypoestrogenic state. Although GSM is usually caused by postmenopausal estrogen loss, it can also be caused by cancer treatments such as chemotherapy, radiation, and systemic endocrine therapy (eg, tamoxifen, aromatase inhibitors). These treatments can substantially decrease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality of life.

Managing GSM in these women poses a dilemma because systemic estrogen-containing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants and moisturizers provide only minimal benefit. Fortunately, there are hormonal options, including locally applied estrogen, intravaginal dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists (ospemifene and bazedoxifene).

Here, we review the clinical management of GSM in breast cancer survivors and women at high risk of breast cancer and the efficacy and safety of available treatments, including their impact on breast cancer risk.

DRYNESS, IRRITATION, ATROPHY

The term GSM describes vulvovaginal and genitourinary symptoms associated with estrogen loss after menopause. Common symptoms are vaginal dryness, dyspareunia, irritation of genital skin, and pruritus.

LOCAL ESTROGEN THERAPY

Systemic estrogen therapy is widely used and effective for GSM, but there are concerns that it could increase the risk of breast cancer. After the Women’s Health Initiative in 2002 showed higher rates of cardiovascular disease and breast cancer with systemic estrogen-progestin use,⁵ the use of this hormone therapy declined by approximately 80%.⁶ Since then, healthcare providers have turned to local (ie, vaginal) estrogen therapies to manage GSM. These therapies have several advantages over systemic hormone therapy:

• Lower risk of adverse effects on the breast and cardiovascular system
• Greater efficacy in treating GSM
• In general, no need for progesterone when low-dose local estrogen is given to a woman with a uterus.⁷

Is locally applied estrogen systemically absorbed?

Despite these advantages, concerns remain as to whether vaginal estrogen therapy has adverse consequences associated with systemic absorption, particularly from atrophic vaginal tissues.

Santen,⁸ in a 2015 review of 33 studies, concluded that systemic absorption from low-dose vaginal estrogen is minimal, which provides some rationale for using it to treat vulvovaginal atrophy in postmenopausal women. This finding also suggests that the US Food and Drug Administration (FDA) “black box” warning of possible toxicities with vaginal estrogen is likely overstated, given that serum estrogen levels remained within normal postmenopausal levels.

Nevertheless, many providers are apprehensive about prescribing vaginal estrogen in women with a history of breast cancer because the threshold for systemic estrogen levels associated with breast cancer recurrence has not been established.

ACOG statement. In 2016, a committee of the American College of Obstetricians and Gynecologists cited data showing that low-dose vaginal estrogens do not result in sustained serum estrogen levels exceeding the normal postmenopausal range, and that the use of vaginal estrogens does not increase the risk of cancer recurrence.⁹ However, they recommend caution with vaginal estrogen use, especially in women with a history of estrogen-dependent breast cancer, reserving it for patients with GSM symptoms nonresponsive to nonhormonal treatment and specifying that it be used in low doses.

Vaginal estrogen formulations

Several types of locally applied estrogens are available, each with different properties and affinity for estrogen receptors. These include conjugated estrogens, 17-beta estradiol, estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: creams, rings, and tablets (Table 2).

Vaginal creams. Two vaginal creams are available, one (Estrace) containing 17-beta estradiol and the other (Premarin) containing conjugated estrogens.

The FDA-approved dosage for 17-beta estradiol is 2 to 4 g/day for 1 or 2 weeks, then gradually reduced to half the dose for a similar time. Maintenance dosing is 1 g 1 to 3 times per week. However, the ACOG statement notes that the FDA-approved dosages are higher than those proven to be effective and currently used in clinical practice, eg, 0.5 g twice a week.⁹

The FDA-approved dosage of conjugated estrogen cream for moderate to severe dyspareunia is 0.5 g daily for 21 days, then off for 7 days, or 0.5 g twice a week.

Vaginal tablets. The vaginal tablet Vagifem and its generic equivalent Yuvafem contain 10 µg of estradiol hemihydrate. The FDA-approved dosage is 10 µg daily for 2 weeks, followed by 10 µg twice a week, inserted into the lower third of the vagina. This dosage is significantly lower than that of estrogen creams.

Vaginal insert. A newly approved vaginal insert (Imvexxy) contains estradiol 4 µg (the lowest dose of vaginal estradiol available) or 10 µg, in a coconut oil vehicle. Its indications are for moderate to severe dyspareunia due to menopause and atrophic vaginitis due to menopause. A study cited in its package insert (www.accessdata.fda.gov/drugsatfda_docs/label/2018/208564s000lbl.pdf) showed that, in patients who used this product, systemic absorption of estradiol remained within the postmenopausal range. Its effects on breast cancer have not yet been studied.

Vaginal rings. Two vaginal rings are marketed. One (Estring) contains 17-beta estradiol, and the other (Femring) contains estradiol acetate. Only the 17-beta estradiol ring delivers a low dose to vaginal tissues, releasing 7.5 µg/day for 90 days. The estradiol acetate ring releases 0.05 mg/day or 0.10 mg/day and is a systemic treatment meant to be used with a progestin, not for local therapy.

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.

Symptoms of GSM are common in breast cancer survivors, both pre- and postmenopausal, especially those treated with tamoxifen or an aromatase inhibitor. Estimates are that 60% of postmenopausal breast cancer survivors and 40% of premenopausal breast cancer survivors suffer from GSM.²⁶ Unfortunately, many women do not seek medical attention for their symptoms.

A variety of hormonal and nonhormonal options are available for these patients. We recommend an interdisciplinary approach to treatment, with the decision to use hormonal options made in collaboration with the patient’s oncologist and the patient herself, in an informed, shared decision-making process that takes into consideration the risks and possible benefits depending on the symptoms.

The first step in selecting a management plan for GSM symptoms in women with breast cancer is to conduct a thorough assessment to provide data for individualizing the care plan. The decision to use a hormonal option should be made in collaboration with a woman’s oncologist and should include an informed decision-making process during which the potential risks and benefits, including the breast cancer impact, are fully disclosed.

Alternatives to systemic estrogen

Vaginal estrogen is an effective and safe option to treat GSM in women with either estrogen receptor-negative or estrogen receptor-positive breast cancer. It often completely cures the symptoms without any noticeable increase in serum estrogen levels.

Vaginal DHEA therapy is a nonestrogen option shown to effectively treat GSM without increasing systemic levels of estrogen or testosterone. This profile makes vaginal DHEA therapy a particularly attractive treatment for symptoms of GSM in women at risk for breast cancer.

Use of an estrogen receptor agonist/antagonist in breast cancer survivors needs careful consideration. Ospemifene has antiestrogenic effects that make it a good option for women with bone loss and those at high risk for breast cancer, but it should not be used concurrently with tamoxifen or raloxifene. Additionally, ospemifene does not cause uterine hyperplasia, so it can be used in women with a uterus.

Although more study is needed, we do have options to improve the overall quality of life in breast cancer survivors with GSM.

Many breast cancer survivors and women at high risk of breast cancer suffer from genitourinary syndrome of menopause (GSM), a term that encompasses any urinary, genital, or sexual dysfunction related to a hypoestrogenic state. Although GSM is usually caused by postmenopausal estrogen loss, it can also be caused by cancer treatments such as chemotherapy, radiation, and systemic endocrine therapy (eg, tamoxifen, aromatase inhibitors). These treatments can substantially decrease systemic estrogen levels, causing GSM symptoms that can profoundly worsen quality of life.

Managing GSM in these women poses a dilemma because systemic estrogen-containing therapies can increase the risk of breast cancer, and nonhormonal vaginal lubricants and moisturizers provide only minimal benefit. Fortunately, there are hormonal options, including locally applied estrogen, intravaginal dehydroepiandrosterone (DHEA), and estrogen receptor agonists/antagonists (ospemifene and bazedoxifene).

Here, we review the clinical management of GSM in breast cancer survivors and women at high risk of breast cancer and the efficacy and safety of available treatments, including their impact on breast cancer risk.

DRYNESS, IRRITATION, ATROPHY

The term GSM describes vulvovaginal and genitourinary symptoms associated with estrogen loss after menopause. Common symptoms are vaginal dryness, dyspareunia, irritation of genital skin, and pruritus.

LOCAL ESTROGEN THERAPY

Systemic estrogen therapy is widely used and effective for GSM, but there are concerns that it could increase the risk of breast cancer. After the Women’s Health Initiative in 2002 showed higher rates of cardiovascular disease and breast cancer with systemic estrogen-progestin use,⁵ the use of this hormone therapy declined by approximately 80%.⁶ Since then, healthcare providers have turned to local (ie, vaginal) estrogen therapies to manage GSM. These therapies have several advantages over systemic hormone therapy:

• Lower risk of adverse effects on the breast and cardiovascular system
• Greater efficacy in treating GSM
• In general, no need for progesterone when low-dose local estrogen is given to a woman with a uterus.⁷

Is locally applied estrogen systemically absorbed?

Despite these advantages, concerns remain as to whether vaginal estrogen therapy has adverse consequences associated with systemic absorption, particularly from atrophic vaginal tissues.

Santen,⁸ in a 2015 review of 33 studies, concluded that systemic absorption from low-dose vaginal estrogen is minimal, which provides some rationale for using it to treat vulvovaginal atrophy in postmenopausal women. This finding also suggests that the US Food and Drug Administration (FDA) “black box” warning of possible toxicities with vaginal estrogen is likely overstated, given that serum estrogen levels remained within normal postmenopausal levels.

Nevertheless, many providers are apprehensive about prescribing vaginal estrogen in women with a history of breast cancer because the threshold for systemic estrogen levels associated with breast cancer recurrence has not been established.

ACOG statement. In 2016, a committee of the American College of Obstetricians and Gynecologists cited data showing that low-dose vaginal estrogens do not result in sustained serum estrogen levels exceeding the normal postmenopausal range, and that the use of vaginal estrogens does not increase the risk of cancer recurrence.⁹ However, they recommend caution with vaginal estrogen use, especially in women with a history of estrogen-dependent breast cancer, reserving it for patients with GSM symptoms nonresponsive to nonhormonal treatment and specifying that it be used in low doses.

Vaginal estrogen formulations

Several types of locally applied estrogens are available, each with different properties and affinity for estrogen receptors. These include conjugated estrogens, 17-beta estradiol, estradiol acetate, and estradiol hemihydrate. Three delivery systems are FDA-approved: creams, rings, and tablets (Table 2).

Vaginal creams. Two vaginal creams are available, one (Estrace) containing 17-beta estradiol and the other (Premarin) containing conjugated estrogens.

The FDA-approved dosage for 17-beta estradiol is 2 to 4 g/day for 1 or 2 weeks, then gradually reduced to half the dose for a similar time. Maintenance dosing is 1 g 1 to 3 times per week. However, the ACOG statement notes that the FDA-approved dosages are higher than those proven to be effective and currently used in clinical practice, eg, 0.5 g twice a week.⁹

The FDA-approved dosage of conjugated estrogen cream for moderate to severe dyspareunia is 0.5 g daily for 21 days, then off for 7 days, or 0.5 g twice a week.

Vaginal tablets. The vaginal tablet Vagifem and its generic equivalent Yuvafem contain 10 µg of estradiol hemihydrate. The FDA-approved dosage is 10 µg daily for 2 weeks, followed by 10 µg twice a week, inserted into the lower third of the vagina. This dosage is significantly lower than that of estrogen creams.

Vaginal insert. A newly approved vaginal insert (Imvexxy) contains estradiol 4 µg (the lowest dose of vaginal estradiol available) or 10 µg, in a coconut oil vehicle. Its indications are for moderate to severe dyspareunia due to menopause and atrophic vaginitis due to menopause. A study cited in its package insert (www.accessdata.fda.gov/drugsatfda_docs/label/2018/208564s000lbl.pdf) showed that, in patients who used this product, systemic absorption of estradiol remained within the postmenopausal range. Its effects on breast cancer have not yet been studied.

Vaginal rings. Two vaginal rings are marketed. One (Estring) contains 17-beta estradiol, and the other (Femring) contains estradiol acetate. Only the 17-beta estradiol ring delivers a low dose to vaginal tissues, releasing 7.5 µg/day for 90 days. The estradiol acetate ring releases 0.05 mg/day or 0.10 mg/day and is a systemic treatment meant to be used with a progestin, not for local therapy.

After menopause, as the ovaries stop making estrogen from androstenedione, some production continues in other tissues, with DHEA as the primary precursor of androgens that are ultimately converted to estrogen. This has led to the theory that the cause of GSM is not estrogen deficiency but androgen deficiency. Evidence reviewed by Labrie et al¹¹ shows that vulvovaginal atrophy is caused by decreased DHEA availability, which in turn causes sex steroid deficiency-related menopausal symptoms.¹¹ Thus, it is reasonable to conclude that menopausal symptoms can be relieved by giving DHEA.

This theory has been borne out in clinical trials, in which DHEA in a vaginal tablet formulation increased the maturation of vaginal cells and lowered vaginal pH, leading to relief of GSM symptoms.¹²

The only DHEA product FDA-approved for treating GSM-related symptoms is prasterone (Intrarosa), indicated for moderate to severe dyspareunia due to vulvovaginal atrophy. The recommended dosing is a single 6.5-mg intravaginal tablet (0.5% prasterone) inserted nightly at bedtime. Its efficacy for treating hypoactive sexual desire disorder in postmenopausal women is being investigated.

Breast cancer implications

Because DHEA is converted to estrogen by aromatization, healthcare providers might hesitate to use it in women who have a history of hormone-sensitive cancer. Data on the safety of intravaginal DHEA use in breast cancer survivors are limited. However, studies have found that prasterone has highly beneficial effects on dyspareunia, vaginal dryness, and objective signs of vulvovaginal atrophy without significant drug-related adverse effects.^12,13 In these studies, serum estrogen levels in women treated with DHEA were within the values observed in normal postmenopausal women. In addition, there are no aromatase enzymes in the endometrium, so even high doses of vaginal DHEA (in contrast to high doses of vaginal estrogen) will not stimulate the endometrium.

Clinically, this evidence indicates that DHEA exerts both estrogenic and androgenic activity in the vagina without increasing serum estrogen levels, making it a good alternative to topical estrogen therapy.

OSPEMIFENE: AN ESTROGEN RECEPTOR AGONIST/ANTAGONIST

Ospemifene (Osphena) is an estrogen receptor agonist/antagonist, a class of drugs previously called selective estrogen receptor modulators (SERMs). It is FDA-approved to treat moderate to severe dyspareunia secondary to vulvar and vaginal atrophy.

Ospemifene has unique estrogenic effects on the vaginal mucosa, having been shown to increase the number of epithelial cells, lower the vaginal pH, and decrease the percentage of parabasal cells seen on Papanicolaou smears after 12 weeks of use.¹⁴

Unlike tamoxifen, another drug of this class, ospemifene does not change the endometrial lining.¹⁴ Similarly, ospemifene acts as an estrogenic agonist in bone and, thus, has the potential for use in preventing and managing osteoporosis or for use in women at risk of fractures.

Breast cancer impact

In preclinical trials, ospemifene was found to have antiestrogenic effects on breast tissue, similar to those seen with tamoxifen.

In a model using human tumor grafts, ospemifene decreased tumor growth in mice implanted with estrogen receptor-positive breast cancer cells.¹⁵

In a mouse model using breast cancer cells that were biologically and histologically similar to those of humans, ospemifene had strong antiestrogenic effects on the breast tissue.¹⁶ The evidence suggests that ospemifene has a favorable effect on vulvar and vaginal atrophy.¹⁷

Ospemifene is FDA-approved to treat moderate to severe dyspareunia secondary to menopause. Recommended dosing is 60 mg/day orally with food.

Its antiestrogenic effects on breast tissue make it a promising option for women with a history of estrogen-receptor positive breast cancer. However, further study is needed to fully understand its effects on human breast tissue. According to the manufacturer’s package insert (www.osphena.com/files/pdf/osphena_prescribing_information.pdf), because the drug has not been adequately studied in women with breast cancer, it should not be used in women with known or suspected breast cancer or a history of breast cancer.

CONJUGATED ESTROGENS PLUS BAZEDOXIFENE

The combination of conjugated estrogens and bazedoxifene (Duavee) is a progesterone-free alternative for treating various menopausal symptoms. Bazedoxifene is another estrogen receptor agonist/antagonist, and it was added to counteract estrogen’s effects on the endometrium, thus replacing progesterone. This protective effect has been validated in clinical trials, which also found a favorable safety profile in breast tissue.^18,19

SMART trials. The efficacy of this combination was studied in a series of large phase 3 multicenter trials called the SMART (Selective Estrogens, Menopause, and Response to Therapy) trials.^20–23 Treated patients had markedly fewer vasomotor symptoms at 1 year, along with an increase in superficial cells and intermediate cells of the vaginal epithelium and a decrease in parabasal cells. They also had a substantial decrease in the incidence of dyspareunia.

Its effects on breast tissue were evaluated in the SMART-5 trial. Therapy had no net impact on breast density, suggesting that it has an estrogen-neutral effect on the breast.²³

These results suggest that combined conjugated estrogens and bazedoxifene could be a noteworthy treatment option for GSM in women with a history of estrogen receptor-positive breast cancer, particularly in those with vasomotor symptoms and bone loss. However, the combination has not been studied specifically in breast cancer survivors.

Dosage. The FDA-approved dosing is 20 mg/0.45 mg per day orally to treat vasomotor symptoms, GSM, and osteoporosis in postmenopausal women with a uterus.

LASER THERAPY AND RADIOFREQUENCY HEAT: AN OFF-LABEL OPTION

Low-dose radiofrequency thermal therapy, delivered by carbon dioxide laser or by radiofrequency heat, has been used with some success to treat urinary stress incontinence and vaginal laxity in postpartum women. It may be an option for GSM, although it is not FDA-approved for this indication, and the FDA has recently issued a warning about it.²⁴

Marketing literature promotes laser therapy as an effective option that stimulates vaginal connective tissue to produce new collagen, which then promotes improved blood flow and tissue regeneration for vaginal lubrication and elasticity.

A study comparing fractional carbon dioxide vaginal laser treatment and local estrogen therapy in postmenopausal women with vulvovaginal atrophy found that laser therapy was an effective treatment for vulvovaginal atrophy (dyspareunia, dryness, and burning), both alone and with local estrogen.²⁵

Despite the promising effects of laser therapy for treating vulvovaginal atrophy in GSM, studies have not determined its short-term or long-term safety profile. Furthermore, laser therapy does not improve impaired sexual function, ie, decreased libido, arousal, and sexual satisfaction. Another important consideration is that the cost of laser therapy in 2017 was estimated to be $2,000 to $3,000 per treatment, not covered by healthcare insurance.

Symptoms of GSM are common in breast cancer survivors, both pre- and postmenopausal, especially those treated with tamoxifen or an aromatase inhibitor. Estimates are that 60% of postmenopausal breast cancer survivors and 40% of premenopausal breast cancer survivors suffer from GSM.²⁶ Unfortunately, many women do not seek medical attention for their symptoms.

A variety of hormonal and nonhormonal options are available for these patients. We recommend an interdisciplinary approach to treatment, with the decision to use hormonal options made in collaboration with the patient’s oncologist and the patient herself, in an informed, shared decision-making process that takes into consideration the risks and possible benefits depending on the symptoms.

The first step in selecting a management plan for GSM symptoms in women with breast cancer is to conduct a thorough assessment to provide data for individualizing the care plan. The decision to use a hormonal option should be made in collaboration with a woman’s oncologist and should include an informed decision-making process during which the potential risks and benefits, including the breast cancer impact, are fully disclosed.

Alternatives to systemic estrogen

Vaginal estrogen is an effective and safe option to treat GSM in women with either estrogen receptor-negative or estrogen receptor-positive breast cancer. It often completely cures the symptoms without any noticeable increase in serum estrogen levels.

Vaginal DHEA therapy is a nonestrogen option shown to effectively treat GSM without increasing systemic levels of estrogen or testosterone. This profile makes vaginal DHEA therapy a particularly attractive treatment for symptoms of GSM in women at risk for breast cancer.

Use of an estrogen receptor agonist/antagonist in breast cancer survivors needs careful consideration. Ospemifene has antiestrogenic effects that make it a good option for women with bone loss and those at high risk for breast cancer, but it should not be used concurrently with tamoxifen or raloxifene. Additionally, ospemifene does not cause uterine hyperplasia, so it can be used in women with a uterus.

Although more study is needed, we do have options to improve the overall quality of life in breast cancer survivors with GSM.

In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and 9 other professional associations published a new guideline on high blood pressure in adults.¹ Their document addresses a range of topics relevant to preventing, diagnosing, and managing hypertension. It incorporates evidence from randomized controlled trials, including the Systolic Blood Pressure Intervention Trial (SPRINT),² systematic reviews, and expert opinion.

The new guidelines contain many noteworthy changes, some of which are generating intense debate and discussion. Here, we provide our opinions to help practicing clinicians broaden their perspective and make informed decisions about management.

ACC AND AHA ARE NOW RESPONSIBLE FOR HYPERTENSION GUIDELINES

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), organized by the National Heart, Lung, and Blood Institute, began issuing hypertension guidelines in 1977. Based on observational and clinical trial data, succeeding JNC reports recommended ever-lower blood pressure goals, with emphasis shifting to treatment of systolic hypertension.

The last official JNC report—JNC 7—was published in 2003.³ In 2013, the Institute transferred the responsibility for cardiovascular prevention guidelines to the ACC and AHA.⁴

A report from the panel members appointed to JNC 8 was published independently in 2014.⁵ It focused on a few key questions and used evidence limited to randomized controlled trials. In this report, the panel relaxed the goals for many subgroups, leading to criticism from many professional societies and from some members of the panel writing group.⁶

WHAT'S NEW IN THE 2017 GUIDELINES?

The new ACC/AHA guidelines contain a number of changes from previous documents that have been the topic of debate.

New definition and classification of hypertension

Strong recommendation, based on moderate-quality evidence­.

Our opinion. While this new classification is intended to promote closer monitoring and earlier intervention to lower cardiovascular event rates, creating a new level of disease may lead to more pharmacologic treatment for those with lower risk, without emphasis on lifestyle modifications.

Emphasis on measurement technique and out-of-office measurements

Strong recommendation, based on expert opinion, for accurate measurement of blood pressure in the office, high-quality evidence from systematic review for out-of-office measurement.

Appropriate management of hypertension entails accurate blood pressure measurement. While office-based measurement remains the most commonly used method, this “snapshot” may not reflect a patient’s true baseline blood pressure.

Out-of-office measurements. Based on the results of a systematic review commissioned by the guideline committee, out-of-office measurements are now recommended to confirm the diagnosis of hypertension and to assess response to therapy.

Ambulatory blood pressure monitoring should be strongly considered as the preferred method for out-of-office monitoring; home blood pressure monitoring can be done if ambulatory monitoring is not feasible. Ambulatory monitoring provides additional information on nighttime blood pressure, including the dipping status (normal defined as a nighttime blood pressure decrease of 10% to 20%). Ambulatory monitoring predicts long-term cardiovascular outcomes independent of office blood pressure, and elevated nighttime pressure and non-dipping have been shown to be independently associated with increased cardiovascular mortality rates.^8,9 Unfortunately, despite evidence supporting its use, ambulatory blood pressure monitoring is not widely available for a variety of reasons, including high cost (roughly $2,000–$4,000) and minimal reimbursement.

Out-of-office measurements can also detect white coat hypertension and masked hypertension. White coat hypertension is defined as blood pressure that is elevated in the office but normal in an out-of-office setting, and masked hypertension is blood pressure that is normal in the office and elevated in an out-of-office setting. Currently, pharmacologic therapy is not recommended to treat white coat hypertension, and treatment for masked hypertension should be the same as for sustained hypertension.

While the guidelines do not comment specifically on manual office measurement vs automated office measurements using devices that take multiple measurements with the patient alone in the room to reduce the white coat effect, they acknowledge “increasing evidence” favoring the use of automated office measurement.

Proper technique for measuring blood pressure is appropriately emphasized; correct patient positioning, allowing a period of rest, and using the appropriate cuff size are all important. Unfortunately, many busy clinical practices may not follow correct technique when measuring blood pressure in the office, leading to misdiagnosis and unnecessary pharmacologic therapy that may result in adverse events.

Of note, the SPRINT trial, which informed many of the new guideline recommendations, followed a strict protocol of blood pressure measurement with an automated device, checking sitting blood pressure 3 times at 1-minute intervals, with the patient alone in the room and without an observer present at many of the sites.¹⁰

Most guidelines^11,12 agree on an average of at least 135/85 mm Hg as the threshold for diagnosing hypertension by home monitoring, or an average daytime pressure of at least 135/85 mm Hg by ambulatory monitoring, corresponding with office-based blood pressure of 140/90 mm Hg.­ However, the new guidelines recommend a lower threshold of 130/80 mm Hg for both home monitoring and average daytime ambulatory monitoring, corresponding with an office blood pressure of 130/80 mm Hg. They do not specify whether the office-based measurement is manual or automated.

Our opinion. Since office-based measurement will likely remain the principal method for managing hypertension due to constraints with ambulatory or home monitoring, the use of automated devices for office measurement should be strongly considered. Studies have shown that, compared with routine office measurements, automated measurements more closely approximate those obtained by ambulatory and home blood pressure monitoring.¹³

Risk-based approach to hypertension management

The algorithm for hypertension management now incorporates objective assessment of cardiovascular risk. Specifically, it calls for estimation of the 10-year risk of atherosclerotic cardiovascular disease, defined as coronary heart disease death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

The information required to estimate risk includes age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, use of blood pressure-lowering medication, diabetes status, and smoking status. The guideline recommends an easy-to-use online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator).

A 10-year risk of 10% or more is designated as the cutoff between high risk and low risk. However, this is not based on trial evidence, and the risk calculator has not been verified in prospective trials to show that its use reduces cardiovascular events. The SPRINT trial,² which was a study of blood pressure-lowering in high-risk patients, used a 10-year risk of 15% or more based on the Framingham risk score to delineate high risk.

Additionally, the 10-year risk calculator is valid only in patients ages 40 through 79, and some studies indicate that it may overestimate risk in older adults.^14,15 This overestimation may lead to patients being started on pharmacologic therapy when it may not truly be indicated. The risk calculator controversy has been discussed in a previous issue of this journal.¹⁶

Blood pressure goals

Strong recommendation for known cardiovascular disease or atherosclerotic cardiovascular disease risk 10% or greater, weak recommendation for risk less than 10%, based on moderate-quality evidence for systolic blood pressure, expert opinion for diastolic.

The guidelines recommend a blood pressure goal of less than 130/80 mm Hg for all patients, including the elderly and patients with chronic kidney disease or diabetes.

The SPRINT trial,² which showed better cardiovascular outcomes in the intensive treatment group (aiming for systolic pressure < 120 mm Hg) compared with a standard treatment group (aiming for systolic pressure < 140 mm Hg), excluded participants with diabetes and severe chronic kidney disease (estimated glomerular filtration rate < 20 mL/min/m² and proteinuria > 1 g/day), and those who were in nursing homes or had dementia.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial showed that intensive blood pressure control did not have cardiovascular benefits compared with standard therapy.¹⁷ However, many now believe that the study may have been underpowered due to its design, and a meta-analysis of the results from SPRINT and ACCORD suggested that findings from both trials were consistent, favoring intensive blood pressure control in a high-risk population.¹⁸

While the totality of evidence favors a lower achieved blood pressure for many patients, this lower goal may be difficult to achieve in many, particularly those with vascular stiffness, which is common in the elderly. These patients also tend to have low diastolic pressure, and lowering diastolic pressure below 60 mm Hg in those with documented coronary artery disease could increase the risk of adverse cardiovascular outcomes.^19,20 The guidelines do not address the potential issues with lowering diastolic blood pressure.

Our opinion. While a “universal” blood pressure goal may simplify decision-making, we believe it is important to individualize goals, taking into account patient characteristics, lifestyle factors, medication side effects, patient preferences, cost issues, and adherence to therapy.

The goal blood pressure should also consider the method of measurement. Systolic blood pressure readings have been reported to be 5 to 10 mm Hg lower with automated office measurement than with routine office measurement.²¹

It is also not clear that the magnitude of absolute benefit from pursuing more intensive blood pressure control with antihypertensive therapy in patients with high cardiovascular risk (as in SPRINT) would translate to similar benefits in a lower-risk population. Thus, we believe that in patients with lower cardiovascular risk, a goal blood pressure of less than 140/90 mm Hg (if routine office measurement is done) and less than 135/85 mm Hg (if automated office measurement is done) would be reasonable.

We also believe that it is reasonable to relax these goals in the very elderly (age ≥ 80), especially those who are frail and at risk of falls, with low diastolic pressures. In these patients, we recommend individualizing blood pressure goals that can be achieved without significant side effects from antihypertensive therapy.

Nonpharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials

Nonpharmacologic therapy and lifestyle modification are appropriately emphasized in the new guidelines. Most of the lifestyle changes that are recommended are in concordance with prior JNC 7 recommendations.³

Recognizing the roles of sodium and potassium in the pathogenesis of hypertension, the guidelines emphasize a diet that is higher in potassium, the DASH (Dietary Approaches to Stop Hypertension) diet, and a low-sodium diet. The recommended optimal goal of sodium intake of less than 1,500 mg/day may be difficult to achieve with a Western diet, and there is debate about the potential adverse effects of a very-low sodium diet.²² The general recommendation for sodium intake of less than 2,300 mg/day is supported in the literature, and it is unclear if further reduction has additional beneficial effects on blood pressure.²³

The guidelines recommend a 3- to 6-month reassessment of patients who are prescribed risk-factor modification, but are unclear about initiation of pharmacologic therapy or other steps if these low-risk patients have not responded to lifestyle modifications alone at the time of reassessment.

Pharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials for systolic blood pressure, expert opinion for diastolic blood pressure for those with atherosclerotic cardiovascular disease risk 10% or greater, and limited data for those with risk less than 10%.

Pharmacologic therapy is recommended in patients with stage 1 hypertension and pre-existing cardiovascular disease or 10-year risk of atherosclerotic cardiovascular disease of 10% or more, and in those with stage 2 hypertension even if their 10-year risk is less than 10%.

In the absence of compelling indications, the primary drugs recommended for initial therapy are:

• Thiazide or thiazide-type diuretics (preferably chlorthalidone)
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Calcium channel blockers (CCBs).

In black adults, thiazide diuretics or CCBs are recommended for initial therapy. Beta-blockers are not recommended as first-line agents in the absence of a compelling indication, although meta-analyses that suggested beta-blockers are less effective than other classes of agents included trials that used beta-blockers in doses now considered suboptimal. ACE inhibitors or ARBs are recommended as initial therapy in proteinuric patients with chronic kidney disease or diabetes. Combining an ACE inhibitor and an ARB or renin inhibitor is potentially harmful and is not recommended. The guidelines provide a helpful table describing important characteristics and available dosage forms of the commonly used antihypertensive agents.

These recommendations are concordant with the JNC 8 panel recommendations,⁵ and differ from JNC 7, which recommended thiazide-type diuretics as first-line therapy.³ The European guidelines recommend that all major classes of antihypertensive agents, including beta-blockers, are suitable for initiation of therapy.²⁴ The UK National Institute for Clinical Excellence guidelines adopt an age-based approach to deciding initial therapy—with ACE inhibitors or ARBs favored in those below the age of 55 and CCBs in those who are 55 and older.²⁵

Starting with a single antihypertensive agent is recommended for stage 1 hypertension with increased cardiovascular risk, and starting with 2 agents (either separately or in fixed-dose combination) is recommended for stage 2 hypertension. The guidelines emphasize a team-based approach to improve hypertension care, using adjunctive interventions such as telehealth strategies and leveraging electronic medical records to guide quality improvement initiatives.

Our opinion. We agree with Bakris and Sorrentino^₂₆ that general patient profiles should be considered to decide on efficient pharmacologic management in clinical practice—thiazide diuretics would be best in those who are volume-expanded; ACE inhibitors, ARBs, or CCBs in those who are obese or have metabolic syndrome; and beta-blockers or nondihydropyridine CCBs in those who are hyperadrenergic. More patients will likely be classified as having resistant hypertension based on the blood pressure goal of less than 130/80 mm Hg, which may require greater use of mineralocorticoid receptor antagonists such as spironolactone.

STRENGTHS AND LIMITATIONS

The new guidelines stress correct technique of blood pressure measurement, out-of-office and self-monitoring of blood pressure, and lifestyle modifications. In addition, they comprehensively review topics relevant to hypertension management of practical use for healthcare providers, including resistant hypertension, secondary hypertension, hypertensive crises, and special populations. The guidelines also incorporate multiple lines of evidence rather than just randomized controlled trials (which may not be available for every scenario).

There will be ongoing debate and discussion about the new definition and classification of hypertension, and the “conversion” of previously healthy adults to a new disease category. The blood pressure goals will also be debated: Should the goal for a young patient be applied to an elderly patient? The pathophysiology of the disease process should be considered rather than a one-size-fits-all approach. For example, older patients with stiff arteries and low diastolic blood pressure will have more difficulty achieving a lower systolic pressure, are more likely to experience medication side effects, and may have adherence issues due to polypharmacy.

A clinical trial, with strict adherence to protocols and rigorous follow-up procedures, is different from real-world clinical practice. Busy clinical practices with time and space constraints may forgo the steps needed for accurate blood pressure measurement in the office and may not reinforce lifestyle modifications, instead opting for more pharmacologic therapy to achieve a blood pressure goal that may become mandated by healthcare payment models without consideration for clinical judgment and individual patient characteristics.

The ACC/AHA guidelines have not been universally endorsed. The American College of Physicians and the American Academy of Family Physicians released their own guidelines for older adults earlier in 2017, echoing the recommendations from the panel appointed to JNC 8.²⁷ Contrasting recommendations can unfortunately lead to confusion among healthcare providers and patients and can undermine confidence and trust in the healthcare system.

In the background of ongoing debate, where battle lines have been drawn by key stakeholders with regard to their contrasting positions, it is even more important for the practicing clinician who is in the front lines of hypertension management to be knowledgeable about the pros and cons of different recommendations as they apply to individual patients, and to be able to clearly communicate this with patients when deciding on a treatment plan.

FINAL THOUGHTS

• Accurate measurement of blood pressure in the office is imperative—position the patient properly, use an appropriately sized  cuff, and allow for a period of rest. Consider using automated office measurement to minimize potential white coat effect.
• Out-of-office blood pressure monitoring is recommended to confirm the diagnosis of hypertension and for monitoring response to therapy. Ambulatory monitoring is preferred, but home blood pressure monitoring can be done if ambulatory monitoring is unavailable or unfeasible.
• Nonpharmacologic therapy should be emphasized for everyone, regardless of blood pressure level.
• Guidelines should be used as a framework for management. Individualize decisions about blood pressure goals and pharmacologic therapy based on patient characteristics and clinical judgment.

In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and 9 other professional associations published a new guideline on high blood pressure in adults.¹ Their document addresses a range of topics relevant to preventing, diagnosing, and managing hypertension. It incorporates evidence from randomized controlled trials, including the Systolic Blood Pressure Intervention Trial (SPRINT),² systematic reviews, and expert opinion.

The new guidelines contain many noteworthy changes, some of which are generating intense debate and discussion. Here, we provide our opinions to help practicing clinicians broaden their perspective and make informed decisions about management.

ACC AND AHA ARE NOW RESPONSIBLE FOR HYPERTENSION GUIDELINES

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), organized by the National Heart, Lung, and Blood Institute, began issuing hypertension guidelines in 1977. Based on observational and clinical trial data, succeeding JNC reports recommended ever-lower blood pressure goals, with emphasis shifting to treatment of systolic hypertension.

The last official JNC report—JNC 7—was published in 2003.³ In 2013, the Institute transferred the responsibility for cardiovascular prevention guidelines to the ACC and AHA.⁴

A report from the panel members appointed to JNC 8 was published independently in 2014.⁵ It focused on a few key questions and used evidence limited to randomized controlled trials. In this report, the panel relaxed the goals for many subgroups, leading to criticism from many professional societies and from some members of the panel writing group.⁶

WHAT'S NEW IN THE 2017 GUIDELINES?

The new ACC/AHA guidelines contain a number of changes from previous documents that have been the topic of debate.

New definition and classification of hypertension

Strong recommendation, based on moderate-quality evidence­.

Our opinion. While this new classification is intended to promote closer monitoring and earlier intervention to lower cardiovascular event rates, creating a new level of disease may lead to more pharmacologic treatment for those with lower risk, without emphasis on lifestyle modifications.

Emphasis on measurement technique and out-of-office measurements

Strong recommendation, based on expert opinion, for accurate measurement of blood pressure in the office, high-quality evidence from systematic review for out-of-office measurement.

Appropriate management of hypertension entails accurate blood pressure measurement. While office-based measurement remains the most commonly used method, this “snapshot” may not reflect a patient’s true baseline blood pressure.

Out-of-office measurements. Based on the results of a systematic review commissioned by the guideline committee, out-of-office measurements are now recommended to confirm the diagnosis of hypertension and to assess response to therapy.

Ambulatory blood pressure monitoring should be strongly considered as the preferred method for out-of-office monitoring; home blood pressure monitoring can be done if ambulatory monitoring is not feasible. Ambulatory monitoring provides additional information on nighttime blood pressure, including the dipping status (normal defined as a nighttime blood pressure decrease of 10% to 20%). Ambulatory monitoring predicts long-term cardiovascular outcomes independent of office blood pressure, and elevated nighttime pressure and non-dipping have been shown to be independently associated with increased cardiovascular mortality rates.^8,9 Unfortunately, despite evidence supporting its use, ambulatory blood pressure monitoring is not widely available for a variety of reasons, including high cost (roughly $2,000–$4,000) and minimal reimbursement.

Out-of-office measurements can also detect white coat hypertension and masked hypertension. White coat hypertension is defined as blood pressure that is elevated in the office but normal in an out-of-office setting, and masked hypertension is blood pressure that is normal in the office and elevated in an out-of-office setting. Currently, pharmacologic therapy is not recommended to treat white coat hypertension, and treatment for masked hypertension should be the same as for sustained hypertension.

While the guidelines do not comment specifically on manual office measurement vs automated office measurements using devices that take multiple measurements with the patient alone in the room to reduce the white coat effect, they acknowledge “increasing evidence” favoring the use of automated office measurement.

Proper technique for measuring blood pressure is appropriately emphasized; correct patient positioning, allowing a period of rest, and using the appropriate cuff size are all important. Unfortunately, many busy clinical practices may not follow correct technique when measuring blood pressure in the office, leading to misdiagnosis and unnecessary pharmacologic therapy that may result in adverse events.

Of note, the SPRINT trial, which informed many of the new guideline recommendations, followed a strict protocol of blood pressure measurement with an automated device, checking sitting blood pressure 3 times at 1-minute intervals, with the patient alone in the room and without an observer present at many of the sites.¹⁰

Most guidelines^11,12 agree on an average of at least 135/85 mm Hg as the threshold for diagnosing hypertension by home monitoring, or an average daytime pressure of at least 135/85 mm Hg by ambulatory monitoring, corresponding with office-based blood pressure of 140/90 mm Hg.­ However, the new guidelines recommend a lower threshold of 130/80 mm Hg for both home monitoring and average daytime ambulatory monitoring, corresponding with an office blood pressure of 130/80 mm Hg. They do not specify whether the office-based measurement is manual or automated.

Our opinion. Since office-based measurement will likely remain the principal method for managing hypertension due to constraints with ambulatory or home monitoring, the use of automated devices for office measurement should be strongly considered. Studies have shown that, compared with routine office measurements, automated measurements more closely approximate those obtained by ambulatory and home blood pressure monitoring.¹³

Risk-based approach to hypertension management

The algorithm for hypertension management now incorporates objective assessment of cardiovascular risk. Specifically, it calls for estimation of the 10-year risk of atherosclerotic cardiovascular disease, defined as coronary heart disease death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

The information required to estimate risk includes age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, use of blood pressure-lowering medication, diabetes status, and smoking status. The guideline recommends an easy-to-use online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator).

A 10-year risk of 10% or more is designated as the cutoff between high risk and low risk. However, this is not based on trial evidence, and the risk calculator has not been verified in prospective trials to show that its use reduces cardiovascular events. The SPRINT trial,² which was a study of blood pressure-lowering in high-risk patients, used a 10-year risk of 15% or more based on the Framingham risk score to delineate high risk.

Additionally, the 10-year risk calculator is valid only in patients ages 40 through 79, and some studies indicate that it may overestimate risk in older adults.^14,15 This overestimation may lead to patients being started on pharmacologic therapy when it may not truly be indicated. The risk calculator controversy has been discussed in a previous issue of this journal.¹⁶

Blood pressure goals

Strong recommendation for known cardiovascular disease or atherosclerotic cardiovascular disease risk 10% or greater, weak recommendation for risk less than 10%, based on moderate-quality evidence for systolic blood pressure, expert opinion for diastolic.

The guidelines recommend a blood pressure goal of less than 130/80 mm Hg for all patients, including the elderly and patients with chronic kidney disease or diabetes.

The SPRINT trial,² which showed better cardiovascular outcomes in the intensive treatment group (aiming for systolic pressure < 120 mm Hg) compared with a standard treatment group (aiming for systolic pressure < 140 mm Hg), excluded participants with diabetes and severe chronic kidney disease (estimated glomerular filtration rate < 20 mL/min/m² and proteinuria > 1 g/day), and those who were in nursing homes or had dementia.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial showed that intensive blood pressure control did not have cardiovascular benefits compared with standard therapy.¹⁷ However, many now believe that the study may have been underpowered due to its design, and a meta-analysis of the results from SPRINT and ACCORD suggested that findings from both trials were consistent, favoring intensive blood pressure control in a high-risk population.¹⁸

While the totality of evidence favors a lower achieved blood pressure for many patients, this lower goal may be difficult to achieve in many, particularly those with vascular stiffness, which is common in the elderly. These patients also tend to have low diastolic pressure, and lowering diastolic pressure below 60 mm Hg in those with documented coronary artery disease could increase the risk of adverse cardiovascular outcomes.^19,20 The guidelines do not address the potential issues with lowering diastolic blood pressure.

Our opinion. While a “universal” blood pressure goal may simplify decision-making, we believe it is important to individualize goals, taking into account patient characteristics, lifestyle factors, medication side effects, patient preferences, cost issues, and adherence to therapy.

The goal blood pressure should also consider the method of measurement. Systolic blood pressure readings have been reported to be 5 to 10 mm Hg lower with automated office measurement than with routine office measurement.²¹

It is also not clear that the magnitude of absolute benefit from pursuing more intensive blood pressure control with antihypertensive therapy in patients with high cardiovascular risk (as in SPRINT) would translate to similar benefits in a lower-risk population. Thus, we believe that in patients with lower cardiovascular risk, a goal blood pressure of less than 140/90 mm Hg (if routine office measurement is done) and less than 135/85 mm Hg (if automated office measurement is done) would be reasonable.

We also believe that it is reasonable to relax these goals in the very elderly (age ≥ 80), especially those who are frail and at risk of falls, with low diastolic pressures. In these patients, we recommend individualizing blood pressure goals that can be achieved without significant side effects from antihypertensive therapy.

Nonpharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials

Nonpharmacologic therapy and lifestyle modification are appropriately emphasized in the new guidelines. Most of the lifestyle changes that are recommended are in concordance with prior JNC 7 recommendations.³

Recognizing the roles of sodium and potassium in the pathogenesis of hypertension, the guidelines emphasize a diet that is higher in potassium, the DASH (Dietary Approaches to Stop Hypertension) diet, and a low-sodium diet. The recommended optimal goal of sodium intake of less than 1,500 mg/day may be difficult to achieve with a Western diet, and there is debate about the potential adverse effects of a very-low sodium diet.²² The general recommendation for sodium intake of less than 2,300 mg/day is supported in the literature, and it is unclear if further reduction has additional beneficial effects on blood pressure.²³

The guidelines recommend a 3- to 6-month reassessment of patients who are prescribed risk-factor modification, but are unclear about initiation of pharmacologic therapy or other steps if these low-risk patients have not responded to lifestyle modifications alone at the time of reassessment.

Pharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials for systolic blood pressure, expert opinion for diastolic blood pressure for those with atherosclerotic cardiovascular disease risk 10% or greater, and limited data for those with risk less than 10%.

Pharmacologic therapy is recommended in patients with stage 1 hypertension and pre-existing cardiovascular disease or 10-year risk of atherosclerotic cardiovascular disease of 10% or more, and in those with stage 2 hypertension even if their 10-year risk is less than 10%.

In the absence of compelling indications, the primary drugs recommended for initial therapy are:

• Thiazide or thiazide-type diuretics (preferably chlorthalidone)
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Calcium channel blockers (CCBs).

In black adults, thiazide diuretics or CCBs are recommended for initial therapy. Beta-blockers are not recommended as first-line agents in the absence of a compelling indication, although meta-analyses that suggested beta-blockers are less effective than other classes of agents included trials that used beta-blockers in doses now considered suboptimal. ACE inhibitors or ARBs are recommended as initial therapy in proteinuric patients with chronic kidney disease or diabetes. Combining an ACE inhibitor and an ARB or renin inhibitor is potentially harmful and is not recommended. The guidelines provide a helpful table describing important characteristics and available dosage forms of the commonly used antihypertensive agents.

These recommendations are concordant with the JNC 8 panel recommendations,⁵ and differ from JNC 7, which recommended thiazide-type diuretics as first-line therapy.³ The European guidelines recommend that all major classes of antihypertensive agents, including beta-blockers, are suitable for initiation of therapy.²⁴ The UK National Institute for Clinical Excellence guidelines adopt an age-based approach to deciding initial therapy—with ACE inhibitors or ARBs favored in those below the age of 55 and CCBs in those who are 55 and older.²⁵

Starting with a single antihypertensive agent is recommended for stage 1 hypertension with increased cardiovascular risk, and starting with 2 agents (either separately or in fixed-dose combination) is recommended for stage 2 hypertension. The guidelines emphasize a team-based approach to improve hypertension care, using adjunctive interventions such as telehealth strategies and leveraging electronic medical records to guide quality improvement initiatives.

Our opinion. We agree with Bakris and Sorrentino^₂₆ that general patient profiles should be considered to decide on efficient pharmacologic management in clinical practice—thiazide diuretics would be best in those who are volume-expanded; ACE inhibitors, ARBs, or CCBs in those who are obese or have metabolic syndrome; and beta-blockers or nondihydropyridine CCBs in those who are hyperadrenergic. More patients will likely be classified as having resistant hypertension based on the blood pressure goal of less than 130/80 mm Hg, which may require greater use of mineralocorticoid receptor antagonists such as spironolactone.

STRENGTHS AND LIMITATIONS

The new guidelines stress correct technique of blood pressure measurement, out-of-office and self-monitoring of blood pressure, and lifestyle modifications. In addition, they comprehensively review topics relevant to hypertension management of practical use for healthcare providers, including resistant hypertension, secondary hypertension, hypertensive crises, and special populations. The guidelines also incorporate multiple lines of evidence rather than just randomized controlled trials (which may not be available for every scenario).

There will be ongoing debate and discussion about the new definition and classification of hypertension, and the “conversion” of previously healthy adults to a new disease category. The blood pressure goals will also be debated: Should the goal for a young patient be applied to an elderly patient? The pathophysiology of the disease process should be considered rather than a one-size-fits-all approach. For example, older patients with stiff arteries and low diastolic blood pressure will have more difficulty achieving a lower systolic pressure, are more likely to experience medication side effects, and may have adherence issues due to polypharmacy.

A clinical trial, with strict adherence to protocols and rigorous follow-up procedures, is different from real-world clinical practice. Busy clinical practices with time and space constraints may forgo the steps needed for accurate blood pressure measurement in the office and may not reinforce lifestyle modifications, instead opting for more pharmacologic therapy to achieve a blood pressure goal that may become mandated by healthcare payment models without consideration for clinical judgment and individual patient characteristics.

The ACC/AHA guidelines have not been universally endorsed. The American College of Physicians and the American Academy of Family Physicians released their own guidelines for older adults earlier in 2017, echoing the recommendations from the panel appointed to JNC 8.²⁷ Contrasting recommendations can unfortunately lead to confusion among healthcare providers and patients and can undermine confidence and trust in the healthcare system.

In the background of ongoing debate, where battle lines have been drawn by key stakeholders with regard to their contrasting positions, it is even more important for the practicing clinician who is in the front lines of hypertension management to be knowledgeable about the pros and cons of different recommendations as they apply to individual patients, and to be able to clearly communicate this with patients when deciding on a treatment plan.

FINAL THOUGHTS

• Accurate measurement of blood pressure in the office is imperative—position the patient properly, use an appropriately sized  cuff, and allow for a period of rest. Consider using automated office measurement to minimize potential white coat effect.
• Out-of-office blood pressure monitoring is recommended to confirm the diagnosis of hypertension and for monitoring response to therapy. Ambulatory monitoring is preferred, but home blood pressure monitoring can be done if ambulatory monitoring is unavailable or unfeasible.
• Nonpharmacologic therapy should be emphasized for everyone, regardless of blood pressure level.
• Guidelines should be used as a framework for management. Individualize decisions about blood pressure goals and pharmacologic therapy based on patient characteristics and clinical judgment.

In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and 9 other professional associations published a new guideline on high blood pressure in adults.¹ Their document addresses a range of topics relevant to preventing, diagnosing, and managing hypertension. It incorporates evidence from randomized controlled trials, including the Systolic Blood Pressure Intervention Trial (SPRINT),² systematic reviews, and expert opinion.

The new guidelines contain many noteworthy changes, some of which are generating intense debate and discussion. Here, we provide our opinions to help practicing clinicians broaden their perspective and make informed decisions about management.

ACC AND AHA ARE NOW RESPONSIBLE FOR HYPERTENSION GUIDELINES

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), organized by the National Heart, Lung, and Blood Institute, began issuing hypertension guidelines in 1977. Based on observational and clinical trial data, succeeding JNC reports recommended ever-lower blood pressure goals, with emphasis shifting to treatment of systolic hypertension.

The last official JNC report—JNC 7—was published in 2003.³ In 2013, the Institute transferred the responsibility for cardiovascular prevention guidelines to the ACC and AHA.⁴

A report from the panel members appointed to JNC 8 was published independently in 2014.⁵ It focused on a few key questions and used evidence limited to randomized controlled trials. In this report, the panel relaxed the goals for many subgroups, leading to criticism from many professional societies and from some members of the panel writing group.⁶

WHAT'S NEW IN THE 2017 GUIDELINES?

The new ACC/AHA guidelines contain a number of changes from previous documents that have been the topic of debate.

New definition and classification of hypertension

Strong recommendation, based on moderate-quality evidence­.

Our opinion. While this new classification is intended to promote closer monitoring and earlier intervention to lower cardiovascular event rates, creating a new level of disease may lead to more pharmacologic treatment for those with lower risk, without emphasis on lifestyle modifications.

Emphasis on measurement technique and out-of-office measurements

Strong recommendation, based on expert opinion, for accurate measurement of blood pressure in the office, high-quality evidence from systematic review for out-of-office measurement.

Appropriate management of hypertension entails accurate blood pressure measurement. While office-based measurement remains the most commonly used method, this “snapshot” may not reflect a patient’s true baseline blood pressure.

Out-of-office measurements. Based on the results of a systematic review commissioned by the guideline committee, out-of-office measurements are now recommended to confirm the diagnosis of hypertension and to assess response to therapy.

Ambulatory blood pressure monitoring should be strongly considered as the preferred method for out-of-office monitoring; home blood pressure monitoring can be done if ambulatory monitoring is not feasible. Ambulatory monitoring provides additional information on nighttime blood pressure, including the dipping status (normal defined as a nighttime blood pressure decrease of 10% to 20%). Ambulatory monitoring predicts long-term cardiovascular outcomes independent of office blood pressure, and elevated nighttime pressure and non-dipping have been shown to be independently associated with increased cardiovascular mortality rates.^8,9 Unfortunately, despite evidence supporting its use, ambulatory blood pressure monitoring is not widely available for a variety of reasons, including high cost (roughly $2,000–$4,000) and minimal reimbursement.

Out-of-office measurements can also detect white coat hypertension and masked hypertension. White coat hypertension is defined as blood pressure that is elevated in the office but normal in an out-of-office setting, and masked hypertension is blood pressure that is normal in the office and elevated in an out-of-office setting. Currently, pharmacologic therapy is not recommended to treat white coat hypertension, and treatment for masked hypertension should be the same as for sustained hypertension.

While the guidelines do not comment specifically on manual office measurement vs automated office measurements using devices that take multiple measurements with the patient alone in the room to reduce the white coat effect, they acknowledge “increasing evidence” favoring the use of automated office measurement.

Proper technique for measuring blood pressure is appropriately emphasized; correct patient positioning, allowing a period of rest, and using the appropriate cuff size are all important. Unfortunately, many busy clinical practices may not follow correct technique when measuring blood pressure in the office, leading to misdiagnosis and unnecessary pharmacologic therapy that may result in adverse events.

Of note, the SPRINT trial, which informed many of the new guideline recommendations, followed a strict protocol of blood pressure measurement with an automated device, checking sitting blood pressure 3 times at 1-minute intervals, with the patient alone in the room and without an observer present at many of the sites.¹⁰

Most guidelines^11,12 agree on an average of at least 135/85 mm Hg as the threshold for diagnosing hypertension by home monitoring, or an average daytime pressure of at least 135/85 mm Hg by ambulatory monitoring, corresponding with office-based blood pressure of 140/90 mm Hg.­ However, the new guidelines recommend a lower threshold of 130/80 mm Hg for both home monitoring and average daytime ambulatory monitoring, corresponding with an office blood pressure of 130/80 mm Hg. They do not specify whether the office-based measurement is manual or automated.

Our opinion. Since office-based measurement will likely remain the principal method for managing hypertension due to constraints with ambulatory or home monitoring, the use of automated devices for office measurement should be strongly considered. Studies have shown that, compared with routine office measurements, automated measurements more closely approximate those obtained by ambulatory and home blood pressure monitoring.¹³

Risk-based approach to hypertension management

The algorithm for hypertension management now incorporates objective assessment of cardiovascular risk. Specifically, it calls for estimation of the 10-year risk of atherosclerotic cardiovascular disease, defined as coronary heart disease death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

The information required to estimate risk includes age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, use of blood pressure-lowering medication, diabetes status, and smoking status. The guideline recommends an easy-to-use online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator).

A 10-year risk of 10% or more is designated as the cutoff between high risk and low risk. However, this is not based on trial evidence, and the risk calculator has not been verified in prospective trials to show that its use reduces cardiovascular events. The SPRINT trial,² which was a study of blood pressure-lowering in high-risk patients, used a 10-year risk of 15% or more based on the Framingham risk score to delineate high risk.

Additionally, the 10-year risk calculator is valid only in patients ages 40 through 79, and some studies indicate that it may overestimate risk in older adults.^14,15 This overestimation may lead to patients being started on pharmacologic therapy when it may not truly be indicated. The risk calculator controversy has been discussed in a previous issue of this journal.¹⁶

Blood pressure goals

Strong recommendation for known cardiovascular disease or atherosclerotic cardiovascular disease risk 10% or greater, weak recommendation for risk less than 10%, based on moderate-quality evidence for systolic blood pressure, expert opinion for diastolic.

The guidelines recommend a blood pressure goal of less than 130/80 mm Hg for all patients, including the elderly and patients with chronic kidney disease or diabetes.

The SPRINT trial,² which showed better cardiovascular outcomes in the intensive treatment group (aiming for systolic pressure < 120 mm Hg) compared with a standard treatment group (aiming for systolic pressure < 140 mm Hg), excluded participants with diabetes and severe chronic kidney disease (estimated glomerular filtration rate < 20 mL/min/m² and proteinuria > 1 g/day), and those who were in nursing homes or had dementia.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial showed that intensive blood pressure control did not have cardiovascular benefits compared with standard therapy.¹⁷ However, many now believe that the study may have been underpowered due to its design, and a meta-analysis of the results from SPRINT and ACCORD suggested that findings from both trials were consistent, favoring intensive blood pressure control in a high-risk population.¹⁸

While the totality of evidence favors a lower achieved blood pressure for many patients, this lower goal may be difficult to achieve in many, particularly those with vascular stiffness, which is common in the elderly. These patients also tend to have low diastolic pressure, and lowering diastolic pressure below 60 mm Hg in those with documented coronary artery disease could increase the risk of adverse cardiovascular outcomes.^19,20 The guidelines do not address the potential issues with lowering diastolic blood pressure.

Our opinion. While a “universal” blood pressure goal may simplify decision-making, we believe it is important to individualize goals, taking into account patient characteristics, lifestyle factors, medication side effects, patient preferences, cost issues, and adherence to therapy.

The goal blood pressure should also consider the method of measurement. Systolic blood pressure readings have been reported to be 5 to 10 mm Hg lower with automated office measurement than with routine office measurement.²¹

It is also not clear that the magnitude of absolute benefit from pursuing more intensive blood pressure control with antihypertensive therapy in patients with high cardiovascular risk (as in SPRINT) would translate to similar benefits in a lower-risk population. Thus, we believe that in patients with lower cardiovascular risk, a goal blood pressure of less than 140/90 mm Hg (if routine office measurement is done) and less than 135/85 mm Hg (if automated office measurement is done) would be reasonable.

We also believe that it is reasonable to relax these goals in the very elderly (age ≥ 80), especially those who are frail and at risk of falls, with low diastolic pressures. In these patients, we recommend individualizing blood pressure goals that can be achieved without significant side effects from antihypertensive therapy.

Nonpharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials

Nonpharmacologic therapy and lifestyle modification are appropriately emphasized in the new guidelines. Most of the lifestyle changes that are recommended are in concordance with prior JNC 7 recommendations.³

Recognizing the roles of sodium and potassium in the pathogenesis of hypertension, the guidelines emphasize a diet that is higher in potassium, the DASH (Dietary Approaches to Stop Hypertension) diet, and a low-sodium diet. The recommended optimal goal of sodium intake of less than 1,500 mg/day may be difficult to achieve with a Western diet, and there is debate about the potential adverse effects of a very-low sodium diet.²² The general recommendation for sodium intake of less than 2,300 mg/day is supported in the literature, and it is unclear if further reduction has additional beneficial effects on blood pressure.²³

The guidelines recommend a 3- to 6-month reassessment of patients who are prescribed risk-factor modification, but are unclear about initiation of pharmacologic therapy or other steps if these low-risk patients have not responded to lifestyle modifications alone at the time of reassessment.

Pharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials for systolic blood pressure, expert opinion for diastolic blood pressure for those with atherosclerotic cardiovascular disease risk 10% or greater, and limited data for those with risk less than 10%.

Pharmacologic therapy is recommended in patients with stage 1 hypertension and pre-existing cardiovascular disease or 10-year risk of atherosclerotic cardiovascular disease of 10% or more, and in those with stage 2 hypertension even if their 10-year risk is less than 10%.

In the absence of compelling indications, the primary drugs recommended for initial therapy are:

• Thiazide or thiazide-type diuretics (preferably chlorthalidone)
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Calcium channel blockers (CCBs).

In black adults, thiazide diuretics or CCBs are recommended for initial therapy. Beta-blockers are not recommended as first-line agents in the absence of a compelling indication, although meta-analyses that suggested beta-blockers are less effective than other classes of agents included trials that used beta-blockers in doses now considered suboptimal. ACE inhibitors or ARBs are recommended as initial therapy in proteinuric patients with chronic kidney disease or diabetes. Combining an ACE inhibitor and an ARB or renin inhibitor is potentially harmful and is not recommended. The guidelines provide a helpful table describing important characteristics and available dosage forms of the commonly used antihypertensive agents.

These recommendations are concordant with the JNC 8 panel recommendations,⁵ and differ from JNC 7, which recommended thiazide-type diuretics as first-line therapy.³ The European guidelines recommend that all major classes of antihypertensive agents, including beta-blockers, are suitable for initiation of therapy.²⁴ The UK National Institute for Clinical Excellence guidelines adopt an age-based approach to deciding initial therapy—with ACE inhibitors or ARBs favored in those below the age of 55 and CCBs in those who are 55 and older.²⁵

Starting with a single antihypertensive agent is recommended for stage 1 hypertension with increased cardiovascular risk, and starting with 2 agents (either separately or in fixed-dose combination) is recommended for stage 2 hypertension. The guidelines emphasize a team-based approach to improve hypertension care, using adjunctive interventions such as telehealth strategies and leveraging electronic medical records to guide quality improvement initiatives.

Our opinion. We agree with Bakris and Sorrentino^₂₆ that general patient profiles should be considered to decide on efficient pharmacologic management in clinical practice—thiazide diuretics would be best in those who are volume-expanded; ACE inhibitors, ARBs, or CCBs in those who are obese or have metabolic syndrome; and beta-blockers or nondihydropyridine CCBs in those who are hyperadrenergic. More patients will likely be classified as having resistant hypertension based on the blood pressure goal of less than 130/80 mm Hg, which may require greater use of mineralocorticoid receptor antagonists such as spironolactone.

STRENGTHS AND LIMITATIONS

The new guidelines stress correct technique of blood pressure measurement, out-of-office and self-monitoring of blood pressure, and lifestyle modifications. In addition, they comprehensively review topics relevant to hypertension management of practical use for healthcare providers, including resistant hypertension, secondary hypertension, hypertensive crises, and special populations. The guidelines also incorporate multiple lines of evidence rather than just randomized controlled trials (which may not be available for every scenario).

There will be ongoing debate and discussion about the new definition and classification of hypertension, and the “conversion” of previously healthy adults to a new disease category. The blood pressure goals will also be debated: Should the goal for a young patient be applied to an elderly patient? The pathophysiology of the disease process should be considered rather than a one-size-fits-all approach. For example, older patients with stiff arteries and low diastolic blood pressure will have more difficulty achieving a lower systolic pressure, are more likely to experience medication side effects, and may have adherence issues due to polypharmacy.

A clinical trial, with strict adherence to protocols and rigorous follow-up procedures, is different from real-world clinical practice. Busy clinical practices with time and space constraints may forgo the steps needed for accurate blood pressure measurement in the office and may not reinforce lifestyle modifications, instead opting for more pharmacologic therapy to achieve a blood pressure goal that may become mandated by healthcare payment models without consideration for clinical judgment and individual patient characteristics.

The ACC/AHA guidelines have not been universally endorsed. The American College of Physicians and the American Academy of Family Physicians released their own guidelines for older adults earlier in 2017, echoing the recommendations from the panel appointed to JNC 8.²⁷ Contrasting recommendations can unfortunately lead to confusion among healthcare providers and patients and can undermine confidence and trust in the healthcare system.

In the background of ongoing debate, where battle lines have been drawn by key stakeholders with regard to their contrasting positions, it is even more important for the practicing clinician who is in the front lines of hypertension management to be knowledgeable about the pros and cons of different recommendations as they apply to individual patients, and to be able to clearly communicate this with patients when deciding on a treatment plan.

FINAL THOUGHTS

• Accurate measurement of blood pressure in the office is imperative—position the patient properly, use an appropriately sized  cuff, and allow for a period of rest. Consider using automated office measurement to minimize potential white coat effect.
• Out-of-office blood pressure monitoring is recommended to confirm the diagnosis of hypertension and for monitoring response to therapy. Ambulatory monitoring is preferred, but home blood pressure monitoring can be done if ambulatory monitoring is unavailable or unfeasible.
• Nonpharmacologic therapy should be emphasized for everyone, regardless of blood pressure level.
• Guidelines should be used as a framework for management. Individualize decisions about blood pressure goals and pharmacologic therapy based on patient characteristics and clinical judgment.

From the University of Michigan Medical School, Ann Arbor, MI.

Abstract

• Objective: Existing research has demonstrated overall low rates of residents establishing care with a primary care physician (PCP). We conducted a survey-based study to better understand chronic illness, PCP utilization, and prescription medication use patterns in resident physician populations.
• Methods: In 2017, we invited internal and family medicine trainees from a convenience sample of U.S. residency programs to participate in a survey. We compared the characteristics of residents who had established care with a PCP to those who had not.
• Results: The response rate was 45% (348/766 residents). The majority (n = 205, 59%) of respondents stated they had established care with a PCP primarily for routine preventative care (n = 159, 79%) and access in the event of an emergency (n = 132, 66%). However, 31% (n = 103) denied having had a wellness visit in over 3 years. Nearly a quarter of residents (n = 77, 23%) reported a chronic medical illness and 14% (n = 45) reported a preexisting mental health condition prior to residency. One-third (n = 111, 33%) reported taking a long-term prescription medication. Compared to residents who had not established care, those with a PCP (n = 205) more often reported a chronic condition (P < 0.001), seeing a subspecialist (P = 0.01), or taking long-term prescription medications (P < 0.001). One in 5 (n = 62,19%) respondents reported receiving prescriptions for an acute illness from an individual with whom they did not have a doctor-patient relationship.
• Conclusion: Medical residents have a substantial burden of chronic illness that may not be met through interactions with PCPs. Further understanding their medical needs and barriers to accessing care is necessary to ensure trainee well-being.

Keywords: Medical education-graduate, physician behavior, survey research, access to care.

Although internal medicine (IM) and family medicine (FM) residents must learn to provide high-quality primary care to their patients, little is known about whether they appropriately access such care themselves. Resident burnout and resilience has received attention [1,2], but there has been limited focus on understanding the burden of chronic medical and mental illness among residents. In particular, little is known about whether residents access primary care physicians (PCPs)—for either acute or chronic medical needs—and about resident self-medication practices.

Residency is often characterized by a life-changing geographic relocation. Even residents who do not relocate may still need to establish care with a new PCP due to health insurance or loss of access to a student clinic [3]. Establishing primary care with a new doctor typically requires scheduling a new patient visit, often with a wait time of several days to weeks [4,5]. Furthermore, lack of time, erratic schedules, and concerns about privacy and the stigma of being ill as a physician are barriers to establishing care [6-8]. Individuals who have not established primary care may experience delays in routine preventative health services, screening for chronic medical and mental health conditions, as well as access to care during acute illnesses [9,10]. Worse, they may engage in potentially unsafe practices, such as having colleagues write prescriptions for them, or even self-prescribing [8,11,12].

Existing research has demonstrated overall low rates of residents establishing care with a PCP [6–8,13]. However, these studies have either been limited to large academic centers or conducted outside the United States. Improving resident well-being may prove challenging without a clear understanding of current primary care utilization practices, the burden of chronic illness among residents, and patterns of prescription medication use and needs. Therefore, we conducted a survey-based study to understand primary care utilization and the burden of chronic illness among residents. We also assessed whether lack of primary care is associated with potentially risky behaviors, such as self-prescribing of medications.

Methods

Study Setting and Participants

The survey was distributed to current residents at IM and FM programs within the United States in 2017. Individual programs were recruited by directly contacting program directors or chief medical residents via email. Rather than contacting sites directly through standard templated emails, we identified programs both through personal contacts as well as the Electronic Residency Application Service list of accredited IM training programs. We elected to use this approach in order to increase response rates and to ensure that a sample representative of the trainee population was constructed. Programs were located in the Northeast, Midwest, South, and Pacific regions, and included small community-based programs and large academic centers.

Development of the Survey

The survey instrument was developed by the authors and reviewed by residents and PCPs at the University of Michigan to ensure relevance and comprehension of questions (The survey is available in the Appendix.). Once finalized, the survey was programmed into an online survey tool (Qualtrics, Provo, UT) and pilot-tested before being disseminated to the sampling frame. Data collected in the survey included: respondent’s utilization of a PCP, burden of chronic illness, long-term prescription medications, prescribing source, and demographic characteristics.

Each participating program distributed the survey to their residents through an email containing an anonymous hyperlink. The survey was available for completion for 4 weeks. We asked participating programs to send email reminders to encourage participation. Participants were given the option of receiving a $10 Amazon gift card after completion. All responses were recorded anonymously. The study received a “not regulated” status by the University of Michigan Institutional Review Board (HUM 00123888).

Statistical Analysis

Descriptive statistics were used to tabulate results. Respondents were encouraged, but not required, to answer all questions. Therefore, the response rate for each question was calculated using the total number of responses for that question as the denominator. Bivariable comparisons were made using Chi-squared or Fisher’s exact tests, as appropriate, for categorical data. A P value < 0.05, with 2-sided alpha, was considered statistically significant. All statistical analyses were conducted using Stata 13 SE (StataCorp, College Station, TX).

Results

Respondent Characteristics

Of the 29 programs contacted, 10 agreed to participate within the study timeframe. Of 766 potential respondents, 348 (45%) residents answered the survey (Table 1). The majority of respondents (n = 276, 82%) were from IM programs. Respondents were from all training years as follows: postgraduate year 1 residents (PGY-1, or interns; n = 130, 39%), PGY-2 residents (n = 98, 29%), PGY-3 residents (n = 93, 28%), and PGY-4 residents (n = 12, 4%). Most respondents were from the South (n = 130, 39%) and Midwest (n = 123, 37%) regions, and over half (n = 179, 54%) were female. Most respondents (n = 285, 86%) stated that they did not have children. The majority (n = 236, 71%) were completing residency in an area where they had not previously lived for more than 1 year.

Primary Care Utilization

Among the 348 respondents, 59% (n = 205) reported having established care with a PCP. An additional 6% (n = 21) had established care with an obstetrician/gynecologist for routine needs (Table 2). The 2 most common reasons for establishing care with a PCP were routine primary care needs, including contraception (n = 159, 79%), and access to a physician in the event of an acute medical need (n = 132, 66%).

Among respondents who had established care with a PCP, most (n = 188, 94%) had completed at least 1 appointment. However, among these 188 respondents, 68% (n = 127) stated that they had not made an acute visit in more than 12 months. When asked about wellness visits, almost one third of respondents (n = 103, 31%) stated that they had not been seen for a wellness visit in the past 3 years.

Burden of Chronic Illness

Most respondents (n = 223, 67%) stated that they did not have a chronic medical or mental health condition prior to residency (Table 3). However, 23% (n = 77) of respondents stated that they had been diagnosed with a chronic medical illness prior to residency, and 14% (n = 45) indicated they had been diagnosed with a mental health condition prior to residency. Almost one fifth of respondents (n = 60, 18%) reported seeing a subspecialist for a medical illness, and 33% (n = 111) reported taking a long-term prescription medication. With respect to major medical issues, the majority of residents (n = 239, 72%) denied experiencing events such as pregnancy, hospitalization, surgery, or an emergency department (ED) visit during training.

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Inappropriate Prescriptions

While the majority of respondents denied writing a prescription for themselves for an acute or chronic medical condition, almost one fifth (n = 62, 19%) had received a prescription for an acute medical need from a provider outside of a clinical relationship (ie, from someone other than their PCP or specialty provider). Notably, 5% (n = 15) reported that this had occurred at least 2 or 3 times in the past 12 months (Table 4). Compared to respondents not taking long-term prescription medications, respondents who were already taking long-term prescription medications more frequently reported inappropriately receiving chronic prescriptions outside of an established clinical relationship (n = 14, 13% vs. n = 14, 6%; P = 0.05) and more often self-prescribed medications for acute needs (n = 12, 11% vs. n = 7, 3%; P = 0.005).

Important differences were noted between residents who had a PCP versus those who did not (Table 5). For example, a higher percentage of residents with a PCP indicated they had been diagnosed with a chronic medical illness (n = 55, 28% vs. n = 22, 16%; P = 0.01) or a chronic mental health condition (n = 34, 17% vs. n = 11, 8%; P = 0.02) before residency. Additionally, a higher percentage of residents with a PCP (n = 70, 35% vs. n = 25, 18%; P = 0.001) reported experiencing medical events such as pregnancy, hospitalization, surgery, ED visit, or new diagnosis of a chronic medical illness during residency. Finally, a higher percentage of respondents with a PCP stated that they had visited a subspecialist for a medical illness (n = 44, 22% vs. n = 16,12%; P = 0.01) or were taking long-term prescription medications (n = 86, 43% vs. n = 25; 18%; P < 0.001). When comparing PGY-1 to PGY-2–PGY-4 residents, the former reported having established a medical relationship with a PCP significantly less frequently (n = 56, 43% vs. n = 142, 70%; P < 0.001).

Discussion

This survey-based study of medical residents across the United States suggests that a substantial proportion do not establish relationships with PCPs. Additionally, our data suggest that despite establishing care, few residents subsequently visited their PCP during training for wellness visits or routine care. Self-reported rates of chronic medical and mental health conditions were substantial in our sample. Furthermore, inappropriate self-prescription and the receipt of prescriptions outside of a medical relationship were also reported. These findings suggest that future studies that focus on the unique medical and mental health needs of physicians in training, as well as interventions to encourage care in this vulnerable period, are necessary.

We observed that most respondents that established primary care were female trainees. Although it is impossible to know with certainty, one hypothesis behind this discrepancy is that women routinely need to access preventative care for gynecologic needs such as pap smears, contraception, and potentially pregnancy and preconception counseling [14,15]. Similarly, residents with a chronic medical or mental health condition prior to residency established care with a local PCP at a significantly greater frequency than those without such diagnoses. While selection bias cannot be excluded, this finding suggests that illness is a driving factor in establishing care. There also appears to be an association between accessing the medical system (either for prescription medications or subspecialist care) and having established care with a PCP. Collectively, these data suggest that individuals without a compelling reason to access medical services might have barriers to accessing care in the event of medical needs or may not receive routine preventative care [9,10].

In general, we found that rates of reported inappropriate prescriptions were lower than those reported in prior studies where a comparable resident population was surveyed [8,12,16]. Inclusion of multiple institutions, differences in temporality, social desirability bias, and reporting bias might have influenced our findings in this regard. Surprisingly, we found that having a PCP did not influence likelihood of inappropriate prescription receipt, perhaps suggesting that this behavior reflects some degree of universal difficulty in accessing care. Alternatively, this finding might relate to a cultural tendency to self-prescribe among resident physicians. The fact that individuals on chronic medications more often both received and wrote inappropriate prescriptions suggests this problem might be more pronounced in individuals who take medications more often, as these residents have specific needs [12]. Future studies targeting these individuals thus appear warranted.

Our study has several limitations. First, our sample size was modest and the response rate of 45% was low. However, to our knowledge, this remains among the largest survey on this topic, and our response rate is comparable to similar trainee studies [8,11,13]. Second, we designed and created a novel survey for this study. While the questions were pilot-tested with users prior to dissemination, validation of the instrument was not performed. Third, since the study population was restricted to residents in fields that participate in primary care, our findings may not be generalizable to patterns of PCP use in other specialties [6].

These limitations aside, our study has important strengths. This is the first national study of its kind with specific questions addressing primary care access and utilization, prescription medication use and related practices, and the prevalence of medical conditions among trainees. Important differences in the rates of establishing primary care between male and female respondents, first- year and senior residents, and those with and without chronic disease suggest a need to target specific resident groups (males, interns, those without pre-existing conditions) for wellness-related interventions. Such interventions could include distribution of a list of local providers to first year residents, advanced protected time for doctor’s appointments, and safeguards to ensure health information is protected from potential supervisors. Future studies should also include residents from non-primary care oriented specialties such as surgery, emergency medicine, and anesthesiology to obtain results that are more generalizable to the resident population as a whole. Additionally, the rates of inappropriate prescriptions were not insignificant and warrant further evaluation of the driving forces behind these behaviors.

Conclusion

Medical residents have a substantial burden of chronic illness that may not be met through interactions with PCPs. More research into barriers that residents face while accessing care and an assessment of interventions to facilitate their access to care is important to promote trainee well-being. Without such direction and initiative, it may prove harder for physicians to heal themselves or those for whom they provide care.

Acknowledgments: We thank Suzanne Winter, the study coordinator, for her support with editing and formatting the manuscript, Latoya Kuhn for performing the statistical analysis and creating data tables, and Dr. Namita Sachdev and Dr. Renuka Tipirneni for providing feedback on the survey instrument. We also thank the involved programs for their participation.

Corresponding author: Vineet Chopra, NCRC 2800 Plymouth Rd., Bldg 16, 432, Ann Arbor, MI 48109, [email protected].

Financial disclosures: None.

Previous presentations: Results were presented at the Annual Michigan Medicine 2017 Internal Medicine Research Symposium.

From the University of Michigan Medical School, Ann Arbor, MI.

Abstract

• Objective: Existing research has demonstrated overall low rates of residents establishing care with a primary care physician (PCP). We conducted a survey-based study to better understand chronic illness, PCP utilization, and prescription medication use patterns in resident physician populations.
• Methods: In 2017, we invited internal and family medicine trainees from a convenience sample of U.S. residency programs to participate in a survey. We compared the characteristics of residents who had established care with a PCP to those who had not.
• Results: The response rate was 45% (348/766 residents). The majority (n = 205, 59%) of respondents stated they had established care with a PCP primarily for routine preventative care (n = 159, 79%) and access in the event of an emergency (n = 132, 66%). However, 31% (n = 103) denied having had a wellness visit in over 3 years. Nearly a quarter of residents (n = 77, 23%) reported a chronic medical illness and 14% (n = 45) reported a preexisting mental health condition prior to residency. One-third (n = 111, 33%) reported taking a long-term prescription medication. Compared to residents who had not established care, those with a PCP (n = 205) more often reported a chronic condition (P < 0.001), seeing a subspecialist (P = 0.01), or taking long-term prescription medications (P < 0.001). One in 5 (n = 62,19%) respondents reported receiving prescriptions for an acute illness from an individual with whom they did not have a doctor-patient relationship.
• Conclusion: Medical residents have a substantial burden of chronic illness that may not be met through interactions with PCPs. Further understanding their medical needs and barriers to accessing care is necessary to ensure trainee well-being.

Keywords: Medical education-graduate, physician behavior, survey research, access to care.

Although internal medicine (IM) and family medicine (FM) residents must learn to provide high-quality primary care to their patients, little is known about whether they appropriately access such care themselves. Resident burnout and resilience has received attention [1,2], but there has been limited focus on understanding the burden of chronic medical and mental illness among residents. In particular, little is known about whether residents access primary care physicians (PCPs)—for either acute or chronic medical needs—and about resident self-medication practices.

Residency is often characterized by a life-changing geographic relocation. Even residents who do not relocate may still need to establish care with a new PCP due to health insurance or loss of access to a student clinic [3]. Establishing primary care with a new doctor typically requires scheduling a new patient visit, often with a wait time of several days to weeks [4,5]. Furthermore, lack of time, erratic schedules, and concerns about privacy and the stigma of being ill as a physician are barriers to establishing care [6-8]. Individuals who have not established primary care may experience delays in routine preventative health services, screening for chronic medical and mental health conditions, as well as access to care during acute illnesses [9,10]. Worse, they may engage in potentially unsafe practices, such as having colleagues write prescriptions for them, or even self-prescribing [8,11,12].

Existing research has demonstrated overall low rates of residents establishing care with a PCP [6–8,13]. However, these studies have either been limited to large academic centers or conducted outside the United States. Improving resident well-being may prove challenging without a clear understanding of current primary care utilization practices, the burden of chronic illness among residents, and patterns of prescription medication use and needs. Therefore, we conducted a survey-based study to understand primary care utilization and the burden of chronic illness among residents. We also assessed whether lack of primary care is associated with potentially risky behaviors, such as self-prescribing of medications.

Methods

Study Setting and Participants

The survey was distributed to current residents at IM and FM programs within the United States in 2017. Individual programs were recruited by directly contacting program directors or chief medical residents via email. Rather than contacting sites directly through standard templated emails, we identified programs both through personal contacts as well as the Electronic Residency Application Service list of accredited IM training programs. We elected to use this approach in order to increase response rates and to ensure that a sample representative of the trainee population was constructed. Programs were located in the Northeast, Midwest, South, and Pacific regions, and included small community-based programs and large academic centers.

Development of the Survey

The survey instrument was developed by the authors and reviewed by residents and PCPs at the University of Michigan to ensure relevance and comprehension of questions (The survey is available in the Appendix.). Once finalized, the survey was programmed into an online survey tool (Qualtrics, Provo, UT) and pilot-tested before being disseminated to the sampling frame. Data collected in the survey included: respondent’s utilization of a PCP, burden of chronic illness, long-term prescription medications, prescribing source, and demographic characteristics.

Each participating program distributed the survey to their residents through an email containing an anonymous hyperlink. The survey was available for completion for 4 weeks. We asked participating programs to send email reminders to encourage participation. Participants were given the option of receiving a $10 Amazon gift card after completion. All responses were recorded anonymously. The study received a “not regulated” status by the University of Michigan Institutional Review Board (HUM 00123888).

Statistical Analysis

Descriptive statistics were used to tabulate results. Respondents were encouraged, but not required, to answer all questions. Therefore, the response rate for each question was calculated using the total number of responses for that question as the denominator. Bivariable comparisons were made using Chi-squared or Fisher’s exact tests, as appropriate, for categorical data. A P value < 0.05, with 2-sided alpha, was considered statistically significant. All statistical analyses were conducted using Stata 13 SE (StataCorp, College Station, TX).

Results

Respondent Characteristics

Of the 29 programs contacted, 10 agreed to participate within the study timeframe. Of 766 potential respondents, 348 (45%) residents answered the survey (Table 1). The majority of respondents (n = 276, 82%) were from IM programs. Respondents were from all training years as follows: postgraduate year 1 residents (PGY-1, or interns; n = 130, 39%), PGY-2 residents (n = 98, 29%), PGY-3 residents (n = 93, 28%), and PGY-4 residents (n = 12, 4%). Most respondents were from the South (n = 130, 39%) and Midwest (n = 123, 37%) regions, and over half (n = 179, 54%) were female. Most respondents (n = 285, 86%) stated that they did not have children. The majority (n = 236, 71%) were completing residency in an area where they had not previously lived for more than 1 year.

Primary Care Utilization

Among the 348 respondents, 59% (n = 205) reported having established care with a PCP. An additional 6% (n = 21) had established care with an obstetrician/gynecologist for routine needs (Table 2). The 2 most common reasons for establishing care with a PCP were routine primary care needs, including contraception (n = 159, 79%), and access to a physician in the event of an acute medical need (n = 132, 66%).

Among respondents who had established care with a PCP, most (n = 188, 94%) had completed at least 1 appointment. However, among these 188 respondents, 68% (n = 127) stated that they had not made an acute visit in more than 12 months. When asked about wellness visits, almost one third of respondents (n = 103, 31%) stated that they had not been seen for a wellness visit in the past 3 years.

Burden of Chronic Illness

Most respondents (n = 223, 67%) stated that they did not have a chronic medical or mental health condition prior to residency (Table 3). However, 23% (n = 77) of respondents stated that they had been diagnosed with a chronic medical illness prior to residency, and 14% (n = 45) indicated they had been diagnosed with a mental health condition prior to residency. Almost one fifth of respondents (n = 60, 18%) reported seeing a subspecialist for a medical illness, and 33% (n = 111) reported taking a long-term prescription medication. With respect to major medical issues, the majority of residents (n = 239, 72%) denied experiencing events such as pregnancy, hospitalization, surgery, or an emergency department (ED) visit during training.

[polldaddy:10116940]

Inappropriate Prescriptions

While the majority of respondents denied writing a prescription for themselves for an acute or chronic medical condition, almost one fifth (n = 62, 19%) had received a prescription for an acute medical need from a provider outside of a clinical relationship (ie, from someone other than their PCP or specialty provider). Notably, 5% (n = 15) reported that this had occurred at least 2 or 3 times in the past 12 months (Table 4). Compared to respondents not taking long-term prescription medications, respondents who were already taking long-term prescription medications more frequently reported inappropriately receiving chronic prescriptions outside of an established clinical relationship (n = 14, 13% vs. n = 14, 6%; P = 0.05) and more often self-prescribed medications for acute needs (n = 12, 11% vs. n = 7, 3%; P = 0.005).

Important differences were noted between residents who had a PCP versus those who did not (Table 5). For example, a higher percentage of residents with a PCP indicated they had been diagnosed with a chronic medical illness (n = 55, 28% vs. n = 22, 16%; P = 0.01) or a chronic mental health condition (n = 34, 17% vs. n = 11, 8%; P = 0.02) before residency. Additionally, a higher percentage of residents with a PCP (n = 70, 35% vs. n = 25, 18%; P = 0.001) reported experiencing medical events such as pregnancy, hospitalization, surgery, ED visit, or new diagnosis of a chronic medical illness during residency. Finally, a higher percentage of respondents with a PCP stated that they had visited a subspecialist for a medical illness (n = 44, 22% vs. n = 16,12%; P = 0.01) or were taking long-term prescription medications (n = 86, 43% vs. n = 25; 18%; P < 0.001). When comparing PGY-1 to PGY-2–PGY-4 residents, the former reported having established a medical relationship with a PCP significantly less frequently (n = 56, 43% vs. n = 142, 70%; P < 0.001).

Discussion

This survey-based study of medical residents across the United States suggests that a substantial proportion do not establish relationships with PCPs. Additionally, our data suggest that despite establishing care, few residents subsequently visited their PCP during training for wellness visits or routine care. Self-reported rates of chronic medical and mental health conditions were substantial in our sample. Furthermore, inappropriate self-prescription and the receipt of prescriptions outside of a medical relationship were also reported. These findings suggest that future studies that focus on the unique medical and mental health needs of physicians in training, as well as interventions to encourage care in this vulnerable period, are necessary.

We observed that most respondents that established primary care were female trainees. Although it is impossible to know with certainty, one hypothesis behind this discrepancy is that women routinely need to access preventative care for gynecologic needs such as pap smears, contraception, and potentially pregnancy and preconception counseling [14,15]. Similarly, residents with a chronic medical or mental health condition prior to residency established care with a local PCP at a significantly greater frequency than those without such diagnoses. While selection bias cannot be excluded, this finding suggests that illness is a driving factor in establishing care. There also appears to be an association between accessing the medical system (either for prescription medications or subspecialist care) and having established care with a PCP. Collectively, these data suggest that individuals without a compelling reason to access medical services might have barriers to accessing care in the event of medical needs or may not receive routine preventative care [9,10].

In general, we found that rates of reported inappropriate prescriptions were lower than those reported in prior studies where a comparable resident population was surveyed [8,12,16]. Inclusion of multiple institutions, differences in temporality, social desirability bias, and reporting bias might have influenced our findings in this regard. Surprisingly, we found that having a PCP did not influence likelihood of inappropriate prescription receipt, perhaps suggesting that this behavior reflects some degree of universal difficulty in accessing care. Alternatively, this finding might relate to a cultural tendency to self-prescribe among resident physicians. The fact that individuals on chronic medications more often both received and wrote inappropriate prescriptions suggests this problem might be more pronounced in individuals who take medications more often, as these residents have specific needs [12]. Future studies targeting these individuals thus appear warranted.

Our study has several limitations. First, our sample size was modest and the response rate of 45% was low. However, to our knowledge, this remains among the largest survey on this topic, and our response rate is comparable to similar trainee studies [8,11,13]. Second, we designed and created a novel survey for this study. While the questions were pilot-tested with users prior to dissemination, validation of the instrument was not performed. Third, since the study population was restricted to residents in fields that participate in primary care, our findings may not be generalizable to patterns of PCP use in other specialties [6].

These limitations aside, our study has important strengths. This is the first national study of its kind with specific questions addressing primary care access and utilization, prescription medication use and related practices, and the prevalence of medical conditions among trainees. Important differences in the rates of establishing primary care between male and female respondents, first- year and senior residents, and those with and without chronic disease suggest a need to target specific resident groups (males, interns, those without pre-existing conditions) for wellness-related interventions. Such interventions could include distribution of a list of local providers to first year residents, advanced protected time for doctor’s appointments, and safeguards to ensure health information is protected from potential supervisors. Future studies should also include residents from non-primary care oriented specialties such as surgery, emergency medicine, and anesthesiology to obtain results that are more generalizable to the resident population as a whole. Additionally, the rates of inappropriate prescriptions were not insignificant and warrant further evaluation of the driving forces behind these behaviors.

Conclusion

Medical residents have a substantial burden of chronic illness that may not be met through interactions with PCPs. More research into barriers that residents face while accessing care and an assessment of interventions to facilitate their access to care is important to promote trainee well-being. Without such direction and initiative, it may prove harder for physicians to heal themselves or those for whom they provide care.

Acknowledgments: We thank Suzanne Winter, the study coordinator, for her support with editing and formatting the manuscript, Latoya Kuhn for performing the statistical analysis and creating data tables, and Dr. Namita Sachdev and Dr. Renuka Tipirneni for providing feedback on the survey instrument. We also thank the involved programs for their participation.

Corresponding author: Vineet Chopra, NCRC 2800 Plymouth Rd., Bldg 16, 432, Ann Arbor, MI 48109, [email protected].

Financial disclosures: None.

Previous presentations: Results were presented at the Annual Michigan Medicine 2017 Internal Medicine Research Symposium.

From the University of Michigan Medical School, Ann Arbor, MI.

Abstract

• Objective: Existing research has demonstrated overall low rates of residents establishing care with a primary care physician (PCP). We conducted a survey-based study to better understand chronic illness, PCP utilization, and prescription medication use patterns in resident physician populations.
• Methods: In 2017, we invited internal and family medicine trainees from a convenience sample of U.S. residency programs to participate in a survey. We compared the characteristics of residents who had established care with a PCP to those who had not.
• Results: The response rate was 45% (348/766 residents). The majority (n = 205, 59%) of respondents stated they had established care with a PCP primarily for routine preventative care (n = 159, 79%) and access in the event of an emergency (n = 132, 66%). However, 31% (n = 103) denied having had a wellness visit in over 3 years. Nearly a quarter of residents (n = 77, 23%) reported a chronic medical illness and 14% (n = 45) reported a preexisting mental health condition prior to residency. One-third (n = 111, 33%) reported taking a long-term prescription medication. Compared to residents who had not established care, those with a PCP (n = 205) more often reported a chronic condition (P < 0.001), seeing a subspecialist (P = 0.01), or taking long-term prescription medications (P < 0.001). One in 5 (n = 62,19%) respondents reported receiving prescriptions for an acute illness from an individual with whom they did not have a doctor-patient relationship.
• Conclusion: Medical residents have a substantial burden of chronic illness that may not be met through interactions with PCPs. Further understanding their medical needs and barriers to accessing care is necessary to ensure trainee well-being.

Keywords: Medical education-graduate, physician behavior, survey research, access to care.

Although internal medicine (IM) and family medicine (FM) residents must learn to provide high-quality primary care to their patients, little is known about whether they appropriately access such care themselves. Resident burnout and resilience has received attention [1,2], but there has been limited focus on understanding the burden of chronic medical and mental illness among residents. In particular, little is known about whether residents access primary care physicians (PCPs)—for either acute or chronic medical needs—and about resident self-medication practices.

Residency is often characterized by a life-changing geographic relocation. Even residents who do not relocate may still need to establish care with a new PCP due to health insurance or loss of access to a student clinic [3]. Establishing primary care with a new doctor typically requires scheduling a new patient visit, often with a wait time of several days to weeks [4,5]. Furthermore, lack of time, erratic schedules, and concerns about privacy and the stigma of being ill as a physician are barriers to establishing care [6-8]. Individuals who have not established primary care may experience delays in routine preventative health services, screening for chronic medical and mental health conditions, as well as access to care during acute illnesses [9,10]. Worse, they may engage in potentially unsafe practices, such as having colleagues write prescriptions for them, or even self-prescribing [8,11,12].

Existing research has demonstrated overall low rates of residents establishing care with a PCP [6–8,13]. However, these studies have either been limited to large academic centers or conducted outside the United States. Improving resident well-being may prove challenging without a clear understanding of current primary care utilization practices, the burden of chronic illness among residents, and patterns of prescription medication use and needs. Therefore, we conducted a survey-based study to understand primary care utilization and the burden of chronic illness among residents. We also assessed whether lack of primary care is associated with potentially risky behaviors, such as self-prescribing of medications.

Methods

Study Setting and Participants

The survey was distributed to current residents at IM and FM programs within the United States in 2017. Individual programs were recruited by directly contacting program directors or chief medical residents via email. Rather than contacting sites directly through standard templated emails, we identified programs both through personal contacts as well as the Electronic Residency Application Service list of accredited IM training programs. We elected to use this approach in order to increase response rates and to ensure that a sample representative of the trainee population was constructed. Programs were located in the Northeast, Midwest, South, and Pacific regions, and included small community-based programs and large academic centers.

Development of the Survey

The survey instrument was developed by the authors and reviewed by residents and PCPs at the University of Michigan to ensure relevance and comprehension of questions (The survey is available in the Appendix.). Once finalized, the survey was programmed into an online survey tool (Qualtrics, Provo, UT) and pilot-tested before being disseminated to the sampling frame. Data collected in the survey included: respondent’s utilization of a PCP, burden of chronic illness, long-term prescription medications, prescribing source, and demographic characteristics.

Each participating program distributed the survey to their residents through an email containing an anonymous hyperlink. The survey was available for completion for 4 weeks. We asked participating programs to send email reminders to encourage participation. Participants were given the option of receiving a $10 Amazon gift card after completion. All responses were recorded anonymously. The study received a “not regulated” status by the University of Michigan Institutional Review Board (HUM 00123888).

Statistical Analysis

Descriptive statistics were used to tabulate results. Respondents were encouraged, but not required, to answer all questions. Therefore, the response rate for each question was calculated using the total number of responses for that question as the denominator. Bivariable comparisons were made using Chi-squared or Fisher’s exact tests, as appropriate, for categorical data. A P value < 0.05, with 2-sided alpha, was considered statistically significant. All statistical analyses were conducted using Stata 13 SE (StataCorp, College Station, TX).

Results

Respondent Characteristics

Of the 29 programs contacted, 10 agreed to participate within the study timeframe. Of 766 potential respondents, 348 (45%) residents answered the survey (Table 1). The majority of respondents (n = 276, 82%) were from IM programs. Respondents were from all training years as follows: postgraduate year 1 residents (PGY-1, or interns; n = 130, 39%), PGY-2 residents (n = 98, 29%), PGY-3 residents (n = 93, 28%), and PGY-4 residents (n = 12, 4%). Most respondents were from the South (n = 130, 39%) and Midwest (n = 123, 37%) regions, and over half (n = 179, 54%) were female. Most respondents (n = 285, 86%) stated that they did not have children. The majority (n = 236, 71%) were completing residency in an area where they had not previously lived for more than 1 year.

Primary Care Utilization

Among the 348 respondents, 59% (n = 205) reported having established care with a PCP. An additional 6% (n = 21) had established care with an obstetrician/gynecologist for routine needs (Table 2). The 2 most common reasons for establishing care with a PCP were routine primary care needs, including contraception (n = 159, 79%), and access to a physician in the event of an acute medical need (n = 132, 66%).

Among respondents who had established care with a PCP, most (n = 188, 94%) had completed at least 1 appointment. However, among these 188 respondents, 68% (n = 127) stated that they had not made an acute visit in more than 12 months. When asked about wellness visits, almost one third of respondents (n = 103, 31%) stated that they had not been seen for a wellness visit in the past 3 years.

Burden of Chronic Illness

Most respondents (n = 223, 67%) stated that they did not have a chronic medical or mental health condition prior to residency (Table 3). However, 23% (n = 77) of respondents stated that they had been diagnosed with a chronic medical illness prior to residency, and 14% (n = 45) indicated they had been diagnosed with a mental health condition prior to residency. Almost one fifth of respondents (n = 60, 18%) reported seeing a subspecialist for a medical illness, and 33% (n = 111) reported taking a long-term prescription medication. With respect to major medical issues, the majority of residents (n = 239, 72%) denied experiencing events such as pregnancy, hospitalization, surgery, or an emergency department (ED) visit during training.

[polldaddy:10116940]

Inappropriate Prescriptions

While the majority of respondents denied writing a prescription for themselves for an acute or chronic medical condition, almost one fifth (n = 62, 19%) had received a prescription for an acute medical need from a provider outside of a clinical relationship (ie, from someone other than their PCP or specialty provider). Notably, 5% (n = 15) reported that this had occurred at least 2 or 3 times in the past 12 months (Table 4). Compared to respondents not taking long-term prescription medications, respondents who were already taking long-term prescription medications more frequently reported inappropriately receiving chronic prescriptions outside of an established clinical relationship (n = 14, 13% vs. n = 14, 6%; P = 0.05) and more often self-prescribed medications for acute needs (n = 12, 11% vs. n = 7, 3%; P = 0.005).

Important differences were noted between residents who had a PCP versus those who did not (Table 5). For example, a higher percentage of residents with a PCP indicated they had been diagnosed with a chronic medical illness (n = 55, 28% vs. n = 22, 16%; P = 0.01) or a chronic mental health condition (n = 34, 17% vs. n = 11, 8%; P = 0.02) before residency. Additionally, a higher percentage of residents with a PCP (n = 70, 35% vs. n = 25, 18%; P = 0.001) reported experiencing medical events such as pregnancy, hospitalization, surgery, ED visit, or new diagnosis of a chronic medical illness during residency. Finally, a higher percentage of respondents with a PCP stated that they had visited a subspecialist for a medical illness (n = 44, 22% vs. n = 16,12%; P = 0.01) or were taking long-term prescription medications (n = 86, 43% vs. n = 25; 18%; P < 0.001). When comparing PGY-1 to PGY-2–PGY-4 residents, the former reported having established a medical relationship with a PCP significantly less frequently (n = 56, 43% vs. n = 142, 70%; P < 0.001).

Discussion

This survey-based study of medical residents across the United States suggests that a substantial proportion do not establish relationships with PCPs. Additionally, our data suggest that despite establishing care, few residents subsequently visited their PCP during training for wellness visits or routine care. Self-reported rates of chronic medical and mental health conditions were substantial in our sample. Furthermore, inappropriate self-prescription and the receipt of prescriptions outside of a medical relationship were also reported. These findings suggest that future studies that focus on the unique medical and mental health needs of physicians in training, as well as interventions to encourage care in this vulnerable period, are necessary.

We observed that most respondents that established primary care were female trainees. Although it is impossible to know with certainty, one hypothesis behind this discrepancy is that women routinely need to access preventative care for gynecologic needs such as pap smears, contraception, and potentially pregnancy and preconception counseling [14,15]. Similarly, residents with a chronic medical or mental health condition prior to residency established care with a local PCP at a significantly greater frequency than those without such diagnoses. While selection bias cannot be excluded, this finding suggests that illness is a driving factor in establishing care. There also appears to be an association between accessing the medical system (either for prescription medications or subspecialist care) and having established care with a PCP. Collectively, these data suggest that individuals without a compelling reason to access medical services might have barriers to accessing care in the event of medical needs or may not receive routine preventative care [9,10].

In general, we found that rates of reported inappropriate prescriptions were lower than those reported in prior studies where a comparable resident population was surveyed [8,12,16]. Inclusion of multiple institutions, differences in temporality, social desirability bias, and reporting bias might have influenced our findings in this regard. Surprisingly, we found that having a PCP did not influence likelihood of inappropriate prescription receipt, perhaps suggesting that this behavior reflects some degree of universal difficulty in accessing care. Alternatively, this finding might relate to a cultural tendency to self-prescribe among resident physicians. The fact that individuals on chronic medications more often both received and wrote inappropriate prescriptions suggests this problem might be more pronounced in individuals who take medications more often, as these residents have specific needs [12]. Future studies targeting these individuals thus appear warranted.

Our study has several limitations. First, our sample size was modest and the response rate of 45% was low. However, to our knowledge, this remains among the largest survey on this topic, and our response rate is comparable to similar trainee studies [8,11,13]. Second, we designed and created a novel survey for this study. While the questions were pilot-tested with users prior to dissemination, validation of the instrument was not performed. Third, since the study population was restricted to residents in fields that participate in primary care, our findings may not be generalizable to patterns of PCP use in other specialties [6].

These limitations aside, our study has important strengths. This is the first national study of its kind with specific questions addressing primary care access and utilization, prescription medication use and related practices, and the prevalence of medical conditions among trainees. Important differences in the rates of establishing primary care between male and female respondents, first- year and senior residents, and those with and without chronic disease suggest a need to target specific resident groups (males, interns, those without pre-existing conditions) for wellness-related interventions. Such interventions could include distribution of a list of local providers to first year residents, advanced protected time for doctor’s appointments, and safeguards to ensure health information is protected from potential supervisors. Future studies should also include residents from non-primary care oriented specialties such as surgery, emergency medicine, and anesthesiology to obtain results that are more generalizable to the resident population as a whole. Additionally, the rates of inappropriate prescriptions were not insignificant and warrant further evaluation of the driving forces behind these behaviors.

Conclusion

Medical residents have a substantial burden of chronic illness that may not be met through interactions with PCPs. More research into barriers that residents face while accessing care and an assessment of interventions to facilitate their access to care is important to promote trainee well-being. Without such direction and initiative, it may prove harder for physicians to heal themselves or those for whom they provide care.

Acknowledgments: We thank Suzanne Winter, the study coordinator, for her support with editing and formatting the manuscript, Latoya Kuhn for performing the statistical analysis and creating data tables, and Dr. Namita Sachdev and Dr. Renuka Tipirneni for providing feedback on the survey instrument. We also thank the involved programs for their participation.

Corresponding author: Vineet Chopra, NCRC 2800 Plymouth Rd., Bldg 16, 432, Ann Arbor, MI 48109, [email protected].

Financial disclosures: None.

Previous presentations: Results were presented at the Annual Michigan Medicine 2017 Internal Medicine Research Symposium.

Overdose death rates for individual drugs show no particular patterns since the turn of the century, but the exponential growth of overall drug mortality actually started before the opioid epidemic, according to an analysis of almost 600,000 unintentional overdose deaths since 1979.

“The current epidemic of overdose deaths due to prescription opioids, heroin, and fentanyl appears to be the most recent manifestation of a more fundamental, longer-term process,” senior author Donald S. Burke, MD, of the University of Pittsburgh, said in a written statement.

Overdose mortality from all types of drugs rose from 1.13 per 100,000 population in 1979 to 16.96 per 100,000 in 2016, based on data for 599,255 deaths from unintentional drug overdoses in the National Vital Statistics System, they reported in Science.

When the investigators plotted annual drug overdose mortality over that 38-year period, they saw a smooth upward exponential curve with a doubling time of about 9 years. “This remarkably smooth, long-term epidemic growth pattern really caught our attention,” Dr. Burke said. “If we can figure it out, we should be able to bend that curve downward.”

The individual drug types that make up the whole, however, are a different story. “There is no regular or predictable pattern to the overdose rates for any of these drugs. Cocaine overdose death rates curved down and up and down and back up over the past 20 years. Methadone deaths have been on a downturn since the mid-2000s. Prescription opioids have been on a fairly steady, steep climb. Heroin deaths shot up in 2010, followed in 2013 by synthetic opioids, such as fentanyl,” lead author Hawre Jalal, MD, PhD, also of the university, said in the statement.

Geographic and demographic analyses produced the same absence of patterns. “Indeed, these findings add to the paradox by revealing how disparate the individual drug epidemics are,” the researchers wrote.

The study was supported by grants from the Centers for Disease Control and Prevention and the Robert Wood Johnson Foundation. The investigators said they have no competing interests.
 

[email protected]

SOURCE: Jalal H et al. Science 2018 Sep 20. doi: 10.1126/science.aau1184.

Overdose death rates for individual drugs show no particular patterns since the turn of the century, but the exponential growth of overall drug mortality actually started before the opioid epidemic, according to an analysis of almost 600,000 unintentional overdose deaths since 1979.

“The current epidemic of overdose deaths due to prescription opioids, heroin, and fentanyl appears to be the most recent manifestation of a more fundamental, longer-term process,” senior author Donald S. Burke, MD, of the University of Pittsburgh, said in a written statement.

Overdose mortality from all types of drugs rose from 1.13 per 100,000 population in 1979 to 16.96 per 100,000 in 2016, based on data for 599,255 deaths from unintentional drug overdoses in the National Vital Statistics System, they reported in Science.

When the investigators plotted annual drug overdose mortality over that 38-year period, they saw a smooth upward exponential curve with a doubling time of about 9 years. “This remarkably smooth, long-term epidemic growth pattern really caught our attention,” Dr. Burke said. “If we can figure it out, we should be able to bend that curve downward.”

The individual drug types that make up the whole, however, are a different story. “There is no regular or predictable pattern to the overdose rates for any of these drugs. Cocaine overdose death rates curved down and up and down and back up over the past 20 years. Methadone deaths have been on a downturn since the mid-2000s. Prescription opioids have been on a fairly steady, steep climb. Heroin deaths shot up in 2010, followed in 2013 by synthetic opioids, such as fentanyl,” lead author Hawre Jalal, MD, PhD, also of the university, said in the statement.

Geographic and demographic analyses produced the same absence of patterns. “Indeed, these findings add to the paradox by revealing how disparate the individual drug epidemics are,” the researchers wrote.

The study was supported by grants from the Centers for Disease Control and Prevention and the Robert Wood Johnson Foundation. The investigators said they have no competing interests.
 

[email protected]

SOURCE: Jalal H et al. Science 2018 Sep 20. doi: 10.1126/science.aau1184.

Overdose death rates for individual drugs show no particular patterns since the turn of the century, but the exponential growth of overall drug mortality actually started before the opioid epidemic, according to an analysis of almost 600,000 unintentional overdose deaths since 1979.

“The current epidemic of overdose deaths due to prescription opioids, heroin, and fentanyl appears to be the most recent manifestation of a more fundamental, longer-term process,” senior author Donald S. Burke, MD, of the University of Pittsburgh, said in a written statement.

Overdose mortality from all types of drugs rose from 1.13 per 100,000 population in 1979 to 16.96 per 100,000 in 2016, based on data for 599,255 deaths from unintentional drug overdoses in the National Vital Statistics System, they reported in Science.

When the investigators plotted annual drug overdose mortality over that 38-year period, they saw a smooth upward exponential curve with a doubling time of about 9 years. “This remarkably smooth, long-term epidemic growth pattern really caught our attention,” Dr. Burke said. “If we can figure it out, we should be able to bend that curve downward.”

The individual drug types that make up the whole, however, are a different story. “There is no regular or predictable pattern to the overdose rates for any of these drugs. Cocaine overdose death rates curved down and up and down and back up over the past 20 years. Methadone deaths have been on a downturn since the mid-2000s. Prescription opioids have been on a fairly steady, steep climb. Heroin deaths shot up in 2010, followed in 2013 by synthetic opioids, such as fentanyl,” lead author Hawre Jalal, MD, PhD, also of the university, said in the statement.

Geographic and demographic analyses produced the same absence of patterns. “Indeed, these findings add to the paradox by revealing how disparate the individual drug epidemics are,” the researchers wrote.

The study was supported by grants from the Centers for Disease Control and Prevention and the Robert Wood Johnson Foundation. The investigators said they have no competing interests.
 

[email protected]

SOURCE: Jalal H et al. Science 2018 Sep 20. doi: 10.1126/science.aau1184.

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bis­phosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

• Fever 20.3% vs 2.5%
• Musculoskeletal symptoms 19.9% vs 4.7% 
• Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the meval­onate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

• Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
• Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bis­phosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

• Fever 20.3% vs 2.5%
• Musculoskeletal symptoms 19.9% vs 4.7% 
• Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the meval­onate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

• Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
• Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bis­phosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

• Fever 20.3% vs 2.5%
• Musculoskeletal symptoms 19.9% vs 4.7% 
• Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the meval­onate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

• Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
• Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

• Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
• Nivolumab and pembrolizumab block programmed cell death protein 1
• Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyper­thyroidism should also be ruled out.⁴

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizu­mab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

• Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
• Nivolumab and pembrolizumab block programmed cell death protein 1
• Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyper­thyroidism should also be ruled out.⁴

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizu­mab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

• Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
• Nivolumab and pembrolizumab block programmed cell death protein 1
• Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyper­thyroidism should also be ruled out.⁴

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizu­mab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

• Coronary artery disease requiring coronary artery bypass grafting
• Ischemic cardiomyopathy
• Severe mitral regurgitation
• Moderate tricuspid regurgitation
• Pulmonary hypertension
• Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
• Hypothyroidism requiring levothyroxine
• Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
• Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

• Acute decompensated heart failure
• Pulmonary embolism
• Exacerbation of asthma
• Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

• Heart failure with reduced ejection fraction
• Bacterial pneumonia
• Idiopathic pulmonary fibrosis
• Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

• Surgical lung biopsy
• Stop amiodarone and start supportive influenza management
• Stop amiodarone and start dronedarone
• Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

• FEV₁ 0.69 L (56% of predicted)
• FVC 1.08 L (64% of predicted)

• 

  FEV₁/FVC ratio 64%
• DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

• No further management, continue to hold amiodarone
• Corticosteroids
• Repeat bronchoalveolar lavage
• Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

• Coronary artery disease requiring coronary artery bypass grafting
• Ischemic cardiomyopathy
• Severe mitral regurgitation
• Moderate tricuspid regurgitation
• Pulmonary hypertension
• Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
• Hypothyroidism requiring levothyroxine
• Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
• Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

• Acute decompensated heart failure
• Pulmonary embolism
• Exacerbation of asthma
• Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

• Heart failure with reduced ejection fraction
• Bacterial pneumonia
• Idiopathic pulmonary fibrosis
• Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

• Surgical lung biopsy
• Stop amiodarone and start supportive influenza management
• Stop amiodarone and start dronedarone
• Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

• FEV₁ 0.69 L (56% of predicted)
• FVC 1.08 L (64% of predicted)

• 

  FEV₁/FVC ratio 64%
• DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

• No further management, continue to hold amiodarone
• Corticosteroids
• Repeat bronchoalveolar lavage
• Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

• Coronary artery disease requiring coronary artery bypass grafting
• Ischemic cardiomyopathy
• Severe mitral regurgitation
• Moderate tricuspid regurgitation
• Pulmonary hypertension
• Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
• Hypothyroidism requiring levothyroxine
• Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
• Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

• Acute decompensated heart failure
• Pulmonary embolism
• Exacerbation of asthma
• Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

• Heart failure with reduced ejection fraction
• Bacterial pneumonia
• Idiopathic pulmonary fibrosis
• Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

• Surgical lung biopsy
• Stop amiodarone and start supportive influenza management
• Stop amiodarone and start dronedarone
• Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

• FEV₁ 0.69 L (56% of predicted)
• FVC 1.08 L (64% of predicted)

• 

  FEV₁/FVC ratio 64%
• DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

• No further management, continue to hold amiodarone
• Corticosteroids
• Repeat bronchoalveolar lavage
• Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

We live in the era of evidence-based medicine, so new interventions must meet criteria for both safety and efficacy before they are adopted. However, we have inherited many practices adopted before the current standards were in place, and we have not always been rigorous in reevaluating traditional remedies. A conservative belief in established practice or the influence of vested interests may account for this lack of rigor in reappraisal.¹ Calcium and vitamin D supplements are possible examples of this phenomenon.

BONE METABOLISM IS TIGHTLY REGULATED

Bone is a connective tissue, its matrix composed principally of type 1 collagen, which provides tensile strength. Hydroxyapatite crystals, composed predominantly of calcium and phosphate, lie between the collagen fibers and provide compressive strength. In a tightly regulated process, osteoblasts lay down the collagenous matrix, and osteoclasts remove it. Mineralization of newly formed bone proceeds if normal levels of extracellular calcium and phosphate are present, in the absence of inhibitors of mineralization.

High calcium intake does not drive bone formation

The endocrine system is critical in maintaining normocalcemia. A decrease in calcium intake results in increased parathyroid hormone secretion, resulting in increased renal tubular calcium reabsorption, increased bone turnover (both formation and resorption), and increased activation of vitamin D leading to increased intestinal absorption of calcium. High calcium intake reverses these changes.

Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. Copyright 2015, The Association for the Publication of the Journal of Internal Medicine.

If calcium intake is very low, hypocalcemia and secondary hyperparathyroidism develop,³ and bone mineralization may be impaired. However, levels of calcium intake in Africa and in East and Southeast Asia are typically less than 400 mg/day,⁴ yet there is no evidence that these levels adversely affect skeletal health. In fact, fracture risk is lower in these regions than in North America, where calcium intake is several times greater.

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

Vitamin D is a biologically inactive secosteroid activated by hydroxylation in the liver and kidney to function as the key regulator of intestinal calcium absorption. As with calcium, its deficiency results in hypocalcemia and impaired bone mineralization.

Paradoxically, high levels of vitamin D stimulate bone resorption and inhibit bone mineralization in mice,⁵ and large doses increase bone resorption markers acutely in clinical studies.⁶ Thus, it is important to ensure an adequate vitamin D supply, but not an oversupply.

In the absence of supplements, most vitamin D is produced in the skin as a result of the action of ultraviolet light (from sunlight) on 7-dehydrocholesterol. Thus, vitamin D deficiency occurs in those deprived of skin exposure to sunlight (eg, due to veiling, living at high latitude, staying permanently indoors), but it has little relationship with diet.

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

Calcium supplements are certainly biologically active. They transiently increase serum calcium concentrations, suppress parathyroid hormone, and reduce bone resorption.² In the first year of use, they increase bone density by about 1% compared with placebo.⁷ However, longer use does not result in further bone density advantage over placebo,⁷ suggesting that the response simply reflects a decreased number of osteoclastic resorption sites and does not indicate a sustained change in bone balance.

A 1% difference in bone density would not be expected to reduce fracture risk, and a number of large, carefully conducted randomized controlled trials published over the last 15 years have failed to demonstrate anti­fracture efficacy for calcium.^8–12 As a result, the US Preventive Services Task Force recommends against the routine use of calcium supplements in community-dwelling adults.¹³

In contrast, in a placebo-controlled trial published in 1992, Chapuy et al¹⁴ found that elderly women residing in nursing homes who received calcium and vitamin D supplements had fewer fractures. At 18 months, by intention-to-treat analysis, nonvertebral fractures had occurred in 160 (12%) of 1,387 women in the supplement group compared with 215 (15%) of 1,403 women in the placebo group (P < .001). However, these women were severely vitamin D-deficient (the mean serum 25-hydroxyvitamin D level at baseline in the placebo group was 13 ng/mL, normal range 15–50), to the extent that many must have had osteomalacia.

Thus, this study shows that calcium and vitamin D are effective in managing osteomalacia, but the subsequent trials^8–12 did not observe any benefit in community-dwelling cohorts. Meta-analyses that pool the Chapuy study with community-based studies generally find that calcium with vitamin D is beneficial, but the heterogeneity of these populations means that such pooling is inappropriate.¹⁵

It is sometimes stated that calcium and vitamin D should always be given with osteoporosis medications because the efficacy of these drugs has only been demonstrated when coadministered with these supplements. This is incorrect. The addition of calcium to alendronate does not alter its effects on bone density,¹⁶ and the antifracture efficacy of both bisphosphonates¹⁷ and estrogen^18,19 has been demonstrated in the absence of supplementation with calcium or vitamin D. The evidence that bisphosphonates prevent fractures in the absence of calcium supplements has recently been strengthened by the results of a randomized controlled trial comparing zoledronate with placebo in women over age 65 with osteopenia.²⁰

Calcium supplements often cause gastrointestinal symptoms, particularly constipation. They have been shown to double the risk of hospital admission due to abdominal symptoms.²¹ In the absence of clear evidence of benefit, these facts alone should militate against their routine use. Calcium supplements also cause hypercalcemia and hypercalciuria²² and increase the risk of renal calculi (by 17% in the Women’s Health Initiative⁸).

Over the last decade, evidence has emerged that calcium supplements may also increase the risk of myocardial infarction, and possibly stroke. This finding was not statistically significant in any single study, but is consistently present in meta-analyses.²³

Evidence from the Women’s Health Initiative

When studies of calcium with vitamin D are added to these meta-analyses, the results are less consistent. This is because such meta-analyses are dominated by the Women's Health Initiative (because of its large size, with 36,282 participants). There have been 2 different analyses of this trial with respect to cardiovascular events.

When the Women’s Health Initiative as a whole was analyzed, there was no significant effect of calcium plus vitamin D on vascular end points. However, there is a significant interaction between body mass index and the effect of supplements, such that nonobese women demonstrated a 17% increase in myocardial infarction.²⁴ This study was unusual in that it included women already taking calcium and vitamin D supplements.

Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040.

There was a significant interaction between baseline use of supplements and the effects of the trial intervention on vascular events, justifying analyzing the supplement-naive individuals separately. In this group of 16,000 women, an increase in clinical myocardial infarction of 22% was found, similar to the findings with calcium supplements alone.²⁵

Thus, there is consistent evidence that introducing a calcium supplement de novo increases the risk of myocardial infarction (Figure 2).^16,25–31 We calculate that treating 1,000 patients with calcium or calcium plus vitamin D for 5 years would cause an additional 6 myocardial infarctions or strokes (number needed to harm 178) and prevent only 3 fractures (number needed to treat 302).²⁵

ARE VITAMIN D SUPPLEMENTS EFFECTIVE?

Vitamin D is highly effective in treating osteomalacia, improving symptoms within days and increasing bone density by as much as 50% over 1 year.^32,33 In contrast, randomized controlled trials of vitamin D supplements alone in people without osteomalacia have not shown increases in bone density or changes in fracture risk.^34–37

Reid IR, Horne AM, Mihov B, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med 2017; 282(5):452–460. Copyright 2017, Assoc for Publication of J Int Med

In 2017, my colleagues and I published a trial showing that vitamin D supplementation increases bone density by 2% to 3% in the spine and femoral neck in participants with baseline 25-hydroxyvitamin D levels below 30- nmol/L (12 ng/mL), but those starting above this level showed no effect (Figure 3).³⁸ And a reanalysis of an earlier study confirmed this 30 nmol/L threshold for an effect of vitamin D on bone density.³⁹ The finding of a clear-cut threshold for vitamin D effects is predicted by the physiologic considerations set out above.

Belief that higher levels of 25-hydroxyvitamin D are better is based on observational data. However, correlation does not prove causation, and it is likely that causation is reversed here. Those with better health are likely to spend more time exercising outdoors, are less likely to be obese, and are less likely to have inflammatory conditions; and as a result, they are more likely to have better vitamin D status. We should now be using trial-based definitions of vitamin D deficiency as opposed to thresholds derived from disease associations in observational studies.

Vitamin D supplements have also been suggested to benefit cardiovascular health and to reduce cancer risk, though current clinical trial data provide no support for these hypotheses.^36,40 Other trials addressing these questions are ongoing.

ARE VITAMIN D SUPPLEMENTS SAFE?

The safety of vitamin D supplements has generally been assessed with respect to the incidence of hypercalcemia. On this basis, very high doses have been promoted. However, there is now evidence that doses of 4,000 IU/day, 60,000 IU/month, and 500,000 IU/year increase the risk of falls and fractures.^41,42

The threshold for bone benefits discussed above (12 ng/mL) is easily exceeded with doses of vitamin D of 400 to 1,000 IU/day. At these levels, vitamin D supplements have no known adverse effects and can be widely endorsed for individuals at risk of deficiency. Supplement doses greater than 2,000 IU/day should be used only in exceptional circumstances, and with appropriate monitoring.

LITTLE USE FOR CALCIUM AND VITAMIN D SUPPLEMENTS

Extensive clinical trials have failed to demonstrate meaningful benefit from calcium supplements in the management of osteoporosis. Calcium supplements are often prescribed in patients who are receiving other treatments for osteoporosis, which may be justified with interventions that have the potential to cause hypocalcemia, but their coadministration with bisphosphonates has been shown to be unnecessary.

Calcium supplements commonly cause gastrointestinal symptoms that are sometimes severe and are likely to contribute to high levels of noncompliance with osteoporosis medications. They increase the risk of kidney stones,⁸ and there is reasonable evidence to suggest an adverse effect on vascular risk as well.²³

Vitamin D deficiency is common in frail elderly people, particularly those with dark skin or living at high latitudes. Low doses of vitamin D are safe and highly effective in preventing osteomalacia. But vitamin D supplements are unnecessary in those who regularly have sun exposure. And high doses of vitamin D have no demonstrated advantage and have been shown to increase the risk of falls and fractures.

Our decision to prescribe calcium and vitamin D supplements should be based on evidence that is of the same quality as for any other intervention we prescribe. Current evidence suggests that there is little reason to prescribe calcium, and that vitamin D should be targeted at those at risk of 25-hydroxyvitamin D levels less than 12 ng/mL.

We live in the era of evidence-based medicine, so new interventions must meet criteria for both safety and efficacy before they are adopted. However, we have inherited many practices adopted before the current standards were in place, and we have not always been rigorous in reevaluating traditional remedies. A conservative belief in established practice or the influence of vested interests may account for this lack of rigor in reappraisal.¹ Calcium and vitamin D supplements are possible examples of this phenomenon.

BONE METABOLISM IS TIGHTLY REGULATED

Bone is a connective tissue, its matrix composed principally of type 1 collagen, which provides tensile strength. Hydroxyapatite crystals, composed predominantly of calcium and phosphate, lie between the collagen fibers and provide compressive strength. In a tightly regulated process, osteoblasts lay down the collagenous matrix, and osteoclasts remove it. Mineralization of newly formed bone proceeds if normal levels of extracellular calcium and phosphate are present, in the absence of inhibitors of mineralization.

High calcium intake does not drive bone formation

The endocrine system is critical in maintaining normocalcemia. A decrease in calcium intake results in increased parathyroid hormone secretion, resulting in increased renal tubular calcium reabsorption, increased bone turnover (both formation and resorption), and increased activation of vitamin D leading to increased intestinal absorption of calcium. High calcium intake reverses these changes.

Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. Copyright 2015, The Association for the Publication of the Journal of Internal Medicine.

If calcium intake is very low, hypocalcemia and secondary hyperparathyroidism develop,³ and bone mineralization may be impaired. However, levels of calcium intake in Africa and in East and Southeast Asia are typically less than 400 mg/day,⁴ yet there is no evidence that these levels adversely affect skeletal health. In fact, fracture risk is lower in these regions than in North America, where calcium intake is several times greater.

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

Vitamin D is a biologically inactive secosteroid activated by hydroxylation in the liver and kidney to function as the key regulator of intestinal calcium absorption. As with calcium, its deficiency results in hypocalcemia and impaired bone mineralization.

Paradoxically, high levels of vitamin D stimulate bone resorption and inhibit bone mineralization in mice,⁵ and large doses increase bone resorption markers acutely in clinical studies.⁶ Thus, it is important to ensure an adequate vitamin D supply, but not an oversupply.

In the absence of supplements, most vitamin D is produced in the skin as a result of the action of ultraviolet light (from sunlight) on 7-dehydrocholesterol. Thus, vitamin D deficiency occurs in those deprived of skin exposure to sunlight (eg, due to veiling, living at high latitude, staying permanently indoors), but it has little relationship with diet.

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

Calcium supplements are certainly biologically active. They transiently increase serum calcium concentrations, suppress parathyroid hormone, and reduce bone resorption.² In the first year of use, they increase bone density by about 1% compared with placebo.⁷ However, longer use does not result in further bone density advantage over placebo,⁷ suggesting that the response simply reflects a decreased number of osteoclastic resorption sites and does not indicate a sustained change in bone balance.

A 1% difference in bone density would not be expected to reduce fracture risk, and a number of large, carefully conducted randomized controlled trials published over the last 15 years have failed to demonstrate anti­fracture efficacy for calcium.^8–12 As a result, the US Preventive Services Task Force recommends against the routine use of calcium supplements in community-dwelling adults.¹³

In contrast, in a placebo-controlled trial published in 1992, Chapuy et al¹⁴ found that elderly women residing in nursing homes who received calcium and vitamin D supplements had fewer fractures. At 18 months, by intention-to-treat analysis, nonvertebral fractures had occurred in 160 (12%) of 1,387 women in the supplement group compared with 215 (15%) of 1,403 women in the placebo group (P < .001). However, these women were severely vitamin D-deficient (the mean serum 25-hydroxyvitamin D level at baseline in the placebo group was 13 ng/mL, normal range 15–50), to the extent that many must have had osteomalacia.

Thus, this study shows that calcium and vitamin D are effective in managing osteomalacia, but the subsequent trials^8–12 did not observe any benefit in community-dwelling cohorts. Meta-analyses that pool the Chapuy study with community-based studies generally find that calcium with vitamin D is beneficial, but the heterogeneity of these populations means that such pooling is inappropriate.¹⁵

It is sometimes stated that calcium and vitamin D should always be given with osteoporosis medications because the efficacy of these drugs has only been demonstrated when coadministered with these supplements. This is incorrect. The addition of calcium to alendronate does not alter its effects on bone density,¹⁶ and the antifracture efficacy of both bisphosphonates¹⁷ and estrogen^18,19 has been demonstrated in the absence of supplementation with calcium or vitamin D. The evidence that bisphosphonates prevent fractures in the absence of calcium supplements has recently been strengthened by the results of a randomized controlled trial comparing zoledronate with placebo in women over age 65 with osteopenia.²⁰

Calcium supplements often cause gastrointestinal symptoms, particularly constipation. They have been shown to double the risk of hospital admission due to abdominal symptoms.²¹ In the absence of clear evidence of benefit, these facts alone should militate against their routine use. Calcium supplements also cause hypercalcemia and hypercalciuria²² and increase the risk of renal calculi (by 17% in the Women’s Health Initiative⁸).

Over the last decade, evidence has emerged that calcium supplements may also increase the risk of myocardial infarction, and possibly stroke. This finding was not statistically significant in any single study, but is consistently present in meta-analyses.²³

Evidence from the Women’s Health Initiative

When studies of calcium with vitamin D are added to these meta-analyses, the results are less consistent. This is because such meta-analyses are dominated by the Women's Health Initiative (because of its large size, with 36,282 participants). There have been 2 different analyses of this trial with respect to cardiovascular events.

When the Women’s Health Initiative as a whole was analyzed, there was no significant effect of calcium plus vitamin D on vascular end points. However, there is a significant interaction between body mass index and the effect of supplements, such that nonobese women demonstrated a 17% increase in myocardial infarction.²⁴ This study was unusual in that it included women already taking calcium and vitamin D supplements.

Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040.

There was a significant interaction between baseline use of supplements and the effects of the trial intervention on vascular events, justifying analyzing the supplement-naive individuals separately. In this group of 16,000 women, an increase in clinical myocardial infarction of 22% was found, similar to the findings with calcium supplements alone.²⁵

Thus, there is consistent evidence that introducing a calcium supplement de novo increases the risk of myocardial infarction (Figure 2).^16,25–31 We calculate that treating 1,000 patients with calcium or calcium plus vitamin D for 5 years would cause an additional 6 myocardial infarctions or strokes (number needed to harm 178) and prevent only 3 fractures (number needed to treat 302).²⁵

ARE VITAMIN D SUPPLEMENTS EFFECTIVE?

Vitamin D is highly effective in treating osteomalacia, improving symptoms within days and increasing bone density by as much as 50% over 1 year.^32,33 In contrast, randomized controlled trials of vitamin D supplements alone in people without osteomalacia have not shown increases in bone density or changes in fracture risk.^34–37

Reid IR, Horne AM, Mihov B, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med 2017; 282(5):452–460. Copyright 2017, Assoc for Publication of J Int Med

In 2017, my colleagues and I published a trial showing that vitamin D supplementation increases bone density by 2% to 3% in the spine and femoral neck in participants with baseline 25-hydroxyvitamin D levels below 30- nmol/L (12 ng/mL), but those starting above this level showed no effect (Figure 3).³⁸ And a reanalysis of an earlier study confirmed this 30 nmol/L threshold for an effect of vitamin D on bone density.³⁹ The finding of a clear-cut threshold for vitamin D effects is predicted by the physiologic considerations set out above.

Belief that higher levels of 25-hydroxyvitamin D are better is based on observational data. However, correlation does not prove causation, and it is likely that causation is reversed here. Those with better health are likely to spend more time exercising outdoors, are less likely to be obese, and are less likely to have inflammatory conditions; and as a result, they are more likely to have better vitamin D status. We should now be using trial-based definitions of vitamin D deficiency as opposed to thresholds derived from disease associations in observational studies.

Vitamin D supplements have also been suggested to benefit cardiovascular health and to reduce cancer risk, though current clinical trial data provide no support for these hypotheses.^36,40 Other trials addressing these questions are ongoing.

ARE VITAMIN D SUPPLEMENTS SAFE?

The safety of vitamin D supplements has generally been assessed with respect to the incidence of hypercalcemia. On this basis, very high doses have been promoted. However, there is now evidence that doses of 4,000 IU/day, 60,000 IU/month, and 500,000 IU/year increase the risk of falls and fractures.^41,42

The threshold for bone benefits discussed above (12 ng/mL) is easily exceeded with doses of vitamin D of 400 to 1,000 IU/day. At these levels, vitamin D supplements have no known adverse effects and can be widely endorsed for individuals at risk of deficiency. Supplement doses greater than 2,000 IU/day should be used only in exceptional circumstances, and with appropriate monitoring.

LITTLE USE FOR CALCIUM AND VITAMIN D SUPPLEMENTS

Extensive clinical trials have failed to demonstrate meaningful benefit from calcium supplements in the management of osteoporosis. Calcium supplements are often prescribed in patients who are receiving other treatments for osteoporosis, which may be justified with interventions that have the potential to cause hypocalcemia, but their coadministration with bisphosphonates has been shown to be unnecessary.

Calcium supplements commonly cause gastrointestinal symptoms that are sometimes severe and are likely to contribute to high levels of noncompliance with osteoporosis medications. They increase the risk of kidney stones,⁸ and there is reasonable evidence to suggest an adverse effect on vascular risk as well.²³

Vitamin D deficiency is common in frail elderly people, particularly those with dark skin or living at high latitudes. Low doses of vitamin D are safe and highly effective in preventing osteomalacia. But vitamin D supplements are unnecessary in those who regularly have sun exposure. And high doses of vitamin D have no demonstrated advantage and have been shown to increase the risk of falls and fractures.

Our decision to prescribe calcium and vitamin D supplements should be based on evidence that is of the same quality as for any other intervention we prescribe. Current evidence suggests that there is little reason to prescribe calcium, and that vitamin D should be targeted at those at risk of 25-hydroxyvitamin D levels less than 12 ng/mL.

We live in the era of evidence-based medicine, so new interventions must meet criteria for both safety and efficacy before they are adopted. However, we have inherited many practices adopted before the current standards were in place, and we have not always been rigorous in reevaluating traditional remedies. A conservative belief in established practice or the influence of vested interests may account for this lack of rigor in reappraisal.¹ Calcium and vitamin D supplements are possible examples of this phenomenon.

BONE METABOLISM IS TIGHTLY REGULATED

Bone is a connective tissue, its matrix composed principally of type 1 collagen, which provides tensile strength. Hydroxyapatite crystals, composed predominantly of calcium and phosphate, lie between the collagen fibers and provide compressive strength. In a tightly regulated process, osteoblasts lay down the collagenous matrix, and osteoclasts remove it. Mineralization of newly formed bone proceeds if normal levels of extracellular calcium and phosphate are present, in the absence of inhibitors of mineralization.

High calcium intake does not drive bone formation

The endocrine system is critical in maintaining normocalcemia. A decrease in calcium intake results in increased parathyroid hormone secretion, resulting in increased renal tubular calcium reabsorption, increased bone turnover (both formation and resorption), and increased activation of vitamin D leading to increased intestinal absorption of calcium. High calcium intake reverses these changes.

Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. J Intern Med 2015; 278(4):354–368. Copyright 2015, The Association for the Publication of the Journal of Internal Medicine.

If calcium intake is very low, hypocalcemia and secondary hyperparathyroidism develop,³ and bone mineralization may be impaired. However, levels of calcium intake in Africa and in East and Southeast Asia are typically less than 400 mg/day,⁴ yet there is no evidence that these levels adversely affect skeletal health. In fact, fracture risk is lower in these regions than in North America, where calcium intake is several times greater.

Thus, some calcium intake is required to maintain circulating concentrations, but there is no mechanism by which high calcium intake can drive bone formation. Quite the opposite, in fact.

Vitamin D deficiency has little relationship with diet

Vitamin D is a biologically inactive secosteroid activated by hydroxylation in the liver and kidney to function as the key regulator of intestinal calcium absorption. As with calcium, its deficiency results in hypocalcemia and impaired bone mineralization.

Paradoxically, high levels of vitamin D stimulate bone resorption and inhibit bone mineralization in mice,⁵ and large doses increase bone resorption markers acutely in clinical studies.⁶ Thus, it is important to ensure an adequate vitamin D supply, but not an oversupply.

In the absence of supplements, most vitamin D is produced in the skin as a result of the action of ultraviolet light (from sunlight) on 7-dehydrocholesterol. Thus, vitamin D deficiency occurs in those deprived of skin exposure to sunlight (eg, due to veiling, living at high latitude, staying permanently indoors), but it has little relationship with diet.

ARE CALCIUM SUPPLEMENTS EFFECTIVE?

Calcium supplements are certainly biologically active. They transiently increase serum calcium concentrations, suppress parathyroid hormone, and reduce bone resorption.² In the first year of use, they increase bone density by about 1% compared with placebo.⁷ However, longer use does not result in further bone density advantage over placebo,⁷ suggesting that the response simply reflects a decreased number of osteoclastic resorption sites and does not indicate a sustained change in bone balance.

A 1% difference in bone density would not be expected to reduce fracture risk, and a number of large, carefully conducted randomized controlled trials published over the last 15 years have failed to demonstrate anti­fracture efficacy for calcium.^8–12 As a result, the US Preventive Services Task Force recommends against the routine use of calcium supplements in community-dwelling adults.¹³

In contrast, in a placebo-controlled trial published in 1992, Chapuy et al¹⁴ found that elderly women residing in nursing homes who received calcium and vitamin D supplements had fewer fractures. At 18 months, by intention-to-treat analysis, nonvertebral fractures had occurred in 160 (12%) of 1,387 women in the supplement group compared with 215 (15%) of 1,403 women in the placebo group (P < .001). However, these women were severely vitamin D-deficient (the mean serum 25-hydroxyvitamin D level at baseline in the placebo group was 13 ng/mL, normal range 15–50), to the extent that many must have had osteomalacia.

Thus, this study shows that calcium and vitamin D are effective in managing osteomalacia, but the subsequent trials^8–12 did not observe any benefit in community-dwelling cohorts. Meta-analyses that pool the Chapuy study with community-based studies generally find that calcium with vitamin D is beneficial, but the heterogeneity of these populations means that such pooling is inappropriate.¹⁵

It is sometimes stated that calcium and vitamin D should always be given with osteoporosis medications because the efficacy of these drugs has only been demonstrated when coadministered with these supplements. This is incorrect. The addition of calcium to alendronate does not alter its effects on bone density,¹⁶ and the antifracture efficacy of both bisphosphonates¹⁷ and estrogen^18,19 has been demonstrated in the absence of supplementation with calcium or vitamin D. The evidence that bisphosphonates prevent fractures in the absence of calcium supplements has recently been strengthened by the results of a randomized controlled trial comparing zoledronate with placebo in women over age 65 with osteopenia.²⁰

Calcium supplements often cause gastrointestinal symptoms, particularly constipation. They have been shown to double the risk of hospital admission due to abdominal symptoms.²¹ In the absence of clear evidence of benefit, these facts alone should militate against their routine use. Calcium supplements also cause hypercalcemia and hypercalciuria²² and increase the risk of renal calculi (by 17% in the Women’s Health Initiative⁸).

Over the last decade, evidence has emerged that calcium supplements may also increase the risk of myocardial infarction, and possibly stroke. This finding was not statistically significant in any single study, but is consistently present in meta-analyses.²³

Evidence from the Women’s Health Initiative

When studies of calcium with vitamin D are added to these meta-analyses, the results are less consistent. This is because such meta-analyses are dominated by the Women's Health Initiative (because of its large size, with 36,282 participants). There have been 2 different analyses of this trial with respect to cardiovascular events.

When the Women’s Health Initiative as a whole was analyzed, there was no significant effect of calcium plus vitamin D on vascular end points. However, there is a significant interaction between body mass index and the effect of supplements, such that nonobese women demonstrated a 17% increase in myocardial infarction.²⁴ This study was unusual in that it included women already taking calcium and vitamin D supplements.

Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011; 342:d2040.

There was a significant interaction between baseline use of supplements and the effects of the trial intervention on vascular events, justifying analyzing the supplement-naive individuals separately. In this group of 16,000 women, an increase in clinical myocardial infarction of 22% was found, similar to the findings with calcium supplements alone.²⁵

Thus, there is consistent evidence that introducing a calcium supplement de novo increases the risk of myocardial infarction (Figure 2).^16,25–31 We calculate that treating 1,000 patients with calcium or calcium plus vitamin D for 5 years would cause an additional 6 myocardial infarctions or strokes (number needed to harm 178) and prevent only 3 fractures (number needed to treat 302).²⁵

ARE VITAMIN D SUPPLEMENTS EFFECTIVE?

Vitamin D is highly effective in treating osteomalacia, improving symptoms within days and increasing bone density by as much as 50% over 1 year.^32,33 In contrast, randomized controlled trials of vitamin D supplements alone in people without osteomalacia have not shown increases in bone density or changes in fracture risk.^34–37

Reid IR, Horne AM, Mihov B, et al. Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med 2017; 282(5):452–460. Copyright 2017, Assoc for Publication of J Int Med

In 2017, my colleagues and I published a trial showing that vitamin D supplementation increases bone density by 2% to 3% in the spine and femoral neck in participants with baseline 25-hydroxyvitamin D levels below 30- nmol/L (12 ng/mL), but those starting above this level showed no effect (Figure 3).³⁸ And a reanalysis of an earlier study confirmed this 30 nmol/L threshold for an effect of vitamin D on bone density.³⁹ The finding of a clear-cut threshold for vitamin D effects is predicted by the physiologic considerations set out above.

Belief that higher levels of 25-hydroxyvitamin D are better is based on observational data. However, correlation does not prove causation, and it is likely that causation is reversed here. Those with better health are likely to spend more time exercising outdoors, are less likely to be obese, and are less likely to have inflammatory conditions; and as a result, they are more likely to have better vitamin D status. We should now be using trial-based definitions of vitamin D deficiency as opposed to thresholds derived from disease associations in observational studies.

Vitamin D supplements have also been suggested to benefit cardiovascular health and to reduce cancer risk, though current clinical trial data provide no support for these hypotheses.^36,40 Other trials addressing these questions are ongoing.

ARE VITAMIN D SUPPLEMENTS SAFE?

The safety of vitamin D supplements has generally been assessed with respect to the incidence of hypercalcemia. On this basis, very high doses have been promoted. However, there is now evidence that doses of 4,000 IU/day, 60,000 IU/month, and 500,000 IU/year increase the risk of falls and fractures.^41,42

The threshold for bone benefits discussed above (12 ng/mL) is easily exceeded with doses of vitamin D of 400 to 1,000 IU/day. At these levels, vitamin D supplements have no known adverse effects and can be widely endorsed for individuals at risk of deficiency. Supplement doses greater than 2,000 IU/day should be used only in exceptional circumstances, and with appropriate monitoring.

LITTLE USE FOR CALCIUM AND VITAMIN D SUPPLEMENTS

Extensive clinical trials have failed to demonstrate meaningful benefit from calcium supplements in the management of osteoporosis. Calcium supplements are often prescribed in patients who are receiving other treatments for osteoporosis, which may be justified with interventions that have the potential to cause hypocalcemia, but their coadministration with bisphosphonates has been shown to be unnecessary.

Calcium supplements commonly cause gastrointestinal symptoms that are sometimes severe and are likely to contribute to high levels of noncompliance with osteoporosis medications. They increase the risk of kidney stones,⁸ and there is reasonable evidence to suggest an adverse effect on vascular risk as well.²³

Vitamin D deficiency is common in frail elderly people, particularly those with dark skin or living at high latitudes. Low doses of vitamin D are safe and highly effective in preventing osteomalacia. But vitamin D supplements are unnecessary in those who regularly have sun exposure. And high doses of vitamin D have no demonstrated advantage and have been shown to increase the risk of falls and fractures.

Our decision to prescribe calcium and vitamin D supplements should be based on evidence that is of the same quality as for any other intervention we prescribe. Current evidence suggests that there is little reason to prescribe calcium, and that vitamin D should be targeted at those at risk of 25-hydroxyvitamin D levels less than 12 ng/mL.