Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.

“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.

Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.

This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.

There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
 

Details of 24-week trial results

The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.

A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.

Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.

Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).

Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.

In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.

The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.

Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.

In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.

“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”

The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.

A version of this article first appeared on Medscape.com.

Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.

“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.

Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.

This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.

There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
 

Details of 24-week trial results

The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.

A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.

Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.

Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).

Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.

In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.

The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.

Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.

In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.

“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”

The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.

A version of this article first appeared on Medscape.com.

Risankizumab (Skyrizi) was effective for treating psoriatic arthritis (PsA) in patients who did not respond to or who could not tolerate other biologics or standard disease-modifying antirheumatic drugs (DMARDs), according to a study presented at the annual European Congress of Rheumatology. It was also well tolerated.

“Treatment with risankizumab resulted in significantly greater improvements in signs and symptoms of psoriatic arthritis, including assessments of disease activity in joints and skin and patient-reported outcomes, compared with placebo, in patients who did not respond to or were intolerant to biologics or DMARDs,” reported Andrew Ostor, MD, of Monash University and Cabrini Hospital, both in Melbourne,. The safety profile was “consistent with that established for risankizumab in the treatment moderate to severe psoriasis,” he told attendees.

Risankizumab is approved in the United States for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is a humanized immunoglobulin G1 monoclonal antibody that selectively inhibits cytokine interleukin-23 by binding to its p19 subunit. IL-23 has been implicated in the development of PsA.

This was a phase 3 trial with “promising results in line with the ACR 20 response [at least 20% improvement in American College of Rheumatology response criteria] of other biologics in psoriatic arthritis,” according to Gaëlle Varkas, MD, PhD, of the Ghent (the Netherlands) University VIB Center for Inflammation Research and the department of rheumatology, Ghent University Hospital. “Especially in patients with severe and/or refractory skin disease or inadequate response at the level of the joint to other DMARDs or biologics, risankizumab is filling a void,” Dr. Varkas, who was not involved in the research, said in an interview.

There were no major safety problems, although long-term data, especially in regard to cancer and cardiovascular effects, “are always of interest, as they can be missed in randomized, controlled trials,” she said. In addition, “efficacy in concomitant axial disease, uveitis, and inflammatory bowel disease might favor one treatment over the other.” Another clinically significant takeaway was risankizumab’s “better effect on skin psoriasis while maintaining the effect on joint manifestations.”
 

Details of 24-week trial results

The phase 3, randomized, placebo-controlled, double-blind KEEPSAKE 2 trial involved 444 patients who had active PsA, defined as at least five swollen joints and at least five tender joints. All the patients either had an inadequate response to or were intolerant of one or two biologics or at least one conventional synthetic DMARD.

A total of 224 patients were randomly assigned to receive 150 mg of subcutaneous risankizumab at baseline and at 4 and 16 weeks after baseline; 220 participants received placebo injections. The primary endpoint was the proportion of patients who had at least 20% improvement in American College of Rheumatology response criteria at week 24.

Demographic and clinical characteristics were similar in both groups at baseline. Among the participants, the total mean number of swollen joints was 13.3, and the total mean number of tender joints was 22.6. The participants had PsA for an average of 8.2 years. The proportions of patients previously treated with biologics and DMARDs were similar in both groups, as were the proportions of patients currently taking glucocorticoids, NSAIDs, or methotrexate or another DMARD. At week 24, there remained 199 patients in the placebo group and 215 in the risankizumab group.

Just over half (51.3%) of patients who took risankizumab achieved at least 20% improvement in their ACR 20 score, compared with just over a quarter (26.5%) of those who received placebo (P < .001). All secondary endpoints also showed statistically significant improvements (P < .001 for all except P < .009 for the Fatigue Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-Fatigue] secondary endpoint).

Scores on the Health Assessment Questionnaire–Disability Index were –0.22 in the risankizumab group and –0.05 in the placebo group (P < .001). In the risankizumab group, 55% of patients achieved at least a 90% reduction in scores on the Psoriasis Area Severity Index, compared with 10.2% of patients who received placebo. Similarly, 25.6% of patients who took risankizumab and 11.4% of patients who received placebo had minimal disease activity 24 weeks after baseline.

In the 36-item Short Form Health Survey Physical Component Summary, the score change among risankizumab patients was 5.9, compared with 2 among the patients who received placebo. The change in FACIT-Fatigue score was 4.9 for patients who took risankizumab and 2.6 for patients who received placebo.

The researchers also assessed how many patients achieved higher levels of response to treatment. At least a 50% improvement in ACR response criteria occurred among 26.3% of patients taking risankizumab and 9.3% of patients taking placebo (P < .001). ACR 70 responses were seen in 12% of patients receiving risankizumab, compared with 5.9% of patients receiving placebo (P < .02). In the risankizumab group, 72.5% of patients had resolution of dactylitis and 42.9% had resolution of enthesitis, compared with 42.1% and 30.4%, respectively, in the placebo group.

Serious adverse events occurred in 4% of patients who received risankizumab and 5.5% of patients who received placebo. Serious infections occurred in 0.9% of those receiving risankizumab and 2.3% of those receiving placebo. Rates of treatment-emergent adverse events were also similar in the risankizumab (55.4%) and placebo (54.8%) groups.

In response to a question about whether it was possible to identify patients who might respond better to IL-23 inhibitors, compared with IL-17 inhibitors, Dr. Ostor acknowledged that rheumatologic practice is not yet proficient at using biomarkers to direct therapy, so the benefit from these drugs lay elsewhere.

“What I think is great is the luxury of choice these days,” Dr. Ostor told attendees. “We have these agents now, including risankizumab, that do work very effectively across the spectrum of the clinical features. It’s just lovely to have these agents available that can truly make a difference to the clinical picture of the individual.”

The trial was sponsored by AbbVie. Dr. Ostor has received research grants or speaking or consulting fees from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Dr. Varkas has received research grants or speaker fees from AbbVie and Pfizer.

A version of this article first appeared on Medscape.com.

A patient’s risk for ischemic events, but not bleeding, after percutaneous coronary intervention (PCI) can be predicted simply based on whether they have one or more guideline-based standardized risk criteria, a large-scale real-world analysis suggests.

Haoyu Wang, MD, and colleagues showed that having at least one high-risk feature, as outlined in the 2018 European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularization, was associated with an increased risk for target vessel failure by 48% and for a patient-oriented composite outcome by 44%.

Moreover, they showed that implantation of at least three stents and the presence of diabetes and diffuse multivessel disease were the only high-risk features from the guidelines that were independent predictors of the two outcomes.

The study of more than 10,000 PCI patients also showed that determining whether patients were at high bleeding risk (HBR) did not modify their ischemic risk.

This, said Dr. Wang, from the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, underscores the importance of applying the high ischemic risk (HIR) criteria from the ESC/EACTS guidelines when tailoring dual antiplatelet therapy (DAPT).

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress on June 2, and published online in the Journal of Atherosclerosis and Thrombosis.

Dr. Wang told theheart.org | Medscape Cardiology that they conducted the study to determine which – HIR or HBR – is “most important to balance when treating patients undergoing PCI and then having dual antiplatelet therapy.”

The results showed that when patients have both a HIR and HBR, it is the ESC/EACTS guideline HIR criteria that have “a higher impact” than the bleeding risk, and that this can be “used to guide our choice of the duration of dual anti-platelet therapy.”

“Maybe we can extend, or use more potent, P2Y12 inhibitors” in those situations, he said.

S. Lale Tokgözoglu, MD, PhD, professor of cardiology, Hacettepe University, Ankara, Turkey, who was not involved in the study, said the HIR assessment “performed well,” adding that the HBR score might have been expected to attenuate its “prognostic advantage.”

She told this news organization that the results “are interesting since previous observations have suggested that Asian patients may be more prone to medication side effects and bleeding.”

These findings emphasize the importance of assessing HIR in daily PCI practice and confirm that it “performs well in different populations in real life,” added Dr. Tokgözoglu, a former president of the EAS.

The ESC/EACTS guidelines aimed to standardize the definition of HIR, Dr. Wang said during the presentation.

They set out 10 high-risk features for ischemic events for patients undergoing revascularization, which included patient medical history, comorbid conditions, and the characteristics of the PCI procedure.

Although the goals of the criteria are to inform decision-making and stimulate research, Dr. Wang said that their “prevalence and prognostic association with clinical outcomes are yet to be established in real-world PCI practice.”

Alongside, the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score was developed to predict out-of-hospital bleeding in patients receiving DAPT after stent implantation.

Although a PRECISE-DAPT score of at least 25 constitutes a patient at high bleeding risk, Dr. Wang pointed out that such patients are typically also at risk for ischemic events after PCI, and it is “unclear” whether being at HBR modifies this risk.

To investigate further, they used the prospective, real-world Fuwai PCI registry to collate an all-comer patient population with unselected use of drug-eluting stents at the National Center for Cardiovascular Diseases at Fuwai Hospital.

They excluded individuals who were treated with balloon angioplasty alone, bioresorbable scaffolds, or bare metal stents, leaving a total population of 10,167 patients who were treated in 2013.

In that cohort, 5,149 patients (50.6%) met at least one risk criterion from the ESC/EACTS guidelines (HIR patients) and 5,018 (49.4%) met none of the risk criteria (non-HIR patients).

The most common criteria were implantation of at least three stents (23.5%); total stent length greater than 60 mm (20.2%); diffuse multivessel disease, especially in diabetic patients (18.5%); and a history of ST-segment elevation myocardial infarction (13.9%).

HIR patients were significantly older than non-HIR patients (average age, 58.86 vs. 57.77 years; P < .001), were more likely to have diabetes mellitus (42.6% vs. 16.9%; P < .001); and were more likely to have already had a myocardial infarction (32.2% vs. 5.2%; P < .001).

HIR patients also had higher average PRECISE-ADAPT scores than those without HIR (11.22 vs. 9.94; P < .001), and were conversely less likely to have the left anterior descending artery as the target vessel than non-HIR patients (86.0% vs. 94.6%; P < .001).

Cox regression analysis taking into account a range of patient and clinical factors revealed that HIR patients were significantly more likely than their non-HIR counterparts to experience target vessel failure (hazard ratio, 1.48; 95% confidence interval, 1.25-1.74; P < .001).

They were also significantly more likely to have a patient-oriented composite outcome, defined as all-cause death, any myocardial infarction, or any revascularization (HR, 1.44; 95% CI, 1.28-1.63; P < .001).

There was also a significantly higher risk for cardiac death in HIR than in non-HIR patients (HR, 1.95; 95% CI, 1.16-3.29; P = .012).

However, there was no significant association between HIR status and clinically relevant bleeding (HR, 0.84; 95% CI, 0.66-1.06; P = .143).

When the researchers looked at individual ischemic risk features, they found that, on fully adjusted analyses, only two were independent predictors of target vessel failure and the patient-oriented composite outcome.

Having at least three stents implanted was significantly associated with target vessel failure (HR, 1.36; 95% CI, 1.02-1.80; P = .038), and borderline significantly associated with the patient oriented composite outcome (HR, 1.23; 95% CI, 1.00-1.53; P = .056).

Diffuse multivessel disease, especially in diabetic patients, was significantly associated with both target vessel failure (HR, 1.24; 95% CI, 1.02-1.51; P = .035) and with the patient-oriented composite outcome (HR, 1.20; 95% CI, 1.04-1.39; P = .012).

Neither risk feature was significantly associated with clinically relevant bleeding, Dr. Wang noted.

Stratifying the patients by HBR status, the team found that rates of target vessel failure, the patient-oriented composite outcome, cardiac death, myocardial infarction, and definite/probable stent thrombosis were higher in patients with both HIR and HBR than those with neither HIR nor HBR (P < .001).

Further stratifying patients by PRECISE-ADAPT scores – 10 or less indicating very low risk, 11-17 indicating low risk, 18-24 indicating moderate risk, and at least 25 indicating high risk – showed that HIR features had a consistent effect on ischemic and bleeding outcomes, regardless of bleeding risk.

No funding declared. No relevant financial relationships declared.

A version of this article first appeared on Medscape.com.

A patient’s risk for ischemic events, but not bleeding, after percutaneous coronary intervention (PCI) can be predicted simply based on whether they have one or more guideline-based standardized risk criteria, a large-scale real-world analysis suggests.

Haoyu Wang, MD, and colleagues showed that having at least one high-risk feature, as outlined in the 2018 European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularization, was associated with an increased risk for target vessel failure by 48% and for a patient-oriented composite outcome by 44%.

Moreover, they showed that implantation of at least three stents and the presence of diabetes and diffuse multivessel disease were the only high-risk features from the guidelines that were independent predictors of the two outcomes.

The study of more than 10,000 PCI patients also showed that determining whether patients were at high bleeding risk (HBR) did not modify their ischemic risk.

This, said Dr. Wang, from the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, underscores the importance of applying the high ischemic risk (HIR) criteria from the ESC/EACTS guidelines when tailoring dual antiplatelet therapy (DAPT).

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress on June 2, and published online in the Journal of Atherosclerosis and Thrombosis.

Dr. Wang told theheart.org | Medscape Cardiology that they conducted the study to determine which – HIR or HBR – is “most important to balance when treating patients undergoing PCI and then having dual antiplatelet therapy.”

The results showed that when patients have both a HIR and HBR, it is the ESC/EACTS guideline HIR criteria that have “a higher impact” than the bleeding risk, and that this can be “used to guide our choice of the duration of dual anti-platelet therapy.”

“Maybe we can extend, or use more potent, P2Y12 inhibitors” in those situations, he said.

S. Lale Tokgözoglu, MD, PhD, professor of cardiology, Hacettepe University, Ankara, Turkey, who was not involved in the study, said the HIR assessment “performed well,” adding that the HBR score might have been expected to attenuate its “prognostic advantage.”

She told this news organization that the results “are interesting since previous observations have suggested that Asian patients may be more prone to medication side effects and bleeding.”

These findings emphasize the importance of assessing HIR in daily PCI practice and confirm that it “performs well in different populations in real life,” added Dr. Tokgözoglu, a former president of the EAS.

The ESC/EACTS guidelines aimed to standardize the definition of HIR, Dr. Wang said during the presentation.

They set out 10 high-risk features for ischemic events for patients undergoing revascularization, which included patient medical history, comorbid conditions, and the characteristics of the PCI procedure.

Although the goals of the criteria are to inform decision-making and stimulate research, Dr. Wang said that their “prevalence and prognostic association with clinical outcomes are yet to be established in real-world PCI practice.”

Alongside, the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score was developed to predict out-of-hospital bleeding in patients receiving DAPT after stent implantation.

Although a PRECISE-DAPT score of at least 25 constitutes a patient at high bleeding risk, Dr. Wang pointed out that such patients are typically also at risk for ischemic events after PCI, and it is “unclear” whether being at HBR modifies this risk.

To investigate further, they used the prospective, real-world Fuwai PCI registry to collate an all-comer patient population with unselected use of drug-eluting stents at the National Center for Cardiovascular Diseases at Fuwai Hospital.

They excluded individuals who were treated with balloon angioplasty alone, bioresorbable scaffolds, or bare metal stents, leaving a total population of 10,167 patients who were treated in 2013.

In that cohort, 5,149 patients (50.6%) met at least one risk criterion from the ESC/EACTS guidelines (HIR patients) and 5,018 (49.4%) met none of the risk criteria (non-HIR patients).

The most common criteria were implantation of at least three stents (23.5%); total stent length greater than 60 mm (20.2%); diffuse multivessel disease, especially in diabetic patients (18.5%); and a history of ST-segment elevation myocardial infarction (13.9%).

HIR patients were significantly older than non-HIR patients (average age, 58.86 vs. 57.77 years; P < .001), were more likely to have diabetes mellitus (42.6% vs. 16.9%; P < .001); and were more likely to have already had a myocardial infarction (32.2% vs. 5.2%; P < .001).

HIR patients also had higher average PRECISE-ADAPT scores than those without HIR (11.22 vs. 9.94; P < .001), and were conversely less likely to have the left anterior descending artery as the target vessel than non-HIR patients (86.0% vs. 94.6%; P < .001).

Cox regression analysis taking into account a range of patient and clinical factors revealed that HIR patients were significantly more likely than their non-HIR counterparts to experience target vessel failure (hazard ratio, 1.48; 95% confidence interval, 1.25-1.74; P < .001).

They were also significantly more likely to have a patient-oriented composite outcome, defined as all-cause death, any myocardial infarction, or any revascularization (HR, 1.44; 95% CI, 1.28-1.63; P < .001).

There was also a significantly higher risk for cardiac death in HIR than in non-HIR patients (HR, 1.95; 95% CI, 1.16-3.29; P = .012).

However, there was no significant association between HIR status and clinically relevant bleeding (HR, 0.84; 95% CI, 0.66-1.06; P = .143).

When the researchers looked at individual ischemic risk features, they found that, on fully adjusted analyses, only two were independent predictors of target vessel failure and the patient-oriented composite outcome.

Having at least three stents implanted was significantly associated with target vessel failure (HR, 1.36; 95% CI, 1.02-1.80; P = .038), and borderline significantly associated with the patient oriented composite outcome (HR, 1.23; 95% CI, 1.00-1.53; P = .056).

Diffuse multivessel disease, especially in diabetic patients, was significantly associated with both target vessel failure (HR, 1.24; 95% CI, 1.02-1.51; P = .035) and with the patient-oriented composite outcome (HR, 1.20; 95% CI, 1.04-1.39; P = .012).

Neither risk feature was significantly associated with clinically relevant bleeding, Dr. Wang noted.

Stratifying the patients by HBR status, the team found that rates of target vessel failure, the patient-oriented composite outcome, cardiac death, myocardial infarction, and definite/probable stent thrombosis were higher in patients with both HIR and HBR than those with neither HIR nor HBR (P < .001).

Further stratifying patients by PRECISE-ADAPT scores – 10 or less indicating very low risk, 11-17 indicating low risk, 18-24 indicating moderate risk, and at least 25 indicating high risk – showed that HIR features had a consistent effect on ischemic and bleeding outcomes, regardless of bleeding risk.

No funding declared. No relevant financial relationships declared.

A version of this article first appeared on Medscape.com.

A patient’s risk for ischemic events, but not bleeding, after percutaneous coronary intervention (PCI) can be predicted simply based on whether they have one or more guideline-based standardized risk criteria, a large-scale real-world analysis suggests.

Haoyu Wang, MD, and colleagues showed that having at least one high-risk feature, as outlined in the 2018 European Society of Cardiology and European Association for Cardiothoracic Surgery (ESC/EACTS) Guidelines on Myocardial Revascularization, was associated with an increased risk for target vessel failure by 48% and for a patient-oriented composite outcome by 44%.

Moreover, they showed that implantation of at least three stents and the presence of diabetes and diffuse multivessel disease were the only high-risk features from the guidelines that were independent predictors of the two outcomes.

The study of more than 10,000 PCI patients also showed that determining whether patients were at high bleeding risk (HBR) did not modify their ischemic risk.

This, said Dr. Wang, from the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, underscores the importance of applying the high ischemic risk (HIR) criteria from the ESC/EACTS guidelines when tailoring dual antiplatelet therapy (DAPT).

The research was presented at the European Atherosclerosis Society 2021 Virtual Congress on June 2, and published online in the Journal of Atherosclerosis and Thrombosis.

Dr. Wang told theheart.org | Medscape Cardiology that they conducted the study to determine which – HIR or HBR – is “most important to balance when treating patients undergoing PCI and then having dual antiplatelet therapy.”

The results showed that when patients have both a HIR and HBR, it is the ESC/EACTS guideline HIR criteria that have “a higher impact” than the bleeding risk, and that this can be “used to guide our choice of the duration of dual anti-platelet therapy.”

“Maybe we can extend, or use more potent, P2Y12 inhibitors” in those situations, he said.

S. Lale Tokgözoglu, MD, PhD, professor of cardiology, Hacettepe University, Ankara, Turkey, who was not involved in the study, said the HIR assessment “performed well,” adding that the HBR score might have been expected to attenuate its “prognostic advantage.”

She told this news organization that the results “are interesting since previous observations have suggested that Asian patients may be more prone to medication side effects and bleeding.”

These findings emphasize the importance of assessing HIR in daily PCI practice and confirm that it “performs well in different populations in real life,” added Dr. Tokgözoglu, a former president of the EAS.

The ESC/EACTS guidelines aimed to standardize the definition of HIR, Dr. Wang said during the presentation.

They set out 10 high-risk features for ischemic events for patients undergoing revascularization, which included patient medical history, comorbid conditions, and the characteristics of the PCI procedure.

Although the goals of the criteria are to inform decision-making and stimulate research, Dr. Wang said that their “prevalence and prognostic association with clinical outcomes are yet to be established in real-world PCI practice.”

Alongside, the Predicting Bleeding Complication in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score was developed to predict out-of-hospital bleeding in patients receiving DAPT after stent implantation.

Although a PRECISE-DAPT score of at least 25 constitutes a patient at high bleeding risk, Dr. Wang pointed out that such patients are typically also at risk for ischemic events after PCI, and it is “unclear” whether being at HBR modifies this risk.

To investigate further, they used the prospective, real-world Fuwai PCI registry to collate an all-comer patient population with unselected use of drug-eluting stents at the National Center for Cardiovascular Diseases at Fuwai Hospital.

They excluded individuals who were treated with balloon angioplasty alone, bioresorbable scaffolds, or bare metal stents, leaving a total population of 10,167 patients who were treated in 2013.

In that cohort, 5,149 patients (50.6%) met at least one risk criterion from the ESC/EACTS guidelines (HIR patients) and 5,018 (49.4%) met none of the risk criteria (non-HIR patients).

The most common criteria were implantation of at least three stents (23.5%); total stent length greater than 60 mm (20.2%); diffuse multivessel disease, especially in diabetic patients (18.5%); and a history of ST-segment elevation myocardial infarction (13.9%).

HIR patients were significantly older than non-HIR patients (average age, 58.86 vs. 57.77 years; P < .001), were more likely to have diabetes mellitus (42.6% vs. 16.9%; P < .001); and were more likely to have already had a myocardial infarction (32.2% vs. 5.2%; P < .001).

HIR patients also had higher average PRECISE-ADAPT scores than those without HIR (11.22 vs. 9.94; P < .001), and were conversely less likely to have the left anterior descending artery as the target vessel than non-HIR patients (86.0% vs. 94.6%; P < .001).

Cox regression analysis taking into account a range of patient and clinical factors revealed that HIR patients were significantly more likely than their non-HIR counterparts to experience target vessel failure (hazard ratio, 1.48; 95% confidence interval, 1.25-1.74; P < .001).

They were also significantly more likely to have a patient-oriented composite outcome, defined as all-cause death, any myocardial infarction, or any revascularization (HR, 1.44; 95% CI, 1.28-1.63; P < .001).

There was also a significantly higher risk for cardiac death in HIR than in non-HIR patients (HR, 1.95; 95% CI, 1.16-3.29; P = .012).

However, there was no significant association between HIR status and clinically relevant bleeding (HR, 0.84; 95% CI, 0.66-1.06; P = .143).

When the researchers looked at individual ischemic risk features, they found that, on fully adjusted analyses, only two were independent predictors of target vessel failure and the patient-oriented composite outcome.

Having at least three stents implanted was significantly associated with target vessel failure (HR, 1.36; 95% CI, 1.02-1.80; P = .038), and borderline significantly associated with the patient oriented composite outcome (HR, 1.23; 95% CI, 1.00-1.53; P = .056).

Diffuse multivessel disease, especially in diabetic patients, was significantly associated with both target vessel failure (HR, 1.24; 95% CI, 1.02-1.51; P = .035) and with the patient-oriented composite outcome (HR, 1.20; 95% CI, 1.04-1.39; P = .012).

Neither risk feature was significantly associated with clinically relevant bleeding, Dr. Wang noted.

Stratifying the patients by HBR status, the team found that rates of target vessel failure, the patient-oriented composite outcome, cardiac death, myocardial infarction, and definite/probable stent thrombosis were higher in patients with both HIR and HBR than those with neither HIR nor HBR (P < .001).

Further stratifying patients by PRECISE-ADAPT scores – 10 or less indicating very low risk, 11-17 indicating low risk, 18-24 indicating moderate risk, and at least 25 indicating high risk – showed that HIR features had a consistent effect on ischemic and bleeding outcomes, regardless of bleeding risk.

No funding declared. No relevant financial relationships declared.

A version of this article first appeared on Medscape.com.

Among the studies we review in this Update are a follow-up of the US Women’s Health Initiative clinical trials and a large observational study from the United Kingdom, which exlore the impact of different hormone therapies (HTs) on breast cancer risk. We look at the interesting patterns found by authors of a study in Canada that analyzed predictors of unnecessary bilateral salpingo-oophorectomy. In addition, we review a study that investigates whether hormone therapy can be effective, alone or adjunctively, in peri- and postmenopausal women with depression. Finally, Dr. Chrisandra Shufelt and Dr. JoAnn Manson summarize highlights from the recent American Heart Association’s scientific statement on the menopause transition and increasing risk factors for cardiovascular disease, and how this period can be viewed as an opportunity to encourage healthy, cardiovascular risk–reducing behaviors.

Studies clarify menopausal HT’s impact on breast cancer risk

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324:369-380. doi: 10.1001/jama.2020.9482.

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020;371:m3873. doi: 10.1136/bmj.m3873.

For many menopausal women, the most worrisome concern related to the use of HT is that it might increase breast cancer risk. In the summer and fall of 2020, 2 important articles were published that addressed how the use of menopausal HT impacts the risk of breast cancer.

The Women’s Health Initiative (WHI) represents the largest and longest-term randomized trial assessing the health impacts of systemic HT. A 2013 WHI report found that with a median of 13 years’ cumulative follow-up, estrogen-only HT (ET) reduced the risk for breast cancer while estrogen-progestin therapy (EPT) increased the risk.¹ In a July 2020 issue of JAMA, WHI investigators analyzed longer-term data (cumulative median follow-up >20 years), which allowed assessment of whether these trends (breast cancer incidence) persisted and if they led to changes in mortality from breast cancer.²

WHI data on breast cancer risk trends in ET vs EPT users

In the ET trial, in which Chlebowski and colleagues studied 10,739 women with prior hysterectomy, 238 versus 296 new cases of breast cancer were diagnosed in women in the ET versus placebo groups, respectively (annualized incidence, 0.30% [ET] vs 0.37% [placebo]; hazard ratio [HR], 0.78; P = .005). ET also was associated with significantly lower mortality from breast cancer: 30 versus 46 deaths (annualized mortality, 0.031% [ET] vs 0.046% [placebo]; HR, 0.60; P = 0.04).

In the EPT trial, which included 16,608 participants with an intact uterus, EPT compared with placebo was associated with significantly elevated risk for incident breast cancer: 584 versus 447 new cases, respectively (annualized incidence, 0.45% [EPT] vs 0.36% [placebo]; HR, 1.28; P<.001). However, mortality from breast cancer was similar in the EPT and placebo groups: 71 and 53 deaths (annualized mortality, 0.045% [EPT] and 0.035% [placebo]; HR, 1.35; P = .11).²

For women with previous hysterectomy who are considering initiating or continuing ET for treatment of bothersome menopausal symptoms, the breast cancer mortality benefit documented in this long-term WHI analysis could, as editorialists point out, “tip the scales” in favor of ET.³ Furthermore, the mortality benefit raises the possibility that ET could be evaluated as a risk-reduction strategy for selected high-risk menopausal women who have undergone hysterectomy. Although tamoxifen and aromatase inhibitors are approved for breast cancer chemoprophylaxis in high-risk menopausal women, these agents have not been found to lower breast cancer mortality.²

UK data analysis and risk for breast cancer in HT users

In an October 2020 issue of BMJ, Vinogradova and colleagues described their analysis of 2 primary care databases in the United Kingdom that in aggregate included roughly 99,000 women with breast cancer diagnosed between 1998 and 2018 (age range, 50–79; mean age at diagnosis, 63; >95% White); these were matched with more than 450,000 women without breast cancer (controls).⁴ Analyses were adjusted for smoking, body mass index (BMI), ethnicity, and mammography.

In this study, ever-use of EPT was associated with an adjusted odds ratio (OR) for breast cancer of 1.26 (95% confidence interval [CI], 1.24–1.29), while ET had an OR of 1.06 (95% CI, 1.03–1.10). In women aged 50 to 59 who used EPT for 5 years or more, 15 additional breast cancers were diagnosed per 10,000 woman-years; for ET users, the attributable risk was 3. Although risk rose with longer HT duration, this trend was less evident with ET than EPT.

In addition, the increased risk associated with ET use was less pronounced in women with a BMI greater than 30 kg/m². Among EPT users, risks were similar with the progestins medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). Likewise, risks were similar regardless of estrogen dose and route of administration (that is, oral vs transdermal). Vaginal estrogen was not associated with a higher or lower risk for breast cancer. Among past users of ET or EPT (with MPA), no increased risk was noted 5 years or more after stopping HT. For users of EPT (with NET or LNG), risks diminished 5 years or more after stopping HT but remained modestly elevated compared with risk in never-users.⁴

In this large observational UK study, ET was associated with minimally elevated risk for breast cancer, while in the WHI study, ET reduced the risk for breast cancer. For EPT, the excess risk in both studies was identical. As the authors note, mean BMI in the UK study participants was slightly lower than that in the WHI participants, a distinction that might explain the differing findings with ET use.

Continue to: Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women...

Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women

Wong J, Murji A, Sunderji Z, et al. Unnecessary bilateral salpingo-oophorectomy at the time of hysterectomy and potential for ovarian preservation. Menopause. 2020;28:8-11. doi: 10.1097/GME.0000000000001652.

While prevention of ovarian cancer is an important benefit of bilateral salpingo-oophorectomy (BSO), performing a BSO at the time of hysterectomy in pre- or perimenopausal patients not only will induce surgical menopause but also is associated with significantly increased overall mortality and an increased risk of mortality due to cardiovascular disease in patients younger than age 45.^5,6 Earlier BSO also has been associated with diabetes, accelerated bone density loss, sexual dysfunction, mood disorders, and decreased cognitive function.⁷

BSO at hysterectomy: How many procedures are not indicated?

To evaluate the prevalence and predictors of unnecessary BSO at the time of hysterectomy, Wong and colleagues conducted a multicenter retrospective review of hysterectomy procedures completed at 6 Canadian hospitals.⁸ Criteria for unnecessary BSO included age younger than 51 years; benign preoperative diagnosis (other than endometriosis, premenstrual dysphoric disorder, and gender dysphoria); and absence of endometriosis and pelvic adhesions.

A total of 2,656 hysterectomies were performed by 75 surgeons (28 fellowship trained and 47 generalists) across 3 community and 3 tertiary care hospitals between 2016 and 2018. At the time of hysterectomy, 749 patients (28%) underwent BSO. Of these, 509 women (68%) had at least 1 indication for concurrent BSO based on preoperative diagnosis.

Key study findings. Concurrent BSO procedures performed at academic hospitals were more likely to have a preoperative indication compared with BSO performed at community sites (70% vs 63%; OR, 1.42; 95% CI, 1.02–1.97; P = .04). BSO was more likely to be indicated when performed by fellowship-trained surgeons compared with surgeries performed by generalist surgeons (75% vs 63%; OR, 1.76; 95% CI, 1.26–2.44, P = .001). BSO procedures performed with vaginal hysterectomy were less likely to be indicated (3 of 20, 15%) when compared with open hysterectomy (74 of 154, 48%) and laparoscopic hysterectomy (432 of 575, 75%).

Of the patients who lacked a preoperative indication for concomitant BSO, 105 of 239 (43.9%) were younger than age 51. Overall, 8% (59 of 749) of patients in the study cohort had an unnecessary BSO based on a combination of preoperative diagnosis, age younger than age 51, and intraoperative factors including absence of endometriosis and adhesions.

Continue to: HT for menopausal depression: Which patients may benefit?

HT for menopausal depression: Which patients may benefit?

Dwyer JB, Aftab A, Radhakrishnan R, et al; APA Council of Research Task Force on Novel Biomarkers and Treatments. Hormonal treatments for major depressive disorder: state of the art. Am J Psychiatry. 2020;177:686- 705. doi:10.1176/appi.ajp.2020.19080848.

The cumulative lifetime prevalence of major depression in US women is 21%.9 An increased risk of mood symptoms and major depressive disorder occurs with the cessation of ovarian hormone production during menopause. In a review of both physiology and clinical studies, an American Psychiatric Association task force found support for several hormone-related strategies for treating depression and highlighted the rapidly advancing, but mixed, findings in this field.¹⁰

Clinical trials that examined mood in peri- and postmenopausal women treated with HT have produced mixed results for a variety of reasons, including differences in psychiatric symptomatology across studies and differences in treatment timing in relation to menopause onset.

HT effectiveness for depression depends on menopausal status

Five studies included in a meta-analysis by Rubinow and colleagues examined the use of ET and EPT as antidepressant monotherapy in peri- or postmenopausal women with major depression.¹¹ Of the 3 higher-quality studies, 2 conducted in perimenopausal women demonstrated the antidepressant efficacy of transdermal estrogen patches compared with placebo. The third study included a mixed population of both peri- and postmenopausal women, and it found that increased estradiol levels (spontaneously occurring or due to ET) were associated with improvement in depression in perimenopausal women but not in postmenopausal women.¹¹

ET also has been investigated as a potential adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs). In a retrospective analysis of a multicenter randomized controlled trial of fluoxetine in patients with depression, women who received ET and fluoxetine demonstrated a greater improvement than those who received fluoxetine monotherapy.¹² One small study that prospectively assessed ET in combination with an antidepressant in postmenopausal women demonstrated no benefit of ET in treating depression.¹³ Another small trial found that while combining transdermal ET with an SSRI accelerated symptom improvement, by the end of the 10-week study, treatment efficacy in the HT plus SSRI group was no greater than that observed in the SSRI-only group.¹⁴

Nineteen studies included in the metaanalysis by Rubinow and colleagues, which examined mood after ET or EPT treatment in nondepressed women, found little evidence of benefit, particularly in women without other physical symptoms of menopause.¹¹

The Kronos Early Estrogen Prevention Study (KEEPS) followed 661 women who received either oral estrogen plus progesterone, transdermal estrogen plus progesterone, or placebo over 4 years.¹⁵ Women with clinical depression were excluded from the study; however, women with mild to moderate mood symptoms who were being treated with an antidepressant were included. Improvements in depressive symptoms and anxiety were observed only in the oral estrogen plus progesterone group compared with the placebo group.¹⁵

In a study of 172 euthymic peri- and postmenopausal women treated for 12 months with transdermal estrogen plus oral progesterone, investigators found that, unlike postmenopausal women and those in the late perimenopausal transition, only women in the early perimenopausal transition had a lower risk of developing depressive symptoms.¹⁶

Bottom line

This complex literature suggests that ET/HT interventions are most likely to be successful when implemented early in the menopausal transition. The clearest indication for the use of HT is for perimenopausal women experiencing depression who are also experiencing menopausal symptoms (for example, bothersome hot flashes). There is little evidence that the use of ET/HT in late perimenopausal or postmenopausal women effectively treats depression; accordingly, HT is not recommended for the treatment of mood disorders in this population. The more ambiguous cases are those of perimenopausal women who are depressed but do not have classic vasomotor symptoms; some evidence supports the antidepressant efficacy of HT in this setting.¹¹ Although some studies suggest that HT can be effective in preventing depression in perimenopausal women, more evidence is needed.¹⁶

 

The menopause transition: A key period for strategizing CVD risk factor reduction

---

Chrisandra L. Shufelt, MD, MS, NCMP

Dr. Shufelt is Associate Director of the Barbra
Streisand Women’s Heart Center, Smidt
Heart Institute, Cedars-Sinai Medical Center,
Los Angeles, California.

JoAnn E. Manson, MD, DrPH, NCMP

Dr. Manson is Professor of Medicine and the
Michael and Lee Bell Professor of Women’s
Health at Harvard Medical School; Professor
in the Department of Epidemiology, Harvard
T.H. Chan School of Public Health; and Chief
of the Division of Preventive Medicine
at Brigham and Women’s Hospital, Boston,
Massachusetts.

The authors report no financial relationships relevant to this article. Dr. Manson is a coauthor of the AHA Scientific Statement discussed in this article.

In the United States, nearly one-half of a woman’s life, on average, will be lived after menopause. For women with natural menopause, the menopause transition (MT) can begin 2 to 7 years before and may extend 1 year past the final menstrual period, which occurs at an average age of 51 years. For women with surgical menopause, the MT occurs abruptly with the sudden loss of endogenous ovarian hormones. Both types of transitions mark a critical time period when reproduction and endogenous sex hormone levels diminish and when cardiovascular disease (CVD) risk factors begin to rise.

The 2020 American Heart Association (AHA) scientific statement, “Menopause transition and cardiovascular disease risk: Implications for timing of early prevention,” highlights the MT as a window of opportunity for CVD prevention.¹

CVD risk factors associated with ovarian aging

In the AHA scientific statement, data from several longitudinal women’s health studies were used to identify which CVD risk factor changes during the MT are related to ovarian aging as opposed to chronologic aging. Independent of aging, those associated with reproductive or ovarian aging included an increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B. Changes in high-density lipoprotein cholesterol (HDL-C) particles and function also occur during the MT, which may explain why higher HDL-C levels during the MT and the postmenopausal years are not as cardioprotective as during the premenopausal period.

Changes in body composition and adipose tissue distribution also are associated with ovarian aging, with reduction in muscle mass and lean body mass and an increase in abdominal/visceral fat and subcutaneous adipose tissue. Although these body composition changes reflect ovarian aging, midlife weight gain is more closely related to chronologic aging.

The risk of the metabolic syndrome constellation of risk factors was found to be more closely associated with ovarian aging, whereas changes in blood pressure, insulin, and glucose individually tracked more closely with chronologic aging. Additionally, the AHA statement notes the research that identified several symptoms during the MT—including vasomotor symptoms, sleep disturbance, and depression—as being associated with more adverse CVD risk factor status and with subclinical measures of atherosclerosis. Additional research on the mechanistic basis for these associations is needed.

Chronologic age and type of menopause

Notably, a woman’s age and type of menopause matter with respect to CVD risk. Higher CVD risk is seen in women with premature onset (age < 40 years) or early onset (age < 45 years) of menopause and in women undergoing surgical menopause (bilateral oophorectomy) before age 45. In general, menopausal hormone therapy (HT) is recommended for women with premature or early menopause, whether natural or surgical, with continuation through at least the average age of natural menopause. In other women, although not recommended for the express purpose of CVD prevention, menopausal HT is appropriate for the treatment of bothersome vasomotor or other menopausal symptoms, especially when therapy is started before age 60 or within 10 years of menopause among women who are not at elevated risk of CVD.

While the AHA statement suggests that some women who begin estrogen early in menopause may experience reduced coronary heart disease risk, major research gaps remain with regard to HT dose, formulation, route of delivery, and recommended duration of treatment.

An opportunity to promote healthy lifestyle behaviors

Translating the AHA’s first-of-its-kind scientific statement into clinical practice requires recognition and awareness of the MT as a unique phase in a woman’s life associated with myriad changes in CVD risk factors. The statement underscores that the MT is an important time to target behavioral changes to promote CVD risk reduction, including lifestyle modifications in the AHA’s Life’s Simple 7 components (increased physical activity, smoking cessation, healthy diet, avoidance of weight gain) as well as vigilant control of blood pressure, cholesterol, and glucose levels. The MT is truly a window of opportunity for reinvigorated efforts to lower women’s CVD risk. ●

Reference

1. El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532. doi: 10.1161/CIR.000000000000912.

Among the studies we review in this Update are a follow-up of the US Women’s Health Initiative clinical trials and a large observational study from the United Kingdom, which exlore the impact of different hormone therapies (HTs) on breast cancer risk. We look at the interesting patterns found by authors of a study in Canada that analyzed predictors of unnecessary bilateral salpingo-oophorectomy. In addition, we review a study that investigates whether hormone therapy can be effective, alone or adjunctively, in peri- and postmenopausal women with depression. Finally, Dr. Chrisandra Shufelt and Dr. JoAnn Manson summarize highlights from the recent American Heart Association’s scientific statement on the menopause transition and increasing risk factors for cardiovascular disease, and how this period can be viewed as an opportunity to encourage healthy, cardiovascular risk–reducing behaviors.

Studies clarify menopausal HT’s impact on breast cancer risk

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324:369-380. doi: 10.1001/jama.2020.9482.

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020;371:m3873. doi: 10.1136/bmj.m3873.

For many menopausal women, the most worrisome concern related to the use of HT is that it might increase breast cancer risk. In the summer and fall of 2020, 2 important articles were published that addressed how the use of menopausal HT impacts the risk of breast cancer.

The Women’s Health Initiative (WHI) represents the largest and longest-term randomized trial assessing the health impacts of systemic HT. A 2013 WHI report found that with a median of 13 years’ cumulative follow-up, estrogen-only HT (ET) reduced the risk for breast cancer while estrogen-progestin therapy (EPT) increased the risk.¹ In a July 2020 issue of JAMA, WHI investigators analyzed longer-term data (cumulative median follow-up >20 years), which allowed assessment of whether these trends (breast cancer incidence) persisted and if they led to changes in mortality from breast cancer.²

WHI data on breast cancer risk trends in ET vs EPT users

In the ET trial, in which Chlebowski and colleagues studied 10,739 women with prior hysterectomy, 238 versus 296 new cases of breast cancer were diagnosed in women in the ET versus placebo groups, respectively (annualized incidence, 0.30% [ET] vs 0.37% [placebo]; hazard ratio [HR], 0.78; P = .005). ET also was associated with significantly lower mortality from breast cancer: 30 versus 46 deaths (annualized mortality, 0.031% [ET] vs 0.046% [placebo]; HR, 0.60; P = 0.04).

In the EPT trial, which included 16,608 participants with an intact uterus, EPT compared with placebo was associated with significantly elevated risk for incident breast cancer: 584 versus 447 new cases, respectively (annualized incidence, 0.45% [EPT] vs 0.36% [placebo]; HR, 1.28; P<.001). However, mortality from breast cancer was similar in the EPT and placebo groups: 71 and 53 deaths (annualized mortality, 0.045% [EPT] and 0.035% [placebo]; HR, 1.35; P = .11).²

For women with previous hysterectomy who are considering initiating or continuing ET for treatment of bothersome menopausal symptoms, the breast cancer mortality benefit documented in this long-term WHI analysis could, as editorialists point out, “tip the scales” in favor of ET.³ Furthermore, the mortality benefit raises the possibility that ET could be evaluated as a risk-reduction strategy for selected high-risk menopausal women who have undergone hysterectomy. Although tamoxifen and aromatase inhibitors are approved for breast cancer chemoprophylaxis in high-risk menopausal women, these agents have not been found to lower breast cancer mortality.²

UK data analysis and risk for breast cancer in HT users

In an October 2020 issue of BMJ, Vinogradova and colleagues described their analysis of 2 primary care databases in the United Kingdom that in aggregate included roughly 99,000 women with breast cancer diagnosed between 1998 and 2018 (age range, 50–79; mean age at diagnosis, 63; >95% White); these were matched with more than 450,000 women without breast cancer (controls).⁴ Analyses were adjusted for smoking, body mass index (BMI), ethnicity, and mammography.

In this study, ever-use of EPT was associated with an adjusted odds ratio (OR) for breast cancer of 1.26 (95% confidence interval [CI], 1.24–1.29), while ET had an OR of 1.06 (95% CI, 1.03–1.10). In women aged 50 to 59 who used EPT for 5 years or more, 15 additional breast cancers were diagnosed per 10,000 woman-years; for ET users, the attributable risk was 3. Although risk rose with longer HT duration, this trend was less evident with ET than EPT.

In addition, the increased risk associated with ET use was less pronounced in women with a BMI greater than 30 kg/m². Among EPT users, risks were similar with the progestins medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). Likewise, risks were similar regardless of estrogen dose and route of administration (that is, oral vs transdermal). Vaginal estrogen was not associated with a higher or lower risk for breast cancer. Among past users of ET or EPT (with MPA), no increased risk was noted 5 years or more after stopping HT. For users of EPT (with NET or LNG), risks diminished 5 years or more after stopping HT but remained modestly elevated compared with risk in never-users.⁴

In this large observational UK study, ET was associated with minimally elevated risk for breast cancer, while in the WHI study, ET reduced the risk for breast cancer. For EPT, the excess risk in both studies was identical. As the authors note, mean BMI in the UK study participants was slightly lower than that in the WHI participants, a distinction that might explain the differing findings with ET use.

Continue to: Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women...

Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women

Wong J, Murji A, Sunderji Z, et al. Unnecessary bilateral salpingo-oophorectomy at the time of hysterectomy and potential for ovarian preservation. Menopause. 2020;28:8-11. doi: 10.1097/GME.0000000000001652.

While prevention of ovarian cancer is an important benefit of bilateral salpingo-oophorectomy (BSO), performing a BSO at the time of hysterectomy in pre- or perimenopausal patients not only will induce surgical menopause but also is associated with significantly increased overall mortality and an increased risk of mortality due to cardiovascular disease in patients younger than age 45.^5,6 Earlier BSO also has been associated with diabetes, accelerated bone density loss, sexual dysfunction, mood disorders, and decreased cognitive function.⁷

BSO at hysterectomy: How many procedures are not indicated?

To evaluate the prevalence and predictors of unnecessary BSO at the time of hysterectomy, Wong and colleagues conducted a multicenter retrospective review of hysterectomy procedures completed at 6 Canadian hospitals.⁸ Criteria for unnecessary BSO included age younger than 51 years; benign preoperative diagnosis (other than endometriosis, premenstrual dysphoric disorder, and gender dysphoria); and absence of endometriosis and pelvic adhesions.

A total of 2,656 hysterectomies were performed by 75 surgeons (28 fellowship trained and 47 generalists) across 3 community and 3 tertiary care hospitals between 2016 and 2018. At the time of hysterectomy, 749 patients (28%) underwent BSO. Of these, 509 women (68%) had at least 1 indication for concurrent BSO based on preoperative diagnosis.

Key study findings. Concurrent BSO procedures performed at academic hospitals were more likely to have a preoperative indication compared with BSO performed at community sites (70% vs 63%; OR, 1.42; 95% CI, 1.02–1.97; P = .04). BSO was more likely to be indicated when performed by fellowship-trained surgeons compared with surgeries performed by generalist surgeons (75% vs 63%; OR, 1.76; 95% CI, 1.26–2.44, P = .001). BSO procedures performed with vaginal hysterectomy were less likely to be indicated (3 of 20, 15%) when compared with open hysterectomy (74 of 154, 48%) and laparoscopic hysterectomy (432 of 575, 75%).

Of the patients who lacked a preoperative indication for concomitant BSO, 105 of 239 (43.9%) were younger than age 51. Overall, 8% (59 of 749) of patients in the study cohort had an unnecessary BSO based on a combination of preoperative diagnosis, age younger than age 51, and intraoperative factors including absence of endometriosis and adhesions.

Continue to: HT for menopausal depression: Which patients may benefit?

HT for menopausal depression: Which patients may benefit?

Dwyer JB, Aftab A, Radhakrishnan R, et al; APA Council of Research Task Force on Novel Biomarkers and Treatments. Hormonal treatments for major depressive disorder: state of the art. Am J Psychiatry. 2020;177:686- 705. doi:10.1176/appi.ajp.2020.19080848.

The cumulative lifetime prevalence of major depression in US women is 21%.9 An increased risk of mood symptoms and major depressive disorder occurs with the cessation of ovarian hormone production during menopause. In a review of both physiology and clinical studies, an American Psychiatric Association task force found support for several hormone-related strategies for treating depression and highlighted the rapidly advancing, but mixed, findings in this field.¹⁰

Clinical trials that examined mood in peri- and postmenopausal women treated with HT have produced mixed results for a variety of reasons, including differences in psychiatric symptomatology across studies and differences in treatment timing in relation to menopause onset.

HT effectiveness for depression depends on menopausal status

Five studies included in a meta-analysis by Rubinow and colleagues examined the use of ET and EPT as antidepressant monotherapy in peri- or postmenopausal women with major depression.¹¹ Of the 3 higher-quality studies, 2 conducted in perimenopausal women demonstrated the antidepressant efficacy of transdermal estrogen patches compared with placebo. The third study included a mixed population of both peri- and postmenopausal women, and it found that increased estradiol levels (spontaneously occurring or due to ET) were associated with improvement in depression in perimenopausal women but not in postmenopausal women.¹¹

ET also has been investigated as a potential adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs). In a retrospective analysis of a multicenter randomized controlled trial of fluoxetine in patients with depression, women who received ET and fluoxetine demonstrated a greater improvement than those who received fluoxetine monotherapy.¹² One small study that prospectively assessed ET in combination with an antidepressant in postmenopausal women demonstrated no benefit of ET in treating depression.¹³ Another small trial found that while combining transdermal ET with an SSRI accelerated symptom improvement, by the end of the 10-week study, treatment efficacy in the HT plus SSRI group was no greater than that observed in the SSRI-only group.¹⁴

Nineteen studies included in the metaanalysis by Rubinow and colleagues, which examined mood after ET or EPT treatment in nondepressed women, found little evidence of benefit, particularly in women without other physical symptoms of menopause.¹¹

The Kronos Early Estrogen Prevention Study (KEEPS) followed 661 women who received either oral estrogen plus progesterone, transdermal estrogen plus progesterone, or placebo over 4 years.¹⁵ Women with clinical depression were excluded from the study; however, women with mild to moderate mood symptoms who were being treated with an antidepressant were included. Improvements in depressive symptoms and anxiety were observed only in the oral estrogen plus progesterone group compared with the placebo group.¹⁵

In a study of 172 euthymic peri- and postmenopausal women treated for 12 months with transdermal estrogen plus oral progesterone, investigators found that, unlike postmenopausal women and those in the late perimenopausal transition, only women in the early perimenopausal transition had a lower risk of developing depressive symptoms.¹⁶

Bottom line

This complex literature suggests that ET/HT interventions are most likely to be successful when implemented early in the menopausal transition. The clearest indication for the use of HT is for perimenopausal women experiencing depression who are also experiencing menopausal symptoms (for example, bothersome hot flashes). There is little evidence that the use of ET/HT in late perimenopausal or postmenopausal women effectively treats depression; accordingly, HT is not recommended for the treatment of mood disorders in this population. The more ambiguous cases are those of perimenopausal women who are depressed but do not have classic vasomotor symptoms; some evidence supports the antidepressant efficacy of HT in this setting.¹¹ Although some studies suggest that HT can be effective in preventing depression in perimenopausal women, more evidence is needed.¹⁶

 

The menopause transition: A key period for strategizing CVD risk factor reduction

---

Chrisandra L. Shufelt, MD, MS, NCMP

Dr. Shufelt is Associate Director of the Barbra
Streisand Women’s Heart Center, Smidt
Heart Institute, Cedars-Sinai Medical Center,
Los Angeles, California.

JoAnn E. Manson, MD, DrPH, NCMP

Dr. Manson is Professor of Medicine and the
Michael and Lee Bell Professor of Women’s
Health at Harvard Medical School; Professor
in the Department of Epidemiology, Harvard
T.H. Chan School of Public Health; and Chief
of the Division of Preventive Medicine
at Brigham and Women’s Hospital, Boston,
Massachusetts.

The authors report no financial relationships relevant to this article. Dr. Manson is a coauthor of the AHA Scientific Statement discussed in this article.

In the United States, nearly one-half of a woman’s life, on average, will be lived after menopause. For women with natural menopause, the menopause transition (MT) can begin 2 to 7 years before and may extend 1 year past the final menstrual period, which occurs at an average age of 51 years. For women with surgical menopause, the MT occurs abruptly with the sudden loss of endogenous ovarian hormones. Both types of transitions mark a critical time period when reproduction and endogenous sex hormone levels diminish and when cardiovascular disease (CVD) risk factors begin to rise.

The 2020 American Heart Association (AHA) scientific statement, “Menopause transition and cardiovascular disease risk: Implications for timing of early prevention,” highlights the MT as a window of opportunity for CVD prevention.¹

CVD risk factors associated with ovarian aging

In the AHA scientific statement, data from several longitudinal women’s health studies were used to identify which CVD risk factor changes during the MT are related to ovarian aging as opposed to chronologic aging. Independent of aging, those associated with reproductive or ovarian aging included an increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B. Changes in high-density lipoprotein cholesterol (HDL-C) particles and function also occur during the MT, which may explain why higher HDL-C levels during the MT and the postmenopausal years are not as cardioprotective as during the premenopausal period.

Changes in body composition and adipose tissue distribution also are associated with ovarian aging, with reduction in muscle mass and lean body mass and an increase in abdominal/visceral fat and subcutaneous adipose tissue. Although these body composition changes reflect ovarian aging, midlife weight gain is more closely related to chronologic aging.

The risk of the metabolic syndrome constellation of risk factors was found to be more closely associated with ovarian aging, whereas changes in blood pressure, insulin, and glucose individually tracked more closely with chronologic aging. Additionally, the AHA statement notes the research that identified several symptoms during the MT—including vasomotor symptoms, sleep disturbance, and depression—as being associated with more adverse CVD risk factor status and with subclinical measures of atherosclerosis. Additional research on the mechanistic basis for these associations is needed.

Chronologic age and type of menopause

Notably, a woman’s age and type of menopause matter with respect to CVD risk. Higher CVD risk is seen in women with premature onset (age < 40 years) or early onset (age < 45 years) of menopause and in women undergoing surgical menopause (bilateral oophorectomy) before age 45. In general, menopausal hormone therapy (HT) is recommended for women with premature or early menopause, whether natural or surgical, with continuation through at least the average age of natural menopause. In other women, although not recommended for the express purpose of CVD prevention, menopausal HT is appropriate for the treatment of bothersome vasomotor or other menopausal symptoms, especially when therapy is started before age 60 or within 10 years of menopause among women who are not at elevated risk of CVD.

While the AHA statement suggests that some women who begin estrogen early in menopause may experience reduced coronary heart disease risk, major research gaps remain with regard to HT dose, formulation, route of delivery, and recommended duration of treatment.

An opportunity to promote healthy lifestyle behaviors

Translating the AHA’s first-of-its-kind scientific statement into clinical practice requires recognition and awareness of the MT as a unique phase in a woman’s life associated with myriad changes in CVD risk factors. The statement underscores that the MT is an important time to target behavioral changes to promote CVD risk reduction, including lifestyle modifications in the AHA’s Life’s Simple 7 components (increased physical activity, smoking cessation, healthy diet, avoidance of weight gain) as well as vigilant control of blood pressure, cholesterol, and glucose levels. The MT is truly a window of opportunity for reinvigorated efforts to lower women’s CVD risk. ●

Reference

1. El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532. doi: 10.1161/CIR.000000000000912.

Among the studies we review in this Update are a follow-up of the US Women’s Health Initiative clinical trials and a large observational study from the United Kingdom, which exlore the impact of different hormone therapies (HTs) on breast cancer risk. We look at the interesting patterns found by authors of a study in Canada that analyzed predictors of unnecessary bilateral salpingo-oophorectomy. In addition, we review a study that investigates whether hormone therapy can be effective, alone or adjunctively, in peri- and postmenopausal women with depression. Finally, Dr. Chrisandra Shufelt and Dr. JoAnn Manson summarize highlights from the recent American Heart Association’s scientific statement on the menopause transition and increasing risk factors for cardiovascular disease, and how this period can be viewed as an opportunity to encourage healthy, cardiovascular risk–reducing behaviors.

Studies clarify menopausal HT’s impact on breast cancer risk

Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of menopausal hormone therapy with breast cancer incidence and mortality during long-term follow-up of the Women’s Health Initiative randomized clinical trials. JAMA. 2020;324:369-380. doi: 10.1001/jama.2020.9482.

Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases. BMJ. 2020;371:m3873. doi: 10.1136/bmj.m3873.

For many menopausal women, the most worrisome concern related to the use of HT is that it might increase breast cancer risk. In the summer and fall of 2020, 2 important articles were published that addressed how the use of menopausal HT impacts the risk of breast cancer.

The Women’s Health Initiative (WHI) represents the largest and longest-term randomized trial assessing the health impacts of systemic HT. A 2013 WHI report found that with a median of 13 years’ cumulative follow-up, estrogen-only HT (ET) reduced the risk for breast cancer while estrogen-progestin therapy (EPT) increased the risk.¹ In a July 2020 issue of JAMA, WHI investigators analyzed longer-term data (cumulative median follow-up >20 years), which allowed assessment of whether these trends (breast cancer incidence) persisted and if they led to changes in mortality from breast cancer.²

WHI data on breast cancer risk trends in ET vs EPT users

In the ET trial, in which Chlebowski and colleagues studied 10,739 women with prior hysterectomy, 238 versus 296 new cases of breast cancer were diagnosed in women in the ET versus placebo groups, respectively (annualized incidence, 0.30% [ET] vs 0.37% [placebo]; hazard ratio [HR], 0.78; P = .005). ET also was associated with significantly lower mortality from breast cancer: 30 versus 46 deaths (annualized mortality, 0.031% [ET] vs 0.046% [placebo]; HR, 0.60; P = 0.04).

In the EPT trial, which included 16,608 participants with an intact uterus, EPT compared with placebo was associated with significantly elevated risk for incident breast cancer: 584 versus 447 new cases, respectively (annualized incidence, 0.45% [EPT] vs 0.36% [placebo]; HR, 1.28; P<.001). However, mortality from breast cancer was similar in the EPT and placebo groups: 71 and 53 deaths (annualized mortality, 0.045% [EPT] and 0.035% [placebo]; HR, 1.35; P = .11).²

For women with previous hysterectomy who are considering initiating or continuing ET for treatment of bothersome menopausal symptoms, the breast cancer mortality benefit documented in this long-term WHI analysis could, as editorialists point out, “tip the scales” in favor of ET.³ Furthermore, the mortality benefit raises the possibility that ET could be evaluated as a risk-reduction strategy for selected high-risk menopausal women who have undergone hysterectomy. Although tamoxifen and aromatase inhibitors are approved for breast cancer chemoprophylaxis in high-risk menopausal women, these agents have not been found to lower breast cancer mortality.²

UK data analysis and risk for breast cancer in HT users

In an October 2020 issue of BMJ, Vinogradova and colleagues described their analysis of 2 primary care databases in the United Kingdom that in aggregate included roughly 99,000 women with breast cancer diagnosed between 1998 and 2018 (age range, 50–79; mean age at diagnosis, 63; >95% White); these were matched with more than 450,000 women without breast cancer (controls).⁴ Analyses were adjusted for smoking, body mass index (BMI), ethnicity, and mammography.

In this study, ever-use of EPT was associated with an adjusted odds ratio (OR) for breast cancer of 1.26 (95% confidence interval [CI], 1.24–1.29), while ET had an OR of 1.06 (95% CI, 1.03–1.10). In women aged 50 to 59 who used EPT for 5 years or more, 15 additional breast cancers were diagnosed per 10,000 woman-years; for ET users, the attributable risk was 3. Although risk rose with longer HT duration, this trend was less evident with ET than EPT.

In addition, the increased risk associated with ET use was less pronounced in women with a BMI greater than 30 kg/m². Among EPT users, risks were similar with the progestins medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). Likewise, risks were similar regardless of estrogen dose and route of administration (that is, oral vs transdermal). Vaginal estrogen was not associated with a higher or lower risk for breast cancer. Among past users of ET or EPT (with MPA), no increased risk was noted 5 years or more after stopping HT. For users of EPT (with NET or LNG), risks diminished 5 years or more after stopping HT but remained modestly elevated compared with risk in never-users.⁴

In this large observational UK study, ET was associated with minimally elevated risk for breast cancer, while in the WHI study, ET reduced the risk for breast cancer. For EPT, the excess risk in both studies was identical. As the authors note, mean BMI in the UK study participants was slightly lower than that in the WHI participants, a distinction that might explain the differing findings with ET use.

Continue to: Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women...

Frequency of nonindicated BSO at the time of hysterectomy in pre- and perimenopausal women

Wong J, Murji A, Sunderji Z, et al. Unnecessary bilateral salpingo-oophorectomy at the time of hysterectomy and potential for ovarian preservation. Menopause. 2020;28:8-11. doi: 10.1097/GME.0000000000001652.

While prevention of ovarian cancer is an important benefit of bilateral salpingo-oophorectomy (BSO), performing a BSO at the time of hysterectomy in pre- or perimenopausal patients not only will induce surgical menopause but also is associated with significantly increased overall mortality and an increased risk of mortality due to cardiovascular disease in patients younger than age 45.^5,6 Earlier BSO also has been associated with diabetes, accelerated bone density loss, sexual dysfunction, mood disorders, and decreased cognitive function.⁷

BSO at hysterectomy: How many procedures are not indicated?

To evaluate the prevalence and predictors of unnecessary BSO at the time of hysterectomy, Wong and colleagues conducted a multicenter retrospective review of hysterectomy procedures completed at 6 Canadian hospitals.⁸ Criteria for unnecessary BSO included age younger than 51 years; benign preoperative diagnosis (other than endometriosis, premenstrual dysphoric disorder, and gender dysphoria); and absence of endometriosis and pelvic adhesions.

A total of 2,656 hysterectomies were performed by 75 surgeons (28 fellowship trained and 47 generalists) across 3 community and 3 tertiary care hospitals between 2016 and 2018. At the time of hysterectomy, 749 patients (28%) underwent BSO. Of these, 509 women (68%) had at least 1 indication for concurrent BSO based on preoperative diagnosis.

Key study findings. Concurrent BSO procedures performed at academic hospitals were more likely to have a preoperative indication compared with BSO performed at community sites (70% vs 63%; OR, 1.42; 95% CI, 1.02–1.97; P = .04). BSO was more likely to be indicated when performed by fellowship-trained surgeons compared with surgeries performed by generalist surgeons (75% vs 63%; OR, 1.76; 95% CI, 1.26–2.44, P = .001). BSO procedures performed with vaginal hysterectomy were less likely to be indicated (3 of 20, 15%) when compared with open hysterectomy (74 of 154, 48%) and laparoscopic hysterectomy (432 of 575, 75%).

Of the patients who lacked a preoperative indication for concomitant BSO, 105 of 239 (43.9%) were younger than age 51. Overall, 8% (59 of 749) of patients in the study cohort had an unnecessary BSO based on a combination of preoperative diagnosis, age younger than age 51, and intraoperative factors including absence of endometriosis and adhesions.

Continue to: HT for menopausal depression: Which patients may benefit?

HT for menopausal depression: Which patients may benefit?

Dwyer JB, Aftab A, Radhakrishnan R, et al; APA Council of Research Task Force on Novel Biomarkers and Treatments. Hormonal treatments for major depressive disorder: state of the art. Am J Psychiatry. 2020;177:686- 705. doi:10.1176/appi.ajp.2020.19080848.

The cumulative lifetime prevalence of major depression in US women is 21%.9 An increased risk of mood symptoms and major depressive disorder occurs with the cessation of ovarian hormone production during menopause. In a review of both physiology and clinical studies, an American Psychiatric Association task force found support for several hormone-related strategies for treating depression and highlighted the rapidly advancing, but mixed, findings in this field.¹⁰

Clinical trials that examined mood in peri- and postmenopausal women treated with HT have produced mixed results for a variety of reasons, including differences in psychiatric symptomatology across studies and differences in treatment timing in relation to menopause onset.

HT effectiveness for depression depends on menopausal status

Five studies included in a meta-analysis by Rubinow and colleagues examined the use of ET and EPT as antidepressant monotherapy in peri- or postmenopausal women with major depression.¹¹ Of the 3 higher-quality studies, 2 conducted in perimenopausal women demonstrated the antidepressant efficacy of transdermal estrogen patches compared with placebo. The third study included a mixed population of both peri- and postmenopausal women, and it found that increased estradiol levels (spontaneously occurring or due to ET) were associated with improvement in depression in perimenopausal women but not in postmenopausal women.¹¹

ET also has been investigated as a potential adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs). In a retrospective analysis of a multicenter randomized controlled trial of fluoxetine in patients with depression, women who received ET and fluoxetine demonstrated a greater improvement than those who received fluoxetine monotherapy.¹² One small study that prospectively assessed ET in combination with an antidepressant in postmenopausal women demonstrated no benefit of ET in treating depression.¹³ Another small trial found that while combining transdermal ET with an SSRI accelerated symptom improvement, by the end of the 10-week study, treatment efficacy in the HT plus SSRI group was no greater than that observed in the SSRI-only group.¹⁴

Nineteen studies included in the metaanalysis by Rubinow and colleagues, which examined mood after ET or EPT treatment in nondepressed women, found little evidence of benefit, particularly in women without other physical symptoms of menopause.¹¹

The Kronos Early Estrogen Prevention Study (KEEPS) followed 661 women who received either oral estrogen plus progesterone, transdermal estrogen plus progesterone, or placebo over 4 years.¹⁵ Women with clinical depression were excluded from the study; however, women with mild to moderate mood symptoms who were being treated with an antidepressant were included. Improvements in depressive symptoms and anxiety were observed only in the oral estrogen plus progesterone group compared with the placebo group.¹⁵

In a study of 172 euthymic peri- and postmenopausal women treated for 12 months with transdermal estrogen plus oral progesterone, investigators found that, unlike postmenopausal women and those in the late perimenopausal transition, only women in the early perimenopausal transition had a lower risk of developing depressive symptoms.¹⁶

Bottom line

This complex literature suggests that ET/HT interventions are most likely to be successful when implemented early in the menopausal transition. The clearest indication for the use of HT is for perimenopausal women experiencing depression who are also experiencing menopausal symptoms (for example, bothersome hot flashes). There is little evidence that the use of ET/HT in late perimenopausal or postmenopausal women effectively treats depression; accordingly, HT is not recommended for the treatment of mood disorders in this population. The more ambiguous cases are those of perimenopausal women who are depressed but do not have classic vasomotor symptoms; some evidence supports the antidepressant efficacy of HT in this setting.¹¹ Although some studies suggest that HT can be effective in preventing depression in perimenopausal women, more evidence is needed.¹⁶

 

The menopause transition: A key period for strategizing CVD risk factor reduction

---

Chrisandra L. Shufelt, MD, MS, NCMP

Dr. Shufelt is Associate Director of the Barbra
Streisand Women’s Heart Center, Smidt
Heart Institute, Cedars-Sinai Medical Center,
Los Angeles, California.

JoAnn E. Manson, MD, DrPH, NCMP

Dr. Manson is Professor of Medicine and the
Michael and Lee Bell Professor of Women’s
Health at Harvard Medical School; Professor
in the Department of Epidemiology, Harvard
T.H. Chan School of Public Health; and Chief
of the Division of Preventive Medicine
at Brigham and Women’s Hospital, Boston,
Massachusetts.

The authors report no financial relationships relevant to this article. Dr. Manson is a coauthor of the AHA Scientific Statement discussed in this article.

In the United States, nearly one-half of a woman’s life, on average, will be lived after menopause. For women with natural menopause, the menopause transition (MT) can begin 2 to 7 years before and may extend 1 year past the final menstrual period, which occurs at an average age of 51 years. For women with surgical menopause, the MT occurs abruptly with the sudden loss of endogenous ovarian hormones. Both types of transitions mark a critical time period when reproduction and endogenous sex hormone levels diminish and when cardiovascular disease (CVD) risk factors begin to rise.

The 2020 American Heart Association (AHA) scientific statement, “Menopause transition and cardiovascular disease risk: Implications for timing of early prevention,” highlights the MT as a window of opportunity for CVD prevention.¹

CVD risk factors associated with ovarian aging

In the AHA scientific statement, data from several longitudinal women’s health studies were used to identify which CVD risk factor changes during the MT are related to ovarian aging as opposed to chronologic aging. Independent of aging, those associated with reproductive or ovarian aging included an increase in serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B. Changes in high-density lipoprotein cholesterol (HDL-C) particles and function also occur during the MT, which may explain why higher HDL-C levels during the MT and the postmenopausal years are not as cardioprotective as during the premenopausal period.

Changes in body composition and adipose tissue distribution also are associated with ovarian aging, with reduction in muscle mass and lean body mass and an increase in abdominal/visceral fat and subcutaneous adipose tissue. Although these body composition changes reflect ovarian aging, midlife weight gain is more closely related to chronologic aging.

The risk of the metabolic syndrome constellation of risk factors was found to be more closely associated with ovarian aging, whereas changes in blood pressure, insulin, and glucose individually tracked more closely with chronologic aging. Additionally, the AHA statement notes the research that identified several symptoms during the MT—including vasomotor symptoms, sleep disturbance, and depression—as being associated with more adverse CVD risk factor status and with subclinical measures of atherosclerosis. Additional research on the mechanistic basis for these associations is needed.

Chronologic age and type of menopause

Notably, a woman’s age and type of menopause matter with respect to CVD risk. Higher CVD risk is seen in women with premature onset (age < 40 years) or early onset (age < 45 years) of menopause and in women undergoing surgical menopause (bilateral oophorectomy) before age 45. In general, menopausal hormone therapy (HT) is recommended for women with premature or early menopause, whether natural or surgical, with continuation through at least the average age of natural menopause. In other women, although not recommended for the express purpose of CVD prevention, menopausal HT is appropriate for the treatment of bothersome vasomotor or other menopausal symptoms, especially when therapy is started before age 60 or within 10 years of menopause among women who are not at elevated risk of CVD.

While the AHA statement suggests that some women who begin estrogen early in menopause may experience reduced coronary heart disease risk, major research gaps remain with regard to HT dose, formulation, route of delivery, and recommended duration of treatment.

An opportunity to promote healthy lifestyle behaviors

Translating the AHA’s first-of-its-kind scientific statement into clinical practice requires recognition and awareness of the MT as a unique phase in a woman’s life associated with myriad changes in CVD risk factors. The statement underscores that the MT is an important time to target behavioral changes to promote CVD risk reduction, including lifestyle modifications in the AHA’s Life’s Simple 7 components (increased physical activity, smoking cessation, healthy diet, avoidance of weight gain) as well as vigilant control of blood pressure, cholesterol, and glucose levels. The MT is truly a window of opportunity for reinvigorated efforts to lower women’s CVD risk. ●

Reference

1. El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention; and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532. doi: 10.1161/CIR.000000000000912.

It may not be always necessary to approach the treatment of HER2-positive, hormone receptor–negative (HER2+/HR–) early breast cancer with added chemotherapy, survival results of a prospective multicenter randomized trial suggest.

In the ADAPT-HER2+/HR– trial, comparing a de-escalated 12-week neoadjuvant regimen consisting of dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel, the three-drug regimen was associated with high pathologic complete response(pCR) rates and excellent 5-year survival, irrespective of whether patients received additional chemotherapy, reported Nadia Harbeck, MD, PhD, of the University of Munich.

“Chemotherapy-free regimens are promising in highly sensitive tumors with early response, but future investigation of such chemotherapy-free regimens need to be focused on selected patients, like those with HER2 3+ tumors, non–basal-like tumors, those showing early response to the de-escalated therapy, and those with predictive RNA signatures such as immune signatures,” she said in an oral abstract session during the American Society of Clinical Oncology annual meeting (Abstract 503).
 

Under the WGS umbrella

The ADAPT HER2+/HR– trial (NCT01779206) is one of several conducted by the West German Study Group (WGS) on therapy for intrinsic breast cancer types.

In this study, 134 patients with HER2-positive, estrogen and progesterone receptor–negative tumors with no metastatic disease and good performance status were assigned on a 5:2 basis to neoadjuvant therapy with trastuzumab at a loading dose of 8 mg/kg for the first cycle followed by 6 mg/kg for subsequent cycles every 3 weeks x 4, plus pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks x 4 (92 patients), or to trastuzumab and pertuzumab at the same dose and schedule plus paclitaxel 80 mg/m² once weekly for 12 weeks.

Patients had surgery within 3 weeks of the end of study therapy unless they did not have a histologically confirmed pCR, in which case they went on to receive standard neoadjuvant therapy prior to surgery.

Adjuvant therapy was performed according to national guidelines, although patients with a pCR after 12 weeks of study therapy could be spared from adjuvant chemotherapy at the investigator’s discretion.

Patients underwent biopsy at 3 weeks for therapy for early response assessment, defined as either a Ki67 decrease of at least 30% from baseline, or low cellularity (less than 500 invasive tumor cells).
 

First survival results

The investigators previously reported the primary pCR endpoint from the trial, which showed a rate of 90% after 12 weeks in the three-drug arm, and a “substantial and clinically meaningful” pCR rate of 34% after the trastuzumab plus pertuzumab alone.

At ASCO 2021, Dr. Harbeck reported the first survival data from the trial.

After a median follow-up of 59.9 months, there were no statistically significant differences between trial arms in either overall survival, invasive disease-free survival (iDFS), or distant disease-free survival (dDFS).

The 5-year iDFS rate in the three-drug arm was 98%, compared with 87% for the dual HER2 blockade-only arm, a difference that was not statistically significant.

The 5-year dDFS rates were 98% and 92% respectively. There were only seven dDFS events during follow-up, Dr. Harbeck noted.

There were only six deaths during follow-up, with overall survival rates of 98% in the paclitaxel-containing arm, and 94% in the anti-HER2 antibodies–only arm, a difference of one overall survival event, Dr. Harbeck said.
 

pCR counts

However, patients who did not have pathologic complete responses at the end of first-line de-escalated therapy had worse outcomes, with a 5-year iDFS rate of 82%, compared with 98% for patients who had achieved a pCR. This translated into a hazard ratio for invasive disease in patients with pCRs of 0.14 (P = .011).

This difference occurred despite the study requirement that all patients who did not have pCR after 12 weeks of initial therapy would receive additional chemotherapy.

Looking at the tumor subtype among patients in the paclitaxel-free arm to see whether they could identify predictors of early response, the researchers found a pCR rate of 36.5% among 85 patients with nonbasal tumors, but 0% among 7 patients with basal tumors.

The investigators identified a population of patients whose tumors could be considered nonsensitive to dual HER2 blockade alone: Those with basal tumors, those tumors with low immunohistochemical HER2 expression, and those without an early response to therapy on biopsy 3 weeks into initial therapy. Among 31 of the 92 patients in the dual HER2 arm who met this description, 2 had pCRs, Dr. Harbeck noted.

The 5-year iDFS rate among patients in the dual blockade–only arm with nonsensitive tumors was 79%, compared with 93% for patients with treatment-responsive types, although there were only 13 invasive events total in this arm.

“If we look at the whole trial population, the negative prognostic impact of what we termed nonsensitive tumors was even significant regarding dDFS, with a hazard ratio of about 5,” she said.
 

‘A consistent theme’

Invited discussant Lisa A. Carey, MD, ScM, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the trial was underpowered for outcomes, but that results nonetheless suggest that patients with strongly HER2-driven tumors might get comparable benefits from less chemotherapy.

“This trial included only hormone receptor–negative, HER2-positive tumors, and these we know are likely to be HER2-enriched in terms of subtype, about three-quarters of them,”she said.

The previously reported pCR rate of 90% in the paclitaxel-containing arm, with 80% of patients requiring no further chemotherapy, resulted in the excellent 5-year iDFS and dDFS in this group, despite the relatively highly clinical stage, with about 60% of patients having clinical stage 2 or higher tumors, and more than 40% being node positive.

The idea that pCR itself can predict which patients could be spared from more intensive chemotherapy “is starting to look like a consistent theme,” she said.

Dr. Carey pointed out that in the KRISTINE trial comparing the combination of trastuzumab emtansine (T-DM1) and pertuzumab with standard chemotherapy in patients with HER2-positive stage I-III breast cancer, although the experimental combination was associated with lower pCR rates and worse event-free survival, rates of iDFS/dDFS were virtually identical for patients in both arms who achieved a pCR.

“So the question is can pCR mean that we can either eliminate additional therapy,” she said, noting that the question is currently being addressed prospectively in two clinical trials, COMPASS-pCR and DECRESCENDO.

ADAPT HER2+/HR- is sponsored by F. Hoffman-La Roche. Dr. Harbeck disclosed institutional research funding from Roche/Genentech, as well as honoraria and consulting/advising for multiple companies. Dr. Carey disclosed institutional research funding and other relationships with various companies.

It may not be always necessary to approach the treatment of HER2-positive, hormone receptor–negative (HER2+/HR–) early breast cancer with added chemotherapy, survival results of a prospective multicenter randomized trial suggest.

In the ADAPT-HER2+/HR– trial, comparing a de-escalated 12-week neoadjuvant regimen consisting of dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel, the three-drug regimen was associated with high pathologic complete response(pCR) rates and excellent 5-year survival, irrespective of whether patients received additional chemotherapy, reported Nadia Harbeck, MD, PhD, of the University of Munich.

“Chemotherapy-free regimens are promising in highly sensitive tumors with early response, but future investigation of such chemotherapy-free regimens need to be focused on selected patients, like those with HER2 3+ tumors, non–basal-like tumors, those showing early response to the de-escalated therapy, and those with predictive RNA signatures such as immune signatures,” she said in an oral abstract session during the American Society of Clinical Oncology annual meeting (Abstract 503).
 

Under the WGS umbrella

The ADAPT HER2+/HR– trial (NCT01779206) is one of several conducted by the West German Study Group (WGS) on therapy for intrinsic breast cancer types.

In this study, 134 patients with HER2-positive, estrogen and progesterone receptor–negative tumors with no metastatic disease and good performance status were assigned on a 5:2 basis to neoadjuvant therapy with trastuzumab at a loading dose of 8 mg/kg for the first cycle followed by 6 mg/kg for subsequent cycles every 3 weeks x 4, plus pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks x 4 (92 patients), or to trastuzumab and pertuzumab at the same dose and schedule plus paclitaxel 80 mg/m² once weekly for 12 weeks.

Patients had surgery within 3 weeks of the end of study therapy unless they did not have a histologically confirmed pCR, in which case they went on to receive standard neoadjuvant therapy prior to surgery.

Adjuvant therapy was performed according to national guidelines, although patients with a pCR after 12 weeks of study therapy could be spared from adjuvant chemotherapy at the investigator’s discretion.

Patients underwent biopsy at 3 weeks for therapy for early response assessment, defined as either a Ki67 decrease of at least 30% from baseline, or low cellularity (less than 500 invasive tumor cells).
 

First survival results

The investigators previously reported the primary pCR endpoint from the trial, which showed a rate of 90% after 12 weeks in the three-drug arm, and a “substantial and clinically meaningful” pCR rate of 34% after the trastuzumab plus pertuzumab alone.

At ASCO 2021, Dr. Harbeck reported the first survival data from the trial.

After a median follow-up of 59.9 months, there were no statistically significant differences between trial arms in either overall survival, invasive disease-free survival (iDFS), or distant disease-free survival (dDFS).

The 5-year iDFS rate in the three-drug arm was 98%, compared with 87% for the dual HER2 blockade-only arm, a difference that was not statistically significant.

The 5-year dDFS rates were 98% and 92% respectively. There were only seven dDFS events during follow-up, Dr. Harbeck noted.

There were only six deaths during follow-up, with overall survival rates of 98% in the paclitaxel-containing arm, and 94% in the anti-HER2 antibodies–only arm, a difference of one overall survival event, Dr. Harbeck said.
 

pCR counts

However, patients who did not have pathologic complete responses at the end of first-line de-escalated therapy had worse outcomes, with a 5-year iDFS rate of 82%, compared with 98% for patients who had achieved a pCR. This translated into a hazard ratio for invasive disease in patients with pCRs of 0.14 (P = .011).

This difference occurred despite the study requirement that all patients who did not have pCR after 12 weeks of initial therapy would receive additional chemotherapy.

Looking at the tumor subtype among patients in the paclitaxel-free arm to see whether they could identify predictors of early response, the researchers found a pCR rate of 36.5% among 85 patients with nonbasal tumors, but 0% among 7 patients with basal tumors.

The investigators identified a population of patients whose tumors could be considered nonsensitive to dual HER2 blockade alone: Those with basal tumors, those tumors with low immunohistochemical HER2 expression, and those without an early response to therapy on biopsy 3 weeks into initial therapy. Among 31 of the 92 patients in the dual HER2 arm who met this description, 2 had pCRs, Dr. Harbeck noted.

The 5-year iDFS rate among patients in the dual blockade–only arm with nonsensitive tumors was 79%, compared with 93% for patients with treatment-responsive types, although there were only 13 invasive events total in this arm.

“If we look at the whole trial population, the negative prognostic impact of what we termed nonsensitive tumors was even significant regarding dDFS, with a hazard ratio of about 5,” she said.
 

‘A consistent theme’

Invited discussant Lisa A. Carey, MD, ScM, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the trial was underpowered for outcomes, but that results nonetheless suggest that patients with strongly HER2-driven tumors might get comparable benefits from less chemotherapy.

“This trial included only hormone receptor–negative, HER2-positive tumors, and these we know are likely to be HER2-enriched in terms of subtype, about three-quarters of them,”she said.

The previously reported pCR rate of 90% in the paclitaxel-containing arm, with 80% of patients requiring no further chemotherapy, resulted in the excellent 5-year iDFS and dDFS in this group, despite the relatively highly clinical stage, with about 60% of patients having clinical stage 2 or higher tumors, and more than 40% being node positive.

The idea that pCR itself can predict which patients could be spared from more intensive chemotherapy “is starting to look like a consistent theme,” she said.

Dr. Carey pointed out that in the KRISTINE trial comparing the combination of trastuzumab emtansine (T-DM1) and pertuzumab with standard chemotherapy in patients with HER2-positive stage I-III breast cancer, although the experimental combination was associated with lower pCR rates and worse event-free survival, rates of iDFS/dDFS were virtually identical for patients in both arms who achieved a pCR.

“So the question is can pCR mean that we can either eliminate additional therapy,” she said, noting that the question is currently being addressed prospectively in two clinical trials, COMPASS-pCR and DECRESCENDO.

ADAPT HER2+/HR- is sponsored by F. Hoffman-La Roche. Dr. Harbeck disclosed institutional research funding from Roche/Genentech, as well as honoraria and consulting/advising for multiple companies. Dr. Carey disclosed institutional research funding and other relationships with various companies.

It may not be always necessary to approach the treatment of HER2-positive, hormone receptor–negative (HER2+/HR–) early breast cancer with added chemotherapy, survival results of a prospective multicenter randomized trial suggest.

In the ADAPT-HER2+/HR– trial, comparing a de-escalated 12-week neoadjuvant regimen consisting of dual HER2 blockade with trastuzumab (Herceptin) and pertuzumab (Perjeta) with or without weekly paclitaxel, the three-drug regimen was associated with high pathologic complete response(pCR) rates and excellent 5-year survival, irrespective of whether patients received additional chemotherapy, reported Nadia Harbeck, MD, PhD, of the University of Munich.

“Chemotherapy-free regimens are promising in highly sensitive tumors with early response, but future investigation of such chemotherapy-free regimens need to be focused on selected patients, like those with HER2 3+ tumors, non–basal-like tumors, those showing early response to the de-escalated therapy, and those with predictive RNA signatures such as immune signatures,” she said in an oral abstract session during the American Society of Clinical Oncology annual meeting (Abstract 503).
 

Under the WGS umbrella

The ADAPT HER2+/HR– trial (NCT01779206) is one of several conducted by the West German Study Group (WGS) on therapy for intrinsic breast cancer types.

In this study, 134 patients with HER2-positive, estrogen and progesterone receptor–negative tumors with no metastatic disease and good performance status were assigned on a 5:2 basis to neoadjuvant therapy with trastuzumab at a loading dose of 8 mg/kg for the first cycle followed by 6 mg/kg for subsequent cycles every 3 weeks x 4, plus pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks x 4 (92 patients), or to trastuzumab and pertuzumab at the same dose and schedule plus paclitaxel 80 mg/m² once weekly for 12 weeks.

Patients had surgery within 3 weeks of the end of study therapy unless they did not have a histologically confirmed pCR, in which case they went on to receive standard neoadjuvant therapy prior to surgery.

Adjuvant therapy was performed according to national guidelines, although patients with a pCR after 12 weeks of study therapy could be spared from adjuvant chemotherapy at the investigator’s discretion.

Patients underwent biopsy at 3 weeks for therapy for early response assessment, defined as either a Ki67 decrease of at least 30% from baseline, or low cellularity (less than 500 invasive tumor cells).
 

First survival results

The investigators previously reported the primary pCR endpoint from the trial, which showed a rate of 90% after 12 weeks in the three-drug arm, and a “substantial and clinically meaningful” pCR rate of 34% after the trastuzumab plus pertuzumab alone.

At ASCO 2021, Dr. Harbeck reported the first survival data from the trial.

After a median follow-up of 59.9 months, there were no statistically significant differences between trial arms in either overall survival, invasive disease-free survival (iDFS), or distant disease-free survival (dDFS).

The 5-year iDFS rate in the three-drug arm was 98%, compared with 87% for the dual HER2 blockade-only arm, a difference that was not statistically significant.

The 5-year dDFS rates were 98% and 92% respectively. There were only seven dDFS events during follow-up, Dr. Harbeck noted.

There were only six deaths during follow-up, with overall survival rates of 98% in the paclitaxel-containing arm, and 94% in the anti-HER2 antibodies–only arm, a difference of one overall survival event, Dr. Harbeck said.
 

pCR counts

However, patients who did not have pathologic complete responses at the end of first-line de-escalated therapy had worse outcomes, with a 5-year iDFS rate of 82%, compared with 98% for patients who had achieved a pCR. This translated into a hazard ratio for invasive disease in patients with pCRs of 0.14 (P = .011).

This difference occurred despite the study requirement that all patients who did not have pCR after 12 weeks of initial therapy would receive additional chemotherapy.

Looking at the tumor subtype among patients in the paclitaxel-free arm to see whether they could identify predictors of early response, the researchers found a pCR rate of 36.5% among 85 patients with nonbasal tumors, but 0% among 7 patients with basal tumors.

The investigators identified a population of patients whose tumors could be considered nonsensitive to dual HER2 blockade alone: Those with basal tumors, those tumors with low immunohistochemical HER2 expression, and those without an early response to therapy on biopsy 3 weeks into initial therapy. Among 31 of the 92 patients in the dual HER2 arm who met this description, 2 had pCRs, Dr. Harbeck noted.

The 5-year iDFS rate among patients in the dual blockade–only arm with nonsensitive tumors was 79%, compared with 93% for patients with treatment-responsive types, although there were only 13 invasive events total in this arm.

“If we look at the whole trial population, the negative prognostic impact of what we termed nonsensitive tumors was even significant regarding dDFS, with a hazard ratio of about 5,” she said.
 

‘A consistent theme’

Invited discussant Lisa A. Carey, MD, ScM, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, noted that the trial was underpowered for outcomes, but that results nonetheless suggest that patients with strongly HER2-driven tumors might get comparable benefits from less chemotherapy.

“This trial included only hormone receptor–negative, HER2-positive tumors, and these we know are likely to be HER2-enriched in terms of subtype, about three-quarters of them,”she said.

The previously reported pCR rate of 90% in the paclitaxel-containing arm, with 80% of patients requiring no further chemotherapy, resulted in the excellent 5-year iDFS and dDFS in this group, despite the relatively highly clinical stage, with about 60% of patients having clinical stage 2 or higher tumors, and more than 40% being node positive.

The idea that pCR itself can predict which patients could be spared from more intensive chemotherapy “is starting to look like a consistent theme,” she said.

Dr. Carey pointed out that in the KRISTINE trial comparing the combination of trastuzumab emtansine (T-DM1) and pertuzumab with standard chemotherapy in patients with HER2-positive stage I-III breast cancer, although the experimental combination was associated with lower pCR rates and worse event-free survival, rates of iDFS/dDFS were virtually identical for patients in both arms who achieved a pCR.

“So the question is can pCR mean that we can either eliminate additional therapy,” she said, noting that the question is currently being addressed prospectively in two clinical trials, COMPASS-pCR and DECRESCENDO.

ADAPT HER2+/HR- is sponsored by F. Hoffman-La Roche. Dr. Harbeck disclosed institutional research funding from Roche/Genentech, as well as honoraria and consulting/advising for multiple companies. Dr. Carey disclosed institutional research funding and other relationships with various companies.

Vaginal dryness, encompassed in the modern term genitourinary syndrome of menopause (GSM) affects up to 40% of menopausal women and up to 60% of postmenopausal breast cancer survivors.^1,2 Premenopausal women also can have vulvovaginal dryness while breastfeeding (lactational amenorrhea) and while taking low-dose contraceptives.³ Vaginal moisturizers and lubricants are the first-line treatment options for vaginal dryness, dyspareunia, and GSM.^4,5 In fact, approximately two-thirds of women have reported using a vaginal lubricant in their lifetime.⁶ Despite such ubiquitous use, many health care providers and patients have questions about the difference between vaginal moisturizers and lubricants and how to best choose a product.

Vaginal moisturizers

Vaginal moisturizers are designed to rehydrate the vaginal epithelium. Much like facial or skin moisturizers, they are intended to be applied regularly, every 2 to 3 days, but may be applied more often depending on the severity of symptoms. Vaginal moisturizers work by increasing the fluid content of the vaginal tissue and by lowering the vaginal pH to mimic that of natural vaginal secretions. Vaginal moisturizers are typically water based and use polymers to hydrate tissues.⁷ They change cell morphology but do not change vaginal maturation, indicating that they bring water to the tissue but do not shift the balance between superficial and basal cells and do not increase vaginal epithelial thickness as seen with vaginal estrogen.⁸ Vaginal moisturizers also have been found to be a safe alternative to vaginal estrogen therapy and may improve markers of vaginal health, including vaginal moisture, vaginal fluid volume, vaginal elasticity, and premenopausal pH.⁹ Commercially available vaginal moisturizers have been shown to be as effective as vaginal estrogens in reducing vaginal symptoms such as itching, irritation, and dyspareunia, but some caution should be taken when interpreting these results as neither vaginal moisturizer nor vaginal estrogen tablet were more effective than placebo in a recent randomized controlled trial.^10,11 Small studies on hyaluronic acid have shown efficacy for the treatment of vaginal dryness.^12,13 Hyaluronic acid is commercially available as a vaginal suppository ovule and as a liquid. It may also be obtained from a reliable compounding pharmacy. Vaginal suppository ovules may be a preferable formulation for women who find the liquids messy or cumbersome to apply.

Lubricants

Lubricants differ from vaginal moisturizers because they are specifically designed to be used during intercourse to provide short-term relief from vaginal dryness. They may be water-, silicone-, mineral oil-, or plant oil-based. The use of water- and silicone-based lubricants is associated with high satisfaction for intercourse as well as masturbation.¹⁴ These products may be particularly beneficial to women whose chief complaint is dyspareunia. In fact, women with dyspareunia report more lubricant use than women without dyspareunia, and the most common reason for lubricant use among these women was to reduce or alleviate pain.¹⁵ Overall, women both with and without dyspareunia have a positive perception regarding lubricant use and prefer sexual intercourse that feels more “wet,” and women in their forties have the most positive perception about lubricant use at the time of intercourse compared with other age groups.¹⁶ Furthermore, the World Health Organization (WHO) recommends that condom-compatible lubricants be used with condoms for menopausal and postmenopausal women.¹⁷ Both water-based and silicone-based lubricants may be used with latex condoms, while oil-based lubricants should be avoided as they can degrade the latex condom. While vaginal moisturizers and lubricants technically differ based on use, patients may use one product for both purposes, and some products are marketed as both a moisturizer and lubricant.

Continue to: Providing counsel to patients...

Providing counsel to patients

Patients often seek advice on how to choose vaginal moisturizers and lubricants. Understanding the compositions of these products and their scientific evidence is useful when helping patients make informed decisions regarding their pelvic health. Most commercially available lubricants are either water- or silicone- based. In one study comparing these two types of lubricants, water-based lubricants were associated with fewer genital symptoms than silicone-based products.¹⁴ Women may want to use a natural or organic product and may prefer plant-based oils such as coconut oil or olive oil. Patients should be counseled that latex condoms are not compatible with petroleum-, mineral oil- or plant oil-based lubricants.

In our practice, we generally recommend silicone-based lubricants, as they are readily available and compatible with latex condoms and generally require a smaller amount than water-based lubricants. They tend to be more expensive than water-based lubricants. For vaginal moisturizers, we often recommend commercially available formulations that can be purchased at local pharmacies or drug stores. However, a patient may need to try different lubricants and moisturizers in order to find a preferred product. We have included in TABLES 1 and 2^7,17,18 a list of commercially available vaginal moisturizers and lubricants with ingredient list, pH, osmolality, common formulation, and cost when available, which has been compiled from WHO and published research data to help guide patient counseling. 

The effects of additives

Water-based moisturizers and lubricants may contain many ingredients, such as glycerols, fragrance, flavors, sweeteners, warming or cooling agents, buffering solutions, parabens and other preservatives, and numbing agents. These substances are added to water-based products to prolong water content, alter viscosity, alter pH, achieve certain sensations, and prevent bacterial contamination.⁷ The addition of these substances, however, will alter osmolality and pH balance of the product, which may be of clinical consequence. Silicone- or oil-based products do not contain water and therefore do not have a pH or an osmolality value.

Hyperosmolar formulations can theoretically injure epithelial tissue. In vitro studies have shown that hyperosmotic vaginal products can induce mild to moderate irritation, while very hyperosmolar formulations can induce severe irritation and tissue damage to vaginal epithelial and cervical cells.^19,20 The WHO recommends that the osmolality of a vaginal product not exceed 380 mOsm/kg, but very few commercially available products meet these criteria so, clinically, the threshold is 1,200 mOsm/kg.¹⁷ It should be noted that most commercially available products exceed the 1,200 mOsm/kg threshold. Vaginal products may be a cause for vaginal irritation and should be considered in the differential diagnosis.

The normal vaginal pH is 3.8–4.5, and vaginal products should be pH balanced to this range. The exact role of pH in these products remains poorly understood. Nonetheless, products with a pH of 3 or lower are not recommended.¹⁸ Concerns about osmolality and pH remain theoretical, as a study of 12 commercially available lubricants of varying osmolality and pH found no cytotoxic effect in vivo.¹⁸

Vaginal moisturizers and lubricants contain many inactive ingredients, the most controversial of which are parabens. These substances are used in many cosmetic products as preservatives and are weakly estrogenic. These substances have been found in breast cancer tissue, but their possible role as a carcinogen remains uncertain.^21,22 Nonetheless, the use of paraben-containing products is not recommended for women who have a history of hormonally-driven cancer or who are at high risk for developing cancer.⁷ Many lubricants contain glycerols (glycerol, glycerine, and propylene glycol) to alter viscosity or alter the water properties. The WHO recommends limits on the content of glycerols in these products.¹⁷ Glycerols have been associated with increased risk of bacterial vaginosis (adjusted odds ratio [aOR], 11.75; 95% confidence interval [CI], 1.96–70.27), and can serve as a food source for candida species, possibly increasing risk of yeast infections.^7,23 Additionally, vaginal moisturizers and lubricants may contain preservatives such as chlorhexidine, which can disrupt normal vaginal flora and may cause tissue irritation.⁷

Continue to: Common concerns to be aware of...

Common concerns to be aware of

Women using vaginal products may be concerned about adverse effects, such as worsening vaginal irritation or infection. Vaginal moisturizers have not been shown to have increased risk of adverse effects compared with vaginal estrogens.^9,10 In vitro studies have shown that vaginal moisturizers and lubricants inhibit the growth of Escherichia coli but may also inhibit Lactobacillus crispatus.²⁴ Clinically, vaginal moisturizers have been shown to improve signs of bacterial vaginosis and have even been used to treat bacterial vaginosis.^25,26 A study of commercially available vaginal lubricants inhibited the growth of L crispatus, which may predispose to irritation and infection.²⁷ Nonetheless, the effect of the vaginal products on the vaginal microbiome and vaginal tissue remains poorly studied. Vaginal moisturizers and lubricants, while often helpful for patients, also can potentially cause irritation or predispose to infections. Providers should consider this when evaluating patients for new onset vaginal symptoms after starting vaginal products.

Bottom line

Vaginal products such as moisturizers and lubricants are often effective treatment options for women suffering from genitourinary syndrome of menopause and may be first-line treatment options, especially for women who may wish to avoid estrogen-containing products. Vaginal moisturizers can be recommended to any women experiencing vaginal irritation due to vaginal dryness while vaginal lubricants should be recommended to sexually active women who experience dyspareunia. Clinicians need to be aware of the formulations of these products and possible side effects in order to appropriately counsel patients. ●

Vaginal dryness, encompassed in the modern term genitourinary syndrome of menopause (GSM) affects up to 40% of menopausal women and up to 60% of postmenopausal breast cancer survivors.^1,2 Premenopausal women also can have vulvovaginal dryness while breastfeeding (lactational amenorrhea) and while taking low-dose contraceptives.³ Vaginal moisturizers and lubricants are the first-line treatment options for vaginal dryness, dyspareunia, and GSM.^4,5 In fact, approximately two-thirds of women have reported using a vaginal lubricant in their lifetime.⁶ Despite such ubiquitous use, many health care providers and patients have questions about the difference between vaginal moisturizers and lubricants and how to best choose a product.

Vaginal moisturizers

Vaginal moisturizers are designed to rehydrate the vaginal epithelium. Much like facial or skin moisturizers, they are intended to be applied regularly, every 2 to 3 days, but may be applied more often depending on the severity of symptoms. Vaginal moisturizers work by increasing the fluid content of the vaginal tissue and by lowering the vaginal pH to mimic that of natural vaginal secretions. Vaginal moisturizers are typically water based and use polymers to hydrate tissues.⁷ They change cell morphology but do not change vaginal maturation, indicating that they bring water to the tissue but do not shift the balance between superficial and basal cells and do not increase vaginal epithelial thickness as seen with vaginal estrogen.⁸ Vaginal moisturizers also have been found to be a safe alternative to vaginal estrogen therapy and may improve markers of vaginal health, including vaginal moisture, vaginal fluid volume, vaginal elasticity, and premenopausal pH.⁹ Commercially available vaginal moisturizers have been shown to be as effective as vaginal estrogens in reducing vaginal symptoms such as itching, irritation, and dyspareunia, but some caution should be taken when interpreting these results as neither vaginal moisturizer nor vaginal estrogen tablet were more effective than placebo in a recent randomized controlled trial.^10,11 Small studies on hyaluronic acid have shown efficacy for the treatment of vaginal dryness.^12,13 Hyaluronic acid is commercially available as a vaginal suppository ovule and as a liquid. It may also be obtained from a reliable compounding pharmacy. Vaginal suppository ovules may be a preferable formulation for women who find the liquids messy or cumbersome to apply.

Lubricants

Lubricants differ from vaginal moisturizers because they are specifically designed to be used during intercourse to provide short-term relief from vaginal dryness. They may be water-, silicone-, mineral oil-, or plant oil-based. The use of water- and silicone-based lubricants is associated with high satisfaction for intercourse as well as masturbation.¹⁴ These products may be particularly beneficial to women whose chief complaint is dyspareunia. In fact, women with dyspareunia report more lubricant use than women without dyspareunia, and the most common reason for lubricant use among these women was to reduce or alleviate pain.¹⁵ Overall, women both with and without dyspareunia have a positive perception regarding lubricant use and prefer sexual intercourse that feels more “wet,” and women in their forties have the most positive perception about lubricant use at the time of intercourse compared with other age groups.¹⁶ Furthermore, the World Health Organization (WHO) recommends that condom-compatible lubricants be used with condoms for menopausal and postmenopausal women.¹⁷ Both water-based and silicone-based lubricants may be used with latex condoms, while oil-based lubricants should be avoided as they can degrade the latex condom. While vaginal moisturizers and lubricants technically differ based on use, patients may use one product for both purposes, and some products are marketed as both a moisturizer and lubricant.

Continue to: Providing counsel to patients...

Providing counsel to patients

Patients often seek advice on how to choose vaginal moisturizers and lubricants. Understanding the compositions of these products and their scientific evidence is useful when helping patients make informed decisions regarding their pelvic health. Most commercially available lubricants are either water- or silicone- based. In one study comparing these two types of lubricants, water-based lubricants were associated with fewer genital symptoms than silicone-based products.¹⁴ Women may want to use a natural or organic product and may prefer plant-based oils such as coconut oil or olive oil. Patients should be counseled that latex condoms are not compatible with petroleum-, mineral oil- or plant oil-based lubricants.

In our practice, we generally recommend silicone-based lubricants, as they are readily available and compatible with latex condoms and generally require a smaller amount than water-based lubricants. They tend to be more expensive than water-based lubricants. For vaginal moisturizers, we often recommend commercially available formulations that can be purchased at local pharmacies or drug stores. However, a patient may need to try different lubricants and moisturizers in order to find a preferred product. We have included in TABLES 1 and 2^7,17,18 a list of commercially available vaginal moisturizers and lubricants with ingredient list, pH, osmolality, common formulation, and cost when available, which has been compiled from WHO and published research data to help guide patient counseling. 

The effects of additives

Water-based moisturizers and lubricants may contain many ingredients, such as glycerols, fragrance, flavors, sweeteners, warming or cooling agents, buffering solutions, parabens and other preservatives, and numbing agents. These substances are added to water-based products to prolong water content, alter viscosity, alter pH, achieve certain sensations, and prevent bacterial contamination.⁷ The addition of these substances, however, will alter osmolality and pH balance of the product, which may be of clinical consequence. Silicone- or oil-based products do not contain water and therefore do not have a pH or an osmolality value.

Hyperosmolar formulations can theoretically injure epithelial tissue. In vitro studies have shown that hyperosmotic vaginal products can induce mild to moderate irritation, while very hyperosmolar formulations can induce severe irritation and tissue damage to vaginal epithelial and cervical cells.^19,20 The WHO recommends that the osmolality of a vaginal product not exceed 380 mOsm/kg, but very few commercially available products meet these criteria so, clinically, the threshold is 1,200 mOsm/kg.¹⁷ It should be noted that most commercially available products exceed the 1,200 mOsm/kg threshold. Vaginal products may be a cause for vaginal irritation and should be considered in the differential diagnosis.

The normal vaginal pH is 3.8–4.5, and vaginal products should be pH balanced to this range. The exact role of pH in these products remains poorly understood. Nonetheless, products with a pH of 3 or lower are not recommended.¹⁸ Concerns about osmolality and pH remain theoretical, as a study of 12 commercially available lubricants of varying osmolality and pH found no cytotoxic effect in vivo.¹⁸

Vaginal moisturizers and lubricants contain many inactive ingredients, the most controversial of which are parabens. These substances are used in many cosmetic products as preservatives and are weakly estrogenic. These substances have been found in breast cancer tissue, but their possible role as a carcinogen remains uncertain.^21,22 Nonetheless, the use of paraben-containing products is not recommended for women who have a history of hormonally-driven cancer or who are at high risk for developing cancer.⁷ Many lubricants contain glycerols (glycerol, glycerine, and propylene glycol) to alter viscosity or alter the water properties. The WHO recommends limits on the content of glycerols in these products.¹⁷ Glycerols have been associated with increased risk of bacterial vaginosis (adjusted odds ratio [aOR], 11.75; 95% confidence interval [CI], 1.96–70.27), and can serve as a food source for candida species, possibly increasing risk of yeast infections.^7,23 Additionally, vaginal moisturizers and lubricants may contain preservatives such as chlorhexidine, which can disrupt normal vaginal flora and may cause tissue irritation.⁷

Continue to: Common concerns to be aware of...

Common concerns to be aware of

Women using vaginal products may be concerned about adverse effects, such as worsening vaginal irritation or infection. Vaginal moisturizers have not been shown to have increased risk of adverse effects compared with vaginal estrogens.^9,10 In vitro studies have shown that vaginal moisturizers and lubricants inhibit the growth of Escherichia coli but may also inhibit Lactobacillus crispatus.²⁴ Clinically, vaginal moisturizers have been shown to improve signs of bacterial vaginosis and have even been used to treat bacterial vaginosis.^25,26 A study of commercially available vaginal lubricants inhibited the growth of L crispatus, which may predispose to irritation and infection.²⁷ Nonetheless, the effect of the vaginal products on the vaginal microbiome and vaginal tissue remains poorly studied. Vaginal moisturizers and lubricants, while often helpful for patients, also can potentially cause irritation or predispose to infections. Providers should consider this when evaluating patients for new onset vaginal symptoms after starting vaginal products.

Bottom line

Vaginal products such as moisturizers and lubricants are often effective treatment options for women suffering from genitourinary syndrome of menopause and may be first-line treatment options, especially for women who may wish to avoid estrogen-containing products. Vaginal moisturizers can be recommended to any women experiencing vaginal irritation due to vaginal dryness while vaginal lubricants should be recommended to sexually active women who experience dyspareunia. Clinicians need to be aware of the formulations of these products and possible side effects in order to appropriately counsel patients. ●

Vaginal dryness, encompassed in the modern term genitourinary syndrome of menopause (GSM) affects up to 40% of menopausal women and up to 60% of postmenopausal breast cancer survivors.^1,2 Premenopausal women also can have vulvovaginal dryness while breastfeeding (lactational amenorrhea) and while taking low-dose contraceptives.³ Vaginal moisturizers and lubricants are the first-line treatment options for vaginal dryness, dyspareunia, and GSM.^4,5 In fact, approximately two-thirds of women have reported using a vaginal lubricant in their lifetime.⁶ Despite such ubiquitous use, many health care providers and patients have questions about the difference between vaginal moisturizers and lubricants and how to best choose a product.

Vaginal moisturizers

Vaginal moisturizers are designed to rehydrate the vaginal epithelium. Much like facial or skin moisturizers, they are intended to be applied regularly, every 2 to 3 days, but may be applied more often depending on the severity of symptoms. Vaginal moisturizers work by increasing the fluid content of the vaginal tissue and by lowering the vaginal pH to mimic that of natural vaginal secretions. Vaginal moisturizers are typically water based and use polymers to hydrate tissues.⁷ They change cell morphology but do not change vaginal maturation, indicating that they bring water to the tissue but do not shift the balance between superficial and basal cells and do not increase vaginal epithelial thickness as seen with vaginal estrogen.⁸ Vaginal moisturizers also have been found to be a safe alternative to vaginal estrogen therapy and may improve markers of vaginal health, including vaginal moisture, vaginal fluid volume, vaginal elasticity, and premenopausal pH.⁹ Commercially available vaginal moisturizers have been shown to be as effective as vaginal estrogens in reducing vaginal symptoms such as itching, irritation, and dyspareunia, but some caution should be taken when interpreting these results as neither vaginal moisturizer nor vaginal estrogen tablet were more effective than placebo in a recent randomized controlled trial.^10,11 Small studies on hyaluronic acid have shown efficacy for the treatment of vaginal dryness.^12,13 Hyaluronic acid is commercially available as a vaginal suppository ovule and as a liquid. It may also be obtained from a reliable compounding pharmacy. Vaginal suppository ovules may be a preferable formulation for women who find the liquids messy or cumbersome to apply.

Lubricants

Lubricants differ from vaginal moisturizers because they are specifically designed to be used during intercourse to provide short-term relief from vaginal dryness. They may be water-, silicone-, mineral oil-, or plant oil-based. The use of water- and silicone-based lubricants is associated with high satisfaction for intercourse as well as masturbation.¹⁴ These products may be particularly beneficial to women whose chief complaint is dyspareunia. In fact, women with dyspareunia report more lubricant use than women without dyspareunia, and the most common reason for lubricant use among these women was to reduce or alleviate pain.¹⁵ Overall, women both with and without dyspareunia have a positive perception regarding lubricant use and prefer sexual intercourse that feels more “wet,” and women in their forties have the most positive perception about lubricant use at the time of intercourse compared with other age groups.¹⁶ Furthermore, the World Health Organization (WHO) recommends that condom-compatible lubricants be used with condoms for menopausal and postmenopausal women.¹⁷ Both water-based and silicone-based lubricants may be used with latex condoms, while oil-based lubricants should be avoided as they can degrade the latex condom. While vaginal moisturizers and lubricants technically differ based on use, patients may use one product for both purposes, and some products are marketed as both a moisturizer and lubricant.

Continue to: Providing counsel to patients...

Providing counsel to patients

Patients often seek advice on how to choose vaginal moisturizers and lubricants. Understanding the compositions of these products and their scientific evidence is useful when helping patients make informed decisions regarding their pelvic health. Most commercially available lubricants are either water- or silicone- based. In one study comparing these two types of lubricants, water-based lubricants were associated with fewer genital symptoms than silicone-based products.¹⁴ Women may want to use a natural or organic product and may prefer plant-based oils such as coconut oil or olive oil. Patients should be counseled that latex condoms are not compatible with petroleum-, mineral oil- or plant oil-based lubricants.

In our practice, we generally recommend silicone-based lubricants, as they are readily available and compatible with latex condoms and generally require a smaller amount than water-based lubricants. They tend to be more expensive than water-based lubricants. For vaginal moisturizers, we often recommend commercially available formulations that can be purchased at local pharmacies or drug stores. However, a patient may need to try different lubricants and moisturizers in order to find a preferred product. We have included in TABLES 1 and 2^7,17,18 a list of commercially available vaginal moisturizers and lubricants with ingredient list, pH, osmolality, common formulation, and cost when available, which has been compiled from WHO and published research data to help guide patient counseling. 

The effects of additives

Water-based moisturizers and lubricants may contain many ingredients, such as glycerols, fragrance, flavors, sweeteners, warming or cooling agents, buffering solutions, parabens and other preservatives, and numbing agents. These substances are added to water-based products to prolong water content, alter viscosity, alter pH, achieve certain sensations, and prevent bacterial contamination.⁷ The addition of these substances, however, will alter osmolality and pH balance of the product, which may be of clinical consequence. Silicone- or oil-based products do not contain water and therefore do not have a pH or an osmolality value.

Hyperosmolar formulations can theoretically injure epithelial tissue. In vitro studies have shown that hyperosmotic vaginal products can induce mild to moderate irritation, while very hyperosmolar formulations can induce severe irritation and tissue damage to vaginal epithelial and cervical cells.^19,20 The WHO recommends that the osmolality of a vaginal product not exceed 380 mOsm/kg, but very few commercially available products meet these criteria so, clinically, the threshold is 1,200 mOsm/kg.¹⁷ It should be noted that most commercially available products exceed the 1,200 mOsm/kg threshold. Vaginal products may be a cause for vaginal irritation and should be considered in the differential diagnosis.

The normal vaginal pH is 3.8–4.5, and vaginal products should be pH balanced to this range. The exact role of pH in these products remains poorly understood. Nonetheless, products with a pH of 3 or lower are not recommended.¹⁸ Concerns about osmolality and pH remain theoretical, as a study of 12 commercially available lubricants of varying osmolality and pH found no cytotoxic effect in vivo.¹⁸

Vaginal moisturizers and lubricants contain many inactive ingredients, the most controversial of which are parabens. These substances are used in many cosmetic products as preservatives and are weakly estrogenic. These substances have been found in breast cancer tissue, but their possible role as a carcinogen remains uncertain.^21,22 Nonetheless, the use of paraben-containing products is not recommended for women who have a history of hormonally-driven cancer or who are at high risk for developing cancer.⁷ Many lubricants contain glycerols (glycerol, glycerine, and propylene glycol) to alter viscosity or alter the water properties. The WHO recommends limits on the content of glycerols in these products.¹⁷ Glycerols have been associated with increased risk of bacterial vaginosis (adjusted odds ratio [aOR], 11.75; 95% confidence interval [CI], 1.96–70.27), and can serve as a food source for candida species, possibly increasing risk of yeast infections.^7,23 Additionally, vaginal moisturizers and lubricants may contain preservatives such as chlorhexidine, which can disrupt normal vaginal flora and may cause tissue irritation.⁷

Continue to: Common concerns to be aware of...

Common concerns to be aware of

Women using vaginal products may be concerned about adverse effects, such as worsening vaginal irritation or infection. Vaginal moisturizers have not been shown to have increased risk of adverse effects compared with vaginal estrogens.^9,10 In vitro studies have shown that vaginal moisturizers and lubricants inhibit the growth of Escherichia coli but may also inhibit Lactobacillus crispatus.²⁴ Clinically, vaginal moisturizers have been shown to improve signs of bacterial vaginosis and have even been used to treat bacterial vaginosis.^25,26 A study of commercially available vaginal lubricants inhibited the growth of L crispatus, which may predispose to irritation and infection.²⁷ Nonetheless, the effect of the vaginal products on the vaginal microbiome and vaginal tissue remains poorly studied. Vaginal moisturizers and lubricants, while often helpful for patients, also can potentially cause irritation or predispose to infections. Providers should consider this when evaluating patients for new onset vaginal symptoms after starting vaginal products.

Bottom line

Vaginal products such as moisturizers and lubricants are often effective treatment options for women suffering from genitourinary syndrome of menopause and may be first-line treatment options, especially for women who may wish to avoid estrogen-containing products. Vaginal moisturizers can be recommended to any women experiencing vaginal irritation due to vaginal dryness while vaginal lubricants should be recommended to sexually active women who experience dyspareunia. Clinicians need to be aware of the formulations of these products and possible side effects in order to appropriately counsel patients. ●

Preconception health influences pregnancy outcomes, and in turn, both preconception health and an APO influence adult cardiometabolic health (FIGURE). This editorial is focused on the link between APOs and later cardiometabolic morbidity and mortality, recognizing that preconception health greatly influences the risk of an APO and lifetime cardiometabolic disease.

Adverse pregnancy outcomes

Major APOs include miscarriage, preterm birth (birth <37 weeks’ gestation), low birth weight (birth weight ≤2,500 g; 5.5 lb), gestational diabetes (GDM), preeclampsia, and placental abruption. In the United States, among all births, reported rates of the following APOs are:^1-3

• preterm birth, 10.2%
• low birth weight, 8.3%
• GDM, 6%
• preeclampsia, 5%
• placental abruption, 1%.

Miscarriage occurs in approximately 10% to 15% of pregnancies, influenced by both the age of the woman and the method used to diagnose pregnancy.⁴ Miscarriage, preterm birth, low birth weight, GDM, preeclampsia, and placental abruption have been reported to be associated with an increased risk of later cardiovascular morbidity and mortality.

APOs and cardiovascular disease

Cardiovascular disease (CVD) affects the majority of people past the age of 60 years and includes 4 major subcategories:

1. coronary heart disease, including myocardial infarction, angina, and heart failure
2. CVD, stroke, and transient ischemic attack
3. peripheral artery disease
4. atherosclerosis of the aorta leading to aortic aneurysm.

Multiple meta-analyses report that APOs are associated with CVD in later life. A comprehensive review reported that the risk of CVD was increased following a pregnancy with one of these APOs: severe preeclampsia (odds ratio [OR], 2.74), GDM (OR, 1.68), preterm birth (OR, 1.93), low birth weight (OR, 1.29), and placental abruption (OR, 1.82).⁵

The link between APOs and CVD may be explained in part by the association of APOs with multiple risk factors for CVD, including chronic hypertension, type 2 diabetes mellitus (T2DM), and dyslipidemia. A meta-analysis of 43 studies reported that, compared with controls, women with a history of preeclampsia have a 3.13 times greater risk of developing chronic hypertension.⁶ Among women with preeclampsia, approximately 20% will develop hypertension within 15 years.⁷ A meta-analysis of 20 studies reported that women with a history of GDM had a 9.51-times greater risk of developing T2DM than women without GDM.⁸ Among women with a history of GDM, over 16 years of follow-up, T2DM was diagnosed in 16.2%, compared with 1.9% of control women.⁸

CVD prevention—Breastfeeding: An antidote for APOs

Pregnancy stresses both the cardiovascular and metabolic systems. Breastfeeding is an antidote to the stresses imposed by pregnancy. Breastfeeding women have lower blood glucose⁹ and blood pressure.¹⁰

Breastfeeding reduces the risk of CVD. In a study of 100,864 parous Australian women, with a mean age of 60 years, ever breastfeeding was associated a lower risk of CVD hospitalization (adjusted hazard ratio [aHR], 0.86; 95% confidence interval [CI], 0.78–0.96; P = .005) and CVD mortality (aHR, 0.66; 95% CI, 0.49–0.89; P = .006).¹¹
 

Continue to: CVD prevention—American Heart Association recommendations...

CVD prevention—American Heart Association recommendations

The American Heart Association¹² recommends lifestyle interventions to reduce the risk of CVD, including:

• Eat a high-quality diet that includes vegetables, fruit, whole grains, beans, legumes, nuts, plant-based protein, lean animal protein, and fish.
• Limit intake of sugary drinks and foods, fatty or processed meats, full-fat dairy products, eggs, highly processed foods, and tropical oils.
• Exercise at least 150 minutes weekly at a moderate activity level, including muscle-strengthening activity.
• Reduce prolonged intervals of sitting.
• Live a tobacco- and nicotine-free life.
• Strive to maintain a normal body mass index.
• Consider using an activity tracker to monitor activity level.
• After 40 years of age calculate CVD risk using a validated calculator such as the American Cardiology Association risk calculator.¹³ This calculator uses age, gender, and lipid and blood pressure measurements to calculate the 10-year risk of atherosclerotic CVD, including coronary death, myocardial infarction, and stroke.

Medications to reduce CVD risk

Historically, ObGyns have not routinely prescribed medications to treat hypertension, dyslipidemia, or to prevent diabetes. The recent increase in the valuation of return ambulatory visits and a reduction in the valuation assigned to procedural care may provide ObGyn practices the additional resources needed to manage some chronic diseases. Physician assistants and nurse practitioners may help ObGyn practices to manage hypertension, dyslipidemia, and prediabetes.

Prior to initiating a medicine, counseling about healthy living, including smoking cessation, exercise, heart-healthy diet, and achieving an optimal body mass index is warranted.

For treatment of stage II hypertension, defined as blood pressure (BP) measurements with systolic BP ≥140 mm Hg and diastolic BP ≥90 mm Hg, therapeutic lifestyle interventions include: optimizing weight, following the DASH diet, restricting dietary sodium, physical activity, and reducing alcohol consumption. Medication treatment for essential hypertension is guided by the magnitude of BP reduction needed to achieve normotension. For women with hypertension needing antihypertensive medication and planning another pregnancy in the near future, labetalol or extended-release nifedipine may be first-line medications. For women who have completed their families or who have no immediate plans for pregnancy, an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide diuretic are commonly prescribed.¹⁴

For the treatment of elevated low-density lipoprotein (LDL) cholesterol in women who have not had a cardiovascular event, statin therapy is often warranted when both the LDL cholesterol is >100 mg/dL and the woman has a calculated 10-year risk of >10% for a cardiovascular event using the American Heart Association or American College of Cardiology calculator. Most women who meet these criteria will be older than age 40 years and many will be under the care of an internal medicine or family medicine specialist, limiting the role of the ObGyn.^15-17

For prevention of diabetes in women with a history of GDM, both weight loss and metformin (1,750 mg daily) have been shown in clinical trials to reduce the risk of developing T2DM.¹⁸ Among 350 women with a history of GDM who were followed for 10 years, metformin 850 mg twice daily reduced the risk of developing T2DM by 40% compared with placebo.¹⁹ In the same study, lifestyle changes without metformin, including loss of 7% of body weight plus 150 minutes of exercise weekly was associated with a 35% reduction in the risk of developing T2DM.¹⁹ Metformin is one of the least expensive prescription medications and is cost-effective for the prevention of T2DM.¹⁸

Low-dose aspirin treatment for the prevention of CVD in women who have not had a cardiovascular event must balance a modest reduction in cardiovascular events with a small increased risk of bleeding events. The US Preventive Services Task Force (USPSTF) recommends low-dose aspirin for a limited group of women, those aged 50 to 59 years of age with a 10-year risk of a cardiovascular event >10% who are willing to take aspirin for 10 years. The USPSTF concluded that there is insufficient evidence to recommend low-dose aspirin prevention of CVD in women aged <50 years.²⁰

Continue to: Beyond the fourth trimester...

Beyond the fourth trimester

The fourth trimester is the 12-week period following birth. At the comprehensive postpartum visit, the American College of Obstetricians and Gynecologists (ACOG) recommends that women with APOs be counseled about their increased lifetime risk of maternal cardiometabolic disease.²¹ In addition, ACOG recommends that at this visit the clinician who will assume primary responsibility for the woman’s ongoing medical care in her primary medical home be clarified. One option is to ensure a high-quality hand-off to an internal medicine or family medicine clinician. Another option is for a clinician in the ObGyn’s office practice, including a physician assistant, nurse practitioner, or office-based ObGyn, to assume some role in the primary care of the woman.

An APO is not only a pregnancy problem

An APO reverberates across a woman’s lifetime, increasing the risk of CVD and diabetes. In the United States the mean age at first birth is 27 years.¹ The mean life expectancy of US women is 81 years.²² Following a birth complicated by an APO there are 5 decades of opportunity to improve health through lifestyle changes and medication treatment of obesity, hypertension, dyslipidemia, and hyperglycemia, thereby reducing the risk of CVD.

Preconception health influences pregnancy outcomes, and in turn, both preconception health and an APO influence adult cardiometabolic health (FIGURE). This editorial is focused on the link between APOs and later cardiometabolic morbidity and mortality, recognizing that preconception health greatly influences the risk of an APO and lifetime cardiometabolic disease.

Adverse pregnancy outcomes

Major APOs include miscarriage, preterm birth (birth <37 weeks’ gestation), low birth weight (birth weight ≤2,500 g; 5.5 lb), gestational diabetes (GDM), preeclampsia, and placental abruption. In the United States, among all births, reported rates of the following APOs are:^1-3

• preterm birth, 10.2%
• low birth weight, 8.3%
• GDM, 6%
• preeclampsia, 5%
• placental abruption, 1%.

Miscarriage occurs in approximately 10% to 15% of pregnancies, influenced by both the age of the woman and the method used to diagnose pregnancy.⁴ Miscarriage, preterm birth, low birth weight, GDM, preeclampsia, and placental abruption have been reported to be associated with an increased risk of later cardiovascular morbidity and mortality.

APOs and cardiovascular disease

Cardiovascular disease (CVD) affects the majority of people past the age of 60 years and includes 4 major subcategories:

1. coronary heart disease, including myocardial infarction, angina, and heart failure
2. CVD, stroke, and transient ischemic attack
3. peripheral artery disease
4. atherosclerosis of the aorta leading to aortic aneurysm.

Multiple meta-analyses report that APOs are associated with CVD in later life. A comprehensive review reported that the risk of CVD was increased following a pregnancy with one of these APOs: severe preeclampsia (odds ratio [OR], 2.74), GDM (OR, 1.68), preterm birth (OR, 1.93), low birth weight (OR, 1.29), and placental abruption (OR, 1.82).⁵

The link between APOs and CVD may be explained in part by the association of APOs with multiple risk factors for CVD, including chronic hypertension, type 2 diabetes mellitus (T2DM), and dyslipidemia. A meta-analysis of 43 studies reported that, compared with controls, women with a history of preeclampsia have a 3.13 times greater risk of developing chronic hypertension.⁶ Among women with preeclampsia, approximately 20% will develop hypertension within 15 years.⁷ A meta-analysis of 20 studies reported that women with a history of GDM had a 9.51-times greater risk of developing T2DM than women without GDM.⁸ Among women with a history of GDM, over 16 years of follow-up, T2DM was diagnosed in 16.2%, compared with 1.9% of control women.⁸

CVD prevention—Breastfeeding: An antidote for APOs

Pregnancy stresses both the cardiovascular and metabolic systems. Breastfeeding is an antidote to the stresses imposed by pregnancy. Breastfeeding women have lower blood glucose⁹ and blood pressure.¹⁰

Breastfeeding reduces the risk of CVD. In a study of 100,864 parous Australian women, with a mean age of 60 years, ever breastfeeding was associated a lower risk of CVD hospitalization (adjusted hazard ratio [aHR], 0.86; 95% confidence interval [CI], 0.78–0.96; P = .005) and CVD mortality (aHR, 0.66; 95% CI, 0.49–0.89; P = .006).¹¹
 

Continue to: CVD prevention—American Heart Association recommendations...

CVD prevention—American Heart Association recommendations

The American Heart Association¹² recommends lifestyle interventions to reduce the risk of CVD, including:

• Eat a high-quality diet that includes vegetables, fruit, whole grains, beans, legumes, nuts, plant-based protein, lean animal protein, and fish.
• Limit intake of sugary drinks and foods, fatty or processed meats, full-fat dairy products, eggs, highly processed foods, and tropical oils.
• Exercise at least 150 minutes weekly at a moderate activity level, including muscle-strengthening activity.
• Reduce prolonged intervals of sitting.
• Live a tobacco- and nicotine-free life.
• Strive to maintain a normal body mass index.
• Consider using an activity tracker to monitor activity level.
• After 40 years of age calculate CVD risk using a validated calculator such as the American Cardiology Association risk calculator.¹³ This calculator uses age, gender, and lipid and blood pressure measurements to calculate the 10-year risk of atherosclerotic CVD, including coronary death, myocardial infarction, and stroke.

Medications to reduce CVD risk

Historically, ObGyns have not routinely prescribed medications to treat hypertension, dyslipidemia, or to prevent diabetes. The recent increase in the valuation of return ambulatory visits and a reduction in the valuation assigned to procedural care may provide ObGyn practices the additional resources needed to manage some chronic diseases. Physician assistants and nurse practitioners may help ObGyn practices to manage hypertension, dyslipidemia, and prediabetes.

Prior to initiating a medicine, counseling about healthy living, including smoking cessation, exercise, heart-healthy diet, and achieving an optimal body mass index is warranted.

For treatment of stage II hypertension, defined as blood pressure (BP) measurements with systolic BP ≥140 mm Hg and diastolic BP ≥90 mm Hg, therapeutic lifestyle interventions include: optimizing weight, following the DASH diet, restricting dietary sodium, physical activity, and reducing alcohol consumption. Medication treatment for essential hypertension is guided by the magnitude of BP reduction needed to achieve normotension. For women with hypertension needing antihypertensive medication and planning another pregnancy in the near future, labetalol or extended-release nifedipine may be first-line medications. For women who have completed their families or who have no immediate plans for pregnancy, an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide diuretic are commonly prescribed.¹⁴

For the treatment of elevated low-density lipoprotein (LDL) cholesterol in women who have not had a cardiovascular event, statin therapy is often warranted when both the LDL cholesterol is >100 mg/dL and the woman has a calculated 10-year risk of >10% for a cardiovascular event using the American Heart Association or American College of Cardiology calculator. Most women who meet these criteria will be older than age 40 years and many will be under the care of an internal medicine or family medicine specialist, limiting the role of the ObGyn.^15-17

For prevention of diabetes in women with a history of GDM, both weight loss and metformin (1,750 mg daily) have been shown in clinical trials to reduce the risk of developing T2DM.¹⁸ Among 350 women with a history of GDM who were followed for 10 years, metformin 850 mg twice daily reduced the risk of developing T2DM by 40% compared with placebo.¹⁹ In the same study, lifestyle changes without metformin, including loss of 7% of body weight plus 150 minutes of exercise weekly was associated with a 35% reduction in the risk of developing T2DM.¹⁹ Metformin is one of the least expensive prescription medications and is cost-effective for the prevention of T2DM.¹⁸

Low-dose aspirin treatment for the prevention of CVD in women who have not had a cardiovascular event must balance a modest reduction in cardiovascular events with a small increased risk of bleeding events. The US Preventive Services Task Force (USPSTF) recommends low-dose aspirin for a limited group of women, those aged 50 to 59 years of age with a 10-year risk of a cardiovascular event >10% who are willing to take aspirin for 10 years. The USPSTF concluded that there is insufficient evidence to recommend low-dose aspirin prevention of CVD in women aged <50 years.²⁰

Continue to: Beyond the fourth trimester...

Beyond the fourth trimester

The fourth trimester is the 12-week period following birth. At the comprehensive postpartum visit, the American College of Obstetricians and Gynecologists (ACOG) recommends that women with APOs be counseled about their increased lifetime risk of maternal cardiometabolic disease.²¹ In addition, ACOG recommends that at this visit the clinician who will assume primary responsibility for the woman’s ongoing medical care in her primary medical home be clarified. One option is to ensure a high-quality hand-off to an internal medicine or family medicine clinician. Another option is for a clinician in the ObGyn’s office practice, including a physician assistant, nurse practitioner, or office-based ObGyn, to assume some role in the primary care of the woman.

An APO is not only a pregnancy problem

An APO reverberates across a woman’s lifetime, increasing the risk of CVD and diabetes. In the United States the mean age at first birth is 27 years.¹ The mean life expectancy of US women is 81 years.²² Following a birth complicated by an APO there are 5 decades of opportunity to improve health through lifestyle changes and medication treatment of obesity, hypertension, dyslipidemia, and hyperglycemia, thereby reducing the risk of CVD.

Preconception health influences pregnancy outcomes, and in turn, both preconception health and an APO influence adult cardiometabolic health (FIGURE). This editorial is focused on the link between APOs and later cardiometabolic morbidity and mortality, recognizing that preconception health greatly influences the risk of an APO and lifetime cardiometabolic disease.

Adverse pregnancy outcomes

Major APOs include miscarriage, preterm birth (birth <37 weeks’ gestation), low birth weight (birth weight ≤2,500 g; 5.5 lb), gestational diabetes (GDM), preeclampsia, and placental abruption. In the United States, among all births, reported rates of the following APOs are:^1-3

• preterm birth, 10.2%
• low birth weight, 8.3%
• GDM, 6%
• preeclampsia, 5%
• placental abruption, 1%.

Miscarriage occurs in approximately 10% to 15% of pregnancies, influenced by both the age of the woman and the method used to diagnose pregnancy.⁴ Miscarriage, preterm birth, low birth weight, GDM, preeclampsia, and placental abruption have been reported to be associated with an increased risk of later cardiovascular morbidity and mortality.

APOs and cardiovascular disease

Cardiovascular disease (CVD) affects the majority of people past the age of 60 years and includes 4 major subcategories:

1. coronary heart disease, including myocardial infarction, angina, and heart failure
2. CVD, stroke, and transient ischemic attack
3. peripheral artery disease
4. atherosclerosis of the aorta leading to aortic aneurysm.

Multiple meta-analyses report that APOs are associated with CVD in later life. A comprehensive review reported that the risk of CVD was increased following a pregnancy with one of these APOs: severe preeclampsia (odds ratio [OR], 2.74), GDM (OR, 1.68), preterm birth (OR, 1.93), low birth weight (OR, 1.29), and placental abruption (OR, 1.82).⁵

The link between APOs and CVD may be explained in part by the association of APOs with multiple risk factors for CVD, including chronic hypertension, type 2 diabetes mellitus (T2DM), and dyslipidemia. A meta-analysis of 43 studies reported that, compared with controls, women with a history of preeclampsia have a 3.13 times greater risk of developing chronic hypertension.⁶ Among women with preeclampsia, approximately 20% will develop hypertension within 15 years.⁷ A meta-analysis of 20 studies reported that women with a history of GDM had a 9.51-times greater risk of developing T2DM than women without GDM.⁸ Among women with a history of GDM, over 16 years of follow-up, T2DM was diagnosed in 16.2%, compared with 1.9% of control women.⁸

CVD prevention—Breastfeeding: An antidote for APOs

Pregnancy stresses both the cardiovascular and metabolic systems. Breastfeeding is an antidote to the stresses imposed by pregnancy. Breastfeeding women have lower blood glucose⁹ and blood pressure.¹⁰

Breastfeeding reduces the risk of CVD. In a study of 100,864 parous Australian women, with a mean age of 60 years, ever breastfeeding was associated a lower risk of CVD hospitalization (adjusted hazard ratio [aHR], 0.86; 95% confidence interval [CI], 0.78–0.96; P = .005) and CVD mortality (aHR, 0.66; 95% CI, 0.49–0.89; P = .006).¹¹
 

Continue to: CVD prevention—American Heart Association recommendations...

CVD prevention—American Heart Association recommendations

The American Heart Association¹² recommends lifestyle interventions to reduce the risk of CVD, including:

• Eat a high-quality diet that includes vegetables, fruit, whole grains, beans, legumes, nuts, plant-based protein, lean animal protein, and fish.
• Limit intake of sugary drinks and foods, fatty or processed meats, full-fat dairy products, eggs, highly processed foods, and tropical oils.
• Exercise at least 150 minutes weekly at a moderate activity level, including muscle-strengthening activity.
• Reduce prolonged intervals of sitting.
• Live a tobacco- and nicotine-free life.
• Strive to maintain a normal body mass index.
• Consider using an activity tracker to monitor activity level.
• After 40 years of age calculate CVD risk using a validated calculator such as the American Cardiology Association risk calculator.¹³ This calculator uses age, gender, and lipid and blood pressure measurements to calculate the 10-year risk of atherosclerotic CVD, including coronary death, myocardial infarction, and stroke.

Medications to reduce CVD risk

Historically, ObGyns have not routinely prescribed medications to treat hypertension, dyslipidemia, or to prevent diabetes. The recent increase in the valuation of return ambulatory visits and a reduction in the valuation assigned to procedural care may provide ObGyn practices the additional resources needed to manage some chronic diseases. Physician assistants and nurse practitioners may help ObGyn practices to manage hypertension, dyslipidemia, and prediabetes.

Prior to initiating a medicine, counseling about healthy living, including smoking cessation, exercise, heart-healthy diet, and achieving an optimal body mass index is warranted.

For treatment of stage II hypertension, defined as blood pressure (BP) measurements with systolic BP ≥140 mm Hg and diastolic BP ≥90 mm Hg, therapeutic lifestyle interventions include: optimizing weight, following the DASH diet, restricting dietary sodium, physical activity, and reducing alcohol consumption. Medication treatment for essential hypertension is guided by the magnitude of BP reduction needed to achieve normotension. For women with hypertension needing antihypertensive medication and planning another pregnancy in the near future, labetalol or extended-release nifedipine may be first-line medications. For women who have completed their families or who have no immediate plans for pregnancy, an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide diuretic are commonly prescribed.¹⁴

For the treatment of elevated low-density lipoprotein (LDL) cholesterol in women who have not had a cardiovascular event, statin therapy is often warranted when both the LDL cholesterol is >100 mg/dL and the woman has a calculated 10-year risk of >10% for a cardiovascular event using the American Heart Association or American College of Cardiology calculator. Most women who meet these criteria will be older than age 40 years and many will be under the care of an internal medicine or family medicine specialist, limiting the role of the ObGyn.^15-17

For prevention of diabetes in women with a history of GDM, both weight loss and metformin (1,750 mg daily) have been shown in clinical trials to reduce the risk of developing T2DM.¹⁸ Among 350 women with a history of GDM who were followed for 10 years, metformin 850 mg twice daily reduced the risk of developing T2DM by 40% compared with placebo.¹⁹ In the same study, lifestyle changes without metformin, including loss of 7% of body weight plus 150 minutes of exercise weekly was associated with a 35% reduction in the risk of developing T2DM.¹⁹ Metformin is one of the least expensive prescription medications and is cost-effective for the prevention of T2DM.¹⁸

Low-dose aspirin treatment for the prevention of CVD in women who have not had a cardiovascular event must balance a modest reduction in cardiovascular events with a small increased risk of bleeding events. The US Preventive Services Task Force (USPSTF) recommends low-dose aspirin for a limited group of women, those aged 50 to 59 years of age with a 10-year risk of a cardiovascular event >10% who are willing to take aspirin for 10 years. The USPSTF concluded that there is insufficient evidence to recommend low-dose aspirin prevention of CVD in women aged <50 years.²⁰

Continue to: Beyond the fourth trimester...

Beyond the fourth trimester

The fourth trimester is the 12-week period following birth. At the comprehensive postpartum visit, the American College of Obstetricians and Gynecologists (ACOG) recommends that women with APOs be counseled about their increased lifetime risk of maternal cardiometabolic disease.²¹ In addition, ACOG recommends that at this visit the clinician who will assume primary responsibility for the woman’s ongoing medical care in her primary medical home be clarified. One option is to ensure a high-quality hand-off to an internal medicine or family medicine clinician. Another option is for a clinician in the ObGyn’s office practice, including a physician assistant, nurse practitioner, or office-based ObGyn, to assume some role in the primary care of the woman.

An APO is not only a pregnancy problem

An APO reverberates across a woman’s lifetime, increasing the risk of CVD and diabetes. In the United States the mean age at first birth is 27 years.¹ The mean life expectancy of US women is 81 years.²² Following a birth complicated by an APO there are 5 decades of opportunity to improve health through lifestyle changes and medication treatment of obesity, hypertension, dyslipidemia, and hyperglycemia, thereby reducing the risk of CVD.

Each clinician has had to develop his or her individual approach and follow their institutional guidance regarding counseling and managing all of their patients’ expectations in this quickly changing climate of vaccination availability and recommendations. For pregnant women specifically, who are at increased risk for severe SARS-COV-2 disease,¹ the availability of varied types of vaccines for COVID-19 is promising, but with limited data available to discuss safety for the mother and the baby, what is the best discussion to guide decision making? OBG Management reached out to several experts, who share here what they do in their practices.

Addressing an uncharted front in the war on COVID-19

Ashley S. Roman, MD, MPH

In December 2020, the US Food and Drug Administration (FDA)’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.² Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.³ Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.⁴ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^5,6

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• the presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes
• potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• the ability to take precautions (social distancing, wearing a mask, etc).

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

Continue to: Benefits outweigh the risks, for now...

Benefits outweigh the risks, for now

Ashley S. Coggins, MD, and Jeanne S. Sheffield, MD

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.⁷ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life.

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers— and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.⁸

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the FDA are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention (CDC)’s V-safe Vaccine Pregnancy Registry.⁹ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.¹⁰ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices. These organizations advise that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered. As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Each clinician has had to develop his or her individual approach and follow their institutional guidance regarding counseling and managing all of their patients’ expectations in this quickly changing climate of vaccination availability and recommendations. For pregnant women specifically, who are at increased risk for severe SARS-COV-2 disease,¹ the availability of varied types of vaccines for COVID-19 is promising, but with limited data available to discuss safety for the mother and the baby, what is the best discussion to guide decision making? OBG Management reached out to several experts, who share here what they do in their practices.

Addressing an uncharted front in the war on COVID-19

Ashley S. Roman, MD, MPH

In December 2020, the US Food and Drug Administration (FDA)’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.² Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.³ Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.⁴ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^5,6

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• the presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes
• potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• the ability to take precautions (social distancing, wearing a mask, etc).

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

Continue to: Benefits outweigh the risks, for now...

Benefits outweigh the risks, for now

Ashley S. Coggins, MD, and Jeanne S. Sheffield, MD

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.⁷ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life.

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers— and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.⁸

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the FDA are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention (CDC)’s V-safe Vaccine Pregnancy Registry.⁹ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.¹⁰ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices. These organizations advise that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered. As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Each clinician has had to develop his or her individual approach and follow their institutional guidance regarding counseling and managing all of their patients’ expectations in this quickly changing climate of vaccination availability and recommendations. For pregnant women specifically, who are at increased risk for severe SARS-COV-2 disease,¹ the availability of varied types of vaccines for COVID-19 is promising, but with limited data available to discuss safety for the mother and the baby, what is the best discussion to guide decision making? OBG Management reached out to several experts, who share here what they do in their practices.

Addressing an uncharted front in the war on COVID-19

Ashley S. Roman, MD, MPH

In December 2020, the US Food and Drug Administration (FDA)’s Emergency Use Authorization of the first COVID-19 vaccine presented us with a new tactic in the war against SARS-COV-2—and a new dilemma for obstetricians. What we had learned about COVID-19 infection in pregnancy by that point was alarming. While the vast majority (>90%) of pregnant women who contract COVID-19 recover without requiring hospitalization, pregnant women are at increased risk for severe illness and mechanical ventilation when compared with their nonpregnant counterparts.² Vertical transmission to the fetus is a rare event, but the increased risk of preterm birth, miscarriage, and preeclampsia makes the fetus a second victim in many cases.³ Moreover, much is still unknown about the long-term impact of severe illness on maternal and fetal health.

Gaining vaccine approval

The COVID-19 vaccine, with its high efficacy rates in the nonpregnant adult population, presents an opportunity to reduce maternal morbidity related to this devastating illness. But unlike other vaccines, such as the flu shot and TDAP, results from prospective studies on COVID-19 vaccination of expectant women are pending. Under the best of circumstances, gaining acceptance of any vaccine during pregnancy faces barriers such as vaccine hesitancy and a general concern from pregnant women about the effect of medical interventions on the fetus. There is no reason to expect that either the mRNA vaccines or the replication-incompetent adenovirus recombinant vector vaccine could cause harm to the developing fetus, but the fact that currently available COVID-19 vaccines use newer technologies complicates the decision for many women.

Nevertheless, what we do know now is much more than we did in December, particularly when it comes to the mRNA vaccines. To date, observational studies of women who received the mRNA vaccine in pregnancy have shown no increased risk of adverse maternal, fetal, or obstetric outcomes.⁴ Emerging data also indicate that antibodies to the SARS-CoV-2 spike protein—the target of all 3 vaccines—is present in cord blood, potentially protecting the infant in the first months of life from contracting COVID-19 if the mother receives the vaccine during pregnancy.^5,6

Our approach to counseling

How can we best help our patients navigate the risks and benefits of the COVID-19 vaccine? First, by acknowledging the obvious: We are in the midst of a pandemic with high rates of community spread, which makes COVID-19 different from any other vaccine-preventable disease at this time. Providing patients with a structure for making an educated decision is essential, taking into account (1) what we know about COVID-19 infection during pregnancy, (2) what we know about vaccine efficacy and safety to date, and (3) individual factors such as:

• the presence of comorbidities such as obesity, heart disease, respiratory disease, and diabetes
• potential exposures—“Do you have children in school or daycare? Do childcare providers or other workers come to your home? What is your occupation?”
• the ability to take precautions (social distancing, wearing a mask, etc).

All things considered, the decision to accept the COVID-19 vaccine or not ultimately belongs to the patient. Given disease prevalence and the latest information on vaccine safety in pregnancy, I have been advising my patients in the second trimester or beyond to receive the vaccine with the caveat that delaying the vaccine until the postpartum period is a completely valid alternative. The most important gift we can offer our patients is to arm them with the necessary information so that they can make the choice best for them and their family as we continue to fight this war on COVID-19.

Continue to: Benefits outweigh the risks, for now...

Benefits outweigh the risks, for now

Ashley S. Coggins, MD, and Jeanne S. Sheffield, MD

Vaccines have been a lifesaving public health measure since 1000 CE, when the Chinese first used smallpox inoculations to induce immunity.⁷ Work by pioneers such as Edward Jenner, Louis Pasteur, and Maurice Hilleman has averted countless millions of vaccine-preventable illnesses and deaths, and vaccines have become a routine part of health maintenance throughout the human life cycle.

Pregnant patients who receive vaccines often have an added benefit of protection provided to their infants through passive transfer of antibodies. Several vaccine platforms have been utilized in pregnancy with well-documented improvements in maternal and obstetric outcomes as well as improved neonatal outcomes in the first several months of life.

Risks of COVID-19 in pregnancy

The COVID-19 pandemic placed a spotlight on medically at-risk groups. Pregnant women are 3 times more likely to require admission to the intensive care unit, have increased requirement for extracorporeal membrane oxygenation treatment, and are up to 70% more likely to die than nonpregnant peers— and this risk increases with the presence of additional comorbidities.

In the case of COVID-19, vaccination trials that have shaped worldwide clinical practice unfortunately followed the historical trend of excluding pregnant patients from participation. This has required clinicians to guide their patients through the decision of whether or not to accept vaccination without having the same reassurances regarding safety and effectiveness afforded to their nonpregnant counterparts. With more than 86,000 pregnant women infected with COVID-19 through April 19, 2021, this lack of information regarding vaccine safety in pregnancy is a significant public health gap.⁸

COVID-19 vaccines

The current COVID-19 vaccines approved for use in the United States under an Emergency Use Authorization issued by the FDA are nonreplicating and thus cannot cause infection in the mother or fetus. These are the Pfizer-BioNTech mRNA vaccine, the Moderna mRNA-1273 vaccine, and the Janssen Biotech Inc. monovalent vaccine. Furthermore, in animal studies that included the Pfizer-BioNTech, Moderna, or Janssen COVID-19 vaccines, no fetal, embryonal, female reproductive, or postnatal development safety concerns were demonstrated.

As of April 19, 2021, 94,335 pregnant women had received a COVID-19 vaccination, and 4,622 of these enrolled in the Centers for Disease Control and Prevention (CDC)’s V-safe Vaccine Pregnancy Registry.⁹ The data reported noted no unexpected pregnancy or infant outcomes related to COVID-19 vaccination in pregnancy. Adverse effects of the vaccine were similar to those in nonpregnant cohorts. Additionally, emerging data suggest passage of immunity to neonates, with maternal antibodies demonstrated in cord blood at time of delivery as well as in breast milk.¹⁰ To date, these data mainly have come from women immunized with the Moderna and Pfizer-BioNTech mRNA vaccines.

Counseling pregnant patients

Our counseling aligns with that of the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC’s Advisory Committee on Immunization Practices. These organizations advise that COVID-19 vaccination should not be withheld from pregnant patients or patients who want to become pregnant. In pregnant patients with comorbidities that place them at higher risk for severe COVID-19 infection, all available formulations of the COVID-19 vaccination should be strongly considered. As evidence for vaccination safety continues to emerge, patients should continue to discuss their individual needs for vaccination in a shared decision-making format with their obstetric providers.

Patients with a disorder of consciousness (DoC) following a moderate to severe traumatic brain injury (TBI) often regain consciousness and even functional independence during rehabilitation, according to a study of 3 decades of TBI survivors.

“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.

To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).

Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).

Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
 

When it comes to TBI patients, don’t give up hope

The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.

“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.

That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?

“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
 

Patience is a virtue for TBI specialists

“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”

“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”

She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.

“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”

The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”

The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.

Patients with a disorder of consciousness (DoC) following a moderate to severe traumatic brain injury (TBI) often regain consciousness and even functional independence during rehabilitation, according to a study of 3 decades of TBI survivors.

“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.

To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).

Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).

Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
 

When it comes to TBI patients, don’t give up hope

The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.

“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.

That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?

“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
 

Patience is a virtue for TBI specialists

“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”

“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”

She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.

“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”

The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”

The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.

Patients with a disorder of consciousness (DoC) following a moderate to severe traumatic brain injury (TBI) often regain consciousness and even functional independence during rehabilitation, according to a study of 3 decades of TBI survivors.

“Caution is warranted in consideration of withdrawing or withholding life-sustaining therapies in patients with severe TBI and DoC,” wrote Robert G. Kowalski, MBBCh, MS, of the department of neurology at the University of Colorado at Denver, Aurora, and colleagues. The study was published in JAMA Neurology.

To determine the likelihood of returning to consciousness in the weeks that follow a serious brain injury, along with any notable contributing factors, the researchers launched a retrospective analysis of 17,470 patients with moderate to severe TBI. All participants had been enrolled in the Traumatic Brain Injury Model Systems database from January 1989 to June 2019 after being admitted to any 1 of 23 inpatient rehabilitation centers. The cohort had a median age of 39 (interquartile range, 25-56), with 74% being male and 66% being white. Their median duration of acute hospital care was 16 days (IQR, 9-26).

Unconsciousness was defined by the researchers as not being able to follow commands or having a Glasgow Coma Scale motor score in the ED of lower than 6 or a Disability Rating Scale motor score greater than 0. Of the overall cohort, 7,547 (57%) patients initially lost consciousness and 2,058 (12%) remained unconscious as they were admitted to rehab. Of that subgroup, 1,674 (82%) recovered consciousness during rehab. The 414 patients who still had a DoC at completion of rehab had a longer median stay (37 days; IQR, 22-65), compared with the patients who recovered consciousness (19 days; IQR, 12-30; P < .001). After multivariable analysis, the factors most associated with recovery of consciousness were the absence of intraventricular hemorrhage (adjusted odds ratio, 0.678; 95% confidence interval, 0.532-0.863; P = .002) and the absence of intracranial mass effect (aOR, 0.759; 95% CI, 0.595-0.968; P = .03).

Though all patients experienced an improvement in functional status during rehabilitation, patients with DoC had an increase in median Functional Independence Measure total score from 19 to 71 while patients without DoC increased from 54 to 96 (change in total score, +43 versus +37; P = .002). After multivariate analysis, younger age and male sex were both associated with better functional outcomes during rehab and at discharge.
 

When it comes to TBI patients, don’t give up hope

The choice to withdraw care in TBI patients is a complicated and daunting one, and this study is further evidence that physicians should delay that decision in many scenarios, wrote Jennifer A. Kim, MD, PhD, and Kevin N. Sheth, MD, of Yale University, New Haven, Conn., in an accompanying editorial.

“By showing that a large proportion of patients with persistent DoC recover during acute rehabilitation, this article further challenges our potential toward overly nihilistic notions of who may or may not ultimately recover consciousness long term,” they added.

That said, they also recognized the questions that still persist: What are the reasons for late-stage withdrawal of lifesaving therapy? What is the recovery rate of all hospitalized patients with TBI, not just those in rehabilitation facilities? And is it possible to detect covert consciousness using MRI and electroencephalography, which this study did not include?

“Defining both good and poor prognostic risk factors is critical to portending recovery,” they wrote, emphasizing the need for physicians to rely on scientifically based predictions when making such important assessments.
 

Patience is a virtue for TBI specialists

“A lot of people write notes on hospital charts, ‘poor prognosis.’ You don’t know, that early in the game, in the acute care setting, how TBI patients are going to do,” said Jamie S. Ullman, MD, of the department of neurosurgery at Hofstra University, Hempstead, N.Y., in an interview. “It’s over the long term that we really have to judge that.”

“Of course, there may be some characteristics that patients might have that may portend for a worse outcome, like brain stem damage,” she added. “But in general, there is plenty of literature to suggest that not only can even the worst-looking patients have some kind of functional outcome but that it takes 18 months or more to actually realize an outcome from a traumatic brain injury.”

She emphasized that each patient with TBI is unique; beyond their current status, you have to consider the significance of their injury, the thoughts of their families or partner, and their own previously stated wishes and willingness to tolerate disability. Nonetheless, this study is another step toward distilling the “nihilistic thinking” that can lead physicians to expect the worst regarding patients who may still have a path toward a functional life.

“As traumatic brain injury specialists,” she said, “we need to see what we can do to give patients as good a chance as possible at a recovery.”

The authors acknowledged their study’s limitations, including an inability to account for 3 decades of variations in treatment regimens and its limited generalizability because of the cohort being composed of only TBI survivors admitted to inpatient rehab. In addition, they noted a possible referential bias for the study’s mostly young TBI patients in rehab facilities, another reason why these findings “may not be directly applicable to the overall population of patients with moderate or severe TBI.”

The study was funded by grants from the National Institute on Disability, Independent Living, and Rehabilitation Research; the Department of Health & Human Services; and the Veterans Health Administration Central Office VA TBI Model Systems Program of Research. The authors reported several potential conflicts of interest, including receiving grants and support from various government agencies and pharmaceutical companies.

Imagine this scenario: You are seated at the dinner table with your family when your smartphone buzzes; you look over, and the push notification reads “new biopsy results!”

PxHere

There is a sudden spill of icy anxiety down your spine as you pick up your phone in your shaking hands. It’s 6 p.m.; your doctor’s office is closed. You open the message, and your worst fears are confirmed ... the cancer is back.

Or is it? You’re not sure. The biopsy sure sounds bad. But you’re an English teacher, not a doctor, and you spend the rest of the night Googling words like “tubulovillous” and “high-grade dysplasia.” You sit awake, terrified in front of the computer screen desperately trying to make sense of the possibly life-changing results. You wish you knew someone who could help you understand; you consider calling your doctor’s emergency line, or your cousin who is an ophthalmologist – anybody who can help you make sense of the results.

Or imagine another scenario: you’re a trans teen who has asked your doctor to refer to you by your preferred pronouns. You’re still presenting as your birth sex, in part because your family would disown you if they knew, and you’re not financially or emotionally ready for that step. You feel proud of yourself for advocating for your needs to your long-time physician, and excited about the resources they’ve included in your after visit summary and the referrals they’d made to gender-confirming specialists.

When you get home, you are confronted with a terrible reality that your doctor’s notes, orders, and recommendations are immediately viewable to anybody with your MyChart login – your parents knew the second your doctor signed the note. They received the notification, logged on as your guardians, and you have effectively been “outed” by the physician who took and oath to care for you and who you trusted implicitly.
 

How the Cures Act is affecting patients

While these examples may sound extreme, they are becoming more and more commonplace thanks to a recently enacted 21st Century Cures Act. The act was originally written to improve communication between physicians and patients. Part of the act stipulates that nearly all medical information – from notes to biopsies to lab results – must be available within 24 hours, published to a patient portal and a notification be sent to the patient by phone.

Oftentimes, this occurs before the ordering physician has even seen the results, much less interpreted them and made a plan for the patient. What happens now, not long after its enactment date, when it has become clear that the Cures Act is causing extreme harm to our patients?

Take, for example, the real example of a physician whose patient found out about her own intrauterine fetal demise by way of an EMR text message alert of “new imaging results!” sent directly to her phone. Or a physician colleague who witnessed firsthand the intrusive unhelpfulness of the Cures Act when she was informed via patient portal releasing her imaging information that she had a large, possibly malignant breast mass. “No phone call,” she said. “No human being for questions or comfort. Just a notification on my phone.”

The stories about the impact of the Cures Act across the medical community are an endless stream of anxiety, hurt, and broken trust. The relationship between a physician and a patient should be sacred, bolstered by communication and mutual respect.

In many ways, the new act feels like a third party to the patient-physician relationship – a digital imposter, oftentimes blurting out personal and life-altering medical information without any of the finesse, context, and perspective of an experienced physician.
 

Breaking ‘bad news’ to a patient

In training, some residents are taught how to “break bad news” to a patient. Some good practices for doing this are to have information available for the patient, provide emotional support, have a plan for their next steps already formulated, and call the appropriate specialist ahead of time if you can.

Above all, it’s most important to let the patient be the one to direct their own care. Give them time to ask questions and answer them honestly and clearly. Ask them how much they want to know and help them to understand the complex change in their usual state of health.

Now, unless physicians are keeping a very close eye on their inbox, results are slipping out to patients in a void. The bad news conversations aren’t happening at all, or if they are, they’re happening at 8 p.m. on a phone call after an exhausted physician ends their shift but has to slog through their results bin, calling all the patients who shouldn’t have to find out their results in solitude.

Reaching out to these patients immediately is an honorable, kind thing to, but for a physician, knowing they need to beat the patient to opening an email creates anxiety. Plus, making these calls at whatever hour the results are released to a patient is another burden added to doctors’ already-full plates.
 

Interpreting results

None of us want to harm our patients. All of us want to be there for them. But this act stands in the way of delivering quality, humanizing medical care.

It is true that patients have a right to access their own medical information. It is also true that waiting anxiously on results can cause undue harm to a patient. But the across-the-board, breakneck speed of information release mandated in this act causes irreparable harm not only to patients, but to the patient-physician relationship.

No patient should find out their cancer recurred while checking their emails at their desk. No patient should first learn of a life-altering diagnosis by way of scrolling through their smartphone in bed. The role of a physician is more than just a healer – we should also be educators, interpreters, partners and, first and foremost, advocates for our patients’ needs.

Our patients are depending on us to stand up and speak out about necessary changes to this act. Result releases should be delayed until they are viewed by a physician. Our patients deserve the dignity and opportunity of a conversation with their medical provider about their test results, and physicians deserve the chance to interpret results and frame the conversation in a way which is conducive to patient understanding and healing.

Dr. Persampiere is a first-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece. You can contact them at [email protected].

Imagine this scenario: You are seated at the dinner table with your family when your smartphone buzzes; you look over, and the push notification reads “new biopsy results!”

PxHere

There is a sudden spill of icy anxiety down your spine as you pick up your phone in your shaking hands. It’s 6 p.m.; your doctor’s office is closed. You open the message, and your worst fears are confirmed ... the cancer is back.

Or is it? You’re not sure. The biopsy sure sounds bad. But you’re an English teacher, not a doctor, and you spend the rest of the night Googling words like “tubulovillous” and “high-grade dysplasia.” You sit awake, terrified in front of the computer screen desperately trying to make sense of the possibly life-changing results. You wish you knew someone who could help you understand; you consider calling your doctor’s emergency line, or your cousin who is an ophthalmologist – anybody who can help you make sense of the results.

Or imagine another scenario: you’re a trans teen who has asked your doctor to refer to you by your preferred pronouns. You’re still presenting as your birth sex, in part because your family would disown you if they knew, and you’re not financially or emotionally ready for that step. You feel proud of yourself for advocating for your needs to your long-time physician, and excited about the resources they’ve included in your after visit summary and the referrals they’d made to gender-confirming specialists.

When you get home, you are confronted with a terrible reality that your doctor’s notes, orders, and recommendations are immediately viewable to anybody with your MyChart login – your parents knew the second your doctor signed the note. They received the notification, logged on as your guardians, and you have effectively been “outed” by the physician who took and oath to care for you and who you trusted implicitly.
 

How the Cures Act is affecting patients

While these examples may sound extreme, they are becoming more and more commonplace thanks to a recently enacted 21st Century Cures Act. The act was originally written to improve communication between physicians and patients. Part of the act stipulates that nearly all medical information – from notes to biopsies to lab results – must be available within 24 hours, published to a patient portal and a notification be sent to the patient by phone.

Oftentimes, this occurs before the ordering physician has even seen the results, much less interpreted them and made a plan for the patient. What happens now, not long after its enactment date, when it has become clear that the Cures Act is causing extreme harm to our patients?

Take, for example, the real example of a physician whose patient found out about her own intrauterine fetal demise by way of an EMR text message alert of “new imaging results!” sent directly to her phone. Or a physician colleague who witnessed firsthand the intrusive unhelpfulness of the Cures Act when she was informed via patient portal releasing her imaging information that she had a large, possibly malignant breast mass. “No phone call,” she said. “No human being for questions or comfort. Just a notification on my phone.”

The stories about the impact of the Cures Act across the medical community are an endless stream of anxiety, hurt, and broken trust. The relationship between a physician and a patient should be sacred, bolstered by communication and mutual respect.

In many ways, the new act feels like a third party to the patient-physician relationship – a digital imposter, oftentimes blurting out personal and life-altering medical information without any of the finesse, context, and perspective of an experienced physician.
 

Breaking ‘bad news’ to a patient

In training, some residents are taught how to “break bad news” to a patient. Some good practices for doing this are to have information available for the patient, provide emotional support, have a plan for their next steps already formulated, and call the appropriate specialist ahead of time if you can.

Above all, it’s most important to let the patient be the one to direct their own care. Give them time to ask questions and answer them honestly and clearly. Ask them how much they want to know and help them to understand the complex change in their usual state of health.

Now, unless physicians are keeping a very close eye on their inbox, results are slipping out to patients in a void. The bad news conversations aren’t happening at all, or if they are, they’re happening at 8 p.m. on a phone call after an exhausted physician ends their shift but has to slog through their results bin, calling all the patients who shouldn’t have to find out their results in solitude.

Reaching out to these patients immediately is an honorable, kind thing to, but for a physician, knowing they need to beat the patient to opening an email creates anxiety. Plus, making these calls at whatever hour the results are released to a patient is another burden added to doctors’ already-full plates.
 

Interpreting results

None of us want to harm our patients. All of us want to be there for them. But this act stands in the way of delivering quality, humanizing medical care.

It is true that patients have a right to access their own medical information. It is also true that waiting anxiously on results can cause undue harm to a patient. But the across-the-board, breakneck speed of information release mandated in this act causes irreparable harm not only to patients, but to the patient-physician relationship.

No patient should find out their cancer recurred while checking their emails at their desk. No patient should first learn of a life-altering diagnosis by way of scrolling through their smartphone in bed. The role of a physician is more than just a healer – we should also be educators, interpreters, partners and, first and foremost, advocates for our patients’ needs.

Our patients are depending on us to stand up and speak out about necessary changes to this act. Result releases should be delayed until they are viewed by a physician. Our patients deserve the dignity and opportunity of a conversation with their medical provider about their test results, and physicians deserve the chance to interpret results and frame the conversation in a way which is conducive to patient understanding and healing.

Dr. Persampiere is a first-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece. You can contact them at [email protected].

Imagine this scenario: You are seated at the dinner table with your family when your smartphone buzzes; you look over, and the push notification reads “new biopsy results!”

PxHere

There is a sudden spill of icy anxiety down your spine as you pick up your phone in your shaking hands. It’s 6 p.m.; your doctor’s office is closed. You open the message, and your worst fears are confirmed ... the cancer is back.

Or is it? You’re not sure. The biopsy sure sounds bad. But you’re an English teacher, not a doctor, and you spend the rest of the night Googling words like “tubulovillous” and “high-grade dysplasia.” You sit awake, terrified in front of the computer screen desperately trying to make sense of the possibly life-changing results. You wish you knew someone who could help you understand; you consider calling your doctor’s emergency line, or your cousin who is an ophthalmologist – anybody who can help you make sense of the results.

Or imagine another scenario: you’re a trans teen who has asked your doctor to refer to you by your preferred pronouns. You’re still presenting as your birth sex, in part because your family would disown you if they knew, and you’re not financially or emotionally ready for that step. You feel proud of yourself for advocating for your needs to your long-time physician, and excited about the resources they’ve included in your after visit summary and the referrals they’d made to gender-confirming specialists.

When you get home, you are confronted with a terrible reality that your doctor’s notes, orders, and recommendations are immediately viewable to anybody with your MyChart login – your parents knew the second your doctor signed the note. They received the notification, logged on as your guardians, and you have effectively been “outed” by the physician who took and oath to care for you and who you trusted implicitly.
 

How the Cures Act is affecting patients

While these examples may sound extreme, they are becoming more and more commonplace thanks to a recently enacted 21st Century Cures Act. The act was originally written to improve communication between physicians and patients. Part of the act stipulates that nearly all medical information – from notes to biopsies to lab results – must be available within 24 hours, published to a patient portal and a notification be sent to the patient by phone.

Oftentimes, this occurs before the ordering physician has even seen the results, much less interpreted them and made a plan for the patient. What happens now, not long after its enactment date, when it has become clear that the Cures Act is causing extreme harm to our patients?

Take, for example, the real example of a physician whose patient found out about her own intrauterine fetal demise by way of an EMR text message alert of “new imaging results!” sent directly to her phone. Or a physician colleague who witnessed firsthand the intrusive unhelpfulness of the Cures Act when she was informed via patient portal releasing her imaging information that she had a large, possibly malignant breast mass. “No phone call,” she said. “No human being for questions or comfort. Just a notification on my phone.”

The stories about the impact of the Cures Act across the medical community are an endless stream of anxiety, hurt, and broken trust. The relationship between a physician and a patient should be sacred, bolstered by communication and mutual respect.

In many ways, the new act feels like a third party to the patient-physician relationship – a digital imposter, oftentimes blurting out personal and life-altering medical information without any of the finesse, context, and perspective of an experienced physician.
 

Breaking ‘bad news’ to a patient

In training, some residents are taught how to “break bad news” to a patient. Some good practices for doing this are to have information available for the patient, provide emotional support, have a plan for their next steps already formulated, and call the appropriate specialist ahead of time if you can.

Above all, it’s most important to let the patient be the one to direct their own care. Give them time to ask questions and answer them honestly and clearly. Ask them how much they want to know and help them to understand the complex change in their usual state of health.

Now, unless physicians are keeping a very close eye on their inbox, results are slipping out to patients in a void. The bad news conversations aren’t happening at all, or if they are, they’re happening at 8 p.m. on a phone call after an exhausted physician ends their shift but has to slog through their results bin, calling all the patients who shouldn’t have to find out their results in solitude.

Reaching out to these patients immediately is an honorable, kind thing to, but for a physician, knowing they need to beat the patient to opening an email creates anxiety. Plus, making these calls at whatever hour the results are released to a patient is another burden added to doctors’ already-full plates.
 

Interpreting results

None of us want to harm our patients. All of us want to be there for them. But this act stands in the way of delivering quality, humanizing medical care.

It is true that patients have a right to access their own medical information. It is also true that waiting anxiously on results can cause undue harm to a patient. But the across-the-board, breakneck speed of information release mandated in this act causes irreparable harm not only to patients, but to the patient-physician relationship.

No patient should find out their cancer recurred while checking their emails at their desk. No patient should first learn of a life-altering diagnosis by way of scrolling through their smartphone in bed. The role of a physician is more than just a healer – we should also be educators, interpreters, partners and, first and foremost, advocates for our patients’ needs.

Our patients are depending on us to stand up and speak out about necessary changes to this act. Result releases should be delayed until they are viewed by a physician. Our patients deserve the dignity and opportunity of a conversation with their medical provider about their test results, and physicians deserve the chance to interpret results and frame the conversation in a way which is conducive to patient understanding and healing.

Dr. Persampiere is a first-year resident in the family medicine residency program at Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece. You can contact them at [email protected].

I’m not an academic. Never will be.

I’m also a crappy statistician. Neither my university nor medical school required statistics classes, so I never really learned them. In medicine you pick up an idea of how to interpret them as part of the job, but I’m certainly not a pro with numbers.

Which brings me to the word of the day, Aduhelm, AKA aducanumab.

A lot of drugs have come and gone in the 30 years since my medical school pharmacology class, but very few with this one’s degree of uncertainty.

Clearly its mechanism works: It removes amyloid from the brain. I don’t think anyone will argue that. But the real question is whether this translates into actual clinical benefit.

The water is murky here, and even its most ardent supporters admit the evidence isn’t exactly overwhelming. To some extent the approval basically puts it in a huge open-label clinical trial, with the Food and Drug Administration saying that it will be withdrawn if success isn’t seen in follow-up studies.

I’m not a statistics person, but I understand that, when numbers are marginal, they can be spun to mean whatever someone wants them to mean. And the stakes here, both medically and financially, are pretty high.

Alzheimer’s disease, unquestionably, is a devastating illness. The best treatments we have for it are modest at best. The demand for new treatments is huge.

But “new” doesn’t mean the same as “effective.” This is where the statistics, and their supporters and detractors, come in.

Patients and their families aren’t (usually) doctors. They want a treatment that’s both effective and reasonably safe, especially for a disease where a tragic prognosis is well established. With this drug (and similar ones in development) we face a balance between uncertain benefits and a clear risk of amyloid-related imaging abnormalities. The best we can do is explain these vagaries to people so they understand the uncertainties involved.

Perhaps more troubling is the possibility lurking in the background: The amyloid comes out, but the prognosis doesn’t improve. This brings us to the possibility (already voiced in journals) that the whole amyloid theory is wrong, and we’ve spent all this time and money chasing the wrong villain. As Morpheus, in The Matrix, implies, our whole reality on this may not be real.

Regrettably, in science (and medicine is a science) the only way to find out what works and what doesn’t is through trial and error. Computer modeling can take us only so far. Whether Aduhelm succeeds or fails will all be in the numbers.

But if it (and similar agents) fail in the general population, then it may be time to accept that we’re chasing the wrong bad guy.

That’s what data and statistics do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m not an academic. Never will be.

I’m also a crappy statistician. Neither my university nor medical school required statistics classes, so I never really learned them. In medicine you pick up an idea of how to interpret them as part of the job, but I’m certainly not a pro with numbers.

Which brings me to the word of the day, Aduhelm, AKA aducanumab.

A lot of drugs have come and gone in the 30 years since my medical school pharmacology class, but very few with this one’s degree of uncertainty.

Clearly its mechanism works: It removes amyloid from the brain. I don’t think anyone will argue that. But the real question is whether this translates into actual clinical benefit.

The water is murky here, and even its most ardent supporters admit the evidence isn’t exactly overwhelming. To some extent the approval basically puts it in a huge open-label clinical trial, with the Food and Drug Administration saying that it will be withdrawn if success isn’t seen in follow-up studies.

I’m not a statistics person, but I understand that, when numbers are marginal, they can be spun to mean whatever someone wants them to mean. And the stakes here, both medically and financially, are pretty high.

Alzheimer’s disease, unquestionably, is a devastating illness. The best treatments we have for it are modest at best. The demand for new treatments is huge.

But “new” doesn’t mean the same as “effective.” This is where the statistics, and their supporters and detractors, come in.

Patients and their families aren’t (usually) doctors. They want a treatment that’s both effective and reasonably safe, especially for a disease where a tragic prognosis is well established. With this drug (and similar ones in development) we face a balance between uncertain benefits and a clear risk of amyloid-related imaging abnormalities. The best we can do is explain these vagaries to people so they understand the uncertainties involved.

Perhaps more troubling is the possibility lurking in the background: The amyloid comes out, but the prognosis doesn’t improve. This brings us to the possibility (already voiced in journals) that the whole amyloid theory is wrong, and we’ve spent all this time and money chasing the wrong villain. As Morpheus, in The Matrix, implies, our whole reality on this may not be real.

Regrettably, in science (and medicine is a science) the only way to find out what works and what doesn’t is through trial and error. Computer modeling can take us only so far. Whether Aduhelm succeeds or fails will all be in the numbers.

But if it (and similar agents) fail in the general population, then it may be time to accept that we’re chasing the wrong bad guy.

That’s what data and statistics do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m not an academic. Never will be.

I’m also a crappy statistician. Neither my university nor medical school required statistics classes, so I never really learned them. In medicine you pick up an idea of how to interpret them as part of the job, but I’m certainly not a pro with numbers.

Which brings me to the word of the day, Aduhelm, AKA aducanumab.

A lot of drugs have come and gone in the 30 years since my medical school pharmacology class, but very few with this one’s degree of uncertainty.

Clearly its mechanism works: It removes amyloid from the brain. I don’t think anyone will argue that. But the real question is whether this translates into actual clinical benefit.

The water is murky here, and even its most ardent supporters admit the evidence isn’t exactly overwhelming. To some extent the approval basically puts it in a huge open-label clinical trial, with the Food and Drug Administration saying that it will be withdrawn if success isn’t seen in follow-up studies.

I’m not a statistics person, but I understand that, when numbers are marginal, they can be spun to mean whatever someone wants them to mean. And the stakes here, both medically and financially, are pretty high.

Alzheimer’s disease, unquestionably, is a devastating illness. The best treatments we have for it are modest at best. The demand for new treatments is huge.

But “new” doesn’t mean the same as “effective.” This is where the statistics, and their supporters and detractors, come in.

Patients and their families aren’t (usually) doctors. They want a treatment that’s both effective and reasonably safe, especially for a disease where a tragic prognosis is well established. With this drug (and similar ones in development) we face a balance between uncertain benefits and a clear risk of amyloid-related imaging abnormalities. The best we can do is explain these vagaries to people so they understand the uncertainties involved.

Perhaps more troubling is the possibility lurking in the background: The amyloid comes out, but the prognosis doesn’t improve. This brings us to the possibility (already voiced in journals) that the whole amyloid theory is wrong, and we’ve spent all this time and money chasing the wrong villain. As Morpheus, in The Matrix, implies, our whole reality on this may not be real.

Regrettably, in science (and medicine is a science) the only way to find out what works and what doesn’t is through trial and error. Computer modeling can take us only so far. Whether Aduhelm succeeds or fails will all be in the numbers.

But if it (and similar agents) fail in the general population, then it may be time to accept that we’re chasing the wrong bad guy.

That’s what data and statistics do.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.