Pulmonology

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Use of asthma medication by pregnant women was not associated with an increased risk of autism, attention-deficit/hyperactivity disorder, or Tourette syndrome for their children, a new study shows.

The drugs included in the study were leukotriene-receptor antagonists (LTRAs), which are often used to treat allergic airway diseases, including asthma and allergic rhinitis.

“Over the years, the U.S. Food and Drug Administration has monitored post-marketing data about the potential harm of neuropsychiatric events (NEs) associated with montelukast, the first type of LTRAs, and issued boxed warnings about serious mental health side effects for montelukast in 2020,” said corresponding author Tsung-Chieh Yao, MD, of Chang Gung Memorial Hospital, Taiwan, in an interview.

However, evidence of a link between NEs and LTRA use has been inconsistent, according to Dr. Yao and colleagues.

“To date, it remains totally unknown whether the exposure to LTRAs during pregnancy is associated with the risk of neuropsychiatric events in offspring,” said Dr. Yao.

To address this question, the researchers used data from National Health Insurance Research Database in Taiwan to identify pregnant women and their offspring from 2009 to 2019. The initial study population included 576,157 mother-offspring pairs, including 1,995 LTRA-exposed and 574,162 nonexposed children.

The women had a diagnosis of asthma or allergic rhinitis; multiple births and children with congenital malformations were excluded. LTRA exposure was defined as any dispensed prescription for LTRAs during pregnancy. Approximately two-thirds of the mothers were aged 30-40 years at the time of delivery.

The findings were published in a research letter in JAMA Network Open.

In the study population at large, the incidence of the three neurodevelopmental disorders ADHD, autism spectrum disorder (ASD), and Tourette syndrome was not significantly different between those children exposed to LTRAs and those not exposed to LTRAs in utero (1.25% vs. 1.32%; 3.31% vs. 4.36%; and 0.45% vs. 0.83%, respectively).

After propensity score matching, the study population included 1,988 LTRA-exposed children and 19,863 nonexposed children. In this group, no significant associations appeared between prenatal LTRA exposure and the risk of attention-deficit/hyperactivity disorder (adjusted hazard ratio, 1.03), autism spectrum disorder (AHR, 1.01), and Tourette syndrome (AHR, 0.63).

Neither duration nor cumulative dose of LTRA use during pregnancy showed an association with ADHD, ASD, or Tourette syndrome in offspring. Duration of LTRA use was categorized as shorter or longer periods of 1-4 weeks vs. more than 4 weeks; cumulative dose was categorized as 1-170 mg vs. 170 mg or higher.

The findings were limited by the lack of randomization, inability to detect long-term risk, and potential lack of generalizability to non-Asian populations, and more research is needed to replicate the results, the researchers noted. However, the current findings were strengthened by the large study population, and suggest that LTRA use in pregnancy does not present a significant risk for NEs in children, which should be reassuring to clinicians and patients, they concluded.

The current study is the first to use the whole of Taiwan population data and extends previous studies by examining the association between LTRA use during pregnancy and risk of neuropsychiatric events in offspring, Dr. Yao said in an interview. “The possibly surprising, but reassuring, finding is that prenatal LTRA exposure did not increase risk of ADHD, ASD, and Tourette syndrome in offspring,” he said.

“Clinicians prescribing LTRAs such as montelukast (Singulair and generics) to pregnant women with asthma or allergic rhinitis may be reassured by our findings,” Dr. Yao added. The results offer real-world evidence to help inform decision-making about the use of LTRAs during pregnancy, although additional research is needed to replicate the study findings in other populations, he said.

The study was supported by the National Health Research Institutes, Taiwan, the Ministry of Science and Technology of Taiwan, the National Science and Technology Council of Taiwan, and the Chang Gung Medical Foundation. The researchers had no financial conflicts to disclose.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Already commonly used in combination for the treatment of pulmonary arterial hypertension (PAH), macitentan and tadalafil are safe and effective in a fixed-dose combination even as first-line therapy, according to a randomized multicenter comparative trial.

The fixed-dose combination “led to a highly significant and marked improvement in pulmonary vascular resistance when compared to macitentan and tadalafil as monotherapies,” Kelly Chin, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

Guidelines encourage rapid PVR reductions

In practice, it is common to start treatment with either the endothelial receptor antagonist (ERA) macitentan, the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, or other frequently used medications for PAH, and to then add additional treatments, according to Dr. Chin. She pointed out, however, that guidelines, including those issued jointly by the European Society of Cardiology and the European Respiratory Society, encourage rapid escalation of therapy to quickly lower pulmonary vascular resistance (PVR).

In general, both macitentan and tadalafil are well tolerated, but the advantage and the safety of rapidly reducing PVR when these are initiated together in a single pill had not been evaluated previously in a major trial. In this double-blind phase III trial, called A DUE, 187 patients in functional class II or III PAH were randomized. The three-arm study included both treatment naive patients and patients who had been on stable doses (> 3 months) of an ERA or a PDE5 inhibitor, explained Dr. Chin, director of pulmonary hypertension at the UT Southwestern, Dallas.

Treatment naive patients, representing about 53% of the study population, were randomized to 10 mg macitentan monotherapy, 40 mg tadalafil monotherapy, or a fixed-dose, single-pill combination containing both. If on a stable dose of an ERA at trial entry, patients were randomized to 10 macitentan as a monotherapy or to the fixed dose combination. Patients entering the trial already on a stable dose of a PDE5 inhibitor were randomized to 40 mg tadalafil or the combination.
 

PVR reduced twofold on combination therapy

Relative to macitentan monotherapy, the percentage change from baseline in PVR by ratio of geometric mean, which was the primary outcome, was about twice as high on the combination (45% vs. 23%) at the end of the 16-week trial. This translates into a 29% PVR reduction (hazard ratio, 0.71; P < .0001).

For combination therapy relative to tadalafil monotherapy, the advantage for the fixed dose combination (44% vs. 22%) was about the same, also providing a nearly 30% relative reduction (HR, 0.72; P < .0001).

The increases in 6-minute walk distance (6MWD) at 16 weeks, a secondary endpoint, numerically favored the combination pill over both macitentan monotherapy (52.9 vs. 39.5 meters; P = .38) and tadalafil (43.4 vs. 15.9 meters; P = .059), but only the improvement relative to tadalafil monotherapy was considered a trend.

The proportion of patients who experienced at least one serious adverse event was higher in the combination arm (14.0%) relative to single agent macitentan (8.6%) or single agent tadalafil (9.1%). The adverse events and serious adverse events more common on the combination included hypotension, fluid retention, and anemia. This latter side effect occurred in 18.7%, 2.9%, and 2.3% in the combination, macitentan monotherapy, and tadalafil arms, respectively.

Several of those invited by the ACC to discuss the paper, including Lee R. Goldberg, MD, section chief of advanced heart failure and cardiac transplant, University of Pennsylvania, Philadelphia, raised concern about the increased rate of anemia among those in the combination pill. Two of the patients (2%) treated with the combination developed a hemoglobin < 8 g/dL.

Overall, nine (8.4%) of those on the fixed-dose combination, two (4.5%) of those randomized to tadalafil monotherapy, and none of the patients randomized to macitentan discontinued therapy due to side effects.
 

Anemia risk unexpected

Based on “the unexpected signal of an anemia risk,” Biykem Bozkurt, MD, PhD, chair of cardiology at Baylor College of Medicine, Houston, said that a larger scale trial with a longer follow-up is needed. While the concept of front-loading two drugs is attractive “for the very challenging PAH population,” she called for further evaluation of this safety signal before clinicians switch from the current practice of starting with one PAH therapy before adding others.

Mitchel L. Zoler/MDedge News

In addition, Dr. Bozkurt said a more definitive study would be helpful in determining whether starting with a fixed-pill combination is better than sequential treatment to improve quality of life. Dr. Bozkurt said it is likely that the lack of significant benefit on 6MWD in this study was due to the relatively small sample size, but an improvement in this measure would be another reason to consider a front-line fixed-dose combination.

Dr. Chin, in an interview, did not agree. She agreed that a larger sample size might have yielded a significant improvement in 6MWD, but she noted this outcome was moving in the right direction and was not the primary endpoint. In her opinion, this phase 3 trial does confirm that fixed-dose combination is well tolerated, has acceptable safety, and markedly improves PVR, fulfilling the guideline goal of controlling PAH more quickly.

Dr. Chin reports financial relationships with Altavant, Arena, Gossamer Bio, Janssen, Merck, ShouTi, and United Therapeutics. Dr. Goldberg reports financial relationships with Abbott, Respicardia/Zoll, and Viscardia. Dr. Bozkurt reports financial relationships with Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Cardurion, LivaNova, Relypsa, Renovacor, Sanofi-Aventis, and Vifor.

Pulmonary function was significantly associated with frailty in community-dwelling older adults over a 5-year period, as indicated by data from more than 1,000 individuals.

The pulmonary function test has been proposed as a predictive tool for clinical outcomes in geriatrics, including hospitalization, mortality, and frailty, but data on the relationship between pulmonary function and frailty in community-dwelling adults are limited and inconsistent, write Walter Sepulveda-Loyola, MD, of Universidad de Las Americas, Santiago, Chile, and colleagues.

In an observational study published in Heart and Lung, the researchers reviewed data from adults older than 64 years who were participants in the Toledo Study for Healthy Aging.

The study population included 1,188 older adults (mean age, 74 years; 54% women). The prevalence of frailty at baseline ranged from 7% to 26%.

Frailty was defined using the frailty phenotype (FP) and the Frailty Trait Scale 5 (FTS5). Pulmonary function was determined on the basis of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), using spirometry.

Overall, at the 5-year follow-up, FEV1 and FVC were inversely associated with prevalence and incidence of frailty in nonadjusted and adjusted models using FP and FTS5.

In adjusted models, FEV1 and FVC, as well as FEV1 and FVC percent predicted value, were significantly associated with the prevalence of frailty, with odds ratios ranging from 0.53 to 0.99. FEV1 and FVC were significantly associated with increased incidence of frailty, with odds ratios ranging from 0.49 to 0.50 (P < .05 for both).

Pulmonary function also was associated with prevalent and incident frailty, hospitalization, and mortality in regression models, including the whole sample and after respiratory diseases were excluded.

Pulmonary function measures below the cutoff points for FEV1 and FVC were significantly associated with frailty, as well as with hospitalization and mortality. The cutoff points for FEV1 were 1.805 L for men and 1.165 L for women; cutoff points for FVC were 2.385 L for men and 1.585 L for women.

“Pulmonary function should be evaluated not only in frail patients, with the aim of detecting patients with poor prognoses regardless of their comorbidity, but also in individuals who are not frail but have an increased risk of developing frailty, as well as other adverse events,” the researchers write.

The study findings were limited by lack of data on pulmonary function variables outside of spirometry and by the need for data from populations with different characteristics to assess whether the same cutoff points are predictive of frailty, the researchers note.

The results were strengthened by the large sample size and additional analysis that excluded other respiratory diseases. Future research should consider adding pulmonary function assessment to the frailty model, the authors write.

Given the relationship between pulmonary function and physical capacity, the current study supports more frequent evaluation of pulmonary function in clinical practice for older adults, including those with no pulmonary disease, they conclude.

The study was supported by the Spanish Ministry of Economy, Industry, and Competitiveness, financed by the European Regional Development Funds, and the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable and the Fundacion Francisco Soria Melguizo. Lead author Dr. Sepulveda-Loyola was supported by the Brazilian National Council for Scientific and Technological Development.

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

Pulmonary function was significantly associated with frailty in community-dwelling older adults over a 5-year period, as indicated by data from more than 1,000 individuals.

The pulmonary function test has been proposed as a predictive tool for clinical outcomes in geriatrics, including hospitalization, mortality, and frailty, but data on the relationship between pulmonary function and frailty in community-dwelling adults are limited and inconsistent, write Walter Sepulveda-Loyola, MD, of Universidad de Las Americas, Santiago, Chile, and colleagues.

In an observational study published in Heart and Lung, the researchers reviewed data from adults older than 64 years who were participants in the Toledo Study for Healthy Aging.

The study population included 1,188 older adults (mean age, 74 years; 54% women). The prevalence of frailty at baseline ranged from 7% to 26%.

Frailty was defined using the frailty phenotype (FP) and the Frailty Trait Scale 5 (FTS5). Pulmonary function was determined on the basis of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), using spirometry.

Overall, at the 5-year follow-up, FEV1 and FVC were inversely associated with prevalence and incidence of frailty in nonadjusted and adjusted models using FP and FTS5.

In adjusted models, FEV1 and FVC, as well as FEV1 and FVC percent predicted value, were significantly associated with the prevalence of frailty, with odds ratios ranging from 0.53 to 0.99. FEV1 and FVC were significantly associated with increased incidence of frailty, with odds ratios ranging from 0.49 to 0.50 (P < .05 for both).

Pulmonary function also was associated with prevalent and incident frailty, hospitalization, and mortality in regression models, including the whole sample and after respiratory diseases were excluded.

Pulmonary function measures below the cutoff points for FEV1 and FVC were significantly associated with frailty, as well as with hospitalization and mortality. The cutoff points for FEV1 were 1.805 L for men and 1.165 L for women; cutoff points for FVC were 2.385 L for men and 1.585 L for women.

“Pulmonary function should be evaluated not only in frail patients, with the aim of detecting patients with poor prognoses regardless of their comorbidity, but also in individuals who are not frail but have an increased risk of developing frailty, as well as other adverse events,” the researchers write.

The study findings were limited by lack of data on pulmonary function variables outside of spirometry and by the need for data from populations with different characteristics to assess whether the same cutoff points are predictive of frailty, the researchers note.

The results were strengthened by the large sample size and additional analysis that excluded other respiratory diseases. Future research should consider adding pulmonary function assessment to the frailty model, the authors write.

Given the relationship between pulmonary function and physical capacity, the current study supports more frequent evaluation of pulmonary function in clinical practice for older adults, including those with no pulmonary disease, they conclude.

The study was supported by the Spanish Ministry of Economy, Industry, and Competitiveness, financed by the European Regional Development Funds, and the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable and the Fundacion Francisco Soria Melguizo. Lead author Dr. Sepulveda-Loyola was supported by the Brazilian National Council for Scientific and Technological Development.

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

Pulmonary function was significantly associated with frailty in community-dwelling older adults over a 5-year period, as indicated by data from more than 1,000 individuals.

The pulmonary function test has been proposed as a predictive tool for clinical outcomes in geriatrics, including hospitalization, mortality, and frailty, but data on the relationship between pulmonary function and frailty in community-dwelling adults are limited and inconsistent, write Walter Sepulveda-Loyola, MD, of Universidad de Las Americas, Santiago, Chile, and colleagues.

In an observational study published in Heart and Lung, the researchers reviewed data from adults older than 64 years who were participants in the Toledo Study for Healthy Aging.

The study population included 1,188 older adults (mean age, 74 years; 54% women). The prevalence of frailty at baseline ranged from 7% to 26%.

Frailty was defined using the frailty phenotype (FP) and the Frailty Trait Scale 5 (FTS5). Pulmonary function was determined on the basis of forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC), using spirometry.

Overall, at the 5-year follow-up, FEV1 and FVC were inversely associated with prevalence and incidence of frailty in nonadjusted and adjusted models using FP and FTS5.

In adjusted models, FEV1 and FVC, as well as FEV1 and FVC percent predicted value, were significantly associated with the prevalence of frailty, with odds ratios ranging from 0.53 to 0.99. FEV1 and FVC were significantly associated with increased incidence of frailty, with odds ratios ranging from 0.49 to 0.50 (P < .05 for both).

Pulmonary function also was associated with prevalent and incident frailty, hospitalization, and mortality in regression models, including the whole sample and after respiratory diseases were excluded.

Pulmonary function measures below the cutoff points for FEV1 and FVC were significantly associated with frailty, as well as with hospitalization and mortality. The cutoff points for FEV1 were 1.805 L for men and 1.165 L for women; cutoff points for FVC were 2.385 L for men and 1.585 L for women.

“Pulmonary function should be evaluated not only in frail patients, with the aim of detecting patients with poor prognoses regardless of their comorbidity, but also in individuals who are not frail but have an increased risk of developing frailty, as well as other adverse events,” the researchers write.

The study findings were limited by lack of data on pulmonary function variables outside of spirometry and by the need for data from populations with different characteristics to assess whether the same cutoff points are predictive of frailty, the researchers note.

The results were strengthened by the large sample size and additional analysis that excluded other respiratory diseases. Future research should consider adding pulmonary function assessment to the frailty model, the authors write.

Given the relationship between pulmonary function and physical capacity, the current study supports more frequent evaluation of pulmonary function in clinical practice for older adults, including those with no pulmonary disease, they conclude.

The study was supported by the Spanish Ministry of Economy, Industry, and Competitiveness, financed by the European Regional Development Funds, and the Centro de Investigacion Biomedica en Red en Fragilidad y Envejecimiento Saludable and the Fundacion Francisco Soria Melguizo. Lead author Dr. Sepulveda-Loyola was supported by the Brazilian National Council for Scientific and Technological Development.

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

If budesonide-formoterol were to become available over the counter (OTC) and used as-needed for mild asthma, it would save lives and cut health care costs, according to a computer modeling study presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio.

Asthma affects 25 million people, about 1 in 13, in the United States. About 28% are uninsured or underinsured, and 70% have mild asthma. Many are using a $30 inhaled epinephrine product (Primatene Mist) – the only FDA-approved asthma inhaler available without a prescription, said Marcus Shaker, MD, MS, professor of pediatrics and medicine at Geisel School of Medicine at Dartmouth, and clinician at Dartmouth Health Children’s, N.H.

A new version of Primatene Mist was reintroduced on the market in 2018 after the product was pulled for containing chlorofluorocarbons in 2011, but it is not recommended by professional medical societies because of safety concerns over epinephrine’s adverse effects, such as increased heart rate and blood pressure.

Drugs in its class (bronchodilators) have long been associated with a higher risk for death or near-death.

Meanwhile, research more than 2 decades ago linked regular use of low-dose inhaled corticosteroids with reduced risk for asthma death.

More recently, two large studies (SYGMA 1 and SYGMA 2) compared maintenance therapy with a low-dose inhaled corticosteroid (budesonide) vs. on-demand treatment with an inhaler containing both a corticosteroid (budesonide) and a long-acting bronchodilator (formoterol).

“Using as-needed budesonide-formoterol led to outcomes that are almost as good as taking a maintenance budesonide dose every day,” said Dr. Shaker.

The Global Initiative for Asthma guidelines now recommend this approach – as-needed inhaled corticosteroids (ICS) plus long-acting bronchodilators – for adults with mild asthma. In the United States, however, the National Heart, Lung, and Blood Institute still suggests daily ICS plus quick-relief therapy as needed.

Dr. Shaker and colleagues used computer modeling to compare the cost-effectiveness of as-needed budesonide-formoterol vs. over-the-counter inhaled epinephrine in underinsured U.S. adults who were self-managing their mild asthma. The study randomly assigned these individuals into three groups: OTC inhaled epinephrine (current reality), OTC budesonide-formoterol (not yet available), or no OTC option. The model assumed that patients treated for an exacerbation were referred to a health care provider and started a regimen of ICS plus as-needed rescue therapy.

In this analysis, which has been submitted for publication, the OTC budesonide-formoterol strategy was associated with 12,495 fewer deaths, prevented nearly 14 million severe asthma exacerbations, and saved more than $68 billion. And “when we looked at OTC budesonide-formoterol vs. having no OTC option at all, budesonide-formoterol was similarly cost-effective,” said Dr. Shaker, who presented the results at an AAAAI oral abstract session.

The cost savings emerged even though in the United States asthma controller therapies (for example, fluticasone) cost about 10 times more than rescue therapies (for instance, salbutamol, OTC epinephrine).

Nevertheless, the results make sense. “If you’re using Primatene Mist, your health costs are predicted to be much greater because you’re going to be in the hospital more. Your asthma is not going to be well-controlled,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., told this news organization. “It’s not only the cost of your ER visit but also the cost of loss of work or school, and loss of daily productivity. There are all these associated costs.”

The analysis “is certainly something policy makers could take a look at,” he said.

He noted that current use of budesonide-formoterol is stymied by difficulties with insurance coverage. The difficulties stem from a mismatch between the updated recommendation for as-needed use and the description printed on the brand-name product (Symbicort).

“On the product label, it says Symbicort should be used on a daily basis,” Dr. Pongdee said. “But if a prescription comes through and says you’re going to use this ‘as needed,’ the health plan may say that’s not appropriate because that’s not on the product label.”

Given these access challenges with the all-in-one inhaler, other researchers have developed a workaround – asking patients to continue their usual care (that is, using a rescue inhaler as needed) but to also administer a controller medication after each rescue. When tested in Black and Latino patients with moderate to severe asthma, this easy strategy (patient activated reliever-triggered inhaled corticosteroid, or PARTICS) reduced severe asthma exacerbations about as well as the all-in-one inhaler.

If the all-in-one budesonide-formoterol does become available OTC, Dr. Shaker stressed that it “would not be a substitute for seeing an allergist and getting appropriate medical care and an evaluation and all the rest. But it’s better than the status quo. It’s the sort of thing where the perfect is not the enemy of the good,” he said.

Dr. Shaker is the AAAAI cochair of the Joint Task Force on Practice Parameters and serves as an editorial board member of the Journal of Allergy and Clinical Immunology in Practice. He is also an associate editor of the Annals of Allergy, Asthma, and Immunology. Dr. Pongdee serves as an at-large director on the AAAAI board of directors. He receives grant funding from GlaxoSmithKline, and Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

If budesonide-formoterol were to become available over the counter (OTC) and used as-needed for mild asthma, it would save lives and cut health care costs, according to a computer modeling study presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio.

Asthma affects 25 million people, about 1 in 13, in the United States. About 28% are uninsured or underinsured, and 70% have mild asthma. Many are using a $30 inhaled epinephrine product (Primatene Mist) – the only FDA-approved asthma inhaler available without a prescription, said Marcus Shaker, MD, MS, professor of pediatrics and medicine at Geisel School of Medicine at Dartmouth, and clinician at Dartmouth Health Children’s, N.H.

A new version of Primatene Mist was reintroduced on the market in 2018 after the product was pulled for containing chlorofluorocarbons in 2011, but it is not recommended by professional medical societies because of safety concerns over epinephrine’s adverse effects, such as increased heart rate and blood pressure.

Drugs in its class (bronchodilators) have long been associated with a higher risk for death or near-death.

Meanwhile, research more than 2 decades ago linked regular use of low-dose inhaled corticosteroids with reduced risk for asthma death.

More recently, two large studies (SYGMA 1 and SYGMA 2) compared maintenance therapy with a low-dose inhaled corticosteroid (budesonide) vs. on-demand treatment with an inhaler containing both a corticosteroid (budesonide) and a long-acting bronchodilator (formoterol).

“Using as-needed budesonide-formoterol led to outcomes that are almost as good as taking a maintenance budesonide dose every day,” said Dr. Shaker.

The Global Initiative for Asthma guidelines now recommend this approach – as-needed inhaled corticosteroids (ICS) plus long-acting bronchodilators – for adults with mild asthma. In the United States, however, the National Heart, Lung, and Blood Institute still suggests daily ICS plus quick-relief therapy as needed.

Dr. Shaker and colleagues used computer modeling to compare the cost-effectiveness of as-needed budesonide-formoterol vs. over-the-counter inhaled epinephrine in underinsured U.S. adults who were self-managing their mild asthma. The study randomly assigned these individuals into three groups: OTC inhaled epinephrine (current reality), OTC budesonide-formoterol (not yet available), or no OTC option. The model assumed that patients treated for an exacerbation were referred to a health care provider and started a regimen of ICS plus as-needed rescue therapy.

In this analysis, which has been submitted for publication, the OTC budesonide-formoterol strategy was associated with 12,495 fewer deaths, prevented nearly 14 million severe asthma exacerbations, and saved more than $68 billion. And “when we looked at OTC budesonide-formoterol vs. having no OTC option at all, budesonide-formoterol was similarly cost-effective,” said Dr. Shaker, who presented the results at an AAAAI oral abstract session.

The cost savings emerged even though in the United States asthma controller therapies (for example, fluticasone) cost about 10 times more than rescue therapies (for instance, salbutamol, OTC epinephrine).

Nevertheless, the results make sense. “If you’re using Primatene Mist, your health costs are predicted to be much greater because you’re going to be in the hospital more. Your asthma is not going to be well-controlled,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., told this news organization. “It’s not only the cost of your ER visit but also the cost of loss of work or school, and loss of daily productivity. There are all these associated costs.”

The analysis “is certainly something policy makers could take a look at,” he said.

He noted that current use of budesonide-formoterol is stymied by difficulties with insurance coverage. The difficulties stem from a mismatch between the updated recommendation for as-needed use and the description printed on the brand-name product (Symbicort).

“On the product label, it says Symbicort should be used on a daily basis,” Dr. Pongdee said. “But if a prescription comes through and says you’re going to use this ‘as needed,’ the health plan may say that’s not appropriate because that’s not on the product label.”

Given these access challenges with the all-in-one inhaler, other researchers have developed a workaround – asking patients to continue their usual care (that is, using a rescue inhaler as needed) but to also administer a controller medication after each rescue. When tested in Black and Latino patients with moderate to severe asthma, this easy strategy (patient activated reliever-triggered inhaled corticosteroid, or PARTICS) reduced severe asthma exacerbations about as well as the all-in-one inhaler.

If the all-in-one budesonide-formoterol does become available OTC, Dr. Shaker stressed that it “would not be a substitute for seeing an allergist and getting appropriate medical care and an evaluation and all the rest. But it’s better than the status quo. It’s the sort of thing where the perfect is not the enemy of the good,” he said.

Dr. Shaker is the AAAAI cochair of the Joint Task Force on Practice Parameters and serves as an editorial board member of the Journal of Allergy and Clinical Immunology in Practice. He is also an associate editor of the Annals of Allergy, Asthma, and Immunology. Dr. Pongdee serves as an at-large director on the AAAAI board of directors. He receives grant funding from GlaxoSmithKline, and Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

If budesonide-formoterol were to become available over the counter (OTC) and used as-needed for mild asthma, it would save lives and cut health care costs, according to a computer modeling study presented at the American Academy of Allergy, Asthma, and Immunology 2023 annual meeting in San Antonio.

Asthma affects 25 million people, about 1 in 13, in the United States. About 28% are uninsured or underinsured, and 70% have mild asthma. Many are using a $30 inhaled epinephrine product (Primatene Mist) – the only FDA-approved asthma inhaler available without a prescription, said Marcus Shaker, MD, MS, professor of pediatrics and medicine at Geisel School of Medicine at Dartmouth, and clinician at Dartmouth Health Children’s, N.H.

A new version of Primatene Mist was reintroduced on the market in 2018 after the product was pulled for containing chlorofluorocarbons in 2011, but it is not recommended by professional medical societies because of safety concerns over epinephrine’s adverse effects, such as increased heart rate and blood pressure.

Drugs in its class (bronchodilators) have long been associated with a higher risk for death or near-death.

Meanwhile, research more than 2 decades ago linked regular use of low-dose inhaled corticosteroids with reduced risk for asthma death.

More recently, two large studies (SYGMA 1 and SYGMA 2) compared maintenance therapy with a low-dose inhaled corticosteroid (budesonide) vs. on-demand treatment with an inhaler containing both a corticosteroid (budesonide) and a long-acting bronchodilator (formoterol).

“Using as-needed budesonide-formoterol led to outcomes that are almost as good as taking a maintenance budesonide dose every day,” said Dr. Shaker.

The Global Initiative for Asthma guidelines now recommend this approach – as-needed inhaled corticosteroids (ICS) plus long-acting bronchodilators – for adults with mild asthma. In the United States, however, the National Heart, Lung, and Blood Institute still suggests daily ICS plus quick-relief therapy as needed.

Dr. Shaker and colleagues used computer modeling to compare the cost-effectiveness of as-needed budesonide-formoterol vs. over-the-counter inhaled epinephrine in underinsured U.S. adults who were self-managing their mild asthma. The study randomly assigned these individuals into three groups: OTC inhaled epinephrine (current reality), OTC budesonide-formoterol (not yet available), or no OTC option. The model assumed that patients treated for an exacerbation were referred to a health care provider and started a regimen of ICS plus as-needed rescue therapy.

In this analysis, which has been submitted for publication, the OTC budesonide-formoterol strategy was associated with 12,495 fewer deaths, prevented nearly 14 million severe asthma exacerbations, and saved more than $68 billion. And “when we looked at OTC budesonide-formoterol vs. having no OTC option at all, budesonide-formoterol was similarly cost-effective,” said Dr. Shaker, who presented the results at an AAAAI oral abstract session.

The cost savings emerged even though in the United States asthma controller therapies (for example, fluticasone) cost about 10 times more than rescue therapies (for instance, salbutamol, OTC epinephrine).

Nevertheless, the results make sense. “If you’re using Primatene Mist, your health costs are predicted to be much greater because you’re going to be in the hospital more. Your asthma is not going to be well-controlled,” Thanai Pongdee, MD, an allergist-immunologist with the Mayo Clinic in Rochester, Minn., told this news organization. “It’s not only the cost of your ER visit but also the cost of loss of work or school, and loss of daily productivity. There are all these associated costs.”

The analysis “is certainly something policy makers could take a look at,” he said.

He noted that current use of budesonide-formoterol is stymied by difficulties with insurance coverage. The difficulties stem from a mismatch between the updated recommendation for as-needed use and the description printed on the brand-name product (Symbicort).

“On the product label, it says Symbicort should be used on a daily basis,” Dr. Pongdee said. “But if a prescription comes through and says you’re going to use this ‘as needed,’ the health plan may say that’s not appropriate because that’s not on the product label.”

Given these access challenges with the all-in-one inhaler, other researchers have developed a workaround – asking patients to continue their usual care (that is, using a rescue inhaler as needed) but to also administer a controller medication after each rescue. When tested in Black and Latino patients with moderate to severe asthma, this easy strategy (patient activated reliever-triggered inhaled corticosteroid, or PARTICS) reduced severe asthma exacerbations about as well as the all-in-one inhaler.

If the all-in-one budesonide-formoterol does become available OTC, Dr. Shaker stressed that it “would not be a substitute for seeing an allergist and getting appropriate medical care and an evaluation and all the rest. But it’s better than the status quo. It’s the sort of thing where the perfect is not the enemy of the good,” he said.

Dr. Shaker is the AAAAI cochair of the Joint Task Force on Practice Parameters and serves as an editorial board member of the Journal of Allergy and Clinical Immunology in Practice. He is also an associate editor of the Annals of Allergy, Asthma, and Immunology. Dr. Pongdee serves as an at-large director on the AAAAI board of directors. He receives grant funding from GlaxoSmithKline, and Mayo Clinic is a trial site for GlaxoSmithKline and AstraZeneca.

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

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

 

 

When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

 

 

Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

 

 

Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; [email protected]

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

 

 

When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

 

 

Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

 

 

Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; [email protected]

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure (mPAP) have led to a reported increase in the number of patients given a diagnosis of PH. Although the evaluation and treatment of PH relies on the specialist, as we explain here, family physicians play a pivotal role in the diagnosis, reduction or elimination of risk factors for PH, and timely referral to a pulmonologist or cardiologist who has expertise in managing the disease. We also address the important finding that adult patients who have been evaluated, treated, and followed based on guidelines—updated just last year—have a longer life expectancy than patients who have not been treated properly or not treated at all.

Last, we summarize the etiology, evaluation, and management of PH in the pediatric population.

What is pulmonary hypertension? A revised definition

Prior to 2018, PH was defined as mPAP (measured by right heart catheterization [RHC]) ≥ 25 mm Hg at rest. Now, based on guidelines developed at the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, PH is defined as mPAP > 20 mm Hg.^1,2 That change was based on studies in which researchers noted higher mortality in adults who had mPAP below the traditional threshold.^3,4 There is no evidence, however, of increased mortality in the pediatric population in this lower mPAP range.⁵

New guidelines that redefine pulmonary hypertension (PH) by a lower mean pulmonary artery pressure have led to a reported increase in the number of patients given a diagnosis of PH.

PH is estimated to be present in approximately 1% of the population.⁶ PH due to other diseases—eg, cardiac disease, lung disease, or a chronic thromboembolic condition—­reflects the prevalence of the causative disease.⁷

How is pulmonary hypertension classified?

Based on the work of a Task Force of the 6th WSPH, PH is classified by underlying pathophysiology, hemodynamics, and functional status. Clinical classification comprises 5 categories, or “groups,” based on underlying pathophysiology (TABLE 1⁶).

Clinical classification

Group 1 PH includes patients with primary pulmonary hypertension, also referred to ­(including in this article) as pulmonary arterial hypertension (PAH). Hemodynamic criteria that define PAH include pulmonary vascular resistance (PVR) > 2 Woods units^a and pulmonary capillary wedge pressure > 15 mm Hg. Idiopathic PAH is the most common diagnosis in this group.

The incidence of PAH is approximately 6 cases for every 1 million adults; prevalence is 48 to 55 cases for every 1 million adults. PAH is more common in women.⁶

Continue to: Less common causes...

Less common causes in Group 1 include connective tissue disorders and exposure to toxins. Drugs and toxins that have a well-defined association with PAH include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Group 2 PH comprises patients whose disease results from left heart dysfunction, the most common cause of PH. This subgroup has an elevated pulmonary artery wedge pressure > 15 mm Hg.⁸ Patients have either isolated postcapillary PH or combined pre-capillary and postcapillary PH.

Group 3 PH comprises patients whose PH is secondary to chronic and hypoxic lung disease. Patients in this group have pre-­capillary PH; even a modest elevation in mPAP (20-29 mm Hg) is associated with a poor prognosis. Group 3 patients have elevated PVR, even with mild PH.² Exertional dyspnea disproportionate to the results of pulmonary function testing, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation with exercise all point to severe PH in these patients.⁹

Group 4 PH encompasses patients with pulmonary artery obstruction, the most common cause of which is related to chronic thromboembolism. Other causes include obstruction of the pulmonary artery from an extrinsic source. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) also have pre-capillary PH, resulting from elevated pulmonary pressures secondary to thromboembolic burden, as well as pulmonary remodeling in unobstructed small arterioles.

Group 5 PH is a miscellaneous group secondary to unclear or multiple causes, including chronic hematologic anemia (eg, sickle cell disease), systemic disorders (eg, sarcoidosis), and metabolic disorders (eg, glycogen storage disease). Patients in Group 5 can have both pre-capillary and postcapillary hypertension.

Classification by functional status

The World Health Organization (WHO) Functional Classification of Patients with Pulmonary Hypertension is divided into 4 classes.¹⁰ This system is used to guide treatment and for prognostic purposes:

Class I. Patients have no limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near-syncope.

Continue to: Class II

Class II. Patients have slight limitation of physical activity. They are comfortable at rest but daily physical activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class III. These patients have marked limitation of physical activity. They are comfortable at rest, but less-than-ordinary activity causes dyspnea, fatigue, chest pain, or near-syncope.

Class IV. Patients are unable to carry out any physical activity without symptoms. They manifest signs of right heart failure. Dyspnea or fatigue, or both, might be present even at rest.

How is the pathophysiology of PH described?

The term pulmonary hypertension refers to an elevation in PAP that can result from any number of causes. Pulmonary arterial hypertension is a subcategory of PH in which a rise in PAP is due to primary pathology in the arteries proper.

As noted, PH results from a variety of pathophysiologic mechanisms, reflected in the classification in TABLE 1.⁶

WSPH Group 1 patients are considered to have PAH; for most, disease is idiopathic. In small-caliber pulmonary arteries, hypertrophy of smooth muscle, endothelial cells, and adventitia leads to increased resistance. Production of nitric oxide and prostacyclins is also impaired in endothelial cells. Genetic mutation, environmental factors such as exposure to stimulant use, and collagen vascular disease have a role in different subtypes of PAH. Portopulmonary hypertension is a subtype of PAH in patients with portal hypertension.

WSPH Groups 2-5. Increased PVR can result from pulmonary vascular congestion due to left heart dysfunction; destruction of the alveolar capillary bed; chronic hypoxic vasoconstriction; and vascular occlusion from thromboembolism.

Continue to: Once approximately...

Once approximately 30% of the pulmonary vasculature is involved, pressure in the pulmonary circulation starts to rise. In all WSPH groups, this increase in PVR results in increased right ventricular afterload that, over time, leads to right ventricular ­dysfunction.^7,11,12

How does PH manifest?

Patients who have PH usually present with dyspnea, fatigue, chest pain, near-syncope, syncope, or lower-extremity edema, or any combination of these symptoms. The nonspecificity of presenting symptoms can lead to a delay in diagnosis.

In addition, suspicion of PH should be raised when a patient:

• presents with skin discoloration (light or dark) or a telangiectatic rash
• presents with difficulty swallowing
• has a history of connective tissue disease or hemolytic anemia
• has risk factors for HIV infection or liver disease
• takes an appetite suppressant
• has been exposed to other toxins known to increase the risk of PH.

A detailed medical history—looking for chronic lung or heart disease, thromboembolism, sleep-disordered breathing, a thyroid disorder, chronic renal failure, or a metabolic disorder—should be obtained.

Common findings on the physical exam in PH include:

• an increased P2 heart sound (pulmonic closure)
• high-pitched holosystolic murmur from tricuspid regurgitation
• pulmonic insufficiency murmur
• jugular venous distension
• hepatojugular reflux
• peripheral edema.

These findings are not specific to PH but, again, their presence warrants consideration of PH.

How best to approach evaluation and diagnosis?

The work-up for PH is broad; FIGURE 1^13,14 provides an outline of how to proceed when there is a concern for PH. For the work-up of symptoms and signs listed earlier, chest radiography and electrocardiography are recommended.

Continue to: Radiographic findings

Radiographic findings that suggest PH include enlargement of central pulmonary arteries and the right ventricle and dilation of the right atrium. Pulmonary vascular congestion might also be seen, secondary to left heart disease.⁷

Electrocardiographic findings of PH are demonstrated by signs of left ventricular hypertrophy, especially in Group 2 PH. Upright R waves in V₁-V₂ with deeper S waves in V₅-V₆ might represent right ventricular hypertrophy or right heart strain. Frequent premature atrial contractions and multifocal atrial tachycardia are also associated with PH.⁷

Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP. The level of BNP might be elevated in PH, but its role in the diagnostic process has not been established. BNP can, however, be used to monitor treatment effectiveness and prognosis.¹⁵ A normal electrocardiogram in tandem with a normal level of BNP or NT-proBNP is associated with a low likelihood of PH.⁶

Transthoracic echocardiography (TTE) is the initial evaluation tool whenever PH is suspected. Echocardiographic findings suggestive of PH include a combination of ­tricuspid regurgitation velocity > 2.8 m/s ­(FIGURE 2); estimated pulmonary artery systolic pressure > 35 mm Hg in younger adults and > 40 mm Hg in older adults; right ventricular hypertrophy or strain; or a combination of these. Other TTE findings suggestive of PH are related to the ventricles, pulmonary artery, inferior vena cava, and right atrium (TABLE 2⁶). The probability of PH based on TTE findings is categorized as low, intermediate, or high (see TABLE 2⁶ and TABLE 3¹⁶ for details).

Older guidelines, still used by some, rely on the estimated pulmonary artery systolic pressure (ePASP) reading on echocardiography.^13,17 However, studies have reported poor correlation between ePASP readings and values obtained from RHC.¹⁸

TTE also provides findings of left heart disease, such as left ventricular systolic and diastolic dysfunction and left-sided valvular pathology. Patients with suspected PH in whom evidence of left heart disease on TTE is insufficient for making the diagnosis should receive further evaluation for their possible status in Groups 3-5 PH.

Ventilation–perfusion (VQ) scan. If CTEPH is suspected, a VQ scan should be performed. The scan is highly sensitive for CTEPH; a normal VQ scan excludes CTEPH. Computed tomography (CT) of the chest is not helpful for identifying chronic thromboembolism.¹³

Continue to: Coagulation assays

Coagulation assays. When CTEPH is suspected, coagulopathy can be assessed by measuring anticardiolipin antibodies, lupus anticoagulant, and anti-b-2-glycoprotein ­antibodies.¹³

Chest CT will show radiographic findings in greater detail. An enlarged pulmonary artery (diameter ≥ 29 mm) or a ratio ≥ 1 of the diameter of the main pulmonary artery to the diameter of the ascending aorta is suggestive of PH.

Other tests. Overnight oximetry and testing for sleep-disordered breathing, performed in an appropriate setting, can be ­considered.^13,14,19

Pulmonary function testing with diffusion capacity for carbon monoxide, high-resolution chest CT, and a 6-minute walk test (6MWT) can be considered in patients who have risk factors for chronic lung disease. Pulmonary function testing, including measurement of the diffusing capacity of the lungs for carbon monoxide, arterial blood gas analysis, and CT, is used to aid in interpreting echocardiographic findings in patients with lung disease in whom PH is suspected.

Testing for comorbidities. A given patient’s predisposing conditions for PH might already be known; if not, laboratory evaluation for conditions such as sickle cell disease, liver disease, thyroid dysfunction, connective tissue disorders (antibody tests of antinuclear antibody, rheumatoid factor, anticentromere, anti-topoisomerase, anti-RNA polymerase III, anti-double stranded DNA, anti-Ro, anti-La, and anti-U1-RNP), and vasculitis (anti-­neutrophil cytoplasmic autoantibodies) should be undertaken.

Analysis of stool and urine for Schistosoma spp parasites can be considered in an appropriate clinical setting.¹³

Right heart catheterization. Once alternative diagnoses are excluded, RHC is recommended to make a definitive diagnosis and assess the contribution of left heart disease. Vasoreactivity—defined as a reduction in mPAP ≥ 10 mm Hg to reach an absolute value of mPAP ≤ 40 mm Hg with increased or unchanged cardiac output—is assessed during RHC by administering nitric oxide or another vasodilator. This definition of vasoreactivity helps guide medical management in patients with PAH.^7,20

Continue to: 6MWT

6MWT. Once the diagnosis of PH is made, a 6MWT helps establish baseline functional performance and will help you to monitor disease progression.

Who can benefit from screening for PH?

Annual evaluation of the risk of PAH is recommended for patients with systemic sclerosis or portal hypertension¹³ and can be considered in patients who have connective tissue disease with overlap features of systemic sclerosis.

Assessment for CTEPH or chronic thromboembolic pulmonary disease is recommended for patients with persistent or new-onset dyspnea or exercise limitation after pulmonary embolism.

Screening echocardiography for PH is recommended for patients who have been referred for liver transplantation.⁶

How risk is stratified

Risk stratification is used to manage PH and assess prognosis.

At diagnosis. Application of a 3-strata model of risk assessment (low, intermediate, high) is recommended.⁶ Pertinent data to determine risk include signs of right heart failure, progression of symptoms and clinical manifestations, report of syncope, WHO functional class, 6MWT, cardiopulmonary exercise testing, biomarkers (BNP or ­NT-proBNP), echocardiography, presence of pericardial effusion, and cardiac magnetic resonance imaging.

At follow-up. Use of a 4-strata model (low, intermediate–low, intermediate–high, and high risk) is recommended. Data used are WHO functional class, 6MWT, and results of either BNP or NT-proBNP testing.⁶

Continue to: When to refer

 

 

When to refer

Specialty consultation^21-23 is recommended for:

• all patients with PAH
• PH patients in clinical Groups 2 and 3 whose disease is disproportionate to the extent of their left heart disease or hypoxic lung disease
• patients in whom there is concern about CTEPH and who therefore require early referral to a specialist for definitive treatment
• patients in whom the cause of PH is unclear or multifactorial (ie, clinical Group 5).

What are the options for managing PH?

Management of PH is based on the cause and classification of the individual patient’s ­disease.

Treatment for WSPH Group 1

Patients require referral to a specialty clinic for diagnosis, treatment, and monitoring of progression.¹⁰

First, regrettably, none of the medications approved by the US Food and Drug Administration for treating PAH prevent progression.⁷

Drugs and toxins associated with pulmonary arterial hypertension include aminorex, fenfluramine, dexfenfluramine, benfluorex, methamphetamines, dasatinib, and toxic rapeseed oil.

Patients with idiopathic, hereditary, or drug-induced PAH with positive vasoreactivity are treated with a calcium channel blocker (CCB). The dosage is titrated to optimize therapy for the individual patient.

The patient is then reassessed after 3 to 6 months of medical therapy. Current treatment is continued if the following goals have been met:

• WHO functional classification is I or II
• BNP < 50 ng/L or NT-proBNP < 300 ng/L
• hemodynamics are normal or near-normal (mPAP ≤ 30 mm Hg and PVR ≤ 4 WU).

If these goals have not been met, treatment is adjusted by following the algorithm described below.

Continue to: The treatment algorithm...

The treatment algorithm for idiopathic-, heritable-, drug-induced, and connective tissue disease–associated PAH highlights the importance of cardiopulmonary comorbidities and risk strata at the time treatment is initiated and then during follow-up.

Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, including obesity, hypertension, diabetes, and coronary artery disease. Pulmonary comorbidities can include signs of mild parenchymal lung disease and are often associated with a low carbon monoxide diffusing capacity (< 45% of predicted value). 

The management algorithm proceeds as follows:

• For patients without cardiopulmonary comorbidities and who are at low or intermediate risk, treatment of PAH with an endothelin receptor antagonist (ERA) plus a phosphodiesterase-5 (PDE5) inhibitor is recommended.
• For patients without cardiopulmonary comorbidities and who are at high risk, treatment with an ERA, a PDE5 inhibitor, and either an IV or subcutaneous prostacyclin analogue (PCA) can be considered.
• Patients in either of the preceding 2 categories should have regular follow-up assessment; at such follow-up, their risk should be stratified based on 4 strata (see “How risk is stratified”):
  • Low risk: Continue initial therapy.
  • Low-to-intermediate risk: Consider adding a prostacyclin receptor agonist to the initial regimen or switch to a PDE5 inhibitor or a soluble guanylate cyclase stimulator.
  • Intermediate-to-high or high risk: Consider adding a PCA (IV epoprostenol or IV or subcutaneous treprostinil). In addition, or alternatively, have the patient evaluated for lung transplantation.
• For patients with cardiopulmonary comorbidity—in any risk category—consider oral monotherapy with a PDE5 inhibitor or an ERA. Provide regular follow-up and individualize therapy.⁶

Treatment for WSPH Groups 2 and 3

Treatment is focused on the underlying cause of PH:

• Patients who have left heart disease with either severe pre-capillary component PH or markers of right ventricular dysfunction, or both, should be referred to a PH center.
• Patients with combined pre-capillary and postcapillary PH in whom pre-capillary PH is severe should be considered for an individualized approach.
• Consider prescribing the ERA bosentan in specific scenarios (eg, the Eisenmenger syndrome of left-right shunting resulting from a congenital cardiac defect) to improve exercise capacity. If PAH persists after corrected adult congenital heart disease, follow the PAH treatment algorithm for Group 1 patients (described earlier).
• For patients in Group 3, those who have severe PH should be referred to a PH center.
• Consider prescribing inhaled treprostinil in PH with interstitial lung disease.

Treatment for WSPH Group 4

Patients with CTEPH are the only ones for whom pulmonary endarterectomy (PEA), the treatment of choice, might be curative. Balloon angioplasty can be considered for inoperable cases⁶; these patients should be placed on lifelong anticoagulant therapy.

The nonspecificity of presenting symptoms of pulmonary hypertension— dyspnea, fatigue, chest pain, near syncope, syncope, lowerextremity edema—can lead to a delay in diagnosis.

Symptomatic patients who have inoperable CTEPH or persistent recurrent PH after PEA are medically managed; the agent of choice is riociguat. Patients who have undergone PEA or balloon angioplasty and those receiving pharmacotherapy should be followed long term.

Treatment for WSPH Group 5

Management of these patients focuses on associated conditions.

Continue to: Which medications for PAH?

 

 

Which medications for PAH?

CCBs. Four options in this class have shown utility, notably in patients who have had a positive vasoreactivity test (see “How best to approach evaluation and diagnosis?”):

• Nifedipine is started at 10 mg tid; target dosage is 20 to 60 mg, bid or tid.
• Diltiazem is started at 60 mg bid; target dosage is 120 to 360 mg bid.
• Amlodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.
• Felodipine is started at 5 mg/d; target dosage is 15 to 30 mg/d.

Felodipine and amlodipine have longer half-lives than other CCBs and are well ­tolerated.

ERA. Used as vasodilators are ambrinsentan (starting dosage, 5 mg/d; target dosage, 10 mg/d), macitentan (starting and target dosage, 10 mg/d), and bosentan (starting dosage, 62.5 mg bid; target dosage, 125 mg bid).

Nitric oxide–cyclic guanosine monophosphate enhancers. These are the PDE5 inhibitors sildenafil (starting and target dosages, 20 mg tid) and tadalafil (starting dosage, 20 or 40 mg/d; target dosage, 40 mg/d), and the guanylate cyclase stimulant riociguat (starting dosage, 1 mg tid; target dosage, 2.5 mg tid). All 3 agents enhance production of the potent vasodilator nitric oxide, production of which is impaired in PH.

Prostanoids. Several options are available:

• Beraprost sodium. For this oral prostacyclin analogue, starting dosage is 20 μg tid; target dosage is the maximum tolerated dosage (as high as 40 μg tid).
• Extended-release beraprost. Starting dosage is 60 μg bid; target dosage is the maximum tolerated dosage (as high as 180 μg bid).
• Oral treprostinil. Starting dosage is 0.25 mg bid or 0.125 mg tid; target dosage is the maximum tolerated dosage.
• Inhaled iloprost. Starting dosage of this prostacyclin analogue is 2.5 μg, 6 to 9 times per day; target dosage is 5 μg, 6 to 9 times per day.
• Inhaled treprostinil. Starting dosage is 18 μg qid; target dosage is 54 to 72 μg qid.
• Eproprostenol is administered by continuous IV infusion, at a starting dosage of 2 ng/kg/min; target dosage is determined by tolerability and effectiveness (typically, 30 ng/kg/min).
• IV treprostinil. Starting dosage 1.25 ng/kg/min; target dosage is determined by tolerability and effectiveness, with a typical dosage of 60 ng/kg/min.

Combination treatment with the agents listed above is often utilized.

Selexipag. This oral selective nonprostainoid prostacyclin receptor agonist is started at 200 μg bid; target dosage is the maximum tolerated, as high as 1600 μg bid.

Continue to: Supportive therapy

 

 

Supportive therapy

The need for oxygen should be addressed in patients with hypoxia in any setting—r­esting, exercise induced, and nocturnal.²⁴ Patients with an arterial blood oxygen pressure < 60 mm Hg (SaO₂ < 90 mm Hg) should be on long-term oxygen therapy.⁶

Common physical findings in pulmonary hypertension include an increased P2 heart sound, high-pitched holosystolic murmur from tricuspid regurgitation, and pulmonic insufficiency murmur.

Diuretics are beneficial in patients with chronic fluid retention from PH that is related to right ventricular failure.²⁴

Pulmonary rehabilitation and exercise. Contrary to common belief that exercise training is contraindicated in patients with PH, exercise training has emerged in the past decade as an effective tool to improve exercise capacity, ventilatory efficiency, and quality of life. While a patient is training, oxygen saturation, measured by pulse oximetry, should be maintained at > 90% throughout the exercise session to avoid hypoxic pulmonary artery vasoconstriction.²⁵

A patient who does not qualify for pulmonary or cardiac rehabilitation should be referred for physical therapy.²⁴

Ongoing follow-up in primary care

Instruct patients not to abruptly discontinue medications that have been prescribed for PH. Ongoing follow-up and monitoring involves assessing right heart function, exercise tolerance, and resting and ambulatory oximetry. Testing for the level of BNP provides prognostic information and allows assessment of treatment response.¹⁵ The frequency of 6MWT, echocardio­graphy, and RHC is decided on a case-by-case basis.

Other considerations

Pregnancy. PAH often affects patients of childbearing age. Because PAH-associated maternal mortality and the risk to the fetus during pregnancy are high, pregnancy is not recommended for patients with PAH. After a diagnosis of PAH in a patient of childbearing age, counseling should be offered at an expert center. Advice on effective contraception methods should be given early on.^10,26-29

Surgery. Every patient with clinically significant PH is at increased risk of perioperative morbidity and death.^30,31 Guidelines recommend that these patients avoid nonessential surgery; if surgery is necessary, care should be provided at a PH expert center.¹⁰

Continue to: Patients with severe PH...

Patients with severe PH should consider surgery for any indication carefully, discussing with the care team their risk and exploring nonsurgical options. Cardiothoracic surgical and liver transplantation services might have highly specific criteria for treating patients with PH, but other essential and nonessential surgeries require individualized risk stratification. Surgery for patients with severe PH and right ventricular dysfunction should be performed at a center equipped to handle high-risk patients.

Other preventive measures. Patients with PAH should^6,10:

• remain current with immunization against influenza virus, SARS-CoV-2, and pneumococcal pneumonia
• avoid high altitudes
• use supplemental oxygen during air travel to keep arterial oxygen saturation > 91%.

Lung transplantation. Patients eligible for transplantation who (1) are at intermediate-to-high risk or high risk or (2) have a REVEAL (Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management) risk score > 7, and who have had an inadequate response to oral combination therapy, should be referred for evaluation for lung transplantation. Placement on the list for lung transplantation is also recommended for patients at high risk of death and who have a REVEAL risk score ≥ 10 despite medical therapy, including a subcutaneous or IV prostacyclin analogue.⁶

PH in infants and children

The Pediatric Task Force of the 6th WSPH has applied the new definition proposed for adult PH (> 20 mm Hg mPAP) to children and infants > 3 months of age (see “Pulmonary hypertension in the pediatric population,” at left^32-36).

CORRESPONDENCE
Madhavi Singh, MD, 1850 East Park Ave., Suite 207, State College, PA 16803; [email protected]

More clinical guidance is needed for monitoring interstitial lung disease (ILD) in patients with rheumatoid arthritis, according to a new commentary.

Though ILD is a leading cause of death among patients with RA, these patients are not routinely screened for ILD, the authors say, and there are currently no guidelines on how to monitor ILD progression in patients with RA.

A.Prof Frank Gaillard, Radiopaedia.org

“ILD associated with rheumatoid arthritis is a disease for which there’s been very little research done, so it’s an area of rheumatology where there are many unknowns,” lead author Elizabeth R. Volkmann, MD, who codirects the connective tissue disease–related interstitial lung disease (CTD-ILD) program at University of California, Los Angeles, told this news organization.

The commentary was published in The Lancet Rheumatology.
 

Defining disease

One of the major unknowns is how to define the disease, she said. RA patients sometimes undergo imaging for other medical reasons, and interstitial lung abnormalities are incidentally detected. These patients can be classified as having “preclinical” or “subclinical” ILD, as they do not yet have symptoms; however, there is no consensus as to what these terms mean, the commentary authors write. “The other problem that we have with these terms is that it sometimes creates the perception that this is a nonworrisome feature of rheumatoid arthritis,” Dr. Volkmann said, although the condition should be followed closely.

“We know we can detect imaging features of ILD in people who may not yet have symptoms, and we need to know when to define a clinically important informality that requires follow-up or treatment,” added John M. Davis III, MD, a rheumatologist at the Mayo Clinic, Rochester, Minn. He was not involved with the work.

Mayo Clinic

Dr. Volkmann proposed eliminating the prefixes “pre” and “sub” when referring to ILD. “In other connective tissue diseases, like systemic sclerosis, for example, we can use the term ‘limited’ or ‘extensive’ ILD, based on the extent of involvement of the ILD on high-resolution computed tomography (HRCT) imaging,” she said. “This could potentially be something that is applied to how we classify patients with RA-ILD.”
 

Tracking ILD progression

Once ILD is identified, monitoring its progression poses challenges, as respiratory symptoms may be difficult to detect. RA patients may already be avoiding exercise because of joint pain, so they may not notice shortness of breath during physical activity, noted Jessica K. Gordon, MD, of the Hospital for Special Surgery, New York, in an interview with this news organization. She was not involved with the commentary. Cough is a potential symptom of ILD, but cough can also be the result of allergies, postnasal drip, or reflux, she said. Making the distinction between “preclinical” and symptomatic disease can be “complicated,” she added; “you may have to really dig.”

Hospital for Special Surgery

Additionally, there has been little research on the outcomes of patients with preclinical or subclinical ILD and clinical ILD, the commentary authors write. “It is therefore conceivable that some patients with rheumatoid arthritis diagnosed with preclinical or subclinical ILD could potentially have worse outcomes if both the rheumatoid arthritis and ILD are not monitored closely,” they note.

To better track RA-associated ILD for patients with and those without symptoms, the authors advocate for monitoring patients using pulmonary testing and CT scanning, as well as evaluating symptoms. How often these assessments should be conducted depends on the individual, they note. In her own practice, Dr. Volkmann sees patients every 3 months to evaluate their symptoms and conduct pulmonary function tests (PFTs). For patients early in the course of ILD, she orders HRCT imaging once per year.

For Dr. Davis, the frequency of follow-up depends on the severity of ILD. “For minimally symptomatic patients without compromised lung function, we would generally follow annually. For patients with symptomatic ILD on stable therapy, we may monitor every 6 months. For patients with active/progressive ILD, we would generally be following at least every 1-3 months,” he said.

Screening and future research

While there is no evidence to recommend screening patients for ILD using CT, there are certain risk factors for ILD in RA patients, including a history of smoking, male sex, and high RA disease activity despite antirheumatic treatment, Dr. Volkmann said. In both of their practices, Dr. Davis and Dr. Volkmann screen with RA via HRCT and PFTs for ILD for patients with known risk factors that predispose them to the lung condition and/or for patients who report respiratory symptoms.

National Jewish Health

“We still don’t have an algorithm [for screening patients], and that is a desperate need in this field,” added Joshua J. Solomon, MD, a pulmonologist at National Jewish Health, Denver, whose research focuses on RA-associated ILD. While recommendations state that all patients with scleroderma should be screened with CT, ILD incidence is lower among patients with RA, and thus these screening recommendations need to be narrowed, he said. But more research is needed to better fine tune recommendations, he said; “The only thing you can do is give some expert consensus until there are good data.”

Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and institutional support for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus. Dr. Gordon, Dr. Davis, and Dr. Solomon report no relevant financial relationships.

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

More clinical guidance is needed for monitoring interstitial lung disease (ILD) in patients with rheumatoid arthritis, according to a new commentary.

Though ILD is a leading cause of death among patients with RA, these patients are not routinely screened for ILD, the authors say, and there are currently no guidelines on how to monitor ILD progression in patients with RA.

A.Prof Frank Gaillard, Radiopaedia.org

“ILD associated with rheumatoid arthritis is a disease for which there’s been very little research done, so it’s an area of rheumatology where there are many unknowns,” lead author Elizabeth R. Volkmann, MD, who codirects the connective tissue disease–related interstitial lung disease (CTD-ILD) program at University of California, Los Angeles, told this news organization.

The commentary was published in The Lancet Rheumatology.
 

Defining disease

One of the major unknowns is how to define the disease, she said. RA patients sometimes undergo imaging for other medical reasons, and interstitial lung abnormalities are incidentally detected. These patients can be classified as having “preclinical” or “subclinical” ILD, as they do not yet have symptoms; however, there is no consensus as to what these terms mean, the commentary authors write. “The other problem that we have with these terms is that it sometimes creates the perception that this is a nonworrisome feature of rheumatoid arthritis,” Dr. Volkmann said, although the condition should be followed closely.

“We know we can detect imaging features of ILD in people who may not yet have symptoms, and we need to know when to define a clinically important informality that requires follow-up or treatment,” added John M. Davis III, MD, a rheumatologist at the Mayo Clinic, Rochester, Minn. He was not involved with the work.

Mayo Clinic

Dr. Volkmann proposed eliminating the prefixes “pre” and “sub” when referring to ILD. “In other connective tissue diseases, like systemic sclerosis, for example, we can use the term ‘limited’ or ‘extensive’ ILD, based on the extent of involvement of the ILD on high-resolution computed tomography (HRCT) imaging,” she said. “This could potentially be something that is applied to how we classify patients with RA-ILD.”
 

Tracking ILD progression

Once ILD is identified, monitoring its progression poses challenges, as respiratory symptoms may be difficult to detect. RA patients may already be avoiding exercise because of joint pain, so they may not notice shortness of breath during physical activity, noted Jessica K. Gordon, MD, of the Hospital for Special Surgery, New York, in an interview with this news organization. She was not involved with the commentary. Cough is a potential symptom of ILD, but cough can also be the result of allergies, postnasal drip, or reflux, she said. Making the distinction between “preclinical” and symptomatic disease can be “complicated,” she added; “you may have to really dig.”

Hospital for Special Surgery

Additionally, there has been little research on the outcomes of patients with preclinical or subclinical ILD and clinical ILD, the commentary authors write. “It is therefore conceivable that some patients with rheumatoid arthritis diagnosed with preclinical or subclinical ILD could potentially have worse outcomes if both the rheumatoid arthritis and ILD are not monitored closely,” they note.

To better track RA-associated ILD for patients with and those without symptoms, the authors advocate for monitoring patients using pulmonary testing and CT scanning, as well as evaluating symptoms. How often these assessments should be conducted depends on the individual, they note. In her own practice, Dr. Volkmann sees patients every 3 months to evaluate their symptoms and conduct pulmonary function tests (PFTs). For patients early in the course of ILD, she orders HRCT imaging once per year.

For Dr. Davis, the frequency of follow-up depends on the severity of ILD. “For minimally symptomatic patients without compromised lung function, we would generally follow annually. For patients with symptomatic ILD on stable therapy, we may monitor every 6 months. For patients with active/progressive ILD, we would generally be following at least every 1-3 months,” he said.

Screening and future research

While there is no evidence to recommend screening patients for ILD using CT, there are certain risk factors for ILD in RA patients, including a history of smoking, male sex, and high RA disease activity despite antirheumatic treatment, Dr. Volkmann said. In both of their practices, Dr. Davis and Dr. Volkmann screen with RA via HRCT and PFTs for ILD for patients with known risk factors that predispose them to the lung condition and/or for patients who report respiratory symptoms.

National Jewish Health

“We still don’t have an algorithm [for screening patients], and that is a desperate need in this field,” added Joshua J. Solomon, MD, a pulmonologist at National Jewish Health, Denver, whose research focuses on RA-associated ILD. While recommendations state that all patients with scleroderma should be screened with CT, ILD incidence is lower among patients with RA, and thus these screening recommendations need to be narrowed, he said. But more research is needed to better fine tune recommendations, he said; “The only thing you can do is give some expert consensus until there are good data.”

Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and institutional support for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus. Dr. Gordon, Dr. Davis, and Dr. Solomon report no relevant financial relationships.

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

More clinical guidance is needed for monitoring interstitial lung disease (ILD) in patients with rheumatoid arthritis, according to a new commentary.

Though ILD is a leading cause of death among patients with RA, these patients are not routinely screened for ILD, the authors say, and there are currently no guidelines on how to monitor ILD progression in patients with RA.

A.Prof Frank Gaillard, Radiopaedia.org

“ILD associated with rheumatoid arthritis is a disease for which there’s been very little research done, so it’s an area of rheumatology where there are many unknowns,” lead author Elizabeth R. Volkmann, MD, who codirects the connective tissue disease–related interstitial lung disease (CTD-ILD) program at University of California, Los Angeles, told this news organization.

The commentary was published in The Lancet Rheumatology.
 

Defining disease

One of the major unknowns is how to define the disease, she said. RA patients sometimes undergo imaging for other medical reasons, and interstitial lung abnormalities are incidentally detected. These patients can be classified as having “preclinical” or “subclinical” ILD, as they do not yet have symptoms; however, there is no consensus as to what these terms mean, the commentary authors write. “The other problem that we have with these terms is that it sometimes creates the perception that this is a nonworrisome feature of rheumatoid arthritis,” Dr. Volkmann said, although the condition should be followed closely.

“We know we can detect imaging features of ILD in people who may not yet have symptoms, and we need to know when to define a clinically important informality that requires follow-up or treatment,” added John M. Davis III, MD, a rheumatologist at the Mayo Clinic, Rochester, Minn. He was not involved with the work.

Mayo Clinic

Dr. Volkmann proposed eliminating the prefixes “pre” and “sub” when referring to ILD. “In other connective tissue diseases, like systemic sclerosis, for example, we can use the term ‘limited’ or ‘extensive’ ILD, based on the extent of involvement of the ILD on high-resolution computed tomography (HRCT) imaging,” she said. “This could potentially be something that is applied to how we classify patients with RA-ILD.”
 

Tracking ILD progression

Once ILD is identified, monitoring its progression poses challenges, as respiratory symptoms may be difficult to detect. RA patients may already be avoiding exercise because of joint pain, so they may not notice shortness of breath during physical activity, noted Jessica K. Gordon, MD, of the Hospital for Special Surgery, New York, in an interview with this news organization. She was not involved with the commentary. Cough is a potential symptom of ILD, but cough can also be the result of allergies, postnasal drip, or reflux, she said. Making the distinction between “preclinical” and symptomatic disease can be “complicated,” she added; “you may have to really dig.”

Hospital for Special Surgery

Additionally, there has been little research on the outcomes of patients with preclinical or subclinical ILD and clinical ILD, the commentary authors write. “It is therefore conceivable that some patients with rheumatoid arthritis diagnosed with preclinical or subclinical ILD could potentially have worse outcomes if both the rheumatoid arthritis and ILD are not monitored closely,” they note.

To better track RA-associated ILD for patients with and those without symptoms, the authors advocate for monitoring patients using pulmonary testing and CT scanning, as well as evaluating symptoms. How often these assessments should be conducted depends on the individual, they note. In her own practice, Dr. Volkmann sees patients every 3 months to evaluate their symptoms and conduct pulmonary function tests (PFTs). For patients early in the course of ILD, she orders HRCT imaging once per year.

For Dr. Davis, the frequency of follow-up depends on the severity of ILD. “For minimally symptomatic patients without compromised lung function, we would generally follow annually. For patients with symptomatic ILD on stable therapy, we may monitor every 6 months. For patients with active/progressive ILD, we would generally be following at least every 1-3 months,” he said.

Screening and future research

While there is no evidence to recommend screening patients for ILD using CT, there are certain risk factors for ILD in RA patients, including a history of smoking, male sex, and high RA disease activity despite antirheumatic treatment, Dr. Volkmann said. In both of their practices, Dr. Davis and Dr. Volkmann screen with RA via HRCT and PFTs for ILD for patients with known risk factors that predispose them to the lung condition and/or for patients who report respiratory symptoms.

National Jewish Health

“We still don’t have an algorithm [for screening patients], and that is a desperate need in this field,” added Joshua J. Solomon, MD, a pulmonologist at National Jewish Health, Denver, whose research focuses on RA-associated ILD. While recommendations state that all patients with scleroderma should be screened with CT, ILD incidence is lower among patients with RA, and thus these screening recommendations need to be narrowed, he said. But more research is needed to better fine tune recommendations, he said; “The only thing you can do is give some expert consensus until there are good data.”

Dr. Volkmann has received consulting and speaking fees from Boehringer Ingelheim and institutional support for performing studies on systemic sclerosis for Kadmon, Forbius, Boehringer Ingelheim, Horizon, and Prometheus. Dr. Gordon, Dr. Davis, and Dr. Solomon report no relevant financial relationships.

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

Both asthma and chronic obstructive pulmonary disease can be challenging to diagnose, and medication-driven episodes of sedation or hypoventilation are often overlooked as causes of acute exacerbations in these conditions, according to a letter published in The Lancet Respiratory Medicine.

“We are concerned about the number of patients we have seen with asthma or chronic obstructive pulmonary disease (COPD) exacerbations who have been prescribed sedative medications,” write Christos V. Chalitsios, PhD, of the University of Nottingham, England, and colleagues.

The authors note that exacerbations are the main complications of both asthma and COPD, and stress the importance of identifying causes and preventive strategies.

Sedatives such as opioids have been shown to depress respiratory drive, reduce muscle tone, and increase the risk of pneumonia, they write. The authors also propose that the risk of sedative-induced aspiration or hypoventilation would be associated with medications including pregabalin, gabapentin, and amitriptyline.

Other mechanisms may be involved in the association between sedatives and exacerbations in asthma and COPD. For example, sedative medications can suppress coughing, which may promote airway mucous compaction and possible infection, the authors write.

Most research involving prevention of asthma and COPD exacerbations has not addressed the potential impact of sedatives taken for reasons outside of obstructive lung disease, the authors say.

“Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs, there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin,” they write.

Polypharmacy is increasingly common and results in many patients with asthma or COPD presenting for treatment of acute exacerbations while on a combination of gabapentin, pregabalin, amitriptyline, and opioids, the authors note; “however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care,” they write. Simply stopping sedatives is not an option for many patients given the addictive nature of these drugs and the unlikely resolution of the condition for which the drugs were prescribed, the authors say. However, “cautious dose reduction” of sedatives is possible once patients understand the reason, they add.

Clinicians may be able to suggest reduced doses and alternative treatments to patients with asthma and COPD while highlighting the risk of respiratory depression and polypharmacy – “potentially reducing the number of exacerbations of obstructive lung disease,” the authors conclude.

The study received no outside funding. The authors have disclosed no relevant financial relationships.

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

Both asthma and chronic obstructive pulmonary disease can be challenging to diagnose, and medication-driven episodes of sedation or hypoventilation are often overlooked as causes of acute exacerbations in these conditions, according to a letter published in The Lancet Respiratory Medicine.

“We are concerned about the number of patients we have seen with asthma or chronic obstructive pulmonary disease (COPD) exacerbations who have been prescribed sedative medications,” write Christos V. Chalitsios, PhD, of the University of Nottingham, England, and colleagues.

The authors note that exacerbations are the main complications of both asthma and COPD, and stress the importance of identifying causes and preventive strategies.

Sedatives such as opioids have been shown to depress respiratory drive, reduce muscle tone, and increase the risk of pneumonia, they write. The authors also propose that the risk of sedative-induced aspiration or hypoventilation would be associated with medications including pregabalin, gabapentin, and amitriptyline.

Other mechanisms may be involved in the association between sedatives and exacerbations in asthma and COPD. For example, sedative medications can suppress coughing, which may promote airway mucous compaction and possible infection, the authors write.

Most research involving prevention of asthma and COPD exacerbations has not addressed the potential impact of sedatives taken for reasons outside of obstructive lung disease, the authors say.

“Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs, there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin,” they write.

Polypharmacy is increasingly common and results in many patients with asthma or COPD presenting for treatment of acute exacerbations while on a combination of gabapentin, pregabalin, amitriptyline, and opioids, the authors note; “however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care,” they write. Simply stopping sedatives is not an option for many patients given the addictive nature of these drugs and the unlikely resolution of the condition for which the drugs were prescribed, the authors say. However, “cautious dose reduction” of sedatives is possible once patients understand the reason, they add.

Clinicians may be able to suggest reduced doses and alternative treatments to patients with asthma and COPD while highlighting the risk of respiratory depression and polypharmacy – “potentially reducing the number of exacerbations of obstructive lung disease,” the authors conclude.

The study received no outside funding. The authors have disclosed no relevant financial relationships.

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

Both asthma and chronic obstructive pulmonary disease can be challenging to diagnose, and medication-driven episodes of sedation or hypoventilation are often overlooked as causes of acute exacerbations in these conditions, according to a letter published in The Lancet Respiratory Medicine.

“We are concerned about the number of patients we have seen with asthma or chronic obstructive pulmonary disease (COPD) exacerbations who have been prescribed sedative medications,” write Christos V. Chalitsios, PhD, of the University of Nottingham, England, and colleagues.

The authors note that exacerbations are the main complications of both asthma and COPD, and stress the importance of identifying causes and preventive strategies.

Sedatives such as opioids have been shown to depress respiratory drive, reduce muscle tone, and increase the risk of pneumonia, they write. The authors also propose that the risk of sedative-induced aspiration or hypoventilation would be associated with medications including pregabalin, gabapentin, and amitriptyline.

Other mechanisms may be involved in the association between sedatives and exacerbations in asthma and COPD. For example, sedative medications can suppress coughing, which may promote airway mucous compaction and possible infection, the authors write.

Most research involving prevention of asthma and COPD exacerbations has not addressed the potential impact of sedatives taken for reasons outside of obstructive lung disease, the authors say.

“Although the risk of sedation and hypoventilation events are known to be increased by opioids and antipsychotic drugs, there has not been a systematic assessment of commonly prescribed medications with potential respiratory side-effects, including gabapentin, amitriptyline, and pregabalin,” they write.

Polypharmacy is increasingly common and results in many patients with asthma or COPD presenting for treatment of acute exacerbations while on a combination of gabapentin, pregabalin, amitriptyline, and opioids, the authors note; “however, there is little data or disease-specific guidance on how best to manage this problem, which often starts with a prescription in primary care,” they write. Simply stopping sedatives is not an option for many patients given the addictive nature of these drugs and the unlikely resolution of the condition for which the drugs were prescribed, the authors say. However, “cautious dose reduction” of sedatives is possible once patients understand the reason, they add.

Clinicians may be able to suggest reduced doses and alternative treatments to patients with asthma and COPD while highlighting the risk of respiratory depression and polypharmacy – “potentially reducing the number of exacerbations of obstructive lung disease,” the authors conclude.

The study received no outside funding. The authors have disclosed no relevant financial relationships.

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

Insomnia – difficulty falling or staying asleep – was associated with a 69% greater risk of having a myocardial infarction than among adults without insomnia, according to new research.

Those who slept 5 or fewer hours per night had the highest risk for MI, and those with both diabetes and insomnia had double the risk for MI, compared with patients without these comorbidities.

amenic181/Getty Images

The findings are from a meta-analysis of studies in more than 1 million patients, almost all without prior MI who were, on average, in their early 50s and followed for 9 years.

Yomna E. Dean, a medical student at Alexandria (Egypt) University, reported these results in a press briefing, and the study was simultaneously published in Clinical Cardiology. It will be presented at the upcoming at the annual scientific sessions of the American College of Cardiology.

“Insomnia and ]at least] 5 hours of sleep are highly associated with increased incidence of MI, an association comparable to that of other MI risk factors and as such, it should be considered as a risk factor for MI and to be incorporated into MI prevention guidelines,” the researchers concluded.

“We believe that [insomnia] should be screened and patients should be educated about the importance of sleep because nowadays insomnia is no longer a disease – sleep deprivation could also be a life choice,” Ms, Dean told a press conference prior to the meeting.

“Clinicians must educate the patients about the importance of sleep in maintaining a healthy heart and encourage proper sleep hygiene,” Ms. Dean reiterated in an email. “And if a patient still has insomnia, other methods should be considered such as cognitive-behavior[al] therapy for insomnia [CBT-I].”
 

Adds to growing evidence

This study does not allow any conclusion about whether treating insomnia will reduce heart attack risk, Jennifer L. Martin, PhD, president of the American Academy of Sleep Medicine, noted in a comment. Nor does it report the diversity of study participants, since insomnia is also a health equity issue, she noted, and insomnia symptoms and comorbidities were self-reported.

However, this analysis “adds to the growing evidence that poor quality or insufficient sleep is associated with poor health,” said Dr. Martin, professor of medicine at the University of California, Los Angeles, who was not involved with this research.

The study reinforces the recommendation from the American Heart Association, which includes “Get Healthy Sleep” as one of “Life’s Essential 8” for heart health, Dr. Martin noted.

“Particularly in primary care where disease prevention and health promotion are important, clinicians should be asking all patients about their sleep – just like they ask about diet and exercise – as a key aspect of maintaining heart health,” she said.

Advice about basic sleep hygiene advice is a first step, she noted.

When improved sleep hygiene is not enough to address chronic insomnia, the AASM’s clinical practice guidelines and the guidelines of the Department of Veterans Affairs/Department of Defense, recommend first-line treatment with CBT-I, typically offered by a sleep specialist or mental health clinician.

Similarly, the American College of Physicians suggests that sleeping pills should be reserved for short-term use in patients who may not benefit sufficiently from CBT-I.
 

Sleeping too little, too much, equally harmful

“Studies have found that insomnia and subsequent sleep deprivation puts the body under stress,” Ms. Dean said. “This triggers cortisol release which could accelerate atherosclerosis,” and increase risk of MI.

For this analysis, the researchers identified nine observational studies, published from 1998 to 2019, with data on incident MI in adults who had insomnia.

The diagnosis of insomnia was based on ICD diagnostic codes or on the DSM‐5, which defines insomnia as the presence of any of the following three symptoms: difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening with inability to return to sleep. Patients with sleep apnea were excluded.

The studies were in populations in China, Germany, Norway, Taiwan, United Kingdom, and United States, in 1.1 million adults aged 18 and older. The patients had a mean age of 52 years and 13% had insomnia.

During follow-up, 2,406 of 153,881 patients with insomnia, and 12,398 of 1,030,375 patients without insomnia had an MI.

In the pooled analysis, patients with insomnia had a significantly increased risk of MI (relative risk, 1.69; P < .00001), after adjusting for age, gender, diabetes, hypertension, high cholesterol, and smoking.

Sleeping 5 hours or less was associated with a greater risk for MI than sleeping 6 hours, or 7-8 hours, but sleeping 9 hours or more was just as harmful.

Patients who had difficulty initiating and maintaining sleep – two symptoms of insomnia – had a 13% increased risk for MI compared with other patients (RR, 1.13; P = .003).

However, patients who had nonrestorative sleep and daytime dysfunction despite adequate sleep – which is common – did not have an increased risk of MI, compared with other patients (RR, 1.06; P = .46).

Women with insomnia had a 2.24-fold greater risk for MI than other women, whereas men with insomnia had a 2.03-fold greater risk for MI than other men.

Patients with insomnia had a greater risk for MI than those without insomnia in subgroups based on patients’ age (< 65 and > 65), follow up duration (≤ 5 years and > 5 years), and comorbidities (diabetes, hypertension, and hyperlipidemia).

The authors reported no relevant financial relationships.

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

Insomnia – difficulty falling or staying asleep – was associated with a 69% greater risk of having a myocardial infarction than among adults without insomnia, according to new research.

Those who slept 5 or fewer hours per night had the highest risk for MI, and those with both diabetes and insomnia had double the risk for MI, compared with patients without these comorbidities.

amenic181/Getty Images

The findings are from a meta-analysis of studies in more than 1 million patients, almost all without prior MI who were, on average, in their early 50s and followed for 9 years.

Yomna E. Dean, a medical student at Alexandria (Egypt) University, reported these results in a press briefing, and the study was simultaneously published in Clinical Cardiology. It will be presented at the upcoming at the annual scientific sessions of the American College of Cardiology.

“Insomnia and ]at least] 5 hours of sleep are highly associated with increased incidence of MI, an association comparable to that of other MI risk factors and as such, it should be considered as a risk factor for MI and to be incorporated into MI prevention guidelines,” the researchers concluded.

“We believe that [insomnia] should be screened and patients should be educated about the importance of sleep because nowadays insomnia is no longer a disease – sleep deprivation could also be a life choice,” Ms, Dean told a press conference prior to the meeting.

“Clinicians must educate the patients about the importance of sleep in maintaining a healthy heart and encourage proper sleep hygiene,” Ms. Dean reiterated in an email. “And if a patient still has insomnia, other methods should be considered such as cognitive-behavior[al] therapy for insomnia [CBT-I].”
 

Adds to growing evidence

This study does not allow any conclusion about whether treating insomnia will reduce heart attack risk, Jennifer L. Martin, PhD, president of the American Academy of Sleep Medicine, noted in a comment. Nor does it report the diversity of study participants, since insomnia is also a health equity issue, she noted, and insomnia symptoms and comorbidities were self-reported.

However, this analysis “adds to the growing evidence that poor quality or insufficient sleep is associated with poor health,” said Dr. Martin, professor of medicine at the University of California, Los Angeles, who was not involved with this research.

The study reinforces the recommendation from the American Heart Association, which includes “Get Healthy Sleep” as one of “Life’s Essential 8” for heart health, Dr. Martin noted.

“Particularly in primary care where disease prevention and health promotion are important, clinicians should be asking all patients about their sleep – just like they ask about diet and exercise – as a key aspect of maintaining heart health,” she said.

Advice about basic sleep hygiene advice is a first step, she noted.

When improved sleep hygiene is not enough to address chronic insomnia, the AASM’s clinical practice guidelines and the guidelines of the Department of Veterans Affairs/Department of Defense, recommend first-line treatment with CBT-I, typically offered by a sleep specialist or mental health clinician.

Similarly, the American College of Physicians suggests that sleeping pills should be reserved for short-term use in patients who may not benefit sufficiently from CBT-I.
 

Sleeping too little, too much, equally harmful

“Studies have found that insomnia and subsequent sleep deprivation puts the body under stress,” Ms. Dean said. “This triggers cortisol release which could accelerate atherosclerosis,” and increase risk of MI.

For this analysis, the researchers identified nine observational studies, published from 1998 to 2019, with data on incident MI in adults who had insomnia.

The diagnosis of insomnia was based on ICD diagnostic codes or on the DSM‐5, which defines insomnia as the presence of any of the following three symptoms: difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening with inability to return to sleep. Patients with sleep apnea were excluded.

The studies were in populations in China, Germany, Norway, Taiwan, United Kingdom, and United States, in 1.1 million adults aged 18 and older. The patients had a mean age of 52 years and 13% had insomnia.

During follow-up, 2,406 of 153,881 patients with insomnia, and 12,398 of 1,030,375 patients without insomnia had an MI.

In the pooled analysis, patients with insomnia had a significantly increased risk of MI (relative risk, 1.69; P < .00001), after adjusting for age, gender, diabetes, hypertension, high cholesterol, and smoking.

Sleeping 5 hours or less was associated with a greater risk for MI than sleeping 6 hours, or 7-8 hours, but sleeping 9 hours or more was just as harmful.

Patients who had difficulty initiating and maintaining sleep – two symptoms of insomnia – had a 13% increased risk for MI compared with other patients (RR, 1.13; P = .003).

However, patients who had nonrestorative sleep and daytime dysfunction despite adequate sleep – which is common – did not have an increased risk of MI, compared with other patients (RR, 1.06; P = .46).

Women with insomnia had a 2.24-fold greater risk for MI than other women, whereas men with insomnia had a 2.03-fold greater risk for MI than other men.

Patients with insomnia had a greater risk for MI than those without insomnia in subgroups based on patients’ age (< 65 and > 65), follow up duration (≤ 5 years and > 5 years), and comorbidities (diabetes, hypertension, and hyperlipidemia).

The authors reported no relevant financial relationships.

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

Insomnia – difficulty falling or staying asleep – was associated with a 69% greater risk of having a myocardial infarction than among adults without insomnia, according to new research.

Those who slept 5 or fewer hours per night had the highest risk for MI, and those with both diabetes and insomnia had double the risk for MI, compared with patients without these comorbidities.

amenic181/Getty Images

The findings are from a meta-analysis of studies in more than 1 million patients, almost all without prior MI who were, on average, in their early 50s and followed for 9 years.

Yomna E. Dean, a medical student at Alexandria (Egypt) University, reported these results in a press briefing, and the study was simultaneously published in Clinical Cardiology. It will be presented at the upcoming at the annual scientific sessions of the American College of Cardiology.

“Insomnia and ]at least] 5 hours of sleep are highly associated with increased incidence of MI, an association comparable to that of other MI risk factors and as such, it should be considered as a risk factor for MI and to be incorporated into MI prevention guidelines,” the researchers concluded.

“We believe that [insomnia] should be screened and patients should be educated about the importance of sleep because nowadays insomnia is no longer a disease – sleep deprivation could also be a life choice,” Ms, Dean told a press conference prior to the meeting.

“Clinicians must educate the patients about the importance of sleep in maintaining a healthy heart and encourage proper sleep hygiene,” Ms. Dean reiterated in an email. “And if a patient still has insomnia, other methods should be considered such as cognitive-behavior[al] therapy for insomnia [CBT-I].”
 

Adds to growing evidence

This study does not allow any conclusion about whether treating insomnia will reduce heart attack risk, Jennifer L. Martin, PhD, president of the American Academy of Sleep Medicine, noted in a comment. Nor does it report the diversity of study participants, since insomnia is also a health equity issue, she noted, and insomnia symptoms and comorbidities were self-reported.

However, this analysis “adds to the growing evidence that poor quality or insufficient sleep is associated with poor health,” said Dr. Martin, professor of medicine at the University of California, Los Angeles, who was not involved with this research.

The study reinforces the recommendation from the American Heart Association, which includes “Get Healthy Sleep” as one of “Life’s Essential 8” for heart health, Dr. Martin noted.

“Particularly in primary care where disease prevention and health promotion are important, clinicians should be asking all patients about their sleep – just like they ask about diet and exercise – as a key aspect of maintaining heart health,” she said.

Advice about basic sleep hygiene advice is a first step, she noted.

When improved sleep hygiene is not enough to address chronic insomnia, the AASM’s clinical practice guidelines and the guidelines of the Department of Veterans Affairs/Department of Defense, recommend first-line treatment with CBT-I, typically offered by a sleep specialist or mental health clinician.

Similarly, the American College of Physicians suggests that sleeping pills should be reserved for short-term use in patients who may not benefit sufficiently from CBT-I.
 

Sleeping too little, too much, equally harmful

“Studies have found that insomnia and subsequent sleep deprivation puts the body under stress,” Ms. Dean said. “This triggers cortisol release which could accelerate atherosclerosis,” and increase risk of MI.

For this analysis, the researchers identified nine observational studies, published from 1998 to 2019, with data on incident MI in adults who had insomnia.

The diagnosis of insomnia was based on ICD diagnostic codes or on the DSM‐5, which defines insomnia as the presence of any of the following three symptoms: difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening with inability to return to sleep. Patients with sleep apnea were excluded.

The studies were in populations in China, Germany, Norway, Taiwan, United Kingdom, and United States, in 1.1 million adults aged 18 and older. The patients had a mean age of 52 years and 13% had insomnia.

During follow-up, 2,406 of 153,881 patients with insomnia, and 12,398 of 1,030,375 patients without insomnia had an MI.

In the pooled analysis, patients with insomnia had a significantly increased risk of MI (relative risk, 1.69; P < .00001), after adjusting for age, gender, diabetes, hypertension, high cholesterol, and smoking.

Sleeping 5 hours or less was associated with a greater risk for MI than sleeping 6 hours, or 7-8 hours, but sleeping 9 hours or more was just as harmful.

Patients who had difficulty initiating and maintaining sleep – two symptoms of insomnia – had a 13% increased risk for MI compared with other patients (RR, 1.13; P = .003).

However, patients who had nonrestorative sleep and daytime dysfunction despite adequate sleep – which is common – did not have an increased risk of MI, compared with other patients (RR, 1.06; P = .46).

Women with insomnia had a 2.24-fold greater risk for MI than other women, whereas men with insomnia had a 2.03-fold greater risk for MI than other men.

Patients with insomnia had a greater risk for MI than those without insomnia in subgroups based on patients’ age (< 65 and > 65), follow up duration (≤ 5 years and > 5 years), and comorbidities (diabetes, hypertension, and hyperlipidemia).

The authors reported no relevant financial relationships.

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

FRANCE – Conducted every 5 years since 2005, the Cancer Survey documents the knowledge, perceptions, and way of life of the French people in relation to cancer. The French National Cancer Institute (InCA), in partnership with Public Health France (SPF), has published the results of its 2021 survey. The researchers analyzed responses to telephone interviews of a representative sample of almost 5,000 individuals aged 15-85 years.

This study shows how thinking has changed over time and how difficult it is to alter preconceived notions.
 

Is cancer hereditary?

The report shows that 67.7% of respondents believe that cancer is a hereditary disease. Respondents were asked to explain their answer. “Data show that medical practices for cancer treatment substantiate this belief [that cancer is hereditary],” wrote the authors of the report.

“Indeed, health care professionals almost systematically ask questions about family history of breast cancer and, when a family member has been diagnosed with cancer, medical monitoring of other family members is often sought out, thus reinforcing the belief that cancer is hereditary,” they said.

Furthermore, there seems to be confusion regarding the role of genes in the development of cancer. A person can inherit cancer-predisposing genes, not cancer itself. The authors highlighted their concern that this confusion may “lead people to think that prevention measures are unnecessary because cancer is inherited.”
 

Misconceptions about smoking

About 41% of smokers think that the length of time one has been smoking is the biggest determining factor for developing cancer; 58.1% think the number of cigarettes smoked per day has a bigger impact.

Experts at InCA and SPF put the debate to rest, stating that prolonged exposure to carcinogenic substances is far more toxic. As for the danger threshold concerning the number of cigarettes smoked per day, respondents believed this to be 9.2 cigarettes per day, on average. They believed that the danger threshold for the number of years as an active smoker is 13.4, on average.

“The [survey] respondents clearly understand that smoking carries a risk, but many smokers think that light smoking or smoking for a short period of time doesn’t carry any risks.” Yet it is understood that even occasional tobacco consumption increases mortality.

This was not the only misconception regarding smoking and its relationship with cancer. About 34% of survey respondents agreed with the following statement: “Smoking doesn’t cause cancer unless you’re a heavy smoker and have smoked for a long time.” Furthermore, 43.3% agreed with the statement, “Pollution is more likely to cause cancer than smoking,” 54.6% think that “exercising cleans your lungs of tobacco,” and 61.6% think that “a smoker can prevent developing cancer caused by smoking if they know to quit on time.”
 

Overweight and obesity

Although diet and excess weight represent the third and fourth biggest avoidable cancer risk factors, after smoking and alcohol, only 30% of survey respondents knew of this link.

“Among the causes of cancer known and cited by respondents without prompting, excessive weight and obesity were mentioned only 100 times out of 12,558 responses,” highlighted the authors of the report. The explanation put forward by the authors is that discourse about diet has been more focused on diet as a protective health factor, especially in preventing cardiovascular diseases. “The link between cancer and diet is less prominent in the public space,” they noted.
 

Breastfeeding and cancer

About 63% of survey respondents, which for the first time included both women and men, believe that breastfeeding does not affect mothers’ risk of breast cancer, but this is a misconception. And almost 1 in 3 respondents said that breastfeeding provides health benefits for the mother.

Artificial UV rays

Exposure to UV rays, whether of natural or artificial origin, is a major risk factor for skin cancer. However, 1 in 5 people (20.9%) think that a session in a tanning bed is less harmful than sun exposure.

Daily stress

Regarding psychological factors linked to cancer, the authors noted that risk factors not supported by scientific evidence were, ironically, cited more often by respondents than proven risk factors. There is a real knowledge gap between scientific data and the beliefs of the French people. For example, “working at night” is largely not seen as a risk factor, but data show that it presents a clear risk. However, “not being able to express one’s feelings,” “having been weakened by traumatic experiences,” and “being exposed to the stress of modern life” are seen as risk factors of cancer, without any scientific evidence.

Cigarettes and e-cigarettes

About 53% of respondents agreed that “e-cigarettes are just as harmful or more harmful than traditional cigarettes.” Nicotine and the flavors in e-cigarettes are largely perceived as “very” or “extremely” harmful to the health of a person. However, the authors note that “no published study on nicotine substitutes has shown harmful effects on the health of a person, let alone determined it a risk factor for cancer. The nicotine doses in e-cigarettes are similar to traditional nicotine substitutes, and no cytotoxic effect of nicotine in its inhaled form has been found.” There seems to be confusion between dependence and risk of cancer.

Alcohol consumption

Eight of 10 respondents believe that “some people can drink a lot of alcohol all their life without ever getting cancer,” which goes against the scientific literature. The authors of the report state that the negative effects of alcohol on health seem poorly understood. Although alcohol is the second biggest cause of cancer, only a third of survey respondents cited it without having been prompted as one of the main causes of cancer. And 23.5% even think that “in terms of decreasing your risk of cancer, it’s better to drink a little wine than to drink no wine at all.”

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

FRANCE – Conducted every 5 years since 2005, the Cancer Survey documents the knowledge, perceptions, and way of life of the French people in relation to cancer. The French National Cancer Institute (InCA), in partnership with Public Health France (SPF), has published the results of its 2021 survey. The researchers analyzed responses to telephone interviews of a representative sample of almost 5,000 individuals aged 15-85 years.

This study shows how thinking has changed over time and how difficult it is to alter preconceived notions.
 

Is cancer hereditary?

The report shows that 67.7% of respondents believe that cancer is a hereditary disease. Respondents were asked to explain their answer. “Data show that medical practices for cancer treatment substantiate this belief [that cancer is hereditary],” wrote the authors of the report.

“Indeed, health care professionals almost systematically ask questions about family history of breast cancer and, when a family member has been diagnosed with cancer, medical monitoring of other family members is often sought out, thus reinforcing the belief that cancer is hereditary,” they said.

Furthermore, there seems to be confusion regarding the role of genes in the development of cancer. A person can inherit cancer-predisposing genes, not cancer itself. The authors highlighted their concern that this confusion may “lead people to think that prevention measures are unnecessary because cancer is inherited.”
 

Misconceptions about smoking

About 41% of smokers think that the length of time one has been smoking is the biggest determining factor for developing cancer; 58.1% think the number of cigarettes smoked per day has a bigger impact.

Experts at InCA and SPF put the debate to rest, stating that prolonged exposure to carcinogenic substances is far more toxic. As for the danger threshold concerning the number of cigarettes smoked per day, respondents believed this to be 9.2 cigarettes per day, on average. They believed that the danger threshold for the number of years as an active smoker is 13.4, on average.

“The [survey] respondents clearly understand that smoking carries a risk, but many smokers think that light smoking or smoking for a short period of time doesn’t carry any risks.” Yet it is understood that even occasional tobacco consumption increases mortality.

This was not the only misconception regarding smoking and its relationship with cancer. About 34% of survey respondents agreed with the following statement: “Smoking doesn’t cause cancer unless you’re a heavy smoker and have smoked for a long time.” Furthermore, 43.3% agreed with the statement, “Pollution is more likely to cause cancer than smoking,” 54.6% think that “exercising cleans your lungs of tobacco,” and 61.6% think that “a smoker can prevent developing cancer caused by smoking if they know to quit on time.”
 

Overweight and obesity

Although diet and excess weight represent the third and fourth biggest avoidable cancer risk factors, after smoking and alcohol, only 30% of survey respondents knew of this link.

“Among the causes of cancer known and cited by respondents without prompting, excessive weight and obesity were mentioned only 100 times out of 12,558 responses,” highlighted the authors of the report. The explanation put forward by the authors is that discourse about diet has been more focused on diet as a protective health factor, especially in preventing cardiovascular diseases. “The link between cancer and diet is less prominent in the public space,” they noted.
 

Breastfeeding and cancer

About 63% of survey respondents, which for the first time included both women and men, believe that breastfeeding does not affect mothers’ risk of breast cancer, but this is a misconception. And almost 1 in 3 respondents said that breastfeeding provides health benefits for the mother.

Artificial UV rays

Exposure to UV rays, whether of natural or artificial origin, is a major risk factor for skin cancer. However, 1 in 5 people (20.9%) think that a session in a tanning bed is less harmful than sun exposure.

Daily stress

Regarding psychological factors linked to cancer, the authors noted that risk factors not supported by scientific evidence were, ironically, cited more often by respondents than proven risk factors. There is a real knowledge gap between scientific data and the beliefs of the French people. For example, “working at night” is largely not seen as a risk factor, but data show that it presents a clear risk. However, “not being able to express one’s feelings,” “having been weakened by traumatic experiences,” and “being exposed to the stress of modern life” are seen as risk factors of cancer, without any scientific evidence.

Cigarettes and e-cigarettes

About 53% of respondents agreed that “e-cigarettes are just as harmful or more harmful than traditional cigarettes.” Nicotine and the flavors in e-cigarettes are largely perceived as “very” or “extremely” harmful to the health of a person. However, the authors note that “no published study on nicotine substitutes has shown harmful effects on the health of a person, let alone determined it a risk factor for cancer. The nicotine doses in e-cigarettes are similar to traditional nicotine substitutes, and no cytotoxic effect of nicotine in its inhaled form has been found.” There seems to be confusion between dependence and risk of cancer.

Alcohol consumption

Eight of 10 respondents believe that “some people can drink a lot of alcohol all their life without ever getting cancer,” which goes against the scientific literature. The authors of the report state that the negative effects of alcohol on health seem poorly understood. Although alcohol is the second biggest cause of cancer, only a third of survey respondents cited it without having been prompted as one of the main causes of cancer. And 23.5% even think that “in terms of decreasing your risk of cancer, it’s better to drink a little wine than to drink no wine at all.”

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.

FRANCE – Conducted every 5 years since 2005, the Cancer Survey documents the knowledge, perceptions, and way of life of the French people in relation to cancer. The French National Cancer Institute (InCA), in partnership with Public Health France (SPF), has published the results of its 2021 survey. The researchers analyzed responses to telephone interviews of a representative sample of almost 5,000 individuals aged 15-85 years.

This study shows how thinking has changed over time and how difficult it is to alter preconceived notions.
 

Is cancer hereditary?

The report shows that 67.7% of respondents believe that cancer is a hereditary disease. Respondents were asked to explain their answer. “Data show that medical practices for cancer treatment substantiate this belief [that cancer is hereditary],” wrote the authors of the report.

“Indeed, health care professionals almost systematically ask questions about family history of breast cancer and, when a family member has been diagnosed with cancer, medical monitoring of other family members is often sought out, thus reinforcing the belief that cancer is hereditary,” they said.

Furthermore, there seems to be confusion regarding the role of genes in the development of cancer. A person can inherit cancer-predisposing genes, not cancer itself. The authors highlighted their concern that this confusion may “lead people to think that prevention measures are unnecessary because cancer is inherited.”
 

Misconceptions about smoking

About 41% of smokers think that the length of time one has been smoking is the biggest determining factor for developing cancer; 58.1% think the number of cigarettes smoked per day has a bigger impact.

Experts at InCA and SPF put the debate to rest, stating that prolonged exposure to carcinogenic substances is far more toxic. As for the danger threshold concerning the number of cigarettes smoked per day, respondents believed this to be 9.2 cigarettes per day, on average. They believed that the danger threshold for the number of years as an active smoker is 13.4, on average.

“The [survey] respondents clearly understand that smoking carries a risk, but many smokers think that light smoking or smoking for a short period of time doesn’t carry any risks.” Yet it is understood that even occasional tobacco consumption increases mortality.

This was not the only misconception regarding smoking and its relationship with cancer. About 34% of survey respondents agreed with the following statement: “Smoking doesn’t cause cancer unless you’re a heavy smoker and have smoked for a long time.” Furthermore, 43.3% agreed with the statement, “Pollution is more likely to cause cancer than smoking,” 54.6% think that “exercising cleans your lungs of tobacco,” and 61.6% think that “a smoker can prevent developing cancer caused by smoking if they know to quit on time.”
 

Overweight and obesity

Although diet and excess weight represent the third and fourth biggest avoidable cancer risk factors, after smoking and alcohol, only 30% of survey respondents knew of this link.

“Among the causes of cancer known and cited by respondents without prompting, excessive weight and obesity were mentioned only 100 times out of 12,558 responses,” highlighted the authors of the report. The explanation put forward by the authors is that discourse about diet has been more focused on diet as a protective health factor, especially in preventing cardiovascular diseases. “The link between cancer and diet is less prominent in the public space,” they noted.
 

Breastfeeding and cancer

About 63% of survey respondents, which for the first time included both women and men, believe that breastfeeding does not affect mothers’ risk of breast cancer, but this is a misconception. And almost 1 in 3 respondents said that breastfeeding provides health benefits for the mother.

Artificial UV rays

Exposure to UV rays, whether of natural or artificial origin, is a major risk factor for skin cancer. However, 1 in 5 people (20.9%) think that a session in a tanning bed is less harmful than sun exposure.

Daily stress

Regarding psychological factors linked to cancer, the authors noted that risk factors not supported by scientific evidence were, ironically, cited more often by respondents than proven risk factors. There is a real knowledge gap between scientific data and the beliefs of the French people. For example, “working at night” is largely not seen as a risk factor, but data show that it presents a clear risk. However, “not being able to express one’s feelings,” “having been weakened by traumatic experiences,” and “being exposed to the stress of modern life” are seen as risk factors of cancer, without any scientific evidence.

Cigarettes and e-cigarettes

About 53% of respondents agreed that “e-cigarettes are just as harmful or more harmful than traditional cigarettes.” Nicotine and the flavors in e-cigarettes are largely perceived as “very” or “extremely” harmful to the health of a person. However, the authors note that “no published study on nicotine substitutes has shown harmful effects on the health of a person, let alone determined it a risk factor for cancer. The nicotine doses in e-cigarettes are similar to traditional nicotine substitutes, and no cytotoxic effect of nicotine in its inhaled form has been found.” There seems to be confusion between dependence and risk of cancer.

Alcohol consumption

Eight of 10 respondents believe that “some people can drink a lot of alcohol all their life without ever getting cancer,” which goes against the scientific literature. The authors of the report state that the negative effects of alcohol on health seem poorly understood. Although alcohol is the second biggest cause of cancer, only a third of survey respondents cited it without having been prompted as one of the main causes of cancer. And 23.5% even think that “in terms of decreasing your risk of cancer, it’s better to drink a little wine than to drink no wine at all.”

This article was translated from the Medscape French edition. A version of this article appeared on Medscape.com.