BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

Immune checkpoint inhibitor (ICI)–induced inflammatory arthritis (IA) can remain active months and even years after ending ICI therapy, according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.

“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”

Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.

To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.

Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.

According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).

The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.

The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.

SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.

Immune checkpoint inhibitor (ICI)–induced inflammatory arthritis (IA) can remain active months and even years after ending ICI therapy, according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.

“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”

Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.

To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.

Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.

According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).

The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.

The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.

SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.

Immune checkpoint inhibitor (ICI)–induced inflammatory arthritis (IA) can remain active months and even years after ending ICI therapy, according to a new study of long-term outcomes of immune-related adverse events published in Annals of the Rheumatic Diseases.

“This study is one of the largest longitudinal reports to date of patients with ICI-induced IA and the first to evaluate persistence of ICI-induced IA and identify influential factors on outcome,” wrote Tawnie J. Braaten, MD, and coauthors. “Continued clinical and translational investigation on larger longitudinal cohorts will allow for increased understanding of pathophysiology and determination of the best clinical care for patients with ICI-induced IA.”

Dr. Braaten conducted the study at Johns Hopkins University, Baltimore, when she was a postdoctoral fellow there, and she is now in the division of rheumatology at the University of Utah, Salt Lake City.

To determine how long IA can persist after patients cease ICI therapy, along with factors associated with its persistence, the researchers studied 60 patients who were referred to the Johns Hopkins Arthritis Center for IA caused by ICIs. The patients – 32 females and 28 males – had a median follow-up of 9 months after ICI cessation.

Of the 51 patients with 3-month follow-up data, 70.6% had active IA. Of the 41 patients with 6-month follow-up data, 48.8% had active IA. All told, 53.3% of patients had active IA at their last follow-up visit, which occurred anywhere from 1 to 24 months after stopping ICI therapy.

According to univariable analysis, arthritis was less likely to improve in patients with a longer duration of ICI exposure (hazard ratio, 0.93; 95% confidence interval, 0.87-0.99; P = .02), in patients receiving combination ICI therapy (HR, 0.29; 95% CI, 0.12-0.72; P = .008) and in patients with a history of other immune-related adverse events (HR, 0.61; 95% CI, 0.39-0.95; P = .03).

The authors acknowledged their study’s limitations, including a potential selection bias for symptomatic individuals and the possibility that persistent IA sufferers may have pursued follow-up for longer periods of time. In addition, they noted that some patients were omitted from analysis if they were on a blinded clinical trial or had been receiving an investigational immunotherapy agent.

The study was funded via a grant from Bristol-Myers Squibb, an arthritis fellowship award from AbbVie, and additional financial support from the Camille Julia Morgan Arthritis Research and Education Fund, the Jerome L. Greene Foundation, and the National Institutes of Health. The authors reported various conflicts of interest, including receiving honoraria, grants, and research funding from numerous pharmaceutical companies.

SOURCE: Braaten TJ et al. Ann Rheum Dis. 2019 Sep 20. doi: 10.1136/annrheumdis-2019-216109.

PARIS – The 5-year mortality rate associated with untreated moderate aortic stenosis is just as grim as it is for severe aortic stenosis, according to new findings from the largest-ever study of the natural history of aortic stenosis.

“These data provide a clear signal of the expected adverse outcomes for individuals presenting across the globe with a mean aortic valve gradient greater than 20.0 mm Hg or a peak aortic valve velocity above 3.0 m/sec,” Geoff Strange, PhD, said in presenting an analysis from NEDA, the National Echocardiography Database of Australia, at the annual congress of the European Society of Cardiology.

These results, if confirmed in other large datasets, could potentially have enormous implications for the use of transcatheter and surgical aortic valve replacement, interventions which until now have been restricted to patients with severe aortic stenosis (AS) as defined by an aortic valve (AV) mean gradient in excess of 40 mm Hg or a peak AV velocity greater than 4.0 m/sec. This restriction was based on what Dr. Strange considers rather limited and flimsy evidence suggesting that the mortality associated with AS was negligible except in severe AS.

“Cut points used to stratify for interventional strategies are based on very small numbers,” observed Dr. Strange, professor of medicine at the University of Notre Dame in Fremantle, Australia.

The NEDA findings, he added, constitute a call to action: “These data provide the impetus for a contemporary evaluation of the risk-to-benefit ratio of intervention in the moderate AS population,” Dr. Strange declared.

He and his NEDA coinvestigators analyzed echocardiographic data on 241,303 individuals in the Australian database, zeroing in on the 25,827 with untreated mild, moderate, or severe native valve AS. To place the size and scope of this project into perspective, the next-largest study of the natural history of untreated AS included 1,375 individuals – and that study was in turn roughly 10-fold bigger than the handful of other published studies addressing this issue.

A key finding in the NEDA study was that the 5-year all-cause mortality rate of 61.4% in the group with moderate AS wasn’t significantly different from the 64.6% rate in those with severe AS (see graphic).

The investigators performed additional analyses, analyzing peak velocity and mean gradient as continuous variables and stratifying patients into quintiles on that basis. They found that the top quintile for AV velocity started very low, at 1.73 m/sec, while the top quintile for mean AV gradient also started at a surprisingly low level: greater than 9.6 mm Hg. They noted that both all-cause and cardiovascular-specific mortality rates were basically flat until taking what Dr. Strange described as “a sharp pivot point upward” right around 20 mm Hg or 3 m/sec.

“No matter how we looked at these data – whether we looked at patients with or without left heart disease, whether we used the dimensionless index, whether we adjusted for stroke volume index, whether we stratified between age above or below 65, whether we used the gradient, the velocity, or the AV area – this threshold of increasing mortality at around 20 mm Hg or 3 m/sec continued to emerge,” according to Dr. Strange.

He noted that this study used real-world data with hard endpoints – actuarial patient mortality outcomes obtained through linkage to the national database – rather than hypothetical projections based upon Kaplan-Meier curves. A study limitation was that comorbidity data couldn’t be obtained for the AS patients.

Session cochair Patrizio Lancellotti, MD, PhD, commented, “I think this study will change a bit our consideration about patients with moderate AS.”

However, Dr. Lancellotti, who was lead author of the second-largest study of the natural history of aortic stenosis (JAMA Cardiol. 2018 Nov 1;3[11]:1060-8), expressed misgivings about the NEDA system’s lack of a core echocardiographic laboratory for imaging adjudication. That’s a study weakness given that image quality and the accuracy of echocardiographic interpretation are so highly dependent upon an individual cardiologist’s skill, observed Dr. Lancellotti, who is head of cardiology at the University of Liege (Belgium).

Dr. Strange replied that he and his coinvestigators analyzed a random subset of the NEDA data and found very little interlaboratory variability in results.

“All I can say is that the labs that contributed to this study are the most eminent labs across Australia,” he added.

Simultaneously with Dr. Strange’s presentation at the congress, the NEDA study results were published online (J Am Coll Cardiol. Sep 2019. doi: 10.1016/j.jacc.2019.08.004).

Dr. Strange reported having no financial conflicts of interest regarding the NEDA project, which is funded by GlaxoSmithKline, Bayer, and Actelion.

[email protected]

PARIS – The 5-year mortality rate associated with untreated moderate aortic stenosis is just as grim as it is for severe aortic stenosis, according to new findings from the largest-ever study of the natural history of aortic stenosis.

“These data provide a clear signal of the expected adverse outcomes for individuals presenting across the globe with a mean aortic valve gradient greater than 20.0 mm Hg or a peak aortic valve velocity above 3.0 m/sec,” Geoff Strange, PhD, said in presenting an analysis from NEDA, the National Echocardiography Database of Australia, at the annual congress of the European Society of Cardiology.

These results, if confirmed in other large datasets, could potentially have enormous implications for the use of transcatheter and surgical aortic valve replacement, interventions which until now have been restricted to patients with severe aortic stenosis (AS) as defined by an aortic valve (AV) mean gradient in excess of 40 mm Hg or a peak AV velocity greater than 4.0 m/sec. This restriction was based on what Dr. Strange considers rather limited and flimsy evidence suggesting that the mortality associated with AS was negligible except in severe AS.

“Cut points used to stratify for interventional strategies are based on very small numbers,” observed Dr. Strange, professor of medicine at the University of Notre Dame in Fremantle, Australia.

The NEDA findings, he added, constitute a call to action: “These data provide the impetus for a contemporary evaluation of the risk-to-benefit ratio of intervention in the moderate AS population,” Dr. Strange declared.

He and his NEDA coinvestigators analyzed echocardiographic data on 241,303 individuals in the Australian database, zeroing in on the 25,827 with untreated mild, moderate, or severe native valve AS. To place the size and scope of this project into perspective, the next-largest study of the natural history of untreated AS included 1,375 individuals – and that study was in turn roughly 10-fold bigger than the handful of other published studies addressing this issue.

A key finding in the NEDA study was that the 5-year all-cause mortality rate of 61.4% in the group with moderate AS wasn’t significantly different from the 64.6% rate in those with severe AS (see graphic).

The investigators performed additional analyses, analyzing peak velocity and mean gradient as continuous variables and stratifying patients into quintiles on that basis. They found that the top quintile for AV velocity started very low, at 1.73 m/sec, while the top quintile for mean AV gradient also started at a surprisingly low level: greater than 9.6 mm Hg. They noted that both all-cause and cardiovascular-specific mortality rates were basically flat until taking what Dr. Strange described as “a sharp pivot point upward” right around 20 mm Hg or 3 m/sec.

“No matter how we looked at these data – whether we looked at patients with or without left heart disease, whether we used the dimensionless index, whether we adjusted for stroke volume index, whether we stratified between age above or below 65, whether we used the gradient, the velocity, or the AV area – this threshold of increasing mortality at around 20 mm Hg or 3 m/sec continued to emerge,” according to Dr. Strange.

He noted that this study used real-world data with hard endpoints – actuarial patient mortality outcomes obtained through linkage to the national database – rather than hypothetical projections based upon Kaplan-Meier curves. A study limitation was that comorbidity data couldn’t be obtained for the AS patients.

Session cochair Patrizio Lancellotti, MD, PhD, commented, “I think this study will change a bit our consideration about patients with moderate AS.”

However, Dr. Lancellotti, who was lead author of the second-largest study of the natural history of aortic stenosis (JAMA Cardiol. 2018 Nov 1;3[11]:1060-8), expressed misgivings about the NEDA system’s lack of a core echocardiographic laboratory for imaging adjudication. That’s a study weakness given that image quality and the accuracy of echocardiographic interpretation are so highly dependent upon an individual cardiologist’s skill, observed Dr. Lancellotti, who is head of cardiology at the University of Liege (Belgium).

Dr. Strange replied that he and his coinvestigators analyzed a random subset of the NEDA data and found very little interlaboratory variability in results.

“All I can say is that the labs that contributed to this study are the most eminent labs across Australia,” he added.

Simultaneously with Dr. Strange’s presentation at the congress, the NEDA study results were published online (J Am Coll Cardiol. Sep 2019. doi: 10.1016/j.jacc.2019.08.004).

Dr. Strange reported having no financial conflicts of interest regarding the NEDA project, which is funded by GlaxoSmithKline, Bayer, and Actelion.

[email protected]

PARIS – The 5-year mortality rate associated with untreated moderate aortic stenosis is just as grim as it is for severe aortic stenosis, according to new findings from the largest-ever study of the natural history of aortic stenosis.

“These data provide a clear signal of the expected adverse outcomes for individuals presenting across the globe with a mean aortic valve gradient greater than 20.0 mm Hg or a peak aortic valve velocity above 3.0 m/sec,” Geoff Strange, PhD, said in presenting an analysis from NEDA, the National Echocardiography Database of Australia, at the annual congress of the European Society of Cardiology.

These results, if confirmed in other large datasets, could potentially have enormous implications for the use of transcatheter and surgical aortic valve replacement, interventions which until now have been restricted to patients with severe aortic stenosis (AS) as defined by an aortic valve (AV) mean gradient in excess of 40 mm Hg or a peak AV velocity greater than 4.0 m/sec. This restriction was based on what Dr. Strange considers rather limited and flimsy evidence suggesting that the mortality associated with AS was negligible except in severe AS.

“Cut points used to stratify for interventional strategies are based on very small numbers,” observed Dr. Strange, professor of medicine at the University of Notre Dame in Fremantle, Australia.

The NEDA findings, he added, constitute a call to action: “These data provide the impetus for a contemporary evaluation of the risk-to-benefit ratio of intervention in the moderate AS population,” Dr. Strange declared.

He and his NEDA coinvestigators analyzed echocardiographic data on 241,303 individuals in the Australian database, zeroing in on the 25,827 with untreated mild, moderate, or severe native valve AS. To place the size and scope of this project into perspective, the next-largest study of the natural history of untreated AS included 1,375 individuals – and that study was in turn roughly 10-fold bigger than the handful of other published studies addressing this issue.

A key finding in the NEDA study was that the 5-year all-cause mortality rate of 61.4% in the group with moderate AS wasn’t significantly different from the 64.6% rate in those with severe AS (see graphic).

The investigators performed additional analyses, analyzing peak velocity and mean gradient as continuous variables and stratifying patients into quintiles on that basis. They found that the top quintile for AV velocity started very low, at 1.73 m/sec, while the top quintile for mean AV gradient also started at a surprisingly low level: greater than 9.6 mm Hg. They noted that both all-cause and cardiovascular-specific mortality rates were basically flat until taking what Dr. Strange described as “a sharp pivot point upward” right around 20 mm Hg or 3 m/sec.

“No matter how we looked at these data – whether we looked at patients with or without left heart disease, whether we used the dimensionless index, whether we adjusted for stroke volume index, whether we stratified between age above or below 65, whether we used the gradient, the velocity, or the AV area – this threshold of increasing mortality at around 20 mm Hg or 3 m/sec continued to emerge,” according to Dr. Strange.

He noted that this study used real-world data with hard endpoints – actuarial patient mortality outcomes obtained through linkage to the national database – rather than hypothetical projections based upon Kaplan-Meier curves. A study limitation was that comorbidity data couldn’t be obtained for the AS patients.

Session cochair Patrizio Lancellotti, MD, PhD, commented, “I think this study will change a bit our consideration about patients with moderate AS.”

However, Dr. Lancellotti, who was lead author of the second-largest study of the natural history of aortic stenosis (JAMA Cardiol. 2018 Nov 1;3[11]:1060-8), expressed misgivings about the NEDA system’s lack of a core echocardiographic laboratory for imaging adjudication. That’s a study weakness given that image quality and the accuracy of echocardiographic interpretation are so highly dependent upon an individual cardiologist’s skill, observed Dr. Lancellotti, who is head of cardiology at the University of Liege (Belgium).

Dr. Strange replied that he and his coinvestigators analyzed a random subset of the NEDA data and found very little interlaboratory variability in results.

“All I can say is that the labs that contributed to this study are the most eminent labs across Australia,” he added.

Simultaneously with Dr. Strange’s presentation at the congress, the NEDA study results were published online (J Am Coll Cardiol. Sep 2019. doi: 10.1016/j.jacc.2019.08.004).

Dr. Strange reported having no financial conflicts of interest regarding the NEDA project, which is funded by GlaxoSmithKline, Bayer, and Actelion.

[email protected]

At least 50% of patients with irritable bowel syndrome (IBS) described their condition as “extremely bothersome” based on survey data from 3,254 individuals. However, differences in the nature of other symptoms among IBS subtypes, namely IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C), have not been well studied, wrote Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Source: American Gastroenterological Association

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed survey results from 1,587 individuals with IBS-D and 1,667 with IBS-C. The average age of the patients was 47 years, 81% were female, and 90% were white.

Approximately 84% of patients with IBS-C and 93% of those with IBS-D reported abdominal pain, the most common symptom in both groups. Overall, 36% of the 1,885 patients employed or in school reported decreased productivity in those settings.

IBS-C patients were significantly more likely to report that their symptoms caused them to avoid sex, feel self-conscious about their bodies, have trouble concentrating, and feel “not like myself,” compared with IBS-D patients (P less than .004 for all).

IBS-D patients were significantly more likely to report that their symptoms caused them to avoid traveling in general, avoid places without bathrooms, avoid leaving the house, and have trouble making plans, compared with IBS-C patients (P less than .004 for all).

The survey also asked respondents what they would give up for 1 month in exchange for 1 month of relief from IBS symptoms. Overall, approximately 60% said they would give up alcohol, 55% said they would give up caffeine, 40% would give up sex, 24.5% would give up their cell phones, and 21.5% would give up the internet, the researchers wrote.

The study findings were limited by several factors, including the absence of survey respondents with mixed-type IBS, the reliance on self-reports, and the potential for recall bias. Also, the study was not designed to assess the impact of other comorbidities and did not include non-IBS controls, the researchers noted.

However, the results suggest that patients with different IBS subtypes struggle differently in areas of daily function, which has implications for treatment, they wrote.

“This study highlights important differences between IBS-C and IBS-D, which could impact the development and refinement of mind-body therapies for IBS, with tailored treatment goals for each IBS subtype. For example, treatment tailored specifically for IBS-D may be more behaviorally focused (e.g., exposure to specific situations outside the home) while treatment for IBS-C may be more cognitively focused (e.g., evaluating self-esteem and beliefs about self and others) in addition to targeting the bowel dysfunction and pain,” they concluded.

The researchers had no financial conflicts to disclose.

SOURCE: Ballou S et al. Clin Gastroenterol Hepatol. 2019 Aug 13. doi: 10.1016/j.cgh.2019.08.016.

At least 50% of patients with irritable bowel syndrome (IBS) described their condition as “extremely bothersome” based on survey data from 3,254 individuals. However, differences in the nature of other symptoms among IBS subtypes, namely IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C), have not been well studied, wrote Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Source: American Gastroenterological Association

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed survey results from 1,587 individuals with IBS-D and 1,667 with IBS-C. The average age of the patients was 47 years, 81% were female, and 90% were white.

Approximately 84% of patients with IBS-C and 93% of those with IBS-D reported abdominal pain, the most common symptom in both groups. Overall, 36% of the 1,885 patients employed or in school reported decreased productivity in those settings.

IBS-C patients were significantly more likely to report that their symptoms caused them to avoid sex, feel self-conscious about their bodies, have trouble concentrating, and feel “not like myself,” compared with IBS-D patients (P less than .004 for all).

IBS-D patients were significantly more likely to report that their symptoms caused them to avoid traveling in general, avoid places without bathrooms, avoid leaving the house, and have trouble making plans, compared with IBS-C patients (P less than .004 for all).

The survey also asked respondents what they would give up for 1 month in exchange for 1 month of relief from IBS symptoms. Overall, approximately 60% said they would give up alcohol, 55% said they would give up caffeine, 40% would give up sex, 24.5% would give up their cell phones, and 21.5% would give up the internet, the researchers wrote.

The study findings were limited by several factors, including the absence of survey respondents with mixed-type IBS, the reliance on self-reports, and the potential for recall bias. Also, the study was not designed to assess the impact of other comorbidities and did not include non-IBS controls, the researchers noted.

However, the results suggest that patients with different IBS subtypes struggle differently in areas of daily function, which has implications for treatment, they wrote.

“This study highlights important differences between IBS-C and IBS-D, which could impact the development and refinement of mind-body therapies for IBS, with tailored treatment goals for each IBS subtype. For example, treatment tailored specifically for IBS-D may be more behaviorally focused (e.g., exposure to specific situations outside the home) while treatment for IBS-C may be more cognitively focused (e.g., evaluating self-esteem and beliefs about self and others) in addition to targeting the bowel dysfunction and pain,” they concluded.

The researchers had no financial conflicts to disclose.

SOURCE: Ballou S et al. Clin Gastroenterol Hepatol. 2019 Aug 13. doi: 10.1016/j.cgh.2019.08.016.

At least 50% of patients with irritable bowel syndrome (IBS) described their condition as “extremely bothersome” based on survey data from 3,254 individuals. However, differences in the nature of other symptoms among IBS subtypes, namely IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C), have not been well studied, wrote Sarah Ballou, PhD, of Beth Israel Deaconess Medical Center, Boston, and colleagues.

Source: American Gastroenterological Association

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed survey results from 1,587 individuals with IBS-D and 1,667 with IBS-C. The average age of the patients was 47 years, 81% were female, and 90% were white.

Approximately 84% of patients with IBS-C and 93% of those with IBS-D reported abdominal pain, the most common symptom in both groups. Overall, 36% of the 1,885 patients employed or in school reported decreased productivity in those settings.

IBS-C patients were significantly more likely to report that their symptoms caused them to avoid sex, feel self-conscious about their bodies, have trouble concentrating, and feel “not like myself,” compared with IBS-D patients (P less than .004 for all).

IBS-D patients were significantly more likely to report that their symptoms caused them to avoid traveling in general, avoid places without bathrooms, avoid leaving the house, and have trouble making plans, compared with IBS-C patients (P less than .004 for all).

The survey also asked respondents what they would give up for 1 month in exchange for 1 month of relief from IBS symptoms. Overall, approximately 60% said they would give up alcohol, 55% said they would give up caffeine, 40% would give up sex, 24.5% would give up their cell phones, and 21.5% would give up the internet, the researchers wrote.

The study findings were limited by several factors, including the absence of survey respondents with mixed-type IBS, the reliance on self-reports, and the potential for recall bias. Also, the study was not designed to assess the impact of other comorbidities and did not include non-IBS controls, the researchers noted.

However, the results suggest that patients with different IBS subtypes struggle differently in areas of daily function, which has implications for treatment, they wrote.

“This study highlights important differences between IBS-C and IBS-D, which could impact the development and refinement of mind-body therapies for IBS, with tailored treatment goals for each IBS subtype. For example, treatment tailored specifically for IBS-D may be more behaviorally focused (e.g., exposure to specific situations outside the home) while treatment for IBS-C may be more cognitively focused (e.g., evaluating self-esteem and beliefs about self and others) in addition to targeting the bowel dysfunction and pain,” they concluded.

The researchers had no financial conflicts to disclose.

SOURCE: Ballou S et al. Clin Gastroenterol Hepatol. 2019 Aug 13. doi: 10.1016/j.cgh.2019.08.016.

Patients with hidradenitis suppurativa (HS) were found to be at a significantly higher risk of long-term opioid use compared with those who did not have HS, in a retrospective cohort study.

“These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities,” wrote the authors of the study (JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610).

Researchers led by Sarah Reddy, BA, of the Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, N.Y., used data from a health-care database that represents an estimated 17% of the U.S. population. They focused on opioid-naive adults who were in the database for at least 3 years from 2008-2018 and monitored whether they began opioid use and then maintained use for at least 1 year.

Nearly 829,000 patients were in the control group, and 22,277 were in the HS group. The mean age of those with HS was 41 years, 76% were women, and 59% were white.

Over 1 year, the crude incidence of long-term opioid use among HS patients who were opioid naive was 0.33%, compared with 0.14% of controls (P less than .001).

An analysis, adjusted for potential confounding factors, found that compared with controls, those with HS were more likely to develop long-term opioid use (odds ratio [OR], 1.53, 95% confidence interval, 1.20-1.95; P less than .001). In the adjusted analysis, long-term opioid use was increased among those in the HS group who had ever smoked tobacco (OR, 3.64, 95% CI, 2.06-6.41; P less than .001), compared with patients with HS who had never smoked; and those who had a history of depression (OR, 1.97, 95% CI, 1.21-3.19; P = .006), compared with HS patients who had not had depression.

The risk of long-term opioid use among those with HS increased by 2% with each additional year in age.

In addition, 5% of patients with HS and long-term opioid use were diagnosed with opioid use disorder over the study period. “Sex, race/ethnicity, disease duration, established dermatologic care, alcohol abuse, and nonopioid substance abuse were not associated with increased risk of long-term opioid use among patients with HS,” the authors wrote.

Emphasizing that these results “should not further stigmatize” people with HS, they said, “our hope is that the medical community, including dermatologists, will further embrace and engage in an integrated care plan that comprehensively supports the needs of patients with HS, including pain management.”

Future research, they added, “should include evaluating the association between disease severity and risk of opioid use, the role of disease-modifying therapies in reducing opioid use, and the development of effective and appropriate multimodal pain management strategies for HS.”

An educational grant to a study author from AbbVie partially funded the study. No other study funding was reported. Ms. Reddy had no disclosures; one author disclosed having received grants and personal fees from AbbVie and UCB during the study.

SOURCE: Reddy S et al. JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610.

Patients with hidradenitis suppurativa (HS) were found to be at a significantly higher risk of long-term opioid use compared with those who did not have HS, in a retrospective cohort study.

“These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities,” wrote the authors of the study (JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610).

Researchers led by Sarah Reddy, BA, of the Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, N.Y., used data from a health-care database that represents an estimated 17% of the U.S. population. They focused on opioid-naive adults who were in the database for at least 3 years from 2008-2018 and monitored whether they began opioid use and then maintained use for at least 1 year.

Nearly 829,000 patients were in the control group, and 22,277 were in the HS group. The mean age of those with HS was 41 years, 76% were women, and 59% were white.

Over 1 year, the crude incidence of long-term opioid use among HS patients who were opioid naive was 0.33%, compared with 0.14% of controls (P less than .001).

An analysis, adjusted for potential confounding factors, found that compared with controls, those with HS were more likely to develop long-term opioid use (odds ratio [OR], 1.53, 95% confidence interval, 1.20-1.95; P less than .001). In the adjusted analysis, long-term opioid use was increased among those in the HS group who had ever smoked tobacco (OR, 3.64, 95% CI, 2.06-6.41; P less than .001), compared with patients with HS who had never smoked; and those who had a history of depression (OR, 1.97, 95% CI, 1.21-3.19; P = .006), compared with HS patients who had not had depression.

The risk of long-term opioid use among those with HS increased by 2% with each additional year in age.

In addition, 5% of patients with HS and long-term opioid use were diagnosed with opioid use disorder over the study period. “Sex, race/ethnicity, disease duration, established dermatologic care, alcohol abuse, and nonopioid substance abuse were not associated with increased risk of long-term opioid use among patients with HS,” the authors wrote.

Emphasizing that these results “should not further stigmatize” people with HS, they said, “our hope is that the medical community, including dermatologists, will further embrace and engage in an integrated care plan that comprehensively supports the needs of patients with HS, including pain management.”

Future research, they added, “should include evaluating the association between disease severity and risk of opioid use, the role of disease-modifying therapies in reducing opioid use, and the development of effective and appropriate multimodal pain management strategies for HS.”

An educational grant to a study author from AbbVie partially funded the study. No other study funding was reported. Ms. Reddy had no disclosures; one author disclosed having received grants and personal fees from AbbVie and UCB during the study.

SOURCE: Reddy S et al. JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610.

Patients with hidradenitis suppurativa (HS) were found to be at a significantly higher risk of long-term opioid use compared with those who did not have HS, in a retrospective cohort study.

“These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities,” wrote the authors of the study (JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610).

Researchers led by Sarah Reddy, BA, of the Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, N.Y., used data from a health-care database that represents an estimated 17% of the U.S. population. They focused on opioid-naive adults who were in the database for at least 3 years from 2008-2018 and monitored whether they began opioid use and then maintained use for at least 1 year.

Nearly 829,000 patients were in the control group, and 22,277 were in the HS group. The mean age of those with HS was 41 years, 76% were women, and 59% were white.

Over 1 year, the crude incidence of long-term opioid use among HS patients who were opioid naive was 0.33%, compared with 0.14% of controls (P less than .001).

An analysis, adjusted for potential confounding factors, found that compared with controls, those with HS were more likely to develop long-term opioid use (odds ratio [OR], 1.53, 95% confidence interval, 1.20-1.95; P less than .001). In the adjusted analysis, long-term opioid use was increased among those in the HS group who had ever smoked tobacco (OR, 3.64, 95% CI, 2.06-6.41; P less than .001), compared with patients with HS who had never smoked; and those who had a history of depression (OR, 1.97, 95% CI, 1.21-3.19; P = .006), compared with HS patients who had not had depression.

The risk of long-term opioid use among those with HS increased by 2% with each additional year in age.

In addition, 5% of patients with HS and long-term opioid use were diagnosed with opioid use disorder over the study period. “Sex, race/ethnicity, disease duration, established dermatologic care, alcohol abuse, and nonopioid substance abuse were not associated with increased risk of long-term opioid use among patients with HS,” the authors wrote.

Emphasizing that these results “should not further stigmatize” people with HS, they said, “our hope is that the medical community, including dermatologists, will further embrace and engage in an integrated care plan that comprehensively supports the needs of patients with HS, including pain management.”

Future research, they added, “should include evaluating the association between disease severity and risk of opioid use, the role of disease-modifying therapies in reducing opioid use, and the development of effective and appropriate multimodal pain management strategies for HS.”

An educational grant to a study author from AbbVie partially funded the study. No other study funding was reported. Ms. Reddy had no disclosures; one author disclosed having received grants and personal fees from AbbVie and UCB during the study.

SOURCE: Reddy S et al. JAMA Dermatol. 2019 Sep 11. doi: 10.1001/jamadermatol.2019.2610.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

PHILADELPHIA – A heart failure management strategy guided by home lung fluid measurements from the remote dielectric sensing (ReDS) system can significantly reduce recurrent hospitalizations, as long as the technology is used as intended.

Andrew D. Bowser/MDedge News

A ReDS-directed management strategy did not significantly reduce recurrent hospitalizations for acute decompensated heart failure (ADHF) in the traditional intent-to-treat analysis of the randomized, controlled SMILE trial, William T. Abraham, MD, of the Ohio State University, Columbus, said at the annual scientific meeting of the Heart Failure Society of America.

However, use of the Food and Drug Administration–cleared thoracic fluid status monitoring system to guide treatment changes did cut such hospitalizations by 58% in a modified intent-to-treat population that excluded patients who failed to take daily measurements at home and who didn’t receive modified treatment despite actionable readings, Dr. Abraham reported in an oral presentation.

“These observations may support an adherence-based approach to the utilization and reimbursement of ReDS-guided management in recently discharged ADHF patients,” he said.

The ReDS system consists of a device that, within about 90 seconds, provides a measurement of lung fluid via a focused electromagnetic radar beam that passes through the right lung, Dr. Abraham said. Clinicians access data from measurements patients initiate at home through a secure, cloud-based system, and then initiate changes to heart failure management as warranted based on a ReDS-specific treatment algorithm, Dr. Abraham said.

The postmarketing SMILE study of the ReDS system was stopped early because of an administrative decision by the sponsor, according to Dr. Abraham. However, 268 patients enrolled at 43 U.S. sites continued to the end of the study, with an average follow-up of about 6 months, while readmissions were collected and adjudicated by an independent clinical events committee.

A total of 135 patients were randomized to a ReDS-based management strategy, while 133 were randomized to standard of care, the investigator said.

Most of the medication changes made in response to ReDS measurements were increased diuretics because of high lung fluid volume measurements, or decreased diuretics in response to low measurements, though some changes in vasodilator medications were also made, Dr. Abraham said.

The ReDS-directed management approach yielded a “highly nonsignificant” 19% reduction in recurrent or cumulative heart failure readmissions (P = .36); by contrast, after removing nonadherent, noncompliant cases, there were 11 hospitalizations in 91 treatment patients, compared with 43 hospitalizations in 133 control patients, yielding a hazard ratio of 0.42 (95% CI, 0.22-0.82; P = .01).

“This comes back to the adage that, if you don’t use it, you can’t improve clinical outcomes,” he said, explaining that this study’s modified intent-to-treat population was defined by excluding patients who took no ReDS measurements for more than 20 consecutive days; or by clinicians who received at least eight notifications of out-of-range ReDS values yet didn’t implement the ReDS treatment algorithm.

There were no adverse events reported as being definitely related to the use of the device, and five adverse events reported as possibly related to the device, Dr. Abraham said.

SMILE was sponsored by Sensible Medical Innovations. Dr. Abraham reported disclosures (consultant/advisory board) related to Sensible Medical Innovations, Abbott, Boehringer Ingelheim, Victorious Medical, V-Wave Medical, and others.

PHILADELPHIA – A heart failure management strategy guided by home lung fluid measurements from the remote dielectric sensing (ReDS) system can significantly reduce recurrent hospitalizations, as long as the technology is used as intended.

Andrew D. Bowser/MDedge News

A ReDS-directed management strategy did not significantly reduce recurrent hospitalizations for acute decompensated heart failure (ADHF) in the traditional intent-to-treat analysis of the randomized, controlled SMILE trial, William T. Abraham, MD, of the Ohio State University, Columbus, said at the annual scientific meeting of the Heart Failure Society of America.

However, use of the Food and Drug Administration–cleared thoracic fluid status monitoring system to guide treatment changes did cut such hospitalizations by 58% in a modified intent-to-treat population that excluded patients who failed to take daily measurements at home and who didn’t receive modified treatment despite actionable readings, Dr. Abraham reported in an oral presentation.

“These observations may support an adherence-based approach to the utilization and reimbursement of ReDS-guided management in recently discharged ADHF patients,” he said.

The ReDS system consists of a device that, within about 90 seconds, provides a measurement of lung fluid via a focused electromagnetic radar beam that passes through the right lung, Dr. Abraham said. Clinicians access data from measurements patients initiate at home through a secure, cloud-based system, and then initiate changes to heart failure management as warranted based on a ReDS-specific treatment algorithm, Dr. Abraham said.

The postmarketing SMILE study of the ReDS system was stopped early because of an administrative decision by the sponsor, according to Dr. Abraham. However, 268 patients enrolled at 43 U.S. sites continued to the end of the study, with an average follow-up of about 6 months, while readmissions were collected and adjudicated by an independent clinical events committee.

A total of 135 patients were randomized to a ReDS-based management strategy, while 133 were randomized to standard of care, the investigator said.

Most of the medication changes made in response to ReDS measurements were increased diuretics because of high lung fluid volume measurements, or decreased diuretics in response to low measurements, though some changes in vasodilator medications were also made, Dr. Abraham said.

The ReDS-directed management approach yielded a “highly nonsignificant” 19% reduction in recurrent or cumulative heart failure readmissions (P = .36); by contrast, after removing nonadherent, noncompliant cases, there were 11 hospitalizations in 91 treatment patients, compared with 43 hospitalizations in 133 control patients, yielding a hazard ratio of 0.42 (95% CI, 0.22-0.82; P = .01).

“This comes back to the adage that, if you don’t use it, you can’t improve clinical outcomes,” he said, explaining that this study’s modified intent-to-treat population was defined by excluding patients who took no ReDS measurements for more than 20 consecutive days; or by clinicians who received at least eight notifications of out-of-range ReDS values yet didn’t implement the ReDS treatment algorithm.

There were no adverse events reported as being definitely related to the use of the device, and five adverse events reported as possibly related to the device, Dr. Abraham said.

SMILE was sponsored by Sensible Medical Innovations. Dr. Abraham reported disclosures (consultant/advisory board) related to Sensible Medical Innovations, Abbott, Boehringer Ingelheim, Victorious Medical, V-Wave Medical, and others.

PHILADELPHIA – A heart failure management strategy guided by home lung fluid measurements from the remote dielectric sensing (ReDS) system can significantly reduce recurrent hospitalizations, as long as the technology is used as intended.

Andrew D. Bowser/MDedge News

A ReDS-directed management strategy did not significantly reduce recurrent hospitalizations for acute decompensated heart failure (ADHF) in the traditional intent-to-treat analysis of the randomized, controlled SMILE trial, William T. Abraham, MD, of the Ohio State University, Columbus, said at the annual scientific meeting of the Heart Failure Society of America.

However, use of the Food and Drug Administration–cleared thoracic fluid status monitoring system to guide treatment changes did cut such hospitalizations by 58% in a modified intent-to-treat population that excluded patients who failed to take daily measurements at home and who didn’t receive modified treatment despite actionable readings, Dr. Abraham reported in an oral presentation.

“These observations may support an adherence-based approach to the utilization and reimbursement of ReDS-guided management in recently discharged ADHF patients,” he said.

The ReDS system consists of a device that, within about 90 seconds, provides a measurement of lung fluid via a focused electromagnetic radar beam that passes through the right lung, Dr. Abraham said. Clinicians access data from measurements patients initiate at home through a secure, cloud-based system, and then initiate changes to heart failure management as warranted based on a ReDS-specific treatment algorithm, Dr. Abraham said.

The postmarketing SMILE study of the ReDS system was stopped early because of an administrative decision by the sponsor, according to Dr. Abraham. However, 268 patients enrolled at 43 U.S. sites continued to the end of the study, with an average follow-up of about 6 months, while readmissions were collected and adjudicated by an independent clinical events committee.

A total of 135 patients were randomized to a ReDS-based management strategy, while 133 were randomized to standard of care, the investigator said.

Most of the medication changes made in response to ReDS measurements were increased diuretics because of high lung fluid volume measurements, or decreased diuretics in response to low measurements, though some changes in vasodilator medications were also made, Dr. Abraham said.

The ReDS-directed management approach yielded a “highly nonsignificant” 19% reduction in recurrent or cumulative heart failure readmissions (P = .36); by contrast, after removing nonadherent, noncompliant cases, there were 11 hospitalizations in 91 treatment patients, compared with 43 hospitalizations in 133 control patients, yielding a hazard ratio of 0.42 (95% CI, 0.22-0.82; P = .01).

“This comes back to the adage that, if you don’t use it, you can’t improve clinical outcomes,” he said, explaining that this study’s modified intent-to-treat population was defined by excluding patients who took no ReDS measurements for more than 20 consecutive days; or by clinicians who received at least eight notifications of out-of-range ReDS values yet didn’t implement the ReDS treatment algorithm.

There were no adverse events reported as being definitely related to the use of the device, and five adverse events reported as possibly related to the device, Dr. Abraham said.

SMILE was sponsored by Sensible Medical Innovations. Dr. Abraham reported disclosures (consultant/advisory board) related to Sensible Medical Innovations, Abbott, Boehringer Ingelheim, Victorious Medical, V-Wave Medical, and others.

SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”

Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
 

Blinatumomab

Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).

The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).

Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).

The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.

In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).

Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
 

Inotuzumab ozogamicin

Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.

The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.

The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).

Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.

Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.

[email protected]

SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”

Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
 

Blinatumomab

Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).

The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).

Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).

The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.

In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).

Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
 

Inotuzumab ozogamicin

Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.

The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.

The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).

Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.

Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.

[email protected]

SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).

Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.

“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”

Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
 

Blinatumomab

Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).

The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).

Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).

The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.

In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).

Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
 

Inotuzumab ozogamicin

Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.

The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.

The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).

Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.

Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.

[email protected]

Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.

JazzIRT/Getty Images

In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.

Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.

Pain management

While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.

The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.

Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.

“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.

The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.

The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).

Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.

The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.

The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.

Quality improvement

“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.

Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.

With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.

Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.

Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.

“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.

At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.

Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.

In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.

Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.

Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.

Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.

Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.

Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.

JazzIRT/Getty Images

In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.

Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.

Pain management

While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.

The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.

Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.

“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.

The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.

The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).

Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.

The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.

The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.

Quality improvement

“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.

Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.

With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.

Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.

Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.

“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.

At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.

Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.

In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.

Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.

Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.

Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.

Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.

Several initiatives are in the works to improve the management of patients with sickle cell disease in the ED, experts said at a recent webinar held by the National Heart, Lung, and Blood Institute.

JazzIRT/Getty Images

In 2014, the NHLBI released evidence-based guidelines for the management of patients with sickle cell disease. The expert panel provided recommendations on the treatment of acute complications of sickle cell disease, many of which are common reasons for ED visits.

Optimizing the treatment of acute complications, namely vasoocclusive crisis, is essential to ensure improved long-term outcomes, explained Paula Tanabe, PhD, of Duke University, Durham, N.C.

Pain management

While the majority of pain-related ED visits in sickle cell are the result of vasoocclusive crisis, other causes, such as acute chest syndrome, abdominal catastrophes, and splenic sequestration, are also important.

The hallmark of pain management in this population is rapid and aggressive treatment with intravenous opioids. The use of individualized doses is also important, but if not available, an sickle cell disease–specific pain protocol can be used, she explained.

Recent evidence has confirmed the benefit of using an individualized (patient-specific) dosing protocol. Dr. Tanabe reported the results of a randomized pilot study that compared two pain protocols for patients undergoing a vasoocclusive episode in the ED.

“The reason we pursued this project is to generate additional evidence beyond the expert panel,” she said.

The primary outcome of the study was the difference in pain scores from arrival to discharge between patients receiving an individualized or weight-based dosing protocol. Secondary outcomes included safety, pain experience, and side effects, among others.

The researchers found that patients who received an individualized protocol had significantly lower pain scores, compared with a standard weight-based protocol (between-protocol pain score difference, 15.6 plus or minus 5.0; P = .002).

Additionally, patients in the individualized dosing arm were admitted less often than those in the weight-based arm (P = .03), Dr. Tanabe reported.

The findings from the previous study formed the basis for an ongoing study that is further examining the impact of patient-specific dosing in patients who present with a vasoocclusive episode. The COMPARE VOE study is currently enrolling patients and is being funded by NHLBI.

The NHLBI also provides funding to eight Sickle Cell Disease Implementation Consortium sites throughout the United States. The objective of this grant funding is to help implement NHLBI recommendations in the emergency setting.

Quality improvement

“One area [that] we want to improve is how quickly we administer [analgesic therapy] to patients when they are experiencing a vasoocclusive episode,” said Caroline Freiermuth, MD, of the University of Cincinnati.

Some common barriers to delivering rapid analgesia in this setting include difficulties in obtaining intravenous access, high patient volumes, lack of education, and provider biases, she explained.

With respect to high patient volumes, one strategy that may help overcome this barrier is to triage patients as Emergency Severity Index level 2, allowing for accelerated room placement.

Sickle cell patients undergoing vasoocclusive crisis meet the criteria for level 2 based on morbidity, degree of pain, and the level of resources often required.

Another important strategy is improving education related to sickle cell disease, particularly the high morbidity and mortality seen in these patients, Dr. Freiermuth said.

“The median lifespan for patients with HbSS disease is in the 40s, basically half of the lifespan of a typical American,” she said.

At present, acute chest syndrome is the principal cause of death in patients with sickle cell disease, and most frequently occurs during a vasoocclusive episode. As a result, screening for this complication is essential to reduce mortality in the emergency setting.

Dr. Freiermuth explained that one of the best ways to prevent acute chest syndrome is to encourage the use of incentive spirometry in patients undergoing a vasoocclusive episode.

In order to increase the likelihood of obtaining intravenous access, the use of ultrasound may help guide placement. Educating nurses on the proper use of ultrasound-guided placement of intravenous catheters is one practical approach, she said.

Alternatively, opioid analgesia can be administered subcutaneously. Benefits of subcutaneous delivery include comparable pharmacokinetics, less pain, and a reduced likelihood of sterile abscesses that are often seen with intramuscular administration.

Dr. Freiermuth outlined the quality-improvement initiative being tested at her institution, which involves the administration of parenteral opioid therapy during triage for sickle cell patients undergoing a suspected vasoocclusive crisis. The initiative was developed with input from both the emergency and hematology departments at the site.

Early results have shown no significant changes using this approach, but the data is still preliminary. Initial feedback has revealed that time to room placement has been the greatest barrier, she reported.

Dr. Tanabe reported grant/research support from the National Institutes of Health and the Agency for Healthcare Research and Quality. Dr. Freiermuth reported research support from Pfizer.

Autoimmune rheumatic diseases increase the risk of cardiovascular disease. In rheumatoid arthritis and systemic lupus erythematosus, the risk is driven primarily by the inflammatory milieu, leading to accelerated coronary and cerebrovascular atherosclerosis independent of traditional atherosclerotic risk factors.^1–3 The extent of cardiovascular involvement in other rheumatologic diseases has been less well characterized but is an area of growing interest.

In this review, we focus on the cardiovascular complications of systemic sclerosis and review recommendations for monitoring these patients in clinical practice.

SYSTEMIC SCLEROSIS, AN AUTOIMMUNE RHEUMATIC DISEASE

Systemic sclerosis is an autoimmune rheumatic disease characterized by excessive extracellular matrix deposition leading to diffuse fibrosis, endothelial dysfunction, and microvascular injury. It is most common in North America, Southern Europe, and Australia,^4,5 and it affects women more than men in ratios ranging from 3:1 to 14:1.⁶ The mean age at diagnosis is around 50. 

The disease can affect the lungs (interstitial lung disease and pulmonary hypertension), the heart, the kidneys, and the gastrointestinal tract.

Systemic sclerosis has 2 main subtypes: limited cutaneous systemic sclerosis, formerly called CREST syndrome) and diffuse cutaneous systemic sclerosis. The limited cutaneous subtype is characterized by tightening of the skin of the distal extremities (below the elbows and knees) and face, while diffuse cutaneous systemic sclerosis can manifest as more extensive skin tightening also involving proximal extremities and the trunk. Both subtypes can have an effect on the cardiovascular system.

Some cardiovascular risk factors such as dyslipidemia, diabetes mellitus, and high body mass index are less common in patients with systemic sclerosis than in patients with rheumatoid arthritis, while the rates of arterial hypertension, smoking, chronic obstructive pulmonary disease, osteoporosis, and neoplasms are similar between the 2 groups.⁷

HEART INVOLVEMENT HAS SERIOUS CONSEQUENCES

Overt cardiac involvement in systemic sclerosis is associated with a mortality rate of up to 70% over 5 years,^8,9 and about one-fourth of deaths in patients with systemic sclerosis are from cardiac causes.^10,11 Studies in Europe^10,12 showed that many patients with systemic sclerosis have cardiac involvement detectable by magnetic resonance imaging even if they do not have clinical disease. Pulmonary arterial hypertension (PAH) is a complication of both subtypes of systemic sclerosis and portends a higher risk of death.⁸

Thus, it is critical for clinicians to understand the potential comorbid conditions associated with systemic sclerosis, particularly the cardiovascular ones, and to work closely with cardiologists to help optimize the evaluation and management.

MECHANISMS OF CARDIAC DISEASE IN SYSTEMIC SCLEROSIS

Abnormal vasoreactivity, a consequence of an imbalance between endothelium-derived vasoconstrictors and vasodilators, defective angiogenesis, and endothelial injury, leads to tissue ischemia and vascular endothelial growth factor expression, which initiates injury and fibrosis in the myocardium and in other organs.^14–17 Fibrosis involves the myocardium, pericardium, and conduction system.^13,18

Myocardial involvement in systemic sclerosis is thought to be due mainly to abnormal vasoreactivity and microvascular abnormalities such as transient coronary artery spasm leading to repeated focal ischemia.^19,20 Abnormal vasoreactivity has been demonstrated during cardiac catheterization²¹: while mean coronary sinus blood flow in systemic sclerosis patients was normal at rest, vasodilator reserve was significantly reduced in patients with diffuse cutaneous systemic sclerosis after maximal vasodilation with dipyridamole. Additionally, endomyocardial biopsy showed fibrosis and concentric intimal hypertrophy with normal epicardial coronary arteries.²¹

More research into other mechanisms of cardiovascular disease in systemic sclerosis is needed to allow for better preventive care for these patients.

Systemic sclerosis can be associated with World Health Organization (WHO) groups 1, 2, 3, and 4 pulmonary hypertension. WHO group 1, called pulmonary arterial hypertension or PAH, is one of the most common cardiac complications of systemic sclerosis, with a reported prevalence as high as 12%.²² Systemic sclerosis-associated PAH carries a high mortality rate, with a mean survival of only 3 years.²³

With advances in treatments for other complications of systemic sclerosis, the percentage of systemic sclerosis patients who die of PAH has increased from 6% to 33%.²⁴

Compared with patients with idiopathic PAH, those with systemic sclerosis get less of a response from therapy and have poorer outcomes despite lower mean pulmonary artery pressures and similar reductions in cardiac index. However, recent studies have suggested that with aggressive treatment, patients with systemic sclerosis-related PAH can achieve outcomes similar to those with idiopathic PAH.²⁵ Thus, recognizing this condition early is imperative.

Pulmonary arterial hypertension defined

PAH is defined as the combination of all of the following²⁶:

• Mean pulmonary artery pressure > 20 mm Hg at rest
• Normal pulmonary capillary wedge pressure (≤ 15 mm Hg)
• Pulmonary vascular resistance ≥ 3 Wood units on right heart catheterization.

Other causes of pulmonary hypertension such as interstitial lung disease, chronic pulmonary thromboembolic disease, and left heart disease must be excluded.^24,27

Remodeling in the pulmonary arteries

The events that lead to PAH in systemic sclerosis remain unclear but are believed to involve initial inflammation or endothelial injury that leads to a dysequilibrium between proliferative mediators and antiproliferative vasodilators. This dysequilibrium, along with endothelial dysfunction, causes an obliterative vasculopathy in the pulmonary artery branches and arterioles. Sympathetic overactivity, hypoxemia, and ischemia-reperfusion injury additionally promote vascular proliferation, fibrosis, and remodeling, leading to increased pulmonary vascular resistance, PAH, and increased right ventricular pressures.^23,27

The subtype of systemic sclerosis is an important factor in the development and progression of PAH. PAH appears to be the major cause of death in limited cutaneous systemic sclerosis, while interstitial lung disease is the major cause of death in diffuse cutaneous systemic sclerosis.²⁸

Pulmonary arterial hypertension is a late complication of systemic sclerosis

Data from the South Australian Scleroderma Registry²⁹ revealed that PAH tends to be a late complication of systemic sclerosis, occurring around 20 years after disease onset. In this study of 608 patients, no patient with diffuse cutaneous systemic sclerosis developed PAH.

Systemic sclerosis-related PAH initially follows an indolent course with few symptoms until right ventricular function deteriorates. Early in the disease, patients may experience nonspecific symptoms of fatigue, lightheadedness, and dyspnea on exertion.²³ As it progresses, they tend to have worsening dyspnea and may experience exertional syncope, palpitations, and chest pain.

Physical findings may suggest elevated right ventricular pressure and right ventricular failure; these include a loud P2, a prominent jugular a wave, a tricuspid regurgitant murmur, jugular venous distention, and lower-extremity edema.²⁷

Screening for pulmonary arterial hypertension in systemic sclerosis

Significant signs and symptoms usually occur late in the disease; thus, it is important to appropriately screen patients who are at risk so that they can begin aggressive treatment.

Doppler echocardiography is recommended by European and American guidelines to screen for PAH in patients who have systemic sclerosis, and most agree that screening is appropriate even if the patient has no symptoms.³⁰ European consensus documents recommend that transthoracic echocardiography be done annually for the first 5 years of disease and be continued every year in patients at high risk, ie, those with anticentromere antibodies, anti-Th/To antibodies, or interstitial lung disease. Patients not at high risk of developing pulmonary hypertension should also have regular transthoracic echocardiography, though the exact timing is not defined.³¹ While American societies have not issued corresponding recommendations, many experts follow the European recommendations.

Worrisome features on echocardiography in asymptomatic patients should be followed up with right heart catheterization to assess mean right ventricular pressure. These include:

• Estimated right ventricular systolic pressure ≥ 40 mm Hg
• Tricuspid regurgitant jet velocity > 2.8 m/s
• Right atrial enlargement > 53 mm
• Right ventricular enlargement (mid-cavity dimension > 35 mm).³²

Although echocardiography is the most common form of screening, it gives only an estimate of right ventricular systolic pressure, which is imprecise. Other noninvasive markers are helpful and necessary to appropriately screen this population.

Diffusion capacity. The Itinerair study³³ found that a diffusing capacity for carbon monoxide (D_^LCO) of 60% or higher has a high specificity in excluding PAH.

Uric acid has been found to be elevated in patients with systemic sclerosis-related PAH, and levels inversely correlate with 6-minute walking distance.³⁴

Other predictors. N-terminal pro-B-type natriuretic peptide (NT-proBNP), left atrial volume, and the right ventricular myocardial performance index have also been shown to be independent predictors of PAH in patients with systemic sclerosis.³⁵

An algorithm. The DETECT study³⁶ enrolled patients at increased risk who had had systemic sclerosis longer than 3 years and a D_^LCO less than 60%. The investigators developed a 2-step algorithm to determine which patients should be referred for right heart catheterization to try to detect PAH earlier while minimizing the number of missed diagnoses and optimizing the use of invasive diagnostic right heart catheterization.

The first step was to assess serum values of anticentromere antibodies, NT-proBNP, and urate, and clinical features (telangiectasias), forced vital capacity, and electrocardiographic changes of right axis deviation to derive a prediction score. The second step was to assess surface echocardiographic features of the right atrial area and tricuspid regurgitation velocity.

This approach led to right heart catheterization in 62% of patients and was associated with a false-negative rate of 4%. Importantly, of the patients with PAH, 1 in 5 had no symptoms, and 33% had tricuspid regurgitation velocity less than 2.8 m/s. No single measurement performed well in isolation in this study.³⁷

Thus, we recommend that, in addition to routine surface echocardiography, a multimodal approach be used that includes laboratory testing, clinical features, and electrocardiographic findings when screening this high-risk patient population.

Although macrovascular disease has not typically been regarded as a significant systemic feature in systemic sclerosis, myocardial infarction and stroke are more common in patients with systemic sclerosis than in controls.^38,39

Coronary artery disease in systemic sclerosis

Man et al³⁸ reported that the incidence of myocardial infarction in patients with systemic sclerosis was 4.4 per 1,000 persons per year, and the incidence of stroke was 4.8 per 1,000 persons per year, compared with 2.5 per 1,000 persons per year for both myocardial infarction and stroke in healthy controls matched for age, sex, and time of entry.

The Australian Scleroderma Cohort Study³⁹ found a 3-fold higher prevalence of coronary artery disease in systemic sclerosis patients than in controls after factoring in traditional risk factors.

Aviña-Zubieta et al,⁴⁰ in a cohort of 1,239 systemic sclerosis patients, estimated a hazard ratio (HR) of 3.49 for myocardial infarction and 2.35 for stroke compared with age- and sex-matched controls. Not all of these events were related to macrovascular atherosclerosis—vasospasm and microvascular ischemia may have played significant roles in the etiology of clinical manifestations.

Studies of coronary atherosclerosis in systemic sclerosis are limited. An autopsy study⁴¹ of 58 patients with systemic sclerosis and 58 controls matched for age, sex, and ethnicity found that the prevalence of atherosclerosis of small coronary arteries and arterioles was significantly higher in systemic sclerosis patients than in controls (17% vs 2%, P < .01). However, the prevalence of medium-vessel coronary atherosclerosis was similar (48% vs 43%).

Why patients with systemic sclerosis develop atherosclerosis has not yet been determined. Traditional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity are typically no more prevalent in systemic sclerosis patients than in controls,^38,42 and thus do not explain the increased risk of atherosclerotic cardiovascular disease. There is some evidence that novel markers of atherosclerotic risk such as homocysteine,⁴³ lipoprotein[a],⁴⁴ and oxidized low-density lipoprotein⁴⁵ are more prevalent in systemic sclerosis, but these results have not been substantiated in more extensive studies.

Peripheral artery disease

It remains unclear whether peripheral artery disease is more prevalent in systemic sclerosis patients than in controls.

Individual studies have shown mixed results in comparing carotid artery stenosis between systemic sclerosis patients and controls using carotid duplex ultrasonography,⁴⁶ the ankle-brachial index,^46–48 carotid intima-media thickness,^49–54 and brachial flow-mediated dilation.^{51,53,55–58} A meta-analysis found that the carotid intima and media are significantly thicker in systemic sclerosis patients than in controls,⁵⁹ and the magnitude of difference is similar to that in other groups at increased cardiovascular risk, such as those with rheumatoid arthritis, diabetes, and familial hypercholesterolemia.^60–63

A meta-analysis of brachial artery findings showed significantly lower flow-mediated dilation in systemic sclerosis patients than in controls.⁶⁴

Overall, given the inconsistency of study results, systemic sclerosis patients should be screened and managed as in other patients with peripheral artery disease, but the clinician should be aware that there may be a higher risk of peripheral artery disease in these patients.

RIGHT AND LEFT VENTRICULAR DYSFUNCTION

Many patients with systemic sclerosis have right ventricular dysfunction as a consequence of PAH.⁶⁵ It is important to detect diastolic dysfunction in this population, as it may be an even stronger predictor of death than pulmonary hypertension on right heart catheterization (HR 3.7 vs 2.0).⁶⁶

Fewer patients have left ventricular dysfunction. In a multicenter study of 570 systemic sclerosis patients, only 1.4% had left ventricular systolic dysfunction on echocardiography, though 22.6% had left ventricular hypertrophy and 17.7% had left ventricular diastolic dysfunction.⁶⁷ In the European League Against Rheumatism (EULAR) database, the prevalence of reduced left ventricular ejection fraction was 5.4%.⁶⁸

Though traditional echocardiographic screening suggests the prevalence of left ventricular dysfunction in systemic sclerosis patients is low, cardiac magnetic resonance imaging (MRI) may be more sensitive than echocardiography for detecting subclinical myocardial involvement. Cardiac MRI has been shown to detect evidence of myocardial pathology (increased T2 signal, left ventricular thinning, pericardial effusion, reduced left ventricular and right ventricular ejection fraction, left ventricular diastolic dysfunction, and delayed myocardial contrast enhancement) in up to 75% of systemic sclerosis cases studied.⁶⁹

Patients with systemic sclerosis should already be undergoing echocardiography every year to screen for PAH, and screening should also include tissue Doppler imaging to detect various forms of left and right ventricular systolic and diastolic dysfunction that may not be clinically apparent.

Though cardiac MRI can provide useful additional information, it is not currently recommended for routine screening in patients with systemic sclerosis.

Patients with systemic sclerosis are prone to arrhythmias due to both conduction system fibrosis and myocardial damage.

Arrhythmias accounted for 6% of the deaths in the EULAR Scleroderma Trials and Research (EUSTAR) database.¹¹

In the Genetics Versus Environment in Scleroderma Outcome Study (GENISOS),⁷⁰  250 patients who had had systemic sclerosis for at least 3 years were studied during a period of approximately 6 years, during which there were 52 deaths, 29 of which were directly attributable to systemic sclerosis. Multivariable Cox modeling showed that 7 variables predicted mortality:

• Body mass index < 18.5 kg/m²
• Age ≥ 65
• Forced vital capacity < 50% predicted
• Systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg
• Pulmonary fibrosis
• Positive anticentromere antibodies
• Cardiac arrhythmias.

The hazard ratio for death in patients with arrhythmias in this model was 2.18 (95% CI 1.05–4.50, P = .035). Thus, finding arrhythmias in systemic sclerosis patients can provide important prognostic information.

While resting electrocardiography in patients with systemic sclerosis  most commonly shows sinus rhythm, 24-hour electrocardiographic monitoring has revealed nonsustained supraventricular and ventricular arrhythmias in a significant percentage.^71,72 Although difficult to quantify in routine practice, parameters controlled by the autonomic nervous system including heart rate variability and heart rate turbulence have been shown to be impaired in systemic sclerosis, and these measures are associated with an increased risk of malignant arrhythmias and sudden cardiac death.^73,74

Conduction abnormalities

Conduction abnormalities occur in one-fifth to one-third of patients with systemic sclerosis.^75,76 The most common abnormal conduction finding is left bundle branch block, followed by first-degree atrioventricular block. High-degree atrioventricular block is uncommon,⁷⁶ though a few case reports of complete heart block thought to be related to systemic sclerosis have been published.^77–79 An autopsy study showed that the conduction system is relatively spared from myocardial changes seen in systemic sclerosis patients, and thus it is speculated that the conduction disturbances are a consequence of damaged myocardium rather than damage to conduction tissue.⁸⁰

Given the array of electrophysiologic abnormalities that systemic sclerosis patients can have, it is critical to monitor all patients with routine (annual or biannual) electrocardiography; to take possible arrhythmia-related symptoms seriously; and to evaluate them with further workup such as Holter monitoring for 24 hours or even longer, event monitoring, exercise testing, or tilt-table testing.

PERICARDIAL DISEASE

Pericardial disease is clinically apparent in 5% to 16% of patients with systemic sclerosis⁸¹; patients with limited cutaneous systemic sclerosis have more pericardial disease than those with diffuse cutaneous systemic sclerosis (30% vs 16%).⁸² Forty-one percent of systemic sclerosis patients have been shown to have pericardial effusion by echocardiography,⁸¹ but the effusions are typically small and rarely cause tamponade, though tamponade is associated with a poor prognosis.

Large pericardial effusions can develop before skin thickening and diagnosis of systemic sclerosis.^81,83,84 Thus, systemic sclerosis should be considered in patients with pericardial effusions of unknown etiology.

In a small study,⁸⁵ the pericardial fluid in systemic sclerosis was typically exudative, with lactate dehydrogenase greater than 200 U/L, a fluid-serum lactate dehydrogenase ratio greater than 0.6, and a fluid-serum total protein ratio greater than 0.5.

Pericardial effusion can be a sign of impending scleroderma renal crisis,⁸⁶ and thus renal function should be carefully monitored in systemic sclerosis patients with pericardial effusion. Constrictive pericarditis and restrictive cardiomyopathy can rarely occur in systemic sclerosis and may more commonly present with symptoms.

Pericardial disease in systemic sclerosis should be treated in a standard fashion with nonsteroidal anti-inflammatory drugs. Corticosteroids are generally of limited benefit and should be avoided, especially in the setting of scleroderma renal crisis.⁸¹

VALVULAR HEART DISEASE

Based on limited studies, the prevalence of significant valvular heart disease in systemic sclerosis patients does not seem to be higher than that in the general population. While patients with systemic sclerosis and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) have been shown to have a higher frequency of mitral valve prolapse and mild mitral regurgitation,^87,88 these abnormalities do not often progress in severity, and thus their clinical significance is limited.

It is important for physicians caring for patients with systemic sclerosis to be aware of its most common cardiac manifestations, including left and right ventricular systolic and diastolic dysfunction, pulmonary hypertension, conduction abnormalities, arrhythmias, and cardiomyopathy.

Look for volume overload

On clinical examination, assess for clinical markers of volume overload such as distended neck veins, peripheral edema, or an abnormal blood pressure response to the Valsalva maneuver. These findings should prompt measurement of NT-proBNP,⁸⁹ and may warrant prescription of a diuretic.

Electrocardiography to investigate arrhythmias

Electrocardiography should be done if patients describe symptoms of palpitations, and should also include continuous rhythm monitoring with Holter or event monitoring, depending on the frequency of symptoms. Otherwise, patients should routinely undergo electrocardiography once or twice a year.

Q waves are common in systemic sclerosis patients (especially those with diffuse cutaneous systemic sclerosis), notably in the precordial leads, and can occur without coronary artery disease.⁹⁰ Symptoms such as presyncope should be further investigated with Holter monitoring and tilt-table testing.

Assess, modify traditional risk factors

Subclinical atherosclerosis as detected by carotid intima-media thickness is as common in systemic sclerosis as in rheumatoid arthritis.⁶¹ However, traditional risk indices such as SCORE (Systematic Coronary Risk Evaluation), QRISK2, and the American College of Cardiology/American Heart Association indices may underestimate risk in patients who have systemic sclerosis.

Strict hypertension control should be the goal for all systemic sclerosis patients. Though there are no specific guidelines on which antihypertensive medications are preferred, calcium channel blockers or angiotensin II receptor blockers, which are typically used to treat systemic sclerosis-related Raynaud phenomenon, may be appropriate.

Statins reduce vascular complications and are generally well tolerated in patients with systemic sclerosis.^91,92 

Aspirin is not recommended for routine primary prevention in view of data suggesting that its benefits in diabetic patients are counterbalanced by increased bleeding risk.⁹³

Echocardiography to detect pulmonary arterial hypertension

At this time, guidelines for monitoring for cardiovascular manifestations in systemic sclerosis patients are limited. The only well-defined ones are European consensus guidelines, which suggest annual transthoracic echocardiography for the first 5 years after systemic sclerosis is diagnosed and continued annual screening in patients at risk of developing PAH.³¹

We support this strategy, with annual screening for the first 5 years followed by surveillance echocardiography every 2 to 3 years unless there is a high risk of PAH. Specific attention should be paid to right ventricular diastolic function, right atrial volume, and right ventricular myocardial performance index.

Emerging data suggest that the addition of global longitudinal strain of ventricles to  routine echocardiography can help detect subclinical cardiac risk.⁹⁴ Although further study is needed into the predictive value of global longitudinal strain, it is a low-cost and noninvasive addition to standard echocardiography that can help guide risk stratification, and thus we recommend that it be part of the echocardiographic examination for all systemic sclerosis patients.

Pulmonary function testing. In addition to screening for PAH with echocardiography, we recommend obtaining baseline pulmonary function tests, including D_^LCO, at the time systemic sclerosis is diagnosed, with repeat testing annually.

Magnetic resonance imaging

While echocardiography is the gold standard for monitoring systemic sclerosis patients, cardiovascular MRI may have a role in identifying those at higher risk of dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation. In addition to assessing ventricular function, MRI can detect myocardial inflammation, ischemia, and fibrosis that may predispose a patient to develop ventricular tachycardia or fibrillation.⁹⁵ Variables such as T1/T2 mapping, extracellular volume fraction, T2 signal ratio, and early vs late gadolinium enhancement can help identify patients who had past ventricular tachycardia or fibrillation.⁹⁶

Finding an increased risk of arrhythmias may prompt a conversation between the patient and the physician about the need for an implantable cardiac defibrillator.

If cardiac MRI is available and is reimbursed by the patient’s insurance carrier, physicians should strongly consider obtaining at least one baseline scan in systemic sclerosis patients to identify those at risk of highly fatal arrhythmias.

Teamwork is needed

Systemic sclerosis has not traditionally been associated with cardiovascular disease to the extent of other rheumatic conditions, but the cardiovascular system can be affected in various ways that can ultimately lead to an early death. These manifestations may be asymptomatic for long periods, and overt clinical disease portends a poorer prognosis.

Primary care physicians managing these patients should be aware of the cardiovascular complications of systemic sclerosis and should implement appropriate screening tests in conjunction with rheumatologists and cardiologists. It is also essential for general and subspecialty cardiologists to understand the broad spectrum of organ system involvement that can affect systemic sclerosis patients and to tailor their investigation and management recommendations accordingly. By designing a multidisciplinary approach to the treatment of systemic sclerosis patients, physicians can help to optimize cardiovascular risk modification in this vulnerable population.

Autoimmune rheumatic diseases increase the risk of cardiovascular disease. In rheumatoid arthritis and systemic lupus erythematosus, the risk is driven primarily by the inflammatory milieu, leading to accelerated coronary and cerebrovascular atherosclerosis independent of traditional atherosclerotic risk factors.^1–3 The extent of cardiovascular involvement in other rheumatologic diseases has been less well characterized but is an area of growing interest.

In this review, we focus on the cardiovascular complications of systemic sclerosis and review recommendations for monitoring these patients in clinical practice.

SYSTEMIC SCLEROSIS, AN AUTOIMMUNE RHEUMATIC DISEASE

Systemic sclerosis is an autoimmune rheumatic disease characterized by excessive extracellular matrix deposition leading to diffuse fibrosis, endothelial dysfunction, and microvascular injury. It is most common in North America, Southern Europe, and Australia,^4,5 and it affects women more than men in ratios ranging from 3:1 to 14:1.⁶ The mean age at diagnosis is around 50. 

The disease can affect the lungs (interstitial lung disease and pulmonary hypertension), the heart, the kidneys, and the gastrointestinal tract.

Systemic sclerosis has 2 main subtypes: limited cutaneous systemic sclerosis, formerly called CREST syndrome) and diffuse cutaneous systemic sclerosis. The limited cutaneous subtype is characterized by tightening of the skin of the distal extremities (below the elbows and knees) and face, while diffuse cutaneous systemic sclerosis can manifest as more extensive skin tightening also involving proximal extremities and the trunk. Both subtypes can have an effect on the cardiovascular system.

Some cardiovascular risk factors such as dyslipidemia, diabetes mellitus, and high body mass index are less common in patients with systemic sclerosis than in patients with rheumatoid arthritis, while the rates of arterial hypertension, smoking, chronic obstructive pulmonary disease, osteoporosis, and neoplasms are similar between the 2 groups.⁷

HEART INVOLVEMENT HAS SERIOUS CONSEQUENCES

Overt cardiac involvement in systemic sclerosis is associated with a mortality rate of up to 70% over 5 years,^8,9 and about one-fourth of deaths in patients with systemic sclerosis are from cardiac causes.^10,11 Studies in Europe^10,12 showed that many patients with systemic sclerosis have cardiac involvement detectable by magnetic resonance imaging even if they do not have clinical disease. Pulmonary arterial hypertension (PAH) is a complication of both subtypes of systemic sclerosis and portends a higher risk of death.⁸

Thus, it is critical for clinicians to understand the potential comorbid conditions associated with systemic sclerosis, particularly the cardiovascular ones, and to work closely with cardiologists to help optimize the evaluation and management.

MECHANISMS OF CARDIAC DISEASE IN SYSTEMIC SCLEROSIS

Abnormal vasoreactivity, a consequence of an imbalance between endothelium-derived vasoconstrictors and vasodilators, defective angiogenesis, and endothelial injury, leads to tissue ischemia and vascular endothelial growth factor expression, which initiates injury and fibrosis in the myocardium and in other organs.^14–17 Fibrosis involves the myocardium, pericardium, and conduction system.^13,18

Myocardial involvement in systemic sclerosis is thought to be due mainly to abnormal vasoreactivity and microvascular abnormalities such as transient coronary artery spasm leading to repeated focal ischemia.^19,20 Abnormal vasoreactivity has been demonstrated during cardiac catheterization²¹: while mean coronary sinus blood flow in systemic sclerosis patients was normal at rest, vasodilator reserve was significantly reduced in patients with diffuse cutaneous systemic sclerosis after maximal vasodilation with dipyridamole. Additionally, endomyocardial biopsy showed fibrosis and concentric intimal hypertrophy with normal epicardial coronary arteries.²¹

More research into other mechanisms of cardiovascular disease in systemic sclerosis is needed to allow for better preventive care for these patients.

Systemic sclerosis can be associated with World Health Organization (WHO) groups 1, 2, 3, and 4 pulmonary hypertension. WHO group 1, called pulmonary arterial hypertension or PAH, is one of the most common cardiac complications of systemic sclerosis, with a reported prevalence as high as 12%.²² Systemic sclerosis-associated PAH carries a high mortality rate, with a mean survival of only 3 years.²³

With advances in treatments for other complications of systemic sclerosis, the percentage of systemic sclerosis patients who die of PAH has increased from 6% to 33%.²⁴

Compared with patients with idiopathic PAH, those with systemic sclerosis get less of a response from therapy and have poorer outcomes despite lower mean pulmonary artery pressures and similar reductions in cardiac index. However, recent studies have suggested that with aggressive treatment, patients with systemic sclerosis-related PAH can achieve outcomes similar to those with idiopathic PAH.²⁵ Thus, recognizing this condition early is imperative.

Pulmonary arterial hypertension defined

PAH is defined as the combination of all of the following²⁶:

• Mean pulmonary artery pressure > 20 mm Hg at rest
• Normal pulmonary capillary wedge pressure (≤ 15 mm Hg)
• Pulmonary vascular resistance ≥ 3 Wood units on right heart catheterization.

Other causes of pulmonary hypertension such as interstitial lung disease, chronic pulmonary thromboembolic disease, and left heart disease must be excluded.^24,27

Remodeling in the pulmonary arteries

The events that lead to PAH in systemic sclerosis remain unclear but are believed to involve initial inflammation or endothelial injury that leads to a dysequilibrium between proliferative mediators and antiproliferative vasodilators. This dysequilibrium, along with endothelial dysfunction, causes an obliterative vasculopathy in the pulmonary artery branches and arterioles. Sympathetic overactivity, hypoxemia, and ischemia-reperfusion injury additionally promote vascular proliferation, fibrosis, and remodeling, leading to increased pulmonary vascular resistance, PAH, and increased right ventricular pressures.^23,27

The subtype of systemic sclerosis is an important factor in the development and progression of PAH. PAH appears to be the major cause of death in limited cutaneous systemic sclerosis, while interstitial lung disease is the major cause of death in diffuse cutaneous systemic sclerosis.²⁸

Pulmonary arterial hypertension is a late complication of systemic sclerosis

Data from the South Australian Scleroderma Registry²⁹ revealed that PAH tends to be a late complication of systemic sclerosis, occurring around 20 years after disease onset. In this study of 608 patients, no patient with diffuse cutaneous systemic sclerosis developed PAH.

Systemic sclerosis-related PAH initially follows an indolent course with few symptoms until right ventricular function deteriorates. Early in the disease, patients may experience nonspecific symptoms of fatigue, lightheadedness, and dyspnea on exertion.²³ As it progresses, they tend to have worsening dyspnea and may experience exertional syncope, palpitations, and chest pain.

Physical findings may suggest elevated right ventricular pressure and right ventricular failure; these include a loud P2, a prominent jugular a wave, a tricuspid regurgitant murmur, jugular venous distention, and lower-extremity edema.²⁷

Screening for pulmonary arterial hypertension in systemic sclerosis

Significant signs and symptoms usually occur late in the disease; thus, it is important to appropriately screen patients who are at risk so that they can begin aggressive treatment.

Doppler echocardiography is recommended by European and American guidelines to screen for PAH in patients who have systemic sclerosis, and most agree that screening is appropriate even if the patient has no symptoms.³⁰ European consensus documents recommend that transthoracic echocardiography be done annually for the first 5 years of disease and be continued every year in patients at high risk, ie, those with anticentromere antibodies, anti-Th/To antibodies, or interstitial lung disease. Patients not at high risk of developing pulmonary hypertension should also have regular transthoracic echocardiography, though the exact timing is not defined.³¹ While American societies have not issued corresponding recommendations, many experts follow the European recommendations.

Worrisome features on echocardiography in asymptomatic patients should be followed up with right heart catheterization to assess mean right ventricular pressure. These include:

• Estimated right ventricular systolic pressure ≥ 40 mm Hg
• Tricuspid regurgitant jet velocity > 2.8 m/s
• Right atrial enlargement > 53 mm
• Right ventricular enlargement (mid-cavity dimension > 35 mm).³²

Although echocardiography is the most common form of screening, it gives only an estimate of right ventricular systolic pressure, which is imprecise. Other noninvasive markers are helpful and necessary to appropriately screen this population.

Diffusion capacity. The Itinerair study³³ found that a diffusing capacity for carbon monoxide (D_^LCO) of 60% or higher has a high specificity in excluding PAH.

Uric acid has been found to be elevated in patients with systemic sclerosis-related PAH, and levels inversely correlate with 6-minute walking distance.³⁴

Other predictors. N-terminal pro-B-type natriuretic peptide (NT-proBNP), left atrial volume, and the right ventricular myocardial performance index have also been shown to be independent predictors of PAH in patients with systemic sclerosis.³⁵

An algorithm. The DETECT study³⁶ enrolled patients at increased risk who had had systemic sclerosis longer than 3 years and a D_^LCO less than 60%. The investigators developed a 2-step algorithm to determine which patients should be referred for right heart catheterization to try to detect PAH earlier while minimizing the number of missed diagnoses and optimizing the use of invasive diagnostic right heart catheterization.

The first step was to assess serum values of anticentromere antibodies, NT-proBNP, and urate, and clinical features (telangiectasias), forced vital capacity, and electrocardiographic changes of right axis deviation to derive a prediction score. The second step was to assess surface echocardiographic features of the right atrial area and tricuspid regurgitation velocity.

This approach led to right heart catheterization in 62% of patients and was associated with a false-negative rate of 4%. Importantly, of the patients with PAH, 1 in 5 had no symptoms, and 33% had tricuspid regurgitation velocity less than 2.8 m/s. No single measurement performed well in isolation in this study.³⁷

Thus, we recommend that, in addition to routine surface echocardiography, a multimodal approach be used that includes laboratory testing, clinical features, and electrocardiographic findings when screening this high-risk patient population.

Although macrovascular disease has not typically been regarded as a significant systemic feature in systemic sclerosis, myocardial infarction and stroke are more common in patients with systemic sclerosis than in controls.^38,39

Coronary artery disease in systemic sclerosis

Man et al³⁸ reported that the incidence of myocardial infarction in patients with systemic sclerosis was 4.4 per 1,000 persons per year, and the incidence of stroke was 4.8 per 1,000 persons per year, compared with 2.5 per 1,000 persons per year for both myocardial infarction and stroke in healthy controls matched for age, sex, and time of entry.

The Australian Scleroderma Cohort Study³⁹ found a 3-fold higher prevalence of coronary artery disease in systemic sclerosis patients than in controls after factoring in traditional risk factors.

Aviña-Zubieta et al,⁴⁰ in a cohort of 1,239 systemic sclerosis patients, estimated a hazard ratio (HR) of 3.49 for myocardial infarction and 2.35 for stroke compared with age- and sex-matched controls. Not all of these events were related to macrovascular atherosclerosis—vasospasm and microvascular ischemia may have played significant roles in the etiology of clinical manifestations.

Studies of coronary atherosclerosis in systemic sclerosis are limited. An autopsy study⁴¹ of 58 patients with systemic sclerosis and 58 controls matched for age, sex, and ethnicity found that the prevalence of atherosclerosis of small coronary arteries and arterioles was significantly higher in systemic sclerosis patients than in controls (17% vs 2%, P < .01). However, the prevalence of medium-vessel coronary atherosclerosis was similar (48% vs 43%).

Why patients with systemic sclerosis develop atherosclerosis has not yet been determined. Traditional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity are typically no more prevalent in systemic sclerosis patients than in controls,^38,42 and thus do not explain the increased risk of atherosclerotic cardiovascular disease. There is some evidence that novel markers of atherosclerotic risk such as homocysteine,⁴³ lipoprotein[a],⁴⁴ and oxidized low-density lipoprotein⁴⁵ are more prevalent in systemic sclerosis, but these results have not been substantiated in more extensive studies.

Peripheral artery disease

It remains unclear whether peripheral artery disease is more prevalent in systemic sclerosis patients than in controls.

Individual studies have shown mixed results in comparing carotid artery stenosis between systemic sclerosis patients and controls using carotid duplex ultrasonography,⁴⁶ the ankle-brachial index,^46–48 carotid intima-media thickness,^49–54 and brachial flow-mediated dilation.^{51,53,55–58} A meta-analysis found that the carotid intima and media are significantly thicker in systemic sclerosis patients than in controls,⁵⁹ and the magnitude of difference is similar to that in other groups at increased cardiovascular risk, such as those with rheumatoid arthritis, diabetes, and familial hypercholesterolemia.^60–63

A meta-analysis of brachial artery findings showed significantly lower flow-mediated dilation in systemic sclerosis patients than in controls.⁶⁴

Overall, given the inconsistency of study results, systemic sclerosis patients should be screened and managed as in other patients with peripheral artery disease, but the clinician should be aware that there may be a higher risk of peripheral artery disease in these patients.

RIGHT AND LEFT VENTRICULAR DYSFUNCTION

Many patients with systemic sclerosis have right ventricular dysfunction as a consequence of PAH.⁶⁵ It is important to detect diastolic dysfunction in this population, as it may be an even stronger predictor of death than pulmonary hypertension on right heart catheterization (HR 3.7 vs 2.0).⁶⁶

Fewer patients have left ventricular dysfunction. In a multicenter study of 570 systemic sclerosis patients, only 1.4% had left ventricular systolic dysfunction on echocardiography, though 22.6% had left ventricular hypertrophy and 17.7% had left ventricular diastolic dysfunction.⁶⁷ In the European League Against Rheumatism (EULAR) database, the prevalence of reduced left ventricular ejection fraction was 5.4%.⁶⁸

Though traditional echocardiographic screening suggests the prevalence of left ventricular dysfunction in systemic sclerosis patients is low, cardiac magnetic resonance imaging (MRI) may be more sensitive than echocardiography for detecting subclinical myocardial involvement. Cardiac MRI has been shown to detect evidence of myocardial pathology (increased T2 signal, left ventricular thinning, pericardial effusion, reduced left ventricular and right ventricular ejection fraction, left ventricular diastolic dysfunction, and delayed myocardial contrast enhancement) in up to 75% of systemic sclerosis cases studied.⁶⁹

Patients with systemic sclerosis should already be undergoing echocardiography every year to screen for PAH, and screening should also include tissue Doppler imaging to detect various forms of left and right ventricular systolic and diastolic dysfunction that may not be clinically apparent.

Though cardiac MRI can provide useful additional information, it is not currently recommended for routine screening in patients with systemic sclerosis.

Patients with systemic sclerosis are prone to arrhythmias due to both conduction system fibrosis and myocardial damage.

Arrhythmias accounted for 6% of the deaths in the EULAR Scleroderma Trials and Research (EUSTAR) database.¹¹

In the Genetics Versus Environment in Scleroderma Outcome Study (GENISOS),⁷⁰  250 patients who had had systemic sclerosis for at least 3 years were studied during a period of approximately 6 years, during which there were 52 deaths, 29 of which were directly attributable to systemic sclerosis. Multivariable Cox modeling showed that 7 variables predicted mortality:

• Body mass index < 18.5 kg/m²
• Age ≥ 65
• Forced vital capacity < 50% predicted
• Systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg
• Pulmonary fibrosis
• Positive anticentromere antibodies
• Cardiac arrhythmias.

The hazard ratio for death in patients with arrhythmias in this model was 2.18 (95% CI 1.05–4.50, P = .035). Thus, finding arrhythmias in systemic sclerosis patients can provide important prognostic information.

While resting electrocardiography in patients with systemic sclerosis  most commonly shows sinus rhythm, 24-hour electrocardiographic monitoring has revealed nonsustained supraventricular and ventricular arrhythmias in a significant percentage.^71,72 Although difficult to quantify in routine practice, parameters controlled by the autonomic nervous system including heart rate variability and heart rate turbulence have been shown to be impaired in systemic sclerosis, and these measures are associated with an increased risk of malignant arrhythmias and sudden cardiac death.^73,74

Conduction abnormalities

Conduction abnormalities occur in one-fifth to one-third of patients with systemic sclerosis.^75,76 The most common abnormal conduction finding is left bundle branch block, followed by first-degree atrioventricular block. High-degree atrioventricular block is uncommon,⁷⁶ though a few case reports of complete heart block thought to be related to systemic sclerosis have been published.^77–79 An autopsy study showed that the conduction system is relatively spared from myocardial changes seen in systemic sclerosis patients, and thus it is speculated that the conduction disturbances are a consequence of damaged myocardium rather than damage to conduction tissue.⁸⁰

Given the array of electrophysiologic abnormalities that systemic sclerosis patients can have, it is critical to monitor all patients with routine (annual or biannual) electrocardiography; to take possible arrhythmia-related symptoms seriously; and to evaluate them with further workup such as Holter monitoring for 24 hours or even longer, event monitoring, exercise testing, or tilt-table testing.

PERICARDIAL DISEASE

Pericardial disease is clinically apparent in 5% to 16% of patients with systemic sclerosis⁸¹; patients with limited cutaneous systemic sclerosis have more pericardial disease than those with diffuse cutaneous systemic sclerosis (30% vs 16%).⁸² Forty-one percent of systemic sclerosis patients have been shown to have pericardial effusion by echocardiography,⁸¹ but the effusions are typically small and rarely cause tamponade, though tamponade is associated with a poor prognosis.

Large pericardial effusions can develop before skin thickening and diagnosis of systemic sclerosis.^81,83,84 Thus, systemic sclerosis should be considered in patients with pericardial effusions of unknown etiology.

In a small study,⁸⁵ the pericardial fluid in systemic sclerosis was typically exudative, with lactate dehydrogenase greater than 200 U/L, a fluid-serum lactate dehydrogenase ratio greater than 0.6, and a fluid-serum total protein ratio greater than 0.5.

Pericardial effusion can be a sign of impending scleroderma renal crisis,⁸⁶ and thus renal function should be carefully monitored in systemic sclerosis patients with pericardial effusion. Constrictive pericarditis and restrictive cardiomyopathy can rarely occur in systemic sclerosis and may more commonly present with symptoms.

Pericardial disease in systemic sclerosis should be treated in a standard fashion with nonsteroidal anti-inflammatory drugs. Corticosteroids are generally of limited benefit and should be avoided, especially in the setting of scleroderma renal crisis.⁸¹

VALVULAR HEART DISEASE

Based on limited studies, the prevalence of significant valvular heart disease in systemic sclerosis patients does not seem to be higher than that in the general population. While patients with systemic sclerosis and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) have been shown to have a higher frequency of mitral valve prolapse and mild mitral regurgitation,^87,88 these abnormalities do not often progress in severity, and thus their clinical significance is limited.

It is important for physicians caring for patients with systemic sclerosis to be aware of its most common cardiac manifestations, including left and right ventricular systolic and diastolic dysfunction, pulmonary hypertension, conduction abnormalities, arrhythmias, and cardiomyopathy.

Look for volume overload

On clinical examination, assess for clinical markers of volume overload such as distended neck veins, peripheral edema, or an abnormal blood pressure response to the Valsalva maneuver. These findings should prompt measurement of NT-proBNP,⁸⁹ and may warrant prescription of a diuretic.

Electrocardiography to investigate arrhythmias

Electrocardiography should be done if patients describe symptoms of palpitations, and should also include continuous rhythm monitoring with Holter or event monitoring, depending on the frequency of symptoms. Otherwise, patients should routinely undergo electrocardiography once or twice a year.

Q waves are common in systemic sclerosis patients (especially those with diffuse cutaneous systemic sclerosis), notably in the precordial leads, and can occur without coronary artery disease.⁹⁰ Symptoms such as presyncope should be further investigated with Holter monitoring and tilt-table testing.

Assess, modify traditional risk factors

Subclinical atherosclerosis as detected by carotid intima-media thickness is as common in systemic sclerosis as in rheumatoid arthritis.⁶¹ However, traditional risk indices such as SCORE (Systematic Coronary Risk Evaluation), QRISK2, and the American College of Cardiology/American Heart Association indices may underestimate risk in patients who have systemic sclerosis.

Strict hypertension control should be the goal for all systemic sclerosis patients. Though there are no specific guidelines on which antihypertensive medications are preferred, calcium channel blockers or angiotensin II receptor blockers, which are typically used to treat systemic sclerosis-related Raynaud phenomenon, may be appropriate.

Statins reduce vascular complications and are generally well tolerated in patients with systemic sclerosis.^91,92 

Aspirin is not recommended for routine primary prevention in view of data suggesting that its benefits in diabetic patients are counterbalanced by increased bleeding risk.⁹³

Echocardiography to detect pulmonary arterial hypertension

At this time, guidelines for monitoring for cardiovascular manifestations in systemic sclerosis patients are limited. The only well-defined ones are European consensus guidelines, which suggest annual transthoracic echocardiography for the first 5 years after systemic sclerosis is diagnosed and continued annual screening in patients at risk of developing PAH.³¹

We support this strategy, with annual screening for the first 5 years followed by surveillance echocardiography every 2 to 3 years unless there is a high risk of PAH. Specific attention should be paid to right ventricular diastolic function, right atrial volume, and right ventricular myocardial performance index.

Emerging data suggest that the addition of global longitudinal strain of ventricles to  routine echocardiography can help detect subclinical cardiac risk.⁹⁴ Although further study is needed into the predictive value of global longitudinal strain, it is a low-cost and noninvasive addition to standard echocardiography that can help guide risk stratification, and thus we recommend that it be part of the echocardiographic examination for all systemic sclerosis patients.

Pulmonary function testing. In addition to screening for PAH with echocardiography, we recommend obtaining baseline pulmonary function tests, including D_^LCO, at the time systemic sclerosis is diagnosed, with repeat testing annually.

Magnetic resonance imaging

While echocardiography is the gold standard for monitoring systemic sclerosis patients, cardiovascular MRI may have a role in identifying those at higher risk of dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation. In addition to assessing ventricular function, MRI can detect myocardial inflammation, ischemia, and fibrosis that may predispose a patient to develop ventricular tachycardia or fibrillation.⁹⁵ Variables such as T1/T2 mapping, extracellular volume fraction, T2 signal ratio, and early vs late gadolinium enhancement can help identify patients who had past ventricular tachycardia or fibrillation.⁹⁶

Finding an increased risk of arrhythmias may prompt a conversation between the patient and the physician about the need for an implantable cardiac defibrillator.

If cardiac MRI is available and is reimbursed by the patient’s insurance carrier, physicians should strongly consider obtaining at least one baseline scan in systemic sclerosis patients to identify those at risk of highly fatal arrhythmias.

Teamwork is needed

Systemic sclerosis has not traditionally been associated with cardiovascular disease to the extent of other rheumatic conditions, but the cardiovascular system can be affected in various ways that can ultimately lead to an early death. These manifestations may be asymptomatic for long periods, and overt clinical disease portends a poorer prognosis.

Primary care physicians managing these patients should be aware of the cardiovascular complications of systemic sclerosis and should implement appropriate screening tests in conjunction with rheumatologists and cardiologists. It is also essential for general and subspecialty cardiologists to understand the broad spectrum of organ system involvement that can affect systemic sclerosis patients and to tailor their investigation and management recommendations accordingly. By designing a multidisciplinary approach to the treatment of systemic sclerosis patients, physicians can help to optimize cardiovascular risk modification in this vulnerable population.

Autoimmune rheumatic diseases increase the risk of cardiovascular disease. In rheumatoid arthritis and systemic lupus erythematosus, the risk is driven primarily by the inflammatory milieu, leading to accelerated coronary and cerebrovascular atherosclerosis independent of traditional atherosclerotic risk factors.^1–3 The extent of cardiovascular involvement in other rheumatologic diseases has been less well characterized but is an area of growing interest.

In this review, we focus on the cardiovascular complications of systemic sclerosis and review recommendations for monitoring these patients in clinical practice.

SYSTEMIC SCLEROSIS, AN AUTOIMMUNE RHEUMATIC DISEASE

Systemic sclerosis is an autoimmune rheumatic disease characterized by excessive extracellular matrix deposition leading to diffuse fibrosis, endothelial dysfunction, and microvascular injury. It is most common in North America, Southern Europe, and Australia,^4,5 and it affects women more than men in ratios ranging from 3:1 to 14:1.⁶ The mean age at diagnosis is around 50. 

The disease can affect the lungs (interstitial lung disease and pulmonary hypertension), the heart, the kidneys, and the gastrointestinal tract.

Systemic sclerosis has 2 main subtypes: limited cutaneous systemic sclerosis, formerly called CREST syndrome) and diffuse cutaneous systemic sclerosis. The limited cutaneous subtype is characterized by tightening of the skin of the distal extremities (below the elbows and knees) and face, while diffuse cutaneous systemic sclerosis can manifest as more extensive skin tightening also involving proximal extremities and the trunk. Both subtypes can have an effect on the cardiovascular system.

Some cardiovascular risk factors such as dyslipidemia, diabetes mellitus, and high body mass index are less common in patients with systemic sclerosis than in patients with rheumatoid arthritis, while the rates of arterial hypertension, smoking, chronic obstructive pulmonary disease, osteoporosis, and neoplasms are similar between the 2 groups.⁷

HEART INVOLVEMENT HAS SERIOUS CONSEQUENCES

Overt cardiac involvement in systemic sclerosis is associated with a mortality rate of up to 70% over 5 years,^8,9 and about one-fourth of deaths in patients with systemic sclerosis are from cardiac causes.^10,11 Studies in Europe^10,12 showed that many patients with systemic sclerosis have cardiac involvement detectable by magnetic resonance imaging even if they do not have clinical disease. Pulmonary arterial hypertension (PAH) is a complication of both subtypes of systemic sclerosis and portends a higher risk of death.⁸

Thus, it is critical for clinicians to understand the potential comorbid conditions associated with systemic sclerosis, particularly the cardiovascular ones, and to work closely with cardiologists to help optimize the evaluation and management.

MECHANISMS OF CARDIAC DISEASE IN SYSTEMIC SCLEROSIS

Abnormal vasoreactivity, a consequence of an imbalance between endothelium-derived vasoconstrictors and vasodilators, defective angiogenesis, and endothelial injury, leads to tissue ischemia and vascular endothelial growth factor expression, which initiates injury and fibrosis in the myocardium and in other organs.^14–17 Fibrosis involves the myocardium, pericardium, and conduction system.^13,18

Myocardial involvement in systemic sclerosis is thought to be due mainly to abnormal vasoreactivity and microvascular abnormalities such as transient coronary artery spasm leading to repeated focal ischemia.^19,20 Abnormal vasoreactivity has been demonstrated during cardiac catheterization²¹: while mean coronary sinus blood flow in systemic sclerosis patients was normal at rest, vasodilator reserve was significantly reduced in patients with diffuse cutaneous systemic sclerosis after maximal vasodilation with dipyridamole. Additionally, endomyocardial biopsy showed fibrosis and concentric intimal hypertrophy with normal epicardial coronary arteries.²¹

More research into other mechanisms of cardiovascular disease in systemic sclerosis is needed to allow for better preventive care for these patients.

Systemic sclerosis can be associated with World Health Organization (WHO) groups 1, 2, 3, and 4 pulmonary hypertension. WHO group 1, called pulmonary arterial hypertension or PAH, is one of the most common cardiac complications of systemic sclerosis, with a reported prevalence as high as 12%.²² Systemic sclerosis-associated PAH carries a high mortality rate, with a mean survival of only 3 years.²³

With advances in treatments for other complications of systemic sclerosis, the percentage of systemic sclerosis patients who die of PAH has increased from 6% to 33%.²⁴

Compared with patients with idiopathic PAH, those with systemic sclerosis get less of a response from therapy and have poorer outcomes despite lower mean pulmonary artery pressures and similar reductions in cardiac index. However, recent studies have suggested that with aggressive treatment, patients with systemic sclerosis-related PAH can achieve outcomes similar to those with idiopathic PAH.²⁵ Thus, recognizing this condition early is imperative.

Pulmonary arterial hypertension defined

PAH is defined as the combination of all of the following²⁶:

• Mean pulmonary artery pressure > 20 mm Hg at rest
• Normal pulmonary capillary wedge pressure (≤ 15 mm Hg)
• Pulmonary vascular resistance ≥ 3 Wood units on right heart catheterization.

Other causes of pulmonary hypertension such as interstitial lung disease, chronic pulmonary thromboembolic disease, and left heart disease must be excluded.^24,27

Remodeling in the pulmonary arteries

The events that lead to PAH in systemic sclerosis remain unclear but are believed to involve initial inflammation or endothelial injury that leads to a dysequilibrium between proliferative mediators and antiproliferative vasodilators. This dysequilibrium, along with endothelial dysfunction, causes an obliterative vasculopathy in the pulmonary artery branches and arterioles. Sympathetic overactivity, hypoxemia, and ischemia-reperfusion injury additionally promote vascular proliferation, fibrosis, and remodeling, leading to increased pulmonary vascular resistance, PAH, and increased right ventricular pressures.^23,27

The subtype of systemic sclerosis is an important factor in the development and progression of PAH. PAH appears to be the major cause of death in limited cutaneous systemic sclerosis, while interstitial lung disease is the major cause of death in diffuse cutaneous systemic sclerosis.²⁸

Pulmonary arterial hypertension is a late complication of systemic sclerosis

Data from the South Australian Scleroderma Registry²⁹ revealed that PAH tends to be a late complication of systemic sclerosis, occurring around 20 years after disease onset. In this study of 608 patients, no patient with diffuse cutaneous systemic sclerosis developed PAH.

Systemic sclerosis-related PAH initially follows an indolent course with few symptoms until right ventricular function deteriorates. Early in the disease, patients may experience nonspecific symptoms of fatigue, lightheadedness, and dyspnea on exertion.²³ As it progresses, they tend to have worsening dyspnea and may experience exertional syncope, palpitations, and chest pain.

Physical findings may suggest elevated right ventricular pressure and right ventricular failure; these include a loud P2, a prominent jugular a wave, a tricuspid regurgitant murmur, jugular venous distention, and lower-extremity edema.²⁷

Screening for pulmonary arterial hypertension in systemic sclerosis

Significant signs and symptoms usually occur late in the disease; thus, it is important to appropriately screen patients who are at risk so that they can begin aggressive treatment.

Doppler echocardiography is recommended by European and American guidelines to screen for PAH in patients who have systemic sclerosis, and most agree that screening is appropriate even if the patient has no symptoms.³⁰ European consensus documents recommend that transthoracic echocardiography be done annually for the first 5 years of disease and be continued every year in patients at high risk, ie, those with anticentromere antibodies, anti-Th/To antibodies, or interstitial lung disease. Patients not at high risk of developing pulmonary hypertension should also have regular transthoracic echocardiography, though the exact timing is not defined.³¹ While American societies have not issued corresponding recommendations, many experts follow the European recommendations.

Worrisome features on echocardiography in asymptomatic patients should be followed up with right heart catheterization to assess mean right ventricular pressure. These include:

• Estimated right ventricular systolic pressure ≥ 40 mm Hg
• Tricuspid regurgitant jet velocity > 2.8 m/s
• Right atrial enlargement > 53 mm
• Right ventricular enlargement (mid-cavity dimension > 35 mm).³²

Although echocardiography is the most common form of screening, it gives only an estimate of right ventricular systolic pressure, which is imprecise. Other noninvasive markers are helpful and necessary to appropriately screen this population.

Diffusion capacity. The Itinerair study³³ found that a diffusing capacity for carbon monoxide (D_^LCO) of 60% or higher has a high specificity in excluding PAH.

Uric acid has been found to be elevated in patients with systemic sclerosis-related PAH, and levels inversely correlate with 6-minute walking distance.³⁴

Other predictors. N-terminal pro-B-type natriuretic peptide (NT-proBNP), left atrial volume, and the right ventricular myocardial performance index have also been shown to be independent predictors of PAH in patients with systemic sclerosis.³⁵

An algorithm. The DETECT study³⁶ enrolled patients at increased risk who had had systemic sclerosis longer than 3 years and a D_^LCO less than 60%. The investigators developed a 2-step algorithm to determine which patients should be referred for right heart catheterization to try to detect PAH earlier while minimizing the number of missed diagnoses and optimizing the use of invasive diagnostic right heart catheterization.

The first step was to assess serum values of anticentromere antibodies, NT-proBNP, and urate, and clinical features (telangiectasias), forced vital capacity, and electrocardiographic changes of right axis deviation to derive a prediction score. The second step was to assess surface echocardiographic features of the right atrial area and tricuspid regurgitation velocity.

This approach led to right heart catheterization in 62% of patients and was associated with a false-negative rate of 4%. Importantly, of the patients with PAH, 1 in 5 had no symptoms, and 33% had tricuspid regurgitation velocity less than 2.8 m/s. No single measurement performed well in isolation in this study.³⁷

Thus, we recommend that, in addition to routine surface echocardiography, a multimodal approach be used that includes laboratory testing, clinical features, and electrocardiographic findings when screening this high-risk patient population.

Although macrovascular disease has not typically been regarded as a significant systemic feature in systemic sclerosis, myocardial infarction and stroke are more common in patients with systemic sclerosis than in controls.^38,39

Coronary artery disease in systemic sclerosis

Man et al³⁸ reported that the incidence of myocardial infarction in patients with systemic sclerosis was 4.4 per 1,000 persons per year, and the incidence of stroke was 4.8 per 1,000 persons per year, compared with 2.5 per 1,000 persons per year for both myocardial infarction and stroke in healthy controls matched for age, sex, and time of entry.

The Australian Scleroderma Cohort Study³⁹ found a 3-fold higher prevalence of coronary artery disease in systemic sclerosis patients than in controls after factoring in traditional risk factors.

Aviña-Zubieta et al,⁴⁰ in a cohort of 1,239 systemic sclerosis patients, estimated a hazard ratio (HR) of 3.49 for myocardial infarction and 2.35 for stroke compared with age- and sex-matched controls. Not all of these events were related to macrovascular atherosclerosis—vasospasm and microvascular ischemia may have played significant roles in the etiology of clinical manifestations.

Studies of coronary atherosclerosis in systemic sclerosis are limited. An autopsy study⁴¹ of 58 patients with systemic sclerosis and 58 controls matched for age, sex, and ethnicity found that the prevalence of atherosclerosis of small coronary arteries and arterioles was significantly higher in systemic sclerosis patients than in controls (17% vs 2%, P < .01). However, the prevalence of medium-vessel coronary atherosclerosis was similar (48% vs 43%).

Why patients with systemic sclerosis develop atherosclerosis has not yet been determined. Traditional risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity are typically no more prevalent in systemic sclerosis patients than in controls,^38,42 and thus do not explain the increased risk of atherosclerotic cardiovascular disease. There is some evidence that novel markers of atherosclerotic risk such as homocysteine,⁴³ lipoprotein[a],⁴⁴ and oxidized low-density lipoprotein⁴⁵ are more prevalent in systemic sclerosis, but these results have not been substantiated in more extensive studies.

Peripheral artery disease

It remains unclear whether peripheral artery disease is more prevalent in systemic sclerosis patients than in controls.

Individual studies have shown mixed results in comparing carotid artery stenosis between systemic sclerosis patients and controls using carotid duplex ultrasonography,⁴⁶ the ankle-brachial index,^46–48 carotid intima-media thickness,^49–54 and brachial flow-mediated dilation.^{51,53,55–58} A meta-analysis found that the carotid intima and media are significantly thicker in systemic sclerosis patients than in controls,⁵⁹ and the magnitude of difference is similar to that in other groups at increased cardiovascular risk, such as those with rheumatoid arthritis, diabetes, and familial hypercholesterolemia.^60–63

A meta-analysis of brachial artery findings showed significantly lower flow-mediated dilation in systemic sclerosis patients than in controls.⁶⁴

Overall, given the inconsistency of study results, systemic sclerosis patients should be screened and managed as in other patients with peripheral artery disease, but the clinician should be aware that there may be a higher risk of peripheral artery disease in these patients.

RIGHT AND LEFT VENTRICULAR DYSFUNCTION

Many patients with systemic sclerosis have right ventricular dysfunction as a consequence of PAH.⁶⁵ It is important to detect diastolic dysfunction in this population, as it may be an even stronger predictor of death than pulmonary hypertension on right heart catheterization (HR 3.7 vs 2.0).⁶⁶

Fewer patients have left ventricular dysfunction. In a multicenter study of 570 systemic sclerosis patients, only 1.4% had left ventricular systolic dysfunction on echocardiography, though 22.6% had left ventricular hypertrophy and 17.7% had left ventricular diastolic dysfunction.⁶⁷ In the European League Against Rheumatism (EULAR) database, the prevalence of reduced left ventricular ejection fraction was 5.4%.⁶⁸

Though traditional echocardiographic screening suggests the prevalence of left ventricular dysfunction in systemic sclerosis patients is low, cardiac magnetic resonance imaging (MRI) may be more sensitive than echocardiography for detecting subclinical myocardial involvement. Cardiac MRI has been shown to detect evidence of myocardial pathology (increased T2 signal, left ventricular thinning, pericardial effusion, reduced left ventricular and right ventricular ejection fraction, left ventricular diastolic dysfunction, and delayed myocardial contrast enhancement) in up to 75% of systemic sclerosis cases studied.⁶⁹

Patients with systemic sclerosis should already be undergoing echocardiography every year to screen for PAH, and screening should also include tissue Doppler imaging to detect various forms of left and right ventricular systolic and diastolic dysfunction that may not be clinically apparent.

Though cardiac MRI can provide useful additional information, it is not currently recommended for routine screening in patients with systemic sclerosis.

Patients with systemic sclerosis are prone to arrhythmias due to both conduction system fibrosis and myocardial damage.

Arrhythmias accounted for 6% of the deaths in the EULAR Scleroderma Trials and Research (EUSTAR) database.¹¹

In the Genetics Versus Environment in Scleroderma Outcome Study (GENISOS),⁷⁰  250 patients who had had systemic sclerosis for at least 3 years were studied during a period of approximately 6 years, during which there were 52 deaths, 29 of which were directly attributable to systemic sclerosis. Multivariable Cox modeling showed that 7 variables predicted mortality:

• Body mass index < 18.5 kg/m²
• Age ≥ 65
• Forced vital capacity < 50% predicted
• Systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mm Hg
• Pulmonary fibrosis
• Positive anticentromere antibodies
• Cardiac arrhythmias.

The hazard ratio for death in patients with arrhythmias in this model was 2.18 (95% CI 1.05–4.50, P = .035). Thus, finding arrhythmias in systemic sclerosis patients can provide important prognostic information.

While resting electrocardiography in patients with systemic sclerosis  most commonly shows sinus rhythm, 24-hour electrocardiographic monitoring has revealed nonsustained supraventricular and ventricular arrhythmias in a significant percentage.^71,72 Although difficult to quantify in routine practice, parameters controlled by the autonomic nervous system including heart rate variability and heart rate turbulence have been shown to be impaired in systemic sclerosis, and these measures are associated with an increased risk of malignant arrhythmias and sudden cardiac death.^73,74

Conduction abnormalities

Conduction abnormalities occur in one-fifth to one-third of patients with systemic sclerosis.^75,76 The most common abnormal conduction finding is left bundle branch block, followed by first-degree atrioventricular block. High-degree atrioventricular block is uncommon,⁷⁶ though a few case reports of complete heart block thought to be related to systemic sclerosis have been published.^77–79 An autopsy study showed that the conduction system is relatively spared from myocardial changes seen in systemic sclerosis patients, and thus it is speculated that the conduction disturbances are a consequence of damaged myocardium rather than damage to conduction tissue.⁸⁰

Given the array of electrophysiologic abnormalities that systemic sclerosis patients can have, it is critical to monitor all patients with routine (annual or biannual) electrocardiography; to take possible arrhythmia-related symptoms seriously; and to evaluate them with further workup such as Holter monitoring for 24 hours or even longer, event monitoring, exercise testing, or tilt-table testing.

PERICARDIAL DISEASE

Pericardial disease is clinically apparent in 5% to 16% of patients with systemic sclerosis⁸¹; patients with limited cutaneous systemic sclerosis have more pericardial disease than those with diffuse cutaneous systemic sclerosis (30% vs 16%).⁸² Forty-one percent of systemic sclerosis patients have been shown to have pericardial effusion by echocardiography,⁸¹ but the effusions are typically small and rarely cause tamponade, though tamponade is associated with a poor prognosis.

Large pericardial effusions can develop before skin thickening and diagnosis of systemic sclerosis.^81,83,84 Thus, systemic sclerosis should be considered in patients with pericardial effusions of unknown etiology.

In a small study,⁸⁵ the pericardial fluid in systemic sclerosis was typically exudative, with lactate dehydrogenase greater than 200 U/L, a fluid-serum lactate dehydrogenase ratio greater than 0.6, and a fluid-serum total protein ratio greater than 0.5.

Pericardial effusion can be a sign of impending scleroderma renal crisis,⁸⁶ and thus renal function should be carefully monitored in systemic sclerosis patients with pericardial effusion. Constrictive pericarditis and restrictive cardiomyopathy can rarely occur in systemic sclerosis and may more commonly present with symptoms.

Pericardial disease in systemic sclerosis should be treated in a standard fashion with nonsteroidal anti-inflammatory drugs. Corticosteroids are generally of limited benefit and should be avoided, especially in the setting of scleroderma renal crisis.⁸¹

VALVULAR HEART DISEASE

Based on limited studies, the prevalence of significant valvular heart disease in systemic sclerosis patients does not seem to be higher than that in the general population. While patients with systemic sclerosis and CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) have been shown to have a higher frequency of mitral valve prolapse and mild mitral regurgitation,^87,88 these abnormalities do not often progress in severity, and thus their clinical significance is limited.

It is important for physicians caring for patients with systemic sclerosis to be aware of its most common cardiac manifestations, including left and right ventricular systolic and diastolic dysfunction, pulmonary hypertension, conduction abnormalities, arrhythmias, and cardiomyopathy.

Look for volume overload

On clinical examination, assess for clinical markers of volume overload such as distended neck veins, peripheral edema, or an abnormal blood pressure response to the Valsalva maneuver. These findings should prompt measurement of NT-proBNP,⁸⁹ and may warrant prescription of a diuretic.

Electrocardiography to investigate arrhythmias

Electrocardiography should be done if patients describe symptoms of palpitations, and should also include continuous rhythm monitoring with Holter or event monitoring, depending on the frequency of symptoms. Otherwise, patients should routinely undergo electrocardiography once or twice a year.

Q waves are common in systemic sclerosis patients (especially those with diffuse cutaneous systemic sclerosis), notably in the precordial leads, and can occur without coronary artery disease.⁹⁰ Symptoms such as presyncope should be further investigated with Holter monitoring and tilt-table testing.

Assess, modify traditional risk factors

Subclinical atherosclerosis as detected by carotid intima-media thickness is as common in systemic sclerosis as in rheumatoid arthritis.⁶¹ However, traditional risk indices such as SCORE (Systematic Coronary Risk Evaluation), QRISK2, and the American College of Cardiology/American Heart Association indices may underestimate risk in patients who have systemic sclerosis.

Strict hypertension control should be the goal for all systemic sclerosis patients. Though there are no specific guidelines on which antihypertensive medications are preferred, calcium channel blockers or angiotensin II receptor blockers, which are typically used to treat systemic sclerosis-related Raynaud phenomenon, may be appropriate.

Statins reduce vascular complications and are generally well tolerated in patients with systemic sclerosis.^91,92 

Aspirin is not recommended for routine primary prevention in view of data suggesting that its benefits in diabetic patients are counterbalanced by increased bleeding risk.⁹³

Echocardiography to detect pulmonary arterial hypertension

At this time, guidelines for monitoring for cardiovascular manifestations in systemic sclerosis patients are limited. The only well-defined ones are European consensus guidelines, which suggest annual transthoracic echocardiography for the first 5 years after systemic sclerosis is diagnosed and continued annual screening in patients at risk of developing PAH.³¹

We support this strategy, with annual screening for the first 5 years followed by surveillance echocardiography every 2 to 3 years unless there is a high risk of PAH. Specific attention should be paid to right ventricular diastolic function, right atrial volume, and right ventricular myocardial performance index.

Emerging data suggest that the addition of global longitudinal strain of ventricles to  routine echocardiography can help detect subclinical cardiac risk.⁹⁴ Although further study is needed into the predictive value of global longitudinal strain, it is a low-cost and noninvasive addition to standard echocardiography that can help guide risk stratification, and thus we recommend that it be part of the echocardiographic examination for all systemic sclerosis patients.

Pulmonary function testing. In addition to screening for PAH with echocardiography, we recommend obtaining baseline pulmonary function tests, including D_^LCO, at the time systemic sclerosis is diagnosed, with repeat testing annually.

Magnetic resonance imaging

While echocardiography is the gold standard for monitoring systemic sclerosis patients, cardiovascular MRI may have a role in identifying those at higher risk of dangerous arrhythmias such as ventricular tachycardia and ventricular fibrillation. In addition to assessing ventricular function, MRI can detect myocardial inflammation, ischemia, and fibrosis that may predispose a patient to develop ventricular tachycardia or fibrillation.⁹⁵ Variables such as T1/T2 mapping, extracellular volume fraction, T2 signal ratio, and early vs late gadolinium enhancement can help identify patients who had past ventricular tachycardia or fibrillation.⁹⁶

Finding an increased risk of arrhythmias may prompt a conversation between the patient and the physician about the need for an implantable cardiac defibrillator.

If cardiac MRI is available and is reimbursed by the patient’s insurance carrier, physicians should strongly consider obtaining at least one baseline scan in systemic sclerosis patients to identify those at risk of highly fatal arrhythmias.

Teamwork is needed

Systemic sclerosis has not traditionally been associated with cardiovascular disease to the extent of other rheumatic conditions, but the cardiovascular system can be affected in various ways that can ultimately lead to an early death. These manifestations may be asymptomatic for long periods, and overt clinical disease portends a poorer prognosis.

Primary care physicians managing these patients should be aware of the cardiovascular complications of systemic sclerosis and should implement appropriate screening tests in conjunction with rheumatologists and cardiologists. It is also essential for general and subspecialty cardiologists to understand the broad spectrum of organ system involvement that can affect systemic sclerosis patients and to tailor their investigation and management recommendations accordingly. By designing a multidisciplinary approach to the treatment of systemic sclerosis patients, physicians can help to optimize cardiovascular risk modification in this vulnerable population.