Vascular Specialist

NEW ORLEANS – Visceral adiposity, but not body mass index or total body fat, significantly correlated with elevated 24-hour ambulatory systolic blood pressure, greater systolic variability, and masked hypertension in a study from the University of Pennsylvania, Philadelphia.

Subjects in the highest quartile of visceral fat had a 6.3-fold greater odds of masked hypertension – normal in the office, but high at home – compared with those in the lowest quartile (95% confidence interval, 1.2-33.1).

The study findings suggest that central obesity, in particular, should trigger 24-hour ambulatory blood pressure monitoring (ABPM). “Every obese person should get a 24-hour” ABPM, but “we really need to be pushing [it] in people who have central adiposity. These are the patients ... we really need to focus on” because of the risk of masked hypertension, a “ticking time bomb” that greatly increases the risk of cardiovascular events, said lead investigator Jordana B. Cohen, MD, an assistant professor of medicine at the university.

The study also helps explain why body mass index (BMI) hasn’t been consistently linked to masked hypertension in previous studies; some studies likely included subjects with high BMIs but not central obesity.

Waist circumference, a marker of visceral adiposity, also correlated with elevated 24-hour systolic pressure and greater variability, but a trend for masked hypertension was not statistically significant, Dr. Cohen reported at the joint scientific sessions of the American Heart Association (AHA) Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

It’s long been known that visceral fat – fat around the abdominal organs – is metabolically active and associated with greater cardiovascular risk, but its relationship to blood pressure hadn’t been well described, so Dr. Cohen and her team decided to take a look.

They ran whole body dual x-ray absorptiometry scans on 96 hypertensive adults on a stable dose of one antihypertensive drug for at least 2 months and correlated the findings with ABPM. Subjects were an average of 58 years old, almost 60% were women, almost half were black, and 54% were obese, with BMIs of at least 30 kg/m².

After adjustment for age, sex, race, and antihypertensive class, the team found a significant, linear correlation between visceral fat and mean 24-hour systolic blood pressure. Patients with a visceral adiposity of about 0.1 kg/m², for instance, had a mean pressure of around 130 mm Hg, compared with patients with more than 0.6 kg/m², who had a mean of almost 150 mm Hg. Findings were similar for waist circumference over a range of 70-150 cm.

The correlations were weak (r = 0.3), but Dr. Cohen said they might improve with ongoing enrollment. Both measures also correlated with systolic variability.

Overall, the highest quartiles of waist circumference and visceral adiposity correlated with the highest mean systolic pressures and greatest variability, compared with the lowest quartiles. Visceral adiposity was the only measure significantly linked with masked hypertension. Trends in those directions for increasing BMI and total body fat mass were not statistically significant.

Mean BMI in the study was 31.7 kg/m², and mean waist circumference was 104 cm. Mean 24-hour systolic blood pressure was 135 mm Hg and mean 24-hour systolic variability was 13 mm Hg. Almost 30% of the subjects had masked hypertension. Drug classes included beta-blockers, calcium channel blockers, diuretics, ACE-inhibitors, and angiotensin receptor blockers.

Dr. Cohen plans to investigate drug response versus visceral adiposity once the recruitment goal of 150 subjects is reached.

There was no external funding, and the investigators reported that they didn’t have any relevant disclosures.

[email protected]

SOURCE: Cohen JB et al. Joint Hypertension 2019, Abstract P2052.

NEW ORLEANS – Visceral adiposity, but not body mass index or total body fat, significantly correlated with elevated 24-hour ambulatory systolic blood pressure, greater systolic variability, and masked hypertension in a study from the University of Pennsylvania, Philadelphia.

Subjects in the highest quartile of visceral fat had a 6.3-fold greater odds of masked hypertension – normal in the office, but high at home – compared with those in the lowest quartile (95% confidence interval, 1.2-33.1).

The study findings suggest that central obesity, in particular, should trigger 24-hour ambulatory blood pressure monitoring (ABPM). “Every obese person should get a 24-hour” ABPM, but “we really need to be pushing [it] in people who have central adiposity. These are the patients ... we really need to focus on” because of the risk of masked hypertension, a “ticking time bomb” that greatly increases the risk of cardiovascular events, said lead investigator Jordana B. Cohen, MD, an assistant professor of medicine at the university.

The study also helps explain why body mass index (BMI) hasn’t been consistently linked to masked hypertension in previous studies; some studies likely included subjects with high BMIs but not central obesity.

Waist circumference, a marker of visceral adiposity, also correlated with elevated 24-hour systolic pressure and greater variability, but a trend for masked hypertension was not statistically significant, Dr. Cohen reported at the joint scientific sessions of the American Heart Association (AHA) Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

It’s long been known that visceral fat – fat around the abdominal organs – is metabolically active and associated with greater cardiovascular risk, but its relationship to blood pressure hadn’t been well described, so Dr. Cohen and her team decided to take a look.

They ran whole body dual x-ray absorptiometry scans on 96 hypertensive adults on a stable dose of one antihypertensive drug for at least 2 months and correlated the findings with ABPM. Subjects were an average of 58 years old, almost 60% were women, almost half were black, and 54% were obese, with BMIs of at least 30 kg/m².

After adjustment for age, sex, race, and antihypertensive class, the team found a significant, linear correlation between visceral fat and mean 24-hour systolic blood pressure. Patients with a visceral adiposity of about 0.1 kg/m², for instance, had a mean pressure of around 130 mm Hg, compared with patients with more than 0.6 kg/m², who had a mean of almost 150 mm Hg. Findings were similar for waist circumference over a range of 70-150 cm.

The correlations were weak (r = 0.3), but Dr. Cohen said they might improve with ongoing enrollment. Both measures also correlated with systolic variability.

Overall, the highest quartiles of waist circumference and visceral adiposity correlated with the highest mean systolic pressures and greatest variability, compared with the lowest quartiles. Visceral adiposity was the only measure significantly linked with masked hypertension. Trends in those directions for increasing BMI and total body fat mass were not statistically significant.

Mean BMI in the study was 31.7 kg/m², and mean waist circumference was 104 cm. Mean 24-hour systolic blood pressure was 135 mm Hg and mean 24-hour systolic variability was 13 mm Hg. Almost 30% of the subjects had masked hypertension. Drug classes included beta-blockers, calcium channel blockers, diuretics, ACE-inhibitors, and angiotensin receptor blockers.

Dr. Cohen plans to investigate drug response versus visceral adiposity once the recruitment goal of 150 subjects is reached.

There was no external funding, and the investigators reported that they didn’t have any relevant disclosures.

[email protected]

SOURCE: Cohen JB et al. Joint Hypertension 2019, Abstract P2052.

NEW ORLEANS – Visceral adiposity, but not body mass index or total body fat, significantly correlated with elevated 24-hour ambulatory systolic blood pressure, greater systolic variability, and masked hypertension in a study from the University of Pennsylvania, Philadelphia.

Subjects in the highest quartile of visceral fat had a 6.3-fold greater odds of masked hypertension – normal in the office, but high at home – compared with those in the lowest quartile (95% confidence interval, 1.2-33.1).

The study findings suggest that central obesity, in particular, should trigger 24-hour ambulatory blood pressure monitoring (ABPM). “Every obese person should get a 24-hour” ABPM, but “we really need to be pushing [it] in people who have central adiposity. These are the patients ... we really need to focus on” because of the risk of masked hypertension, a “ticking time bomb” that greatly increases the risk of cardiovascular events, said lead investigator Jordana B. Cohen, MD, an assistant professor of medicine at the university.

The study also helps explain why body mass index (BMI) hasn’t been consistently linked to masked hypertension in previous studies; some studies likely included subjects with high BMIs but not central obesity.

Waist circumference, a marker of visceral adiposity, also correlated with elevated 24-hour systolic pressure and greater variability, but a trend for masked hypertension was not statistically significant, Dr. Cohen reported at the joint scientific sessions of the American Heart Association (AHA) Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.

It’s long been known that visceral fat – fat around the abdominal organs – is metabolically active and associated with greater cardiovascular risk, but its relationship to blood pressure hadn’t been well described, so Dr. Cohen and her team decided to take a look.

They ran whole body dual x-ray absorptiometry scans on 96 hypertensive adults on a stable dose of one antihypertensive drug for at least 2 months and correlated the findings with ABPM. Subjects were an average of 58 years old, almost 60% were women, almost half were black, and 54% were obese, with BMIs of at least 30 kg/m².

After adjustment for age, sex, race, and antihypertensive class, the team found a significant, linear correlation between visceral fat and mean 24-hour systolic blood pressure. Patients with a visceral adiposity of about 0.1 kg/m², for instance, had a mean pressure of around 130 mm Hg, compared with patients with more than 0.6 kg/m², who had a mean of almost 150 mm Hg. Findings were similar for waist circumference over a range of 70-150 cm.

The correlations were weak (r = 0.3), but Dr. Cohen said they might improve with ongoing enrollment. Both measures also correlated with systolic variability.

Overall, the highest quartiles of waist circumference and visceral adiposity correlated with the highest mean systolic pressures and greatest variability, compared with the lowest quartiles. Visceral adiposity was the only measure significantly linked with masked hypertension. Trends in those directions for increasing BMI and total body fat mass were not statistically significant.

Mean BMI in the study was 31.7 kg/m², and mean waist circumference was 104 cm. Mean 24-hour systolic blood pressure was 135 mm Hg and mean 24-hour systolic variability was 13 mm Hg. Almost 30% of the subjects had masked hypertension. Drug classes included beta-blockers, calcium channel blockers, diuretics, ACE-inhibitors, and angiotensin receptor blockers.

Dr. Cohen plans to investigate drug response versus visceral adiposity once the recruitment goal of 150 subjects is reached.

There was no external funding, and the investigators reported that they didn’t have any relevant disclosures.

[email protected]

SOURCE: Cohen JB et al. Joint Hypertension 2019, Abstract P2052.

Physician groups are criticizing a judge’s decision to approve the merger of pharmacy chain CVS Health and health insurer Aetna, saying the deal will raise prices and lower quality.

Mathier/Thinkstock

Judge Richard J. Leon of the U.S. District Court for the District of Columbia allowed the merger to move forward on Sept. 4, ruling that the acquisition was legal under antitrust law. The merger was approved by the Department of Justice in October 2018 on the condition that Aetna sell its Medicare prescription drug plan (PDP) business to independently owned competitor, WellCare Health Plans. Judge Leon has been examining the government’s plan since late 2018.

In his decision, Judge Leon acknowledged that the merger will have widespread effects for millions of patients and noted the many industry stakeholders, consumer groups, and state regulatory bodies have raised concerns about the merger.

“Although [the opposition] raised substantial concerns that warranted serious consideration, CVS’s and the government’s witnesses, when combined with the existing record, persuasively support why the markets at issue are not only very competitive today, but are likely to remain so post merger,” Judge Leon wrote. “Consequently, the harms to the public interest the [opposition] raised were not sufficiently established to undermine the government’s conclusion to the contrary. As such, for all of the above reasons, I have concluded that the proposed settlement is well ‘within the reaches’ of the public interest and the government’s motion ... should therefore be granted.”

Patrice A. Harris, MD, president for the American Medical Association, said the judge’s decision fails patients and will likely raise prices, lower quality, reduce choice, and stifle innovation.

“The American people and our health system will not be served well by allowing a merger that combines health insurance giant Aetna Inc. with CVS Health Corporation,” Dr. Harris said in a statement. “For patients and employers struggling with recurrent increases to health insurance premiums, out-of-pocket costs, and prescription drug prices, it’s hard to find any upside to a merger that leaves them with fewer choices. Nothing in the deal guarantees reductions on insurance premiums or prescription drug costs. As for promised efficiency savings, that money will likely go straight to CVS’s bottom line.”

Angus Worthing, MD, government affairs committee chair for the American College of Rheumatology, said his group is concerned that the merger will hinder progress that has been made toward creating cost transparency and will make it easier for costs savings to remain secret.

“We hope that regulators will now actively watch the conduct of the merged company to ensure patients are protected,” Dr. Worthing said in a statement.

In a statement, CVS noted that CVS Health and Aetna have been one company since November 2018, stating that the court’s action “makes that 100 percent clear.”

“We remain focused on transforming the consumer health care experience in America,” they said.

CVS Health announced it would buy Aetna for $69 billion in 2017 and finalized the acquisition in 2018. CVS Health President and CEO Larry J. Merlo said the combined company would connect consumers with the powerful health resources of CVS Health in communities across the country and Aetna’s network of providers to help remove barriers to high quality care and build lasting relationships with patients.

Assistant Attorney General Makan Delrahim of the Justice Department’s antitrust division said the agency was pleased with the court’s decision to approve the government’s plan and finalize the merger.

“The divestiture of Aetna’s individual PDP business provides a comprehensive remedy to the harms the Justice Department identified,” Mr. Delrahim said in a statement. “The entry of the final judgment protects seniors and other vulnerable customers of individual PDPs from the anticompetitive effects that would have occurred if CVS and Aetna had merged their individual PDP businesses.”

[email protected]

Physician groups are criticizing a judge’s decision to approve the merger of pharmacy chain CVS Health and health insurer Aetna, saying the deal will raise prices and lower quality.

Mathier/Thinkstock

Judge Richard J. Leon of the U.S. District Court for the District of Columbia allowed the merger to move forward on Sept. 4, ruling that the acquisition was legal under antitrust law. The merger was approved by the Department of Justice in October 2018 on the condition that Aetna sell its Medicare prescription drug plan (PDP) business to independently owned competitor, WellCare Health Plans. Judge Leon has been examining the government’s plan since late 2018.

In his decision, Judge Leon acknowledged that the merger will have widespread effects for millions of patients and noted the many industry stakeholders, consumer groups, and state regulatory bodies have raised concerns about the merger.

“Although [the opposition] raised substantial concerns that warranted serious consideration, CVS’s and the government’s witnesses, when combined with the existing record, persuasively support why the markets at issue are not only very competitive today, but are likely to remain so post merger,” Judge Leon wrote. “Consequently, the harms to the public interest the [opposition] raised were not sufficiently established to undermine the government’s conclusion to the contrary. As such, for all of the above reasons, I have concluded that the proposed settlement is well ‘within the reaches’ of the public interest and the government’s motion ... should therefore be granted.”

Patrice A. Harris, MD, president for the American Medical Association, said the judge’s decision fails patients and will likely raise prices, lower quality, reduce choice, and stifle innovation.

“The American people and our health system will not be served well by allowing a merger that combines health insurance giant Aetna Inc. with CVS Health Corporation,” Dr. Harris said in a statement. “For patients and employers struggling with recurrent increases to health insurance premiums, out-of-pocket costs, and prescription drug prices, it’s hard to find any upside to a merger that leaves them with fewer choices. Nothing in the deal guarantees reductions on insurance premiums or prescription drug costs. As for promised efficiency savings, that money will likely go straight to CVS’s bottom line.”

Angus Worthing, MD, government affairs committee chair for the American College of Rheumatology, said his group is concerned that the merger will hinder progress that has been made toward creating cost transparency and will make it easier for costs savings to remain secret.

“We hope that regulators will now actively watch the conduct of the merged company to ensure patients are protected,” Dr. Worthing said in a statement.

In a statement, CVS noted that CVS Health and Aetna have been one company since November 2018, stating that the court’s action “makes that 100 percent clear.”

“We remain focused on transforming the consumer health care experience in America,” they said.

CVS Health announced it would buy Aetna for $69 billion in 2017 and finalized the acquisition in 2018. CVS Health President and CEO Larry J. Merlo said the combined company would connect consumers with the powerful health resources of CVS Health in communities across the country and Aetna’s network of providers to help remove barriers to high quality care and build lasting relationships with patients.

Assistant Attorney General Makan Delrahim of the Justice Department’s antitrust division said the agency was pleased with the court’s decision to approve the government’s plan and finalize the merger.

“The divestiture of Aetna’s individual PDP business provides a comprehensive remedy to the harms the Justice Department identified,” Mr. Delrahim said in a statement. “The entry of the final judgment protects seniors and other vulnerable customers of individual PDPs from the anticompetitive effects that would have occurred if CVS and Aetna had merged their individual PDP businesses.”

[email protected]

Physician groups are criticizing a judge’s decision to approve the merger of pharmacy chain CVS Health and health insurer Aetna, saying the deal will raise prices and lower quality.

Mathier/Thinkstock

Judge Richard J. Leon of the U.S. District Court for the District of Columbia allowed the merger to move forward on Sept. 4, ruling that the acquisition was legal under antitrust law. The merger was approved by the Department of Justice in October 2018 on the condition that Aetna sell its Medicare prescription drug plan (PDP) business to independently owned competitor, WellCare Health Plans. Judge Leon has been examining the government’s plan since late 2018.

In his decision, Judge Leon acknowledged that the merger will have widespread effects for millions of patients and noted the many industry stakeholders, consumer groups, and state regulatory bodies have raised concerns about the merger.

“Although [the opposition] raised substantial concerns that warranted serious consideration, CVS’s and the government’s witnesses, when combined with the existing record, persuasively support why the markets at issue are not only very competitive today, but are likely to remain so post merger,” Judge Leon wrote. “Consequently, the harms to the public interest the [opposition] raised were not sufficiently established to undermine the government’s conclusion to the contrary. As such, for all of the above reasons, I have concluded that the proposed settlement is well ‘within the reaches’ of the public interest and the government’s motion ... should therefore be granted.”

Patrice A. Harris, MD, president for the American Medical Association, said the judge’s decision fails patients and will likely raise prices, lower quality, reduce choice, and stifle innovation.

“The American people and our health system will not be served well by allowing a merger that combines health insurance giant Aetna Inc. with CVS Health Corporation,” Dr. Harris said in a statement. “For patients and employers struggling with recurrent increases to health insurance premiums, out-of-pocket costs, and prescription drug prices, it’s hard to find any upside to a merger that leaves them with fewer choices. Nothing in the deal guarantees reductions on insurance premiums or prescription drug costs. As for promised efficiency savings, that money will likely go straight to CVS’s bottom line.”

Angus Worthing, MD, government affairs committee chair for the American College of Rheumatology, said his group is concerned that the merger will hinder progress that has been made toward creating cost transparency and will make it easier for costs savings to remain secret.

“We hope that regulators will now actively watch the conduct of the merged company to ensure patients are protected,” Dr. Worthing said in a statement.

In a statement, CVS noted that CVS Health and Aetna have been one company since November 2018, stating that the court’s action “makes that 100 percent clear.”

“We remain focused on transforming the consumer health care experience in America,” they said.

CVS Health announced it would buy Aetna for $69 billion in 2017 and finalized the acquisition in 2018. CVS Health President and CEO Larry J. Merlo said the combined company would connect consumers with the powerful health resources of CVS Health in communities across the country and Aetna’s network of providers to help remove barriers to high quality care and build lasting relationships with patients.

Assistant Attorney General Makan Delrahim of the Justice Department’s antitrust division said the agency was pleased with the court’s decision to approve the government’s plan and finalize the merger.

“The divestiture of Aetna’s individual PDP business provides a comprehensive remedy to the harms the Justice Department identified,” Mr. Delrahim said in a statement. “The entry of the final judgment protects seniors and other vulnerable customers of individual PDPs from the anticompetitive effects that would have occurred if CVS and Aetna had merged their individual PDP businesses.”

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – A small interfering RNA drug, inclisiran, safely halved LDL cholesterol levels in more than 800 patients in a phase 3, multicenter study, in a big step toward this drug coming onto the market and offering an alternative way to harness the potent cholesterol-lowering power of PCSK9 inhibition.

Mitchel L. Zoler/MDedge News

In the reported study – which enrolled patients with established cardiovascular disease, familial hypercholesterolemia, type 2 diabetes, or a high Framingham Risk Score – participants received inclisiran as a semiannual subcutaneous injection. The safe efficacy this produced showed the viability of a new way to deliver lipid-lowering therapy that guarantees compliance and is convenient for patients.

The prospect of lowering cholesterol with about the same potency as the monoclonal antibodies that block PCSK9 (proprotein convertase subtilisin/kexin type 9) activity but administered as a biannual injection “enables provider control over medication adherence, and may offer patients a meaningful new choice that is safe and convenient and has assured results,” Kausik K. Ray, MD, said at the annual congress of the European Society of Cardiology. The durable effect of the small interfering RNA (siRNA) agent “offers a huge advantage,” and “opens the field,” said Dr. Ray, a cardiologist and professor of public health at Imperial College, London.

He also highlighted the “excellent” safety profile seen in the 811 patients treated with inclisiran, compared with 804 patients in the study who received placebo. After four total injections of inclisiran spaced out over 450 days (about 15 months), the rate of treatment-emergent adverse events and serious events was virtually the same in the two treatment arms, and with no signal of inclisiran causing liver effects, renal or muscle injury, damage to blood components, or malignancy. The serial treatment with inclisiran that patients received – at baseline, 90, 270, and 450 days – produced no severe injection-site reactions, and transient mild or moderate injection-site reactions in just under 5% of patients.

Safety issues, such as more-severe injection-site reactions, thrombocytopenia, hepatotoxicity, and flu-like symptoms, plagued siRNA drugs during their earlier days of development, but more recently next-generation siRNA drugs with modified structures have produced much better safety performance, noted Richard C. Becker, MD, professor of medicine and director of the Heart, Lung, & Vascular Institute at the University of Cincinnati. The new-generation siRNAs such as inclisiran are “very well tolerated,” he said in an interview.

The Food and Drug Administration approved the first siRNA drug in August 2018, and in the year since then a few others have also come onto the U.S. market, Dr. Becker said.

Like other siRNA drugs, the activity of inclisiran comes from a short RNA segment that is antisense to a particular messenger RNA (mRNA) target. In the case of inclisiran, the target is the mRNA for the PCSK9 enzyme produced in hepatocytes, and that decreases the number of LDL cholesterol receptors on the cell’s surface. When the antisense RNA molecule encounters a PCSK9 mRNA, the two bind and the mRNA is then degraded by a normal cell process. This cuts the cell’s production of the PCSK9 protein, resulting in more LDL cholesterol receptors on the cell’s surface that pull more LDL cholesterol from the blood. The blocking of PCSK9 activity by inclisiran is roughly equivalent to the action of the PCSK9 monoclonal antibodies that have now been on the U.S. market for a few years. Also like other siRNA drugs, the RNA of inclisiran is packaged so that, once injected into a patient, the RNA molecules travel to the liver and enter hepatocytes, where they exert their activity.

“No one has concerns about inclisiran being able to lower LDL [cholesterol], and there have been no safety signals. The data we have seen so far look very reassuring, and in particular has been very safe for the liver,” commented Marc S. Sabatine, MD, professor of medicine at Harvard Medical School, Boston, who has led several studies involving PCSK9-targeted drugs and is helping to run ORION-4, a 15,000-patient study of inclisiran designed to assess the drug’s effect on clinical events. Results from ORION-4 are not expected until about 2024.

“The PCSK9 inhibitors in general have been a huge advance for patients, and the more kinds of drugs we have to target PCSK9, the better,” he said in an interview.

The study reported by Dr. Ray, ORION-11, enrolled 1,617 patients with high atherosclerotic disease risk at 70 sites in six European countries and South Africa. The study’s primary efficacy endpoint was reduction from baseline in LDL cholesterol both at 510 days (about 17 months) after the first dose and also throughout the 15-month period that started 3 months after the first dose. The average reduction seen after 510 days was 54%, compared with baseline, and the time-averaged reduction during the 15-month window examined was 50%, Dr. Ray said. The results also showed a consistent reduction in LDL cholesterol in virtually every patient treated with inclisiran.

Two other phase 3 studies of inclisiran with similar design have been completed, and the results will come out before the end of 2019, according to a statement from the Medicines Company, which is developing the drug. The statement also said that the company plans to file their data with the FDA for marketing approval for inclisiran before the end of 2019. In the recent past, the FDA has approved drugs for the indication of lowering LDL cholesterol before evidence is available to prove that the agent has benefits for reducing clinical events.

Future studies of inclisiran will explore the efficacy of a single annual injection of the drug as an approach to primary prevention of cardiovascular disease, Dr. Ray said.

ORION-11 was sponsored by the Medicines Company. Dr. Ray is a consultant to it and to several other companies. Dr. Becker had no relevant disclosures. Dr. Sabatine has received research support from the Medicines Company and several other companies, and has received personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, DalCor Pharmaceuticals, Dyrnamix, and Ionis.

[email protected]

PARIS – For patients with peripheral artery disease, statin therapy is a literal lifeline, nearly halving mortality risk, according to new research presented at the annual congress of the European Society of Cardiology.

Patients with peripheral manifestations of cardiovascular disease “are a population with an extremely high risk to suffer a heart attack or a stroke,” said Joern Dopheide, MD, during a press conference at the meeting. Despite the known benefits of statins, including the reduction of all-cause and cardiovascular death and the reduction of morbidity, adherence to guideline-directed statin therapy is far from optimal, said Dr. Dopheide of Bern (Switzerland) University Hospital.

Patients with peripheral artery disease (PAD) not taking statins had a mortality rate of 34%, more than three times that of patients adherent to an intensified statin regimen. More surprisingly, patients who had been on a statin and then stopped the medication also had a mortality rate of 33%, indistinguishable from those who had never been treated with a statin.

Although statin adherence is low in general, it’s especially low in patients with PAD, said Dr. Dopheide. Still, he said, “few systematic data exist on the prognostic value of statin adherence and the correlation between adherence and cardiovascular outcome in PAD patients.”

Accordingly, Dr. Dopheide and his coinvestigators sought to determine the association between statin adherence and survival in PAD patients. The researchers obtained baseline and follow-up data for a cohort of 691 symptomatic PAD patients seen at a single site, looking at statin dosage, LDL cholesterol levels, and survival.

The patients were followed for a period of 50 months. Dr. Dopheide said that “Over the time course, we were able to increase the statin adherence from about 73% to about 81%, and parallel to that, we were able to reduce the LDL cholesterol levels from about 97 to 83 mg/dL, and we were able to increase the intensity of patients on statin therapy.”

Dr. Dopheide said that he and his colleagues saw a dose-response effect, so that the biggest drop in cholesterol was seen in patients on high statin doses, on more potent statins, or both.

Intensity was increased in some cases by upping statin dose – the mean statin dose climbed from 50 to 58 mg daily during the study period. An alternative strategy was to switch to a more potent statin such as atorvastatin or rosuvastatin; sometimes both intensity and dose were boosted.

“We were able to see that patients who were always on their statin therapy had a pretty low mortality rate of about 20%,” a figure that was halved for patients on more intensive statin therapy, who had a mortality rate of 10% across the study period, said Dr. Dopheide. “Patients in whom we started a statin therapy still profited from it, and had only a 15% mortality,” he added.

Some of the most surprising – and disturbing – study findings involved those who reduced their statin dose: “When patients discontinued their usual dose and decreased it, they suffered an even higher mortality rate, of nearly 43%. So that was kind of surprising and shocking to us.”

Identifying these high-risk patients and keeping them adherent is a substantial clinical challenge, but an important goal, said Dr. Dopheide. “We know that patients with peripheral arterial disease are a little more underrepresented in daily practice; it’s hard to identify them, especially when they are asymptomatic,” he acknowledged. However, once a PAD patient is identified, “One should at least keep the patient on the statin dosage they have,” or initiate statins if needed.

Further, warned Dr. Dopheide, “One should never discontinue statin or decrease the dosage,” adding that PAD patients should be informed that they are at “very high risk for myocardial infarction or stroke.” These patients “should regard their statin therapy as one of the most important and life-saving medications they can take,” he said.

Dr. Dopheide reported no outside sources of funding and no conflicts of interest.

[email protected]

SOURCE: Dopheide, J., et al. ESC Congress 2019, Abstract P5363.

PARIS – For patients with peripheral artery disease, statin therapy is a literal lifeline, nearly halving mortality risk, according to new research presented at the annual congress of the European Society of Cardiology.

Patients with peripheral manifestations of cardiovascular disease “are a population with an extremely high risk to suffer a heart attack or a stroke,” said Joern Dopheide, MD, during a press conference at the meeting. Despite the known benefits of statins, including the reduction of all-cause and cardiovascular death and the reduction of morbidity, adherence to guideline-directed statin therapy is far from optimal, said Dr. Dopheide of Bern (Switzerland) University Hospital.

Patients with peripheral artery disease (PAD) not taking statins had a mortality rate of 34%, more than three times that of patients adherent to an intensified statin regimen. More surprisingly, patients who had been on a statin and then stopped the medication also had a mortality rate of 33%, indistinguishable from those who had never been treated with a statin.

Although statin adherence is low in general, it’s especially low in patients with PAD, said Dr. Dopheide. Still, he said, “few systematic data exist on the prognostic value of statin adherence and the correlation between adherence and cardiovascular outcome in PAD patients.”

Accordingly, Dr. Dopheide and his coinvestigators sought to determine the association between statin adherence and survival in PAD patients. The researchers obtained baseline and follow-up data for a cohort of 691 symptomatic PAD patients seen at a single site, looking at statin dosage, LDL cholesterol levels, and survival.

The patients were followed for a period of 50 months. Dr. Dopheide said that “Over the time course, we were able to increase the statin adherence from about 73% to about 81%, and parallel to that, we were able to reduce the LDL cholesterol levels from about 97 to 83 mg/dL, and we were able to increase the intensity of patients on statin therapy.”

Dr. Dopheide said that he and his colleagues saw a dose-response effect, so that the biggest drop in cholesterol was seen in patients on high statin doses, on more potent statins, or both.

Intensity was increased in some cases by upping statin dose – the mean statin dose climbed from 50 to 58 mg daily during the study period. An alternative strategy was to switch to a more potent statin such as atorvastatin or rosuvastatin; sometimes both intensity and dose were boosted.

“We were able to see that patients who were always on their statin therapy had a pretty low mortality rate of about 20%,” a figure that was halved for patients on more intensive statin therapy, who had a mortality rate of 10% across the study period, said Dr. Dopheide. “Patients in whom we started a statin therapy still profited from it, and had only a 15% mortality,” he added.

Some of the most surprising – and disturbing – study findings involved those who reduced their statin dose: “When patients discontinued their usual dose and decreased it, they suffered an even higher mortality rate, of nearly 43%. So that was kind of surprising and shocking to us.”

Identifying these high-risk patients and keeping them adherent is a substantial clinical challenge, but an important goal, said Dr. Dopheide. “We know that patients with peripheral arterial disease are a little more underrepresented in daily practice; it’s hard to identify them, especially when they are asymptomatic,” he acknowledged. However, once a PAD patient is identified, “One should at least keep the patient on the statin dosage they have,” or initiate statins if needed.

Further, warned Dr. Dopheide, “One should never discontinue statin or decrease the dosage,” adding that PAD patients should be informed that they are at “very high risk for myocardial infarction or stroke.” These patients “should regard their statin therapy as one of the most important and life-saving medications they can take,” he said.

Dr. Dopheide reported no outside sources of funding and no conflicts of interest.

[email protected]

SOURCE: Dopheide, J., et al. ESC Congress 2019, Abstract P5363.

PARIS – For patients with peripheral artery disease, statin therapy is a literal lifeline, nearly halving mortality risk, according to new research presented at the annual congress of the European Society of Cardiology.

Patients with peripheral manifestations of cardiovascular disease “are a population with an extremely high risk to suffer a heart attack or a stroke,” said Joern Dopheide, MD, during a press conference at the meeting. Despite the known benefits of statins, including the reduction of all-cause and cardiovascular death and the reduction of morbidity, adherence to guideline-directed statin therapy is far from optimal, said Dr. Dopheide of Bern (Switzerland) University Hospital.

Patients with peripheral artery disease (PAD) not taking statins had a mortality rate of 34%, more than three times that of patients adherent to an intensified statin regimen. More surprisingly, patients who had been on a statin and then stopped the medication also had a mortality rate of 33%, indistinguishable from those who had never been treated with a statin.

Although statin adherence is low in general, it’s especially low in patients with PAD, said Dr. Dopheide. Still, he said, “few systematic data exist on the prognostic value of statin adherence and the correlation between adherence and cardiovascular outcome in PAD patients.”

Accordingly, Dr. Dopheide and his coinvestigators sought to determine the association between statin adherence and survival in PAD patients. The researchers obtained baseline and follow-up data for a cohort of 691 symptomatic PAD patients seen at a single site, looking at statin dosage, LDL cholesterol levels, and survival.

The patients were followed for a period of 50 months. Dr. Dopheide said that “Over the time course, we were able to increase the statin adherence from about 73% to about 81%, and parallel to that, we were able to reduce the LDL cholesterol levels from about 97 to 83 mg/dL, and we were able to increase the intensity of patients on statin therapy.”

Dr. Dopheide said that he and his colleagues saw a dose-response effect, so that the biggest drop in cholesterol was seen in patients on high statin doses, on more potent statins, or both.

Intensity was increased in some cases by upping statin dose – the mean statin dose climbed from 50 to 58 mg daily during the study period. An alternative strategy was to switch to a more potent statin such as atorvastatin or rosuvastatin; sometimes both intensity and dose were boosted.

“We were able to see that patients who were always on their statin therapy had a pretty low mortality rate of about 20%,” a figure that was halved for patients on more intensive statin therapy, who had a mortality rate of 10% across the study period, said Dr. Dopheide. “Patients in whom we started a statin therapy still profited from it, and had only a 15% mortality,” he added.

Some of the most surprising – and disturbing – study findings involved those who reduced their statin dose: “When patients discontinued their usual dose and decreased it, they suffered an even higher mortality rate, of nearly 43%. So that was kind of surprising and shocking to us.”

Identifying these high-risk patients and keeping them adherent is a substantial clinical challenge, but an important goal, said Dr. Dopheide. “We know that patients with peripheral arterial disease are a little more underrepresented in daily practice; it’s hard to identify them, especially when they are asymptomatic,” he acknowledged. However, once a PAD patient is identified, “One should at least keep the patient on the statin dosage they have,” or initiate statins if needed.

Further, warned Dr. Dopheide, “One should never discontinue statin or decrease the dosage,” adding that PAD patients should be informed that they are at “very high risk for myocardial infarction or stroke.” These patients “should regard their statin therapy as one of the most important and life-saving medications they can take,” he said.

Dr. Dopheide reported no outside sources of funding and no conflicts of interest.

[email protected]

SOURCE: Dopheide, J., et al. ESC Congress 2019, Abstract P5363.

All who attended the 2019 Vascular Annual Meeting can review sessions they attended, as well as “attend” those that they missed. Those who weren’t at VAM can now experience all they missed. Slides and audio presentations of nearly every session are included in VAM on Demand. The cost for one year of access is $199 for VAM attendees and $499 for non-attendees. Those who purchased VAM on Demand before the meeting ended can visit this site to gain access by logging in with their SVS credentials.

All who attended the 2019 Vascular Annual Meeting can review sessions they attended, as well as “attend” those that they missed. Those who weren’t at VAM can now experience all they missed. Slides and audio presentations of nearly every session are included in VAM on Demand. The cost for one year of access is $199 for VAM attendees and $499 for non-attendees. Those who purchased VAM on Demand before the meeting ended can visit this site to gain access by logging in with their SVS credentials.

All who attended the 2019 Vascular Annual Meeting can review sessions they attended, as well as “attend” those that they missed. Those who weren’t at VAM can now experience all they missed. Slides and audio presentations of nearly every session are included in VAM on Demand. The cost for one year of access is $199 for VAM attendees and $499 for non-attendees. Those who purchased VAM on Demand before the meeting ended can visit this site to gain access by logging in with their SVS credentials.

MILAN – Skin manifestations of the vasculitides can point the way to an accurate diagnosis and provide clues about disease severity, Robert Micheletti, MD, said at the World Congress of Dermatology.

In granulomatous vasculitis, histiocytes and giant cells can play a significant role, explained Dr. Micheletti, director of the cutaneous vasculitis clinic at the University of Pennsylvania, Philadelphia. The condition may be secondary to an autoimmune disease such as lupus erythematosus or RA; a granulomatous disease such as Crohn’s disease or sarcoidosis; infections such as tuberculosis, a fungal disease, or herpes or zoster viruses, or lymphoma, Dr. Micheletti said.

However, a primary systemic vasculitis such as granulomatosis with polyangiitis (GPA; formerly known as Wegener’s polyangiitis) or eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss vasculitis), giant cell arteritis, or Takayasu arteritis may also be responsible, he said. Occasionally, the culprit can also be a drug-induced vasculitis.

The physical examination gives clues to the size of involved vessels, which in turn helps to classify the vasculitis, Dr. Micheletti said.

When vasculitis affects small vessels, the skin findings will be palpable purpura, urticarial papules, vesicles, and petechiae, he said, adding that “The small vessel involvement accounts for the small size of the lesions, and complement cascade and inflammation account for the palpability of the lesions and the symptomatology.” As red blood cells extravasate from the affected vessels, nonblanching purpura develop, and gravity’s effect on the deposition of immune complex material dictates how lesions are distributed.

“Manifestations more typical of medium vessel vasculitis include subcutaneous nodules, livedo reticularis, retiform purpura, larger hemorrhagic bullae, and more significant ulceration and necrosis,” he said. “If such lesions are seen, suspect medium-vessel vasculitis or vasculitis overlapping small and medium vessels.” Cutaneous or systemic polyarteritis nodosa, antineutrophilic cytoplasmic autoantibody (ANCA)–associated vasculitis, and cryoglobulinemic vasculitis are examples, he added.

The particularities of renal manifestations of vasculitis also offer clues to the vessels involved. When a vasculitis patient has glomerulonephritis, suspect small-vessel involvement, Dr. Micheletti said. However, vasculitis affecting medium-sized vessels will cause renovascular hypertension and, potentially renal arterial aneurysms.

Nerves are typically spared in small-vessel vasculitis, while wrist or foot drop can be seen in mononeuritis multiplex.

Recently, the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) looked at more than 6,800 patients at over 130 sites around the world, proposing new classification criteria for ANCA-associated vasculitis (AAV) and large-vessel vasculitis. The study found that skin findings are common in AAV, with 30%-50% of cases presenting initially with skin lesions. Petechiae and/or purpura are the most common of the skin manifestations, he said. By contrast, for EGPA, allergic and nonspecific findings were the most common findings.

Although skin biopsy can confirm the diagnosis in up to 94% of AAV cases, it’s underutilized and performed in less than half (24%-44%) of cases, Dr. Micheletti said. The study’s findings “demonstrate the importance of a good skin exam, as well as its utility for diagnosis” of vasculitis, he said.

An additional finding form the DCVAS study was that skin lesions can give clues to severity of vasculitis: “Among 1,184 patients with ANCA-associated vasculitis, those with cutaneous involvement were more likely to have systemic manifestations of disease, more likely to have such severe manifestations as glomerulonephritis, alveolar hemorrhage, and mononeuritis,” said Dr. Micheletti, with a hazard ratio of 2.0 among those individuals who had EGPA or GPA.

“Skin findings have diagnostic and, potentially, prognostic importance,” he said. “Use the physician exam and your clinical acumen to your advantage,” but always confirm vasculitis with a biopsy. “Clinicopathologic correlation is key.” A simple urinalysis will screen for renal involvement, and is of “paramount importance,” he added.

Dr. Micheletti reported that he had no relevant disclosures.

[email protected]

MILAN – Skin manifestations of the vasculitides can point the way to an accurate diagnosis and provide clues about disease severity, Robert Micheletti, MD, said at the World Congress of Dermatology.

In granulomatous vasculitis, histiocytes and giant cells can play a significant role, explained Dr. Micheletti, director of the cutaneous vasculitis clinic at the University of Pennsylvania, Philadelphia. The condition may be secondary to an autoimmune disease such as lupus erythematosus or RA; a granulomatous disease such as Crohn’s disease or sarcoidosis; infections such as tuberculosis, a fungal disease, or herpes or zoster viruses, or lymphoma, Dr. Micheletti said.

However, a primary systemic vasculitis such as granulomatosis with polyangiitis (GPA; formerly known as Wegener’s polyangiitis) or eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss vasculitis), giant cell arteritis, or Takayasu arteritis may also be responsible, he said. Occasionally, the culprit can also be a drug-induced vasculitis.

The physical examination gives clues to the size of involved vessels, which in turn helps to classify the vasculitis, Dr. Micheletti said.

When vasculitis affects small vessels, the skin findings will be palpable purpura, urticarial papules, vesicles, and petechiae, he said, adding that “The small vessel involvement accounts for the small size of the lesions, and complement cascade and inflammation account for the palpability of the lesions and the symptomatology.” As red blood cells extravasate from the affected vessels, nonblanching purpura develop, and gravity’s effect on the deposition of immune complex material dictates how lesions are distributed.

“Manifestations more typical of medium vessel vasculitis include subcutaneous nodules, livedo reticularis, retiform purpura, larger hemorrhagic bullae, and more significant ulceration and necrosis,” he said. “If such lesions are seen, suspect medium-vessel vasculitis or vasculitis overlapping small and medium vessels.” Cutaneous or systemic polyarteritis nodosa, antineutrophilic cytoplasmic autoantibody (ANCA)–associated vasculitis, and cryoglobulinemic vasculitis are examples, he added.

The particularities of renal manifestations of vasculitis also offer clues to the vessels involved. When a vasculitis patient has glomerulonephritis, suspect small-vessel involvement, Dr. Micheletti said. However, vasculitis affecting medium-sized vessels will cause renovascular hypertension and, potentially renal arterial aneurysms.

Nerves are typically spared in small-vessel vasculitis, while wrist or foot drop can be seen in mononeuritis multiplex.

Recently, the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) looked at more than 6,800 patients at over 130 sites around the world, proposing new classification criteria for ANCA-associated vasculitis (AAV) and large-vessel vasculitis. The study found that skin findings are common in AAV, with 30%-50% of cases presenting initially with skin lesions. Petechiae and/or purpura are the most common of the skin manifestations, he said. By contrast, for EGPA, allergic and nonspecific findings were the most common findings.

Although skin biopsy can confirm the diagnosis in up to 94% of AAV cases, it’s underutilized and performed in less than half (24%-44%) of cases, Dr. Micheletti said. The study’s findings “demonstrate the importance of a good skin exam, as well as its utility for diagnosis” of vasculitis, he said.

An additional finding form the DCVAS study was that skin lesions can give clues to severity of vasculitis: “Among 1,184 patients with ANCA-associated vasculitis, those with cutaneous involvement were more likely to have systemic manifestations of disease, more likely to have such severe manifestations as glomerulonephritis, alveolar hemorrhage, and mononeuritis,” said Dr. Micheletti, with a hazard ratio of 2.0 among those individuals who had EGPA or GPA.

“Skin findings have diagnostic and, potentially, prognostic importance,” he said. “Use the physician exam and your clinical acumen to your advantage,” but always confirm vasculitis with a biopsy. “Clinicopathologic correlation is key.” A simple urinalysis will screen for renal involvement, and is of “paramount importance,” he added.

Dr. Micheletti reported that he had no relevant disclosures.

[email protected]

MILAN – Skin manifestations of the vasculitides can point the way to an accurate diagnosis and provide clues about disease severity, Robert Micheletti, MD, said at the World Congress of Dermatology.

In granulomatous vasculitis, histiocytes and giant cells can play a significant role, explained Dr. Micheletti, director of the cutaneous vasculitis clinic at the University of Pennsylvania, Philadelphia. The condition may be secondary to an autoimmune disease such as lupus erythematosus or RA; a granulomatous disease such as Crohn’s disease or sarcoidosis; infections such as tuberculosis, a fungal disease, or herpes or zoster viruses, or lymphoma, Dr. Micheletti said.

However, a primary systemic vasculitis such as granulomatosis with polyangiitis (GPA; formerly known as Wegener’s polyangiitis) or eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss vasculitis), giant cell arteritis, or Takayasu arteritis may also be responsible, he said. Occasionally, the culprit can also be a drug-induced vasculitis.

The physical examination gives clues to the size of involved vessels, which in turn helps to classify the vasculitis, Dr. Micheletti said.

When vasculitis affects small vessels, the skin findings will be palpable purpura, urticarial papules, vesicles, and petechiae, he said, adding that “The small vessel involvement accounts for the small size of the lesions, and complement cascade and inflammation account for the palpability of the lesions and the symptomatology.” As red blood cells extravasate from the affected vessels, nonblanching purpura develop, and gravity’s effect on the deposition of immune complex material dictates how lesions are distributed.

“Manifestations more typical of medium vessel vasculitis include subcutaneous nodules, livedo reticularis, retiform purpura, larger hemorrhagic bullae, and more significant ulceration and necrosis,” he said. “If such lesions are seen, suspect medium-vessel vasculitis or vasculitis overlapping small and medium vessels.” Cutaneous or systemic polyarteritis nodosa, antineutrophilic cytoplasmic autoantibody (ANCA)–associated vasculitis, and cryoglobulinemic vasculitis are examples, he added.

The particularities of renal manifestations of vasculitis also offer clues to the vessels involved. When a vasculitis patient has glomerulonephritis, suspect small-vessel involvement, Dr. Micheletti said. However, vasculitis affecting medium-sized vessels will cause renovascular hypertension and, potentially renal arterial aneurysms.

Nerves are typically spared in small-vessel vasculitis, while wrist or foot drop can be seen in mononeuritis multiplex.

Recently, the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) looked at more than 6,800 patients at over 130 sites around the world, proposing new classification criteria for ANCA-associated vasculitis (AAV) and large-vessel vasculitis. The study found that skin findings are common in AAV, with 30%-50% of cases presenting initially with skin lesions. Petechiae and/or purpura are the most common of the skin manifestations, he said. By contrast, for EGPA, allergic and nonspecific findings were the most common findings.

Although skin biopsy can confirm the diagnosis in up to 94% of AAV cases, it’s underutilized and performed in less than half (24%-44%) of cases, Dr. Micheletti said. The study’s findings “demonstrate the importance of a good skin exam, as well as its utility for diagnosis” of vasculitis, he said.

An additional finding form the DCVAS study was that skin lesions can give clues to severity of vasculitis: “Among 1,184 patients with ANCA-associated vasculitis, those with cutaneous involvement were more likely to have systemic manifestations of disease, more likely to have such severe manifestations as glomerulonephritis, alveolar hemorrhage, and mononeuritis,” said Dr. Micheletti, with a hazard ratio of 2.0 among those individuals who had EGPA or GPA.

“Skin findings have diagnostic and, potentially, prognostic importance,” he said. “Use the physician exam and your clinical acumen to your advantage,” but always confirm vasculitis with a biopsy. “Clinicopathologic correlation is key.” A simple urinalysis will screen for renal involvement, and is of “paramount importance,” he added.

Dr. Micheletti reported that he had no relevant disclosures.

[email protected]

Attend the first ever International Symposium on Pediatric Renovascular Hypertension Nov. 11-12 at the University of Michigan in Ann Arbor. This conference will bring multi-disciplinary experts together to identify best practices in clinical management of unique pediatric patients. An array of distinguished physicians and researchers will highlight the best practices in patient care, recent discovery and ongoing research. Conference admission is free; breakfast, lunch and coffee breaks will be served. Register today.

Attend the first ever International Symposium on Pediatric Renovascular Hypertension Nov. 11-12 at the University of Michigan in Ann Arbor. This conference will bring multi-disciplinary experts together to identify best practices in clinical management of unique pediatric patients. An array of distinguished physicians and researchers will highlight the best practices in patient care, recent discovery and ongoing research. Conference admission is free; breakfast, lunch and coffee breaks will be served. Register today.

Attend the first ever International Symposium on Pediatric Renovascular Hypertension Nov. 11-12 at the University of Michigan in Ann Arbor. This conference will bring multi-disciplinary experts together to identify best practices in clinical management of unique pediatric patients. An array of distinguished physicians and researchers will highlight the best practices in patient care, recent discovery and ongoing research. Conference admission is free; breakfast, lunch and coffee breaks will be served. Register today.

September is PAD month. Did you know that the SVS Foundation offers free patient education fliers that you can easily customize with your own office name and contact information? We have one on PAD, one on Smoking and Vascular Disease, and seven others on various vascular-related topics. All are free and available for download in English and Spanish. Visit this page to view and celebrate PAD month with some patient education.

September is PAD month. Did you know that the SVS Foundation offers free patient education fliers that you can easily customize with your own office name and contact information? We have one on PAD, one on Smoking and Vascular Disease, and seven others on various vascular-related topics. All are free and available for download in English and Spanish. Visit this page to view and celebrate PAD month with some patient education.

September is PAD month. Did you know that the SVS Foundation offers free patient education fliers that you can easily customize with your own office name and contact information? We have one on PAD, one on Smoking and Vascular Disease, and seven others on various vascular-related topics. All are free and available for download in English and Spanish. Visit this page to view and celebrate PAD month with some patient education.

Patients at very high risk of adverse cardiovascular outcomes derive substantial benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, according to results of two analyses from the ODYSSEY OUTCOMES trial.

In one prespecified analysis, the PCSK9 inhibitor alirocumab was linked to improved cardiovascular outcomes in patients with prior coronary artery bypass grafting (CABG), while in the other, researchers wrote that alirocumab showed a “large absolute benefit” in patients with polyvascular disease, which they defined as the presence of concomitant peripheral artery disease, cerebrovascular disease, or both.

These reports on alirocumab outcomes in patients with prior CABG and polyvascular disease appear in the Journal of the American College of Cardiology.

Prior CABG and polyvascular disease were both associated with markedly elevated risks of major adverse coronary events (MACE) and death, investigators wrote in the reports.

The ODYSSEY OUTCOMES trial included 18,924 patients with recent acute coronary syndrome (ACS) and high atherogenic lipoproteins despite intensive statin treatment. The primary outcome was MACE, comprising a composite of coronary heart disease death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% relative risk reduction.

Polyvascular disease

In the trial population, 1,405 patients had polyvascular disease in at least two beds, including a coronary artery, plus either peripheral artery or cerebrovascular, while 149 had polyvascular disease in all three beds. The remainder, including 17,370 patients, were classified as having monovascular disease.

The incidences of MACE for placebo-treated patients with monovascular disease, two-bed polyvascular disease, and three-bed polyvascular disease were 10.0%, 22.2%, and 39.7%, respectively. Alirocumab treatment resulted in an absolute risk reduction for MACE of 1.4%, 1.9%, and 13.0%, for those respective groups (P = .0006).

Similarly, the incidence of the secondary endpoint of death for placebo-treated patients was 3.5%, 10.0%, and 21.8%, and the ARR with alirocumab was 0.4%, 1.3%, and 16.2% (P = .002), according to their reported data.

These results suggest that patients with polyvascular disease are an “easily identifiable subgroup” of ACS patients with a high absolute risk of MACE and death, according to the investigators, led by J. Wouter Jukema, MD, PhD, of Leiden (the Netherlands) University Medical Center.

“The large absolute benefit of PCSK9 inhibition with alirocumab, when added to high-intensity statin therapy, is a potential benefit for this group of patients,” Dr. Jukema and coauthors wrote.

Prior CABG

Of the ODYSSEY OUTCOMES patients, 1,025 had an index CABG after ACS, 1,003 had CABG before ACS, and the remaining 16,896 had no such procedure.

Hazard ratios for both MACE and death in all CABG categories were consistent with the overall results of ODYSSEY OUTCOMES, the investigators wrote. Specifically, alirocumab reduced MACE and death in the overall study, with HRs of 0.85 for both endpoints.

The ARRs in MACE with alirocumab were 1.3% for no CABG, 0.9% for index CABG, and 6.4% for prior CABG (P = .0007), while ARRs in death with the treatment were 0.4%, 0.5%, and 3.6% (P = .03) for those categories, respectively. In this analysis, the investigators calculated the number needed to treat to prevent one primary or secondary endpoint over the median 2.8 years of follow-up. The numbers needed to treat were 16 for prior CABG, 111 for index, and 77 for no prior CABG.

“Although the relative benefit of alirocumab versus placebo is consistent regardless of prior CABG status, those with prior CABG achieve substantially greater absolute risk reduction and consequently lower number needed to treat,” wrote the authors of the analysis, led by Shaun G. Goodman, MD, MSc, of St. Michael’s Hospital, Toronto.

Funding for the ODYSSEY OUTCOMES trial and its subanalyses was provided by Sanofi and Regeneron. Authors of the analyses reported disclosures related to Sanofi, Regeneron, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and others.

SOURCES: Goodman SG et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.07.015; Jukema JW et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.03.013.

Patients at very high risk of adverse cardiovascular outcomes derive substantial benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, according to results of two analyses from the ODYSSEY OUTCOMES trial.

In one prespecified analysis, the PCSK9 inhibitor alirocumab was linked to improved cardiovascular outcomes in patients with prior coronary artery bypass grafting (CABG), while in the other, researchers wrote that alirocumab showed a “large absolute benefit” in patients with polyvascular disease, which they defined as the presence of concomitant peripheral artery disease, cerebrovascular disease, or both.

These reports on alirocumab outcomes in patients with prior CABG and polyvascular disease appear in the Journal of the American College of Cardiology.

Prior CABG and polyvascular disease were both associated with markedly elevated risks of major adverse coronary events (MACE) and death, investigators wrote in the reports.

The ODYSSEY OUTCOMES trial included 18,924 patients with recent acute coronary syndrome (ACS) and high atherogenic lipoproteins despite intensive statin treatment. The primary outcome was MACE, comprising a composite of coronary heart disease death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% relative risk reduction.

Polyvascular disease

In the trial population, 1,405 patients had polyvascular disease in at least two beds, including a coronary artery, plus either peripheral artery or cerebrovascular, while 149 had polyvascular disease in all three beds. The remainder, including 17,370 patients, were classified as having monovascular disease.

The incidences of MACE for placebo-treated patients with monovascular disease, two-bed polyvascular disease, and three-bed polyvascular disease were 10.0%, 22.2%, and 39.7%, respectively. Alirocumab treatment resulted in an absolute risk reduction for MACE of 1.4%, 1.9%, and 13.0%, for those respective groups (P = .0006).

Similarly, the incidence of the secondary endpoint of death for placebo-treated patients was 3.5%, 10.0%, and 21.8%, and the ARR with alirocumab was 0.4%, 1.3%, and 16.2% (P = .002), according to their reported data.

These results suggest that patients with polyvascular disease are an “easily identifiable subgroup” of ACS patients with a high absolute risk of MACE and death, according to the investigators, led by J. Wouter Jukema, MD, PhD, of Leiden (the Netherlands) University Medical Center.

“The large absolute benefit of PCSK9 inhibition with alirocumab, when added to high-intensity statin therapy, is a potential benefit for this group of patients,” Dr. Jukema and coauthors wrote.

Prior CABG

Of the ODYSSEY OUTCOMES patients, 1,025 had an index CABG after ACS, 1,003 had CABG before ACS, and the remaining 16,896 had no such procedure.

Hazard ratios for both MACE and death in all CABG categories were consistent with the overall results of ODYSSEY OUTCOMES, the investigators wrote. Specifically, alirocumab reduced MACE and death in the overall study, with HRs of 0.85 for both endpoints.

The ARRs in MACE with alirocumab were 1.3% for no CABG, 0.9% for index CABG, and 6.4% for prior CABG (P = .0007), while ARRs in death with the treatment were 0.4%, 0.5%, and 3.6% (P = .03) for those categories, respectively. In this analysis, the investigators calculated the number needed to treat to prevent one primary or secondary endpoint over the median 2.8 years of follow-up. The numbers needed to treat were 16 for prior CABG, 111 for index, and 77 for no prior CABG.

“Although the relative benefit of alirocumab versus placebo is consistent regardless of prior CABG status, those with prior CABG achieve substantially greater absolute risk reduction and consequently lower number needed to treat,” wrote the authors of the analysis, led by Shaun G. Goodman, MD, MSc, of St. Michael’s Hospital, Toronto.

Funding for the ODYSSEY OUTCOMES trial and its subanalyses was provided by Sanofi and Regeneron. Authors of the analyses reported disclosures related to Sanofi, Regeneron, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and others.

SOURCES: Goodman SG et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.07.015; Jukema JW et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.03.013.

Patients at very high risk of adverse cardiovascular outcomes derive substantial benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, according to results of two analyses from the ODYSSEY OUTCOMES trial.

In one prespecified analysis, the PCSK9 inhibitor alirocumab was linked to improved cardiovascular outcomes in patients with prior coronary artery bypass grafting (CABG), while in the other, researchers wrote that alirocumab showed a “large absolute benefit” in patients with polyvascular disease, which they defined as the presence of concomitant peripheral artery disease, cerebrovascular disease, or both.

These reports on alirocumab outcomes in patients with prior CABG and polyvascular disease appear in the Journal of the American College of Cardiology.

Prior CABG and polyvascular disease were both associated with markedly elevated risks of major adverse coronary events (MACE) and death, investigators wrote in the reports.

The ODYSSEY OUTCOMES trial included 18,924 patients with recent acute coronary syndrome (ACS) and high atherogenic lipoproteins despite intensive statin treatment. The primary outcome was MACE, comprising a composite of coronary heart disease death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% relative risk reduction.

Polyvascular disease

In the trial population, 1,405 patients had polyvascular disease in at least two beds, including a coronary artery, plus either peripheral artery or cerebrovascular, while 149 had polyvascular disease in all three beds. The remainder, including 17,370 patients, were classified as having monovascular disease.

The incidences of MACE for placebo-treated patients with monovascular disease, two-bed polyvascular disease, and three-bed polyvascular disease were 10.0%, 22.2%, and 39.7%, respectively. Alirocumab treatment resulted in an absolute risk reduction for MACE of 1.4%, 1.9%, and 13.0%, for those respective groups (P = .0006).

Similarly, the incidence of the secondary endpoint of death for placebo-treated patients was 3.5%, 10.0%, and 21.8%, and the ARR with alirocumab was 0.4%, 1.3%, and 16.2% (P = .002), according to their reported data.

These results suggest that patients with polyvascular disease are an “easily identifiable subgroup” of ACS patients with a high absolute risk of MACE and death, according to the investigators, led by J. Wouter Jukema, MD, PhD, of Leiden (the Netherlands) University Medical Center.

“The large absolute benefit of PCSK9 inhibition with alirocumab, when added to high-intensity statin therapy, is a potential benefit for this group of patients,” Dr. Jukema and coauthors wrote.

Prior CABG

Of the ODYSSEY OUTCOMES patients, 1,025 had an index CABG after ACS, 1,003 had CABG before ACS, and the remaining 16,896 had no such procedure.

Hazard ratios for both MACE and death in all CABG categories were consistent with the overall results of ODYSSEY OUTCOMES, the investigators wrote. Specifically, alirocumab reduced MACE and death in the overall study, with HRs of 0.85 for both endpoints.

The ARRs in MACE with alirocumab were 1.3% for no CABG, 0.9% for index CABG, and 6.4% for prior CABG (P = .0007), while ARRs in death with the treatment were 0.4%, 0.5%, and 3.6% (P = .03) for those categories, respectively. In this analysis, the investigators calculated the number needed to treat to prevent one primary or secondary endpoint over the median 2.8 years of follow-up. The numbers needed to treat were 16 for prior CABG, 111 for index, and 77 for no prior CABG.

“Although the relative benefit of alirocumab versus placebo is consistent regardless of prior CABG status, those with prior CABG achieve substantially greater absolute risk reduction and consequently lower number needed to treat,” wrote the authors of the analysis, led by Shaun G. Goodman, MD, MSc, of St. Michael’s Hospital, Toronto.

Funding for the ODYSSEY OUTCOMES trial and its subanalyses was provided by Sanofi and Regeneron. Authors of the analyses reported disclosures related to Sanofi, Regeneron, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and others.

SOURCES: Goodman SG et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.07.015; Jukema JW et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.03.013.

If you’re looking to have the best remote user experience on SVSConnect, download the Member Centric app. Don’t limit your time on the community to only when you have a desktop or laptop computer available. The app gives you easy access to the Open Forum, member directory and shared resources directly from your mobile device. You're able to download this from either Google Play or the App Store. Read how to download the app here.

As always, use your SVS credentials to sign in and reach out to [email protected] with questions.

If you’re looking to have the best remote user experience on SVSConnect, download the Member Centric app. Don’t limit your time on the community to only when you have a desktop or laptop computer available. The app gives you easy access to the Open Forum, member directory and shared resources directly from your mobile device. You're able to download this from either Google Play or the App Store. Read how to download the app here.

As always, use your SVS credentials to sign in and reach out to [email protected] with questions.

If you’re looking to have the best remote user experience on SVSConnect, download the Member Centric app. Don’t limit your time on the community to only when you have a desktop or laptop computer available. The app gives you easy access to the Open Forum, member directory and shared resources directly from your mobile device. You're able to download this from either Google Play or the App Store. Read how to download the app here.

As always, use your SVS credentials to sign in and reach out to [email protected] with questions.