Pharmacology

The U.S. Food and Drug Administration approved remdesivir (Veklury) Oct. 22 as a treatment for hospitalized COVID-19 patients aged 12 and up, making it the first and only approved treatment for COVID-19, according to a release from drug manufacturer Gilead Sciences.

The FDA’s initial Emergency Use Authorization (EUA) of the antiviral, issued in May, allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who needed oxygen therapy or mechanical ventilation.

An August EUA expanded treatment to include all adult and pediatric hospitalized COVID-19 patients, regardless of the severity of their disease. The FDA also issued a new EUA for remdesivir Oct. 22 allowing treatment of hospitalized pediatric patients younger than 12 weighing at least 3.5 kg.

Today’s approval is based on three randomized controlled trials, according to Gilead.

Final trial results from one of them, the National Institute of Allergy and Infectious Disease–funded ACTT-1 trial, published earlier in October, showed that hospitalized patients with COVID-19 who received remdesivir had a shorter median recovery time than those who received a placebo – 10 days versus 15 days.

This difference and some related secondary endpoints were statistically significant in the randomized trial, but there was not a statistically significant difference in mortality between the treatment and placebo groups.

The other two trials used for the approval, the SIMPLE trials, were open-label phase 3 trials conducted in countries with a high prevalence of COVID-19 infections, according to Gilead.

The SIMPLE-Severe trial was a randomized, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing plus standard of care in 397 hospitalized adult patients with severe COVID-19. The primary endpoint was clinical status on day 14 assessed on a 7-point ordinal scale, according to Gilead.

The trial found that a 5-day or a 10-day treatment course of Veklury achieved similar clinical outcomes to the ACTT-1 trial (odds ratio, 0.75; 95% confidence interval, 0.51-1.12).

The SIMPLE-Moderate trial was a randomized, controlled, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing durations of Veklury plus standard of care, compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19, Gilead stated in its release.

The primary endpoint was clinical status on day 11 assessed on a 7-point ordinal scale.

The results showed statistically improved clinical outcomes with a 5-day treatment course of Veklury, compared with standard of care (OR, 1.65; 95% CI, 1.0-2.48; P = .017), according to Gilead.

This article first appeared on Medscape.com.

The U.S. Food and Drug Administration approved remdesivir (Veklury) Oct. 22 as a treatment for hospitalized COVID-19 patients aged 12 and up, making it the first and only approved treatment for COVID-19, according to a release from drug manufacturer Gilead Sciences.

The FDA’s initial Emergency Use Authorization (EUA) of the antiviral, issued in May, allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who needed oxygen therapy or mechanical ventilation.

An August EUA expanded treatment to include all adult and pediatric hospitalized COVID-19 patients, regardless of the severity of their disease. The FDA also issued a new EUA for remdesivir Oct. 22 allowing treatment of hospitalized pediatric patients younger than 12 weighing at least 3.5 kg.

Today’s approval is based on three randomized controlled trials, according to Gilead.

Final trial results from one of them, the National Institute of Allergy and Infectious Disease–funded ACTT-1 trial, published earlier in October, showed that hospitalized patients with COVID-19 who received remdesivir had a shorter median recovery time than those who received a placebo – 10 days versus 15 days.

This difference and some related secondary endpoints were statistically significant in the randomized trial, but there was not a statistically significant difference in mortality between the treatment and placebo groups.

The other two trials used for the approval, the SIMPLE trials, were open-label phase 3 trials conducted in countries with a high prevalence of COVID-19 infections, according to Gilead.

The SIMPLE-Severe trial was a randomized, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing plus standard of care in 397 hospitalized adult patients with severe COVID-19. The primary endpoint was clinical status on day 14 assessed on a 7-point ordinal scale, according to Gilead.

The trial found that a 5-day or a 10-day treatment course of Veklury achieved similar clinical outcomes to the ACTT-1 trial (odds ratio, 0.75; 95% confidence interval, 0.51-1.12).

The SIMPLE-Moderate trial was a randomized, controlled, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing durations of Veklury plus standard of care, compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19, Gilead stated in its release.

The primary endpoint was clinical status on day 11 assessed on a 7-point ordinal scale.

The results showed statistically improved clinical outcomes with a 5-day treatment course of Veklury, compared with standard of care (OR, 1.65; 95% CI, 1.0-2.48; P = .017), according to Gilead.

This article first appeared on Medscape.com.

The U.S. Food and Drug Administration approved remdesivir (Veklury) Oct. 22 as a treatment for hospitalized COVID-19 patients aged 12 and up, making it the first and only approved treatment for COVID-19, according to a release from drug manufacturer Gilead Sciences.

The FDA’s initial Emergency Use Authorization (EUA) of the antiviral, issued in May, allowed the drug to be used only for patients with severe COVID-19, specifically, COVID-19 patients with low blood oxygen levels or who needed oxygen therapy or mechanical ventilation.

An August EUA expanded treatment to include all adult and pediatric hospitalized COVID-19 patients, regardless of the severity of their disease. The FDA also issued a new EUA for remdesivir Oct. 22 allowing treatment of hospitalized pediatric patients younger than 12 weighing at least 3.5 kg.

Today’s approval is based on three randomized controlled trials, according to Gilead.

Final trial results from one of them, the National Institute of Allergy and Infectious Disease–funded ACTT-1 trial, published earlier in October, showed that hospitalized patients with COVID-19 who received remdesivir had a shorter median recovery time than those who received a placebo – 10 days versus 15 days.

This difference and some related secondary endpoints were statistically significant in the randomized trial, but there was not a statistically significant difference in mortality between the treatment and placebo groups.

The other two trials used for the approval, the SIMPLE trials, were open-label phase 3 trials conducted in countries with a high prevalence of COVID-19 infections, according to Gilead.

The SIMPLE-Severe trial was a randomized, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing plus standard of care in 397 hospitalized adult patients with severe COVID-19. The primary endpoint was clinical status on day 14 assessed on a 7-point ordinal scale, according to Gilead.

The trial found that a 5-day or a 10-day treatment course of Veklury achieved similar clinical outcomes to the ACTT-1 trial (odds ratio, 0.75; 95% confidence interval, 0.51-1.12).

The SIMPLE-Moderate trial was a randomized, controlled, multicenter study that evaluated the efficacy and safety of 5-day and 10-day dosing durations of Veklury plus standard of care, compared with standard of care alone in 600 hospitalized adult patients with moderate COVID-19, Gilead stated in its release.

The primary endpoint was clinical status on day 11 assessed on a 7-point ordinal scale.

The results showed statistically improved clinical outcomes with a 5-day treatment course of Veklury, compared with standard of care (OR, 1.65; 95% CI, 1.0-2.48; P = .017), according to Gilead.

This article first appeared on Medscape.com.

Among individuals admitted to hospitals with sepsis, statin users had a lower mortality, compared with nonstatin users, according to a recent analysis focused on a large and diverse cohort of patients in California.

Mortality hazard ratios at 30 and 90 days were lower by about 20% for statin users admitted for sepsis, compared with nonstatin users, according to results of the retrospective cohort study.

Hydrophilic and synthetic statins had more favorable mortality outcomes, compared with lipophilic and fungal-derived statins, respectively, added investigator Brannen Liang, MD, a third-year internal medicine resident at Kaiser Permanente Los Angeles Medical Center.

These findings suggest a potential benefit of statins in patients with sepsis, with certain types of statins having a greater protective effect than others, according to Dr. Liang, who presented the original research in a presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

“I think there’s potential for extending the use of statins to other indications, such as sepsis,” Dr. Liang said in an interview, though he also cautioned that the present study is hypothesis generating and more research is necessary.

Using a certain statin type over another (i.e., a hydrophilic, synthetic statin) might be a consideration for populations who are at greater risk for sepsis, such as the immunocompromised, patients with diabetes, or elderly and who also require a statin for an indication such as hyperlipidemia, he added.

While the link between statin use and sepsis mortality outcomes is not new, this study is unique in that it replicates results of earlier studies in a large and diverse real-world population, Dr. Liang said.

“Numerous studies seem to suggest that statins may play a role in attenuating the mortality of patients admitted to the hospital with sepsis, for whatever reason – whether this is due to their anti-inflammatory effects, their lipid-lowering effects, or if they truly have an antimicrobial effect, which has been studied in vitro and in animal studies,” he said in an interview.

It’s impossible to definitively conclude from retrospective studies such as this whether statins reduce sepsis-related mortality risk, but the present study at least makes the case for using certain types of statins when they are indicated in high-risk patients, said Steven Q. Simpson, MD, FCCP, professor of medicine in the division of pulmonary and critical care medicine at the University of Kansas, Kansas City.

“If you have patients at high risk for sepsis and they need a statin, you could give consideration to using a hydrophilic and synthetic statin, rather than either of the other choices,” said Dr. Simpson, CHEST president-elect and senior advisor to the Solving Sepsis initiative of the Biomedical Advanced Research and Development Authority of the Department of Health & Human Services.

The retrospective cohort study by Dr. Liang and colleagues included a total of 137,019 individuals admitted for sepsis within the Kaiser Permanente Southern California health system between 2008 and 2018. Of that group, 36,908 were taking a statin.

Overall, the mean age of patients admitted for sepsis was 66.9 years, and 50.4% were female. Nearly 50% were White, about 12% were Black, 28% were Hispanic, and 8% were Asian. A diagnosis of ischemic heart disease was reported for 43% of statin users and 23% of nonusers, while diabetes mellitus was reported for 60% of statin users and 37% of nonusers (P < .0001 for both comparisons).

Differences in mortality favored statin users, compared with nonusers, with hazard ratios of 0.79 (95% confidence interval, 0.77-0.82) at 30 days and similarly, 0.79 (95% CI, 0.77-0.81) at 90 days, Dr. Liang reported, noting that the models were adjusted for age, race, sex, and comorbidities.

Further analysis suggested a mortality advantage of lipophilic, compared with hydrophilic statins, and an advantage of fungal-derived statins over synthetic-derived statins, the investigator added.

In the comparison of lipophilic statin users and hydrophilic statin users, the 30- and 90-day mortality HRs were 1.13 (95% CI, 1.02-1.26) and 1.17 (95% CI, 1.07-1.28), respectively, the data show. For fungal-derived statin users, compared with synthetic derived statin users, 30- and 90-day mortality HRs were 1.12 (95% CI, 1.06-1.19) and 1.14 (95% CI, 1.09-1.20), respectively.

Dr. Liang and coauthors disclosed no relevant relationships with respect to the work presented at the CHEST meeting.

SOURCE: Liang B et al. CHEST 2020, Abstract A589.

Among individuals admitted to hospitals with sepsis, statin users had a lower mortality, compared with nonstatin users, according to a recent analysis focused on a large and diverse cohort of patients in California.

Mortality hazard ratios at 30 and 90 days were lower by about 20% for statin users admitted for sepsis, compared with nonstatin users, according to results of the retrospective cohort study.

Hydrophilic and synthetic statins had more favorable mortality outcomes, compared with lipophilic and fungal-derived statins, respectively, added investigator Brannen Liang, MD, a third-year internal medicine resident at Kaiser Permanente Los Angeles Medical Center.

These findings suggest a potential benefit of statins in patients with sepsis, with certain types of statins having a greater protective effect than others, according to Dr. Liang, who presented the original research in a presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

“I think there’s potential for extending the use of statins to other indications, such as sepsis,” Dr. Liang said in an interview, though he also cautioned that the present study is hypothesis generating and more research is necessary.

Using a certain statin type over another (i.e., a hydrophilic, synthetic statin) might be a consideration for populations who are at greater risk for sepsis, such as the immunocompromised, patients with diabetes, or elderly and who also require a statin for an indication such as hyperlipidemia, he added.

While the link between statin use and sepsis mortality outcomes is not new, this study is unique in that it replicates results of earlier studies in a large and diverse real-world population, Dr. Liang said.

“Numerous studies seem to suggest that statins may play a role in attenuating the mortality of patients admitted to the hospital with sepsis, for whatever reason – whether this is due to their anti-inflammatory effects, their lipid-lowering effects, or if they truly have an antimicrobial effect, which has been studied in vitro and in animal studies,” he said in an interview.

It’s impossible to definitively conclude from retrospective studies such as this whether statins reduce sepsis-related mortality risk, but the present study at least makes the case for using certain types of statins when they are indicated in high-risk patients, said Steven Q. Simpson, MD, FCCP, professor of medicine in the division of pulmonary and critical care medicine at the University of Kansas, Kansas City.

“If you have patients at high risk for sepsis and they need a statin, you could give consideration to using a hydrophilic and synthetic statin, rather than either of the other choices,” said Dr. Simpson, CHEST president-elect and senior advisor to the Solving Sepsis initiative of the Biomedical Advanced Research and Development Authority of the Department of Health & Human Services.

The retrospective cohort study by Dr. Liang and colleagues included a total of 137,019 individuals admitted for sepsis within the Kaiser Permanente Southern California health system between 2008 and 2018. Of that group, 36,908 were taking a statin.

Overall, the mean age of patients admitted for sepsis was 66.9 years, and 50.4% were female. Nearly 50% were White, about 12% were Black, 28% were Hispanic, and 8% were Asian. A diagnosis of ischemic heart disease was reported for 43% of statin users and 23% of nonusers, while diabetes mellitus was reported for 60% of statin users and 37% of nonusers (P < .0001 for both comparisons).

Differences in mortality favored statin users, compared with nonusers, with hazard ratios of 0.79 (95% confidence interval, 0.77-0.82) at 30 days and similarly, 0.79 (95% CI, 0.77-0.81) at 90 days, Dr. Liang reported, noting that the models were adjusted for age, race, sex, and comorbidities.

Further analysis suggested a mortality advantage of lipophilic, compared with hydrophilic statins, and an advantage of fungal-derived statins over synthetic-derived statins, the investigator added.

In the comparison of lipophilic statin users and hydrophilic statin users, the 30- and 90-day mortality HRs were 1.13 (95% CI, 1.02-1.26) and 1.17 (95% CI, 1.07-1.28), respectively, the data show. For fungal-derived statin users, compared with synthetic derived statin users, 30- and 90-day mortality HRs were 1.12 (95% CI, 1.06-1.19) and 1.14 (95% CI, 1.09-1.20), respectively.

Dr. Liang and coauthors disclosed no relevant relationships with respect to the work presented at the CHEST meeting.

SOURCE: Liang B et al. CHEST 2020, Abstract A589.

Among individuals admitted to hospitals with sepsis, statin users had a lower mortality, compared with nonstatin users, according to a recent analysis focused on a large and diverse cohort of patients in California.

Mortality hazard ratios at 30 and 90 days were lower by about 20% for statin users admitted for sepsis, compared with nonstatin users, according to results of the retrospective cohort study.

Hydrophilic and synthetic statins had more favorable mortality outcomes, compared with lipophilic and fungal-derived statins, respectively, added investigator Brannen Liang, MD, a third-year internal medicine resident at Kaiser Permanente Los Angeles Medical Center.

These findings suggest a potential benefit of statins in patients with sepsis, with certain types of statins having a greater protective effect than others, according to Dr. Liang, who presented the original research in a presentation at the annual meeting of the American College of Chest Physicians, held virtually this year.

“I think there’s potential for extending the use of statins to other indications, such as sepsis,” Dr. Liang said in an interview, though he also cautioned that the present study is hypothesis generating and more research is necessary.

Using a certain statin type over another (i.e., a hydrophilic, synthetic statin) might be a consideration for populations who are at greater risk for sepsis, such as the immunocompromised, patients with diabetes, or elderly and who also require a statin for an indication such as hyperlipidemia, he added.

While the link between statin use and sepsis mortality outcomes is not new, this study is unique in that it replicates results of earlier studies in a large and diverse real-world population, Dr. Liang said.

“Numerous studies seem to suggest that statins may play a role in attenuating the mortality of patients admitted to the hospital with sepsis, for whatever reason – whether this is due to their anti-inflammatory effects, their lipid-lowering effects, or if they truly have an antimicrobial effect, which has been studied in vitro and in animal studies,” he said in an interview.

It’s impossible to definitively conclude from retrospective studies such as this whether statins reduce sepsis-related mortality risk, but the present study at least makes the case for using certain types of statins when they are indicated in high-risk patients, said Steven Q. Simpson, MD, FCCP, professor of medicine in the division of pulmonary and critical care medicine at the University of Kansas, Kansas City.

“If you have patients at high risk for sepsis and they need a statin, you could give consideration to using a hydrophilic and synthetic statin, rather than either of the other choices,” said Dr. Simpson, CHEST president-elect and senior advisor to the Solving Sepsis initiative of the Biomedical Advanced Research and Development Authority of the Department of Health & Human Services.

The retrospective cohort study by Dr. Liang and colleagues included a total of 137,019 individuals admitted for sepsis within the Kaiser Permanente Southern California health system between 2008 and 2018. Of that group, 36,908 were taking a statin.

Overall, the mean age of patients admitted for sepsis was 66.9 years, and 50.4% were female. Nearly 50% were White, about 12% were Black, 28% were Hispanic, and 8% were Asian. A diagnosis of ischemic heart disease was reported for 43% of statin users and 23% of nonusers, while diabetes mellitus was reported for 60% of statin users and 37% of nonusers (P < .0001 for both comparisons).

Differences in mortality favored statin users, compared with nonusers, with hazard ratios of 0.79 (95% confidence interval, 0.77-0.82) at 30 days and similarly, 0.79 (95% CI, 0.77-0.81) at 90 days, Dr. Liang reported, noting that the models were adjusted for age, race, sex, and comorbidities.

Further analysis suggested a mortality advantage of lipophilic, compared with hydrophilic statins, and an advantage of fungal-derived statins over synthetic-derived statins, the investigator added.

In the comparison of lipophilic statin users and hydrophilic statin users, the 30- and 90-day mortality HRs were 1.13 (95% CI, 1.02-1.26) and 1.17 (95% CI, 1.07-1.28), respectively, the data show. For fungal-derived statin users, compared with synthetic derived statin users, 30- and 90-day mortality HRs were 1.12 (95% CI, 1.06-1.19) and 1.14 (95% CI, 1.09-1.20), respectively.

Dr. Liang and coauthors disclosed no relevant relationships with respect to the work presented at the CHEST meeting.

SOURCE: Liang B et al. CHEST 2020, Abstract A589.

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

[email protected]

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

[email protected]

Start most patients newly diagnosed with heart failure with reduced ejection fraction on the disorder’s four foundational drug regimens all at once, all on the day the diagnosis is made, Gregg C. Fonarow, MD, recommended.

Less than 2 months before Dr. Fonarow made that striking statement during the virtual annual meeting of the Heart Failure Society of America, investigators first reported results from the EMPEROR-Reduced trial at the European Society of Cardiology’s virtual annual meeting, showing that the sodium-glucose transporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) successfully cut events in patients with heart failure with reduced ejection fraction (HFrEF). That report, a year after results from a similar trial (DAPA-HF) showed the same outcome using a different drug from the same class, dapagliflozin (Farxiga), cemented the SGLT2 inhibitor drug class as the fourth pillar for treating HFrEF, joining the angiotensin receptor neprilysin inhibitor (ARNI) class (sacubitril valsartan), beta-blockers (like carvedilol), and mineralocorticoid receptor antagonists (like spironolactone).

This rejiggering of the consensus expert approach for treating HFrEF left cardiologists wondering what sequence to use when starting this quadruple therapy. Within weeks, the answer from heart failure opinion leaders was clear:

“Start all four pillars simultaneously. Most patients can tolerate, and will benefit from, a simultaneous start,” declared Dr. Fonarow, professor and chief of cardiology at the University of California, Los Angeles.

His rationale? Patients get benefits from each of these drug classes “surprisingly early,” with improved outcomes in clinical trials appearing within a few weeks, compared with patients in control arms. The consequence is that any delay in starting treatment denies patients time with improved health status, function, and survival.

Study results documented that the four foundational drug classes can produce rapid improvements in health status, left ventricular size and shape, and make clinically meaningful cuts in both first and recurrent hospitalizations for heart failure and in mortality, Dr. Fonarow said. After 30 days on quadruple treatment, a patient’s relative risk for death drops by more than three-quarters, compared with patients not on these medications.

The benefits from each of the four classes involve distinct physiologic pathways and hence are not diminished by concurrent treatment. And immediate initiation avoids the risk of clinical inertia and a negligence to prescribe one or more of the four important drug classes. Introducing the four classes in a sequential manner could mean spending as long as a year to get all four on board and up-titrated to optimal therapeutic levels, he noted.

“Overcome inertia by prescribing [all four drug classes] at the time of diagnosis,” Dr. Fonarow admonished his audience.

The challenge of prescribing inertia

The risk for inertia in prescribing heart failure medications is real. Data collected in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry from more than 3,500 HFrEF patients managed at any of 150 U.S. primary care and cardiology practices starting in late 2015 and continuing through 2017 showed that, among patients eligible for treatment with renin-angiotensin system (RAS) inhibition (with either ARNI or a single RAS inhibiting drug), a beta-blocker, and a mineralocorticoid receptor antagonist (MRA), 22% received all three drug classes. A scant 1% were on target dosages of all three drug classes, noted Stephen J. Greene, MD, in a separate talk at the meeting when he cited his published findings.

The sole formulation currently in the ARNI class, sacubitril/valsartan (Entresto) has in recent years been the poster child for prescribing inertia in HFrEF patients after coming onto the U.S. market for routine use in 2015. A review run by Dr. Greene of more than 9,000 HFrEF patients who were at least 65 years old and discharged from a hospital participating in the Get With the Guidelines–Heart Failure registry during October 2015–September 2017 showed that 8% of eligible patients actually received a sacubitril/valsartan prescription. Separate assessment of outpatients with HFrEF from the same era showed 13% uptake, said D. Greene, a cardiologist at Duke University, Durham, N.C.

Substantial gaps in prescribing evidence-based treatments to HFrEF patients have existed for the past couple of decades, said Dr. Greene. “Even a blockbuster drug like sacubitril/valsartan has been slow to implement.”
 

Quadruple therapy adds an average of 6 years of life

One of the most strongest arguments favoring the start-four-at-once approach was detailed in what’s quickly become a widely cited analysis published in July 2020 by a team of researchers led by Muthiah Vaduganathan, MD. Using data from three key pivotal trials they estimated that timely treatment with all four drug classes would on average produce an extra 6 years of overall survival in a 55-year old HFrEF patient, and an added 8 years free from cardiovascular death or first hospitalization for heart failure, compared with less comprehensive treatment. The analysis also showed a significant 3-year average boost in overall survival among HFrEF patients who were 80 years old when using quadruple therapy compared with the “conventional medical therapy” used on control patients in the three trials examined.

Dr. Greene called these findings “remarkable.”

Mitchel L. Zoler/Frontline Medical News

“Four drugs use five mechanistic pathways to produce 6 added years of survival,” summed up Dr. Vaduganathan during a separate talk at the virtual meeting.

In addition to this substantial potential for a meaningful impact on patents’ lives, he cited other factors that add to the case for early prescription of the pharmaceutical gauntlet: avoiding missed treatment opportunities that occur with slower, step-wise drug introduction; simplifying, streamlining, and standardizing the care pathway, which helps avoid care inequities and disrupts the potential for inertia; magnifying benefit when comprehensive treatment starts sooner; and providing additive benefits without drug-drug interactions.

“Upfront treatment at the time of [HFrEF] diagnosis or hospitalization is an approach that disrupts treatment inertia,” emphasized Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston.
 

New approaches needed to encourage quick uptake

“Efficacy alone has not been enough for efficient uptake in U.S. practice” of sacubitril/valsartan, other RAS inhibitors, beta-blockers, and MRAs, noted Dr. Greene.

He was more optimistic about prospects for relatively quick uptake of early SGLT2 inhibitor treatment as part of routine HFrEF management given all the positives that this new HFrEF treatment offers, including some “unique features” among HFrEF drugs. These include the simplicity of the regimen, which involves a single dosage for everyone that’s taken once daily; minimal blood pressure effects and no adverse renal effects while also producing substantial renal protection; and two SGLT2 inhibitors with proven HFrEF benefit (dapagliflozin and empagliflozin), which bodes well for an eventual price drop.

The SGLT2 inhibitors stack up as an “ideal” HFrEF treatment, concluded Dr. Greene, which should facilitate quick uptake. As far as getting clinicians to also add early on the other three members of the core four treatment classes in routine treatment, he conceded that “innovative and evidence-based approaches to improving real-world uptake of guideline-directed medical therapy are urgently needed.”

EMPEROR-Reduced was funded by Boehringer Ingelheim and Lilly, the companies that market empagliflozin (Jardiance). CHAMP-HF was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. Fonarow has been a consultant or adviser to Novartis, as well as to Abbott, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards, Janssen, Medtronic, and Merck. Dr. Greene has received research funding from Novartis, has been a consultant to Amgen and Merck, an adviser to Amgen and Cytokinetics, and has received research funding from Amgen, AstraZeneca, Bristol-Myers Squibb, and Merck. Dr. Vaduganathan has had financial relationships with Boehringer Ingelheim and Novartis, as well as with Amgen, AstraZeneca, Baxter Healthcare, Bayer, Cytokinetics, and Relypsa.

[email protected]

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

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

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

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

We can “stop putting money on vitamin D” to help patients who require critical care, said Todd Rice, MD, FCCP.

“Results from vitamin D trials have not been uniformly one way, but they have been pretty uniformly disappointing,” Dr. Rice, from Vanderbilt University Medical Center, Nashville, Tenn., reported at the annual meeting of the American College of Chest Physicians.

Low levels of vitamin D in critically ill COVID-19 patients have been reported in numerous recent studies, and researchers are looking for ways to boost those levels and improve outcomes.

We are seeing “the exact same story” in the critically ill COVID-19 population as we see in the general ICU population, said Dr. Rice. “The whole scenario is repeating itself. I’m pessimistic.”

Still, vitamin D levels can be elevated so, in theory, “the concept makes sense,” he said. There is evidence that, “when given enterally, the levels rise nicely” and vitamin D is absorbed reasonably well.” But is that enough?

When patients are admitted to the ICU, some biomarkers in the body are too high and others are too low. Vitamin D is often too low. So far, though, “supplementing vitamin D in the ICU has not significantly improved outcomes,” said Dr. Rice.

In the Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial, Dr. Rice and colleagues found no statistical benefit when a 540,000 IU boost of vitamin D was administered to 2,624 critically ill patients, as reported by Medscape Medical News.

“Early administration of high-dose enteral vitamin D₃ did not provide an advantage over placebo with respect to 90-day mortality or other nonfatal outcomes among critically ill, vitamin D–deficient patients,” the researchers write in their recent report.

In fact, VIOLET ended before enrollment had reached the planned 3,000-patient cohort because the statistical analysis clearly did not show benefit. Those enrolled were in the ICU because of, among other things, pneumonia, sepsis, the need for mechanical ventilation or vasopressors, and risk for acute respiratory distress syndrome.

“It doesn’t look like vitamin D is going to be the answer to our critical care problems,” Dr. Rice said in an interview.
 

Maintenance dose needed?

One theory suggests that VIOLET might have failed because a maintenance dose is needed after the initial boost of vitamin D.

In the ongoing VITDALIZE trial, critically ill patients with severe vitamin D deficiency (12 ng/mL or less at admission) receive an initial 540,000-IU dose followed by 4,000 IU per day.

The highly anticipated VITDALIZE results are expected in the middle of next year, Dr. Rice reported, so “let’s wait to see.”

“Vitamin D may not have an acute effect,” he theorized. “We can raise your levels, but that doesn’t give you all the benefits of having a sufficient level for a long period of time.”

Another theory suggests that a low level of vitamin D is simply a signal of the severity of disease, not a direct influence on disease pathology.

Some observational data have shown an association between low levels of vitamin D and outcomes in COVID-19 patients (Nutrients. 2020 May 9;12[5]:1359; medRxiv 2020 Apr 24. doi: 10.1101/2020.04.24.20075838; JAMA Netw Open. 2020;3[9]:e2019722; FEBS J. 2020 Jul 23;10.1111/febs.15495; Clin Endocrinol [Oxf]. 2020 Jul 3;10.1111/cen.14276), but some have shown no association (medRxiv. 2020 Jun 26. doi: 10.1101/2020.06.26.20140921; J Public Health [Oxf]. 2020 Aug 18;42[3]:451-60).

Dr. Rice conducted a search of Clinicaltrials.gov immediately before his presentation on Sunday, and found 41 ongoing interventional studies – “not observational studies” – looking at COVID-19 and vitamin D.

“They’re recruiting, they’re enrolling; hopefully we’ll have data soon,” he said.

Researchers have checked a lot of boxes with a resounding yes on the vitamin D question, so there’s reason to think an association does exist for ICU patients, whether or not they have COVID-19.

“Is there a theoretical benefit of vitamin D in the ICU?” Dr. Rice asked. “Yes. Is vitamin D deficient in patients in the ICU? Yes. Is that deficiency associated with poor outcomes? Yes. Can it be replaced safely? Yes.”

However, “we’re not really sure that it improves outcomes,” he said.
 

A chronic issue?

“Do you think it’s really an issue of the patients being critically ill with vitamin D,” or is it “a chronic issue of having low vitamin D?” asked session moderator Antine Stenbit, MD, PhD, from the University of California, San Diego.

“We don’t know for sure,” Dr. Rice said. Vitamin D might not have a lot of acute effects; it might have effects that are chronic, that work with levels over a period of time, he explained.

“It’s not clear we can correct that with a single dose or with a few days of giving a level that is adequate,” he acknowledged.

Dr. Rice is an investigator in the PETAL network. Dr. Stenbit disclosed no relevant financial relationships.

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

The recall of extended-release metformin continues this month as 76 more lots have been flagged for a possible cancer-causing ingredient.

The Food and Drug Administration announced the latest recall, involving Marksans Pharma Limited and Sun Pharmaceutical Industries products, on Oct. 5. It involves the 500-mg and 700-mg tablets. More than 175 different drug combinations have been recalled since late May.

Consumers can see all the recalled metformin products at this FDA website. The agency says that immediate-release metformin does not appear to have the same contamination problem.

The FDA has been investigating the presence of nitrosamines, known to be possible carcinogens, in the popular diabetes medications since December, when they were first discovered in drugs in other countries. The agency said this month they still do not know the source of nitrosamines in the medications.

The investigation and subsequent recalls follow similar ones for contamination of popular heartburn and blood pressure drugs also for nitrosamines, such as N-Nitrosodimethylamine (NDMA).

The FDA says patients taking metformin products that have been recalled should continue taking the medication until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking the medication without first talking to their doctor.

The agency has asked drug manufacturers to test products before batches are released into the market. The companies must tell the FDA if any product shows levels of nitrosamines above the acceptable limit.

The risk from nitrosamines is not clear. The FDA says they may increase the risk of cancer in people who are exposed to high levels over a long period of time, “but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer.”
 

This article first appeared on WebMD.com.

The recall of extended-release metformin continues this month as 76 more lots have been flagged for a possible cancer-causing ingredient.

The Food and Drug Administration announced the latest recall, involving Marksans Pharma Limited and Sun Pharmaceutical Industries products, on Oct. 5. It involves the 500-mg and 700-mg tablets. More than 175 different drug combinations have been recalled since late May.

Consumers can see all the recalled metformin products at this FDA website. The agency says that immediate-release metformin does not appear to have the same contamination problem.

The FDA has been investigating the presence of nitrosamines, known to be possible carcinogens, in the popular diabetes medications since December, when they were first discovered in drugs in other countries. The agency said this month they still do not know the source of nitrosamines in the medications.

The investigation and subsequent recalls follow similar ones for contamination of popular heartburn and blood pressure drugs also for nitrosamines, such as N-Nitrosodimethylamine (NDMA).

The FDA says patients taking metformin products that have been recalled should continue taking the medication until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking the medication without first talking to their doctor.

The agency has asked drug manufacturers to test products before batches are released into the market. The companies must tell the FDA if any product shows levels of nitrosamines above the acceptable limit.

The risk from nitrosamines is not clear. The FDA says they may increase the risk of cancer in people who are exposed to high levels over a long period of time, “but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer.”
 

This article first appeared on WebMD.com.

The recall of extended-release metformin continues this month as 76 more lots have been flagged for a possible cancer-causing ingredient.

The Food and Drug Administration announced the latest recall, involving Marksans Pharma Limited and Sun Pharmaceutical Industries products, on Oct. 5. It involves the 500-mg and 700-mg tablets. More than 175 different drug combinations have been recalled since late May.

Consumers can see all the recalled metformin products at this FDA website. The agency says that immediate-release metformin does not appear to have the same contamination problem.

The FDA has been investigating the presence of nitrosamines, known to be possible carcinogens, in the popular diabetes medications since December, when they were first discovered in drugs in other countries. The agency said this month they still do not know the source of nitrosamines in the medications.

The investigation and subsequent recalls follow similar ones for contamination of popular heartburn and blood pressure drugs also for nitrosamines, such as N-Nitrosodimethylamine (NDMA).

The FDA says patients taking metformin products that have been recalled should continue taking the medication until a doctor or pharmacist gives them a replacement or a different treatment option. It could be dangerous for patients with type 2 diabetes to stop taking the medication without first talking to their doctor.

The agency has asked drug manufacturers to test products before batches are released into the market. The companies must tell the FDA if any product shows levels of nitrosamines above the acceptable limit.

The risk from nitrosamines is not clear. The FDA says they may increase the risk of cancer in people who are exposed to high levels over a long period of time, “but we do not anticipate that shorter-term exposure at levels above the acceptable intake limit would lead to an increase in the risk of cancer.”
 

This article first appeared on WebMD.com.

The U.S. Food and Drug Administration released new warnings Oct. 15 that most nonsteroidal anti-inflammatory agents (NSAIDs) carry an elevated risk for kidney complications in unborn children when taken around weeks 20 or later in pregnancy.

Citing newly available research, the agency states the risk of low amniotic fluid (known as oligohydramnios) can occur, which in turn can cause rare but serious kidney problems in the offspring. Pregnancy complications also can result.

The FDA action expands on earlier warnings about agents in this drug class, which the FDA previously cautioned about taking after week 30 of pregnancy because of heart-related risks.

Manufacturers of both over-the-counter and prescription NSAIDs – including ibuprofen, naproxen, diclofenac, and celecoxib – will be required to update their labeling with the new warning.

Low-dose (81-mg) aspirin is excluded from this warning.

“Low-dose aspirin may be an important treatment for some women during pregnancy and should be taken under the direction of a healthcare professional,” the agency stated in a news release.

“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, states in the release. “To this end, the agency is using its regulatory authority to inform women and their healthcare providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”

Oligohydramnios can arise quickly – in as little as 2 days – or weeks after starting regular NSAID use in this patient population. The condition usually resolves if a pregnant woman stops taking the NSAID, the agency notes.

If a health care provider believes NSAIDs are necessary between about 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and shortest duration possible, the Drug Safety Communication notes.

As a reminder, health care professionals and patients should report side effects from NSAIDs to the FDA’s MedWatch program.

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

The U.S. Food and Drug Administration released new warnings Oct. 15 that most nonsteroidal anti-inflammatory agents (NSAIDs) carry an elevated risk for kidney complications in unborn children when taken around weeks 20 or later in pregnancy.

Citing newly available research, the agency states the risk of low amniotic fluid (known as oligohydramnios) can occur, which in turn can cause rare but serious kidney problems in the offspring. Pregnancy complications also can result.

The FDA action expands on earlier warnings about agents in this drug class, which the FDA previously cautioned about taking after week 30 of pregnancy because of heart-related risks.

Manufacturers of both over-the-counter and prescription NSAIDs – including ibuprofen, naproxen, diclofenac, and celecoxib – will be required to update their labeling with the new warning.

Low-dose (81-mg) aspirin is excluded from this warning.

“Low-dose aspirin may be an important treatment for some women during pregnancy and should be taken under the direction of a healthcare professional,” the agency stated in a news release.

“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, states in the release. “To this end, the agency is using its regulatory authority to inform women and their healthcare providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”

Oligohydramnios can arise quickly – in as little as 2 days – or weeks after starting regular NSAID use in this patient population. The condition usually resolves if a pregnant woman stops taking the NSAID, the agency notes.

If a health care provider believes NSAIDs are necessary between about 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and shortest duration possible, the Drug Safety Communication notes.

As a reminder, health care professionals and patients should report side effects from NSAIDs to the FDA’s MedWatch program.

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

The U.S. Food and Drug Administration released new warnings Oct. 15 that most nonsteroidal anti-inflammatory agents (NSAIDs) carry an elevated risk for kidney complications in unborn children when taken around weeks 20 or later in pregnancy.

Citing newly available research, the agency states the risk of low amniotic fluid (known as oligohydramnios) can occur, which in turn can cause rare but serious kidney problems in the offspring. Pregnancy complications also can result.

The FDA action expands on earlier warnings about agents in this drug class, which the FDA previously cautioned about taking after week 30 of pregnancy because of heart-related risks.

Manufacturers of both over-the-counter and prescription NSAIDs – including ibuprofen, naproxen, diclofenac, and celecoxib – will be required to update their labeling with the new warning.

Low-dose (81-mg) aspirin is excluded from this warning.

“Low-dose aspirin may be an important treatment for some women during pregnancy and should be taken under the direction of a healthcare professional,” the agency stated in a news release.

“It is important that women understand the benefits and risks of the medications they may take over the course of their pregnancy,” Patrizia Cavazzoni, MD, acting director of FDA’s Center for Drug Evaluation and Research, states in the release. “To this end, the agency is using its regulatory authority to inform women and their healthcare providers about the risks if NSAIDs are used after around 20 weeks of pregnancy and beyond.”

Oligohydramnios can arise quickly – in as little as 2 days – or weeks after starting regular NSAID use in this patient population. The condition usually resolves if a pregnant woman stops taking the NSAID, the agency notes.

If a health care provider believes NSAIDs are necessary between about 20 and 30 weeks of pregnancy, use should be limited to the lowest effective dose and shortest duration possible, the Drug Safety Communication notes.

As a reminder, health care professionals and patients should report side effects from NSAIDs to the FDA’s MedWatch program.

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

Upadacitinib (Rinvoq) proved superior to abatacept in both disease activity and remission in rheumatoid arthritis patients yet led to more adverse events, according to a new study that compared the two drugs.

“Additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis,” wrote Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and her colleagues. The study was published in the New England Journal of Medicine.

The Food and Drug Administration approved upadacitinib for the treatment of rheumatoid arthritis in August 2019.

To compare the Janus kinase (JAK) inhibitor upadacitinib and the biologic disease-modifying antirheumatic drug (DMARD) abatacept as safe and effective treatments for RA, the researchers launched a randomized, double-blind, phase 3 clinical trial dubbed SELECT-CHOICE at 120 sites in 28 countries. All patients had moderate to severe active disease after previously having inadequate responses to at least one biologic DMARD. Slightly more than 82% of the participants were female, with a mean age of 55 years and mean RA duration of 12 years.

Patients were assigned either 15 mg of oral upadacitinib daily (n = 303) or intravenous abatacept at day 1 and weeks 2, 4, 8, 12, 16 and 20 (n = 309) with dosage tied to body weight, each in combination with stable synthetic DMARDs. Disease activity was measured after 12 weeks via the Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP). A DAS28-CRP of more than 5.1 was categorized as high disease activity, while 3.2-5.1 meant moderate disease activity, 2.6-3.2 meant low disease activity, and less than 2.6 indicated remission.

The mean DAS28-CRP at baseline was 5.70 in the upadacitinib group and 5.88 in the abatacept group. After 12 weeks, the mean change from baseline was –2.52 points and –2.00 points, respectively (difference, –0.52 points; 95% confidence interval, –0.69 to –0.35; P < .001 for noninferiority; P < .001 for superiority). In patients with a DAS28-CRP of less than 2.6, the percentage of those having remission was 30% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P < .001 for superiority).

Over the 24-week trial period, the incidence of all adverse events (209 vs. 189) and serious adverse events (10 vs. 5) was higher in the upadacitinib group than in the abatacept group. There were 23 cases of hepatic disorder with upadacitinib, compared with 5 with abatacept; 2 thromboembolic events with upadacitinib, compared with 0 with abatacept; and 2 deaths with upadacitinib, compared with 1 with abatacept.

“The thing that bothers me, actually, is the adverse events,” Daniel E. Furst, MD, professor of medicine (emeritus) and rheumatology at the University of California, Los Angeles, said in an interview. “There were a fair number of them, all of which were a little higher in upadacitinib. They certainly made very little of those.”

He noted several other concerns about the study, including a potential geographic effect stemming from 60% of the study’s centers being in South and Central America and Eastern Europe. “Those patients don’t always have very good medical care,” he said. “They have an inherent, underlying placebo response that can be much different than Western Europe and North America.”

He also questioned their choice of primary endpoint metric.

“I think a much more legitimate way at looking at remission is the CDAI [Clinical Disease Activity Index] rather than the DAS28,” he said. “The DAS28, even at its best, is low disease activity, not true remission.”

“Bottom line,” he added, “this is a legitimate study that supports previous findings. One more important thing that is overlooked, though, is an economic analysis. A true economic analysis would be very important to place this in the armamentarium.”
 

Study affirms upadacitinib’s place in the RA treatment pecking order

By showing that upadacitinib was not only noninferior but superior to abatacept in decreasing disease activity, Rubbert-Roth and colleagues have positioned the JAK inhibitor at “the forefront of treatment for rheumatoid arthritis,” wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, in an accompanying editorial.

Though the authors noted that the 24-week trial was likely too short to make meaningful assumptions about long-term outcomes, they recognized the notably improved treatment outcomes over the study period and stated the importance of “head-to-head trials ... to inform evidence-based clinical decisions.” Similar to Dr. Furst, however, they stated an interest in “detailed data on changes in the CDAI score as a continuous measure.”

They also acknowledged the significant increase in adverse events among patients in the upadacitinib group, underlining the need to learn more in forthcoming, lengthier trials. “Rheumatologists will be looking hard at future data,” they wrote, “to assess whether improved treatment outcomes justify an increased risk of adverse events.”

The study was supported by AbbVie. The authors acknowledged numerous potential conflicts of interest, including receiving research grants and fees from various pharmaceutical companies for consulting, lectures, and being on advisory boards.

SOURCE: Rubbert-Roth A et al. N Engl J Med. 2020 Oct 14. doi: 10.1056/NEJMoa2008250.

Upadacitinib (Rinvoq) proved superior to abatacept in both disease activity and remission in rheumatoid arthritis patients yet led to more adverse events, according to a new study that compared the two drugs.

“Additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis,” wrote Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and her colleagues. The study was published in the New England Journal of Medicine.

The Food and Drug Administration approved upadacitinib for the treatment of rheumatoid arthritis in August 2019.

To compare the Janus kinase (JAK) inhibitor upadacitinib and the biologic disease-modifying antirheumatic drug (DMARD) abatacept as safe and effective treatments for RA, the researchers launched a randomized, double-blind, phase 3 clinical trial dubbed SELECT-CHOICE at 120 sites in 28 countries. All patients had moderate to severe active disease after previously having inadequate responses to at least one biologic DMARD. Slightly more than 82% of the participants were female, with a mean age of 55 years and mean RA duration of 12 years.

Patients were assigned either 15 mg of oral upadacitinib daily (n = 303) or intravenous abatacept at day 1 and weeks 2, 4, 8, 12, 16 and 20 (n = 309) with dosage tied to body weight, each in combination with stable synthetic DMARDs. Disease activity was measured after 12 weeks via the Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP). A DAS28-CRP of more than 5.1 was categorized as high disease activity, while 3.2-5.1 meant moderate disease activity, 2.6-3.2 meant low disease activity, and less than 2.6 indicated remission.

The mean DAS28-CRP at baseline was 5.70 in the upadacitinib group and 5.88 in the abatacept group. After 12 weeks, the mean change from baseline was –2.52 points and –2.00 points, respectively (difference, –0.52 points; 95% confidence interval, –0.69 to –0.35; P < .001 for noninferiority; P < .001 for superiority). In patients with a DAS28-CRP of less than 2.6, the percentage of those having remission was 30% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P < .001 for superiority).

Over the 24-week trial period, the incidence of all adverse events (209 vs. 189) and serious adverse events (10 vs. 5) was higher in the upadacitinib group than in the abatacept group. There were 23 cases of hepatic disorder with upadacitinib, compared with 5 with abatacept; 2 thromboembolic events with upadacitinib, compared with 0 with abatacept; and 2 deaths with upadacitinib, compared with 1 with abatacept.

“The thing that bothers me, actually, is the adverse events,” Daniel E. Furst, MD, professor of medicine (emeritus) and rheumatology at the University of California, Los Angeles, said in an interview. “There were a fair number of them, all of which were a little higher in upadacitinib. They certainly made very little of those.”

He noted several other concerns about the study, including a potential geographic effect stemming from 60% of the study’s centers being in South and Central America and Eastern Europe. “Those patients don’t always have very good medical care,” he said. “They have an inherent, underlying placebo response that can be much different than Western Europe and North America.”

He also questioned their choice of primary endpoint metric.

“I think a much more legitimate way at looking at remission is the CDAI [Clinical Disease Activity Index] rather than the DAS28,” he said. “The DAS28, even at its best, is low disease activity, not true remission.”

“Bottom line,” he added, “this is a legitimate study that supports previous findings. One more important thing that is overlooked, though, is an economic analysis. A true economic analysis would be very important to place this in the armamentarium.”
 

Study affirms upadacitinib’s place in the RA treatment pecking order

By showing that upadacitinib was not only noninferior but superior to abatacept in decreasing disease activity, Rubbert-Roth and colleagues have positioned the JAK inhibitor at “the forefront of treatment for rheumatoid arthritis,” wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, in an accompanying editorial.

Though the authors noted that the 24-week trial was likely too short to make meaningful assumptions about long-term outcomes, they recognized the notably improved treatment outcomes over the study period and stated the importance of “head-to-head trials ... to inform evidence-based clinical decisions.” Similar to Dr. Furst, however, they stated an interest in “detailed data on changes in the CDAI score as a continuous measure.”

They also acknowledged the significant increase in adverse events among patients in the upadacitinib group, underlining the need to learn more in forthcoming, lengthier trials. “Rheumatologists will be looking hard at future data,” they wrote, “to assess whether improved treatment outcomes justify an increased risk of adverse events.”

The study was supported by AbbVie. The authors acknowledged numerous potential conflicts of interest, including receiving research grants and fees from various pharmaceutical companies for consulting, lectures, and being on advisory boards.

SOURCE: Rubbert-Roth A et al. N Engl J Med. 2020 Oct 14. doi: 10.1056/NEJMoa2008250.

Upadacitinib (Rinvoq) proved superior to abatacept in both disease activity and remission in rheumatoid arthritis patients yet led to more adverse events, according to a new study that compared the two drugs.

“Additional data from longer and larger trials are needed to better understand long-term outcomes and safety of upadacitinib as compared with other drugs for the treatment of rheumatoid arthritis,” wrote Andrea Rubbert-Roth, MD, of the Cantonal Clinic St. Gallen in St. Gallen, Switzerland, and her colleagues. The study was published in the New England Journal of Medicine.

The Food and Drug Administration approved upadacitinib for the treatment of rheumatoid arthritis in August 2019.

To compare the Janus kinase (JAK) inhibitor upadacitinib and the biologic disease-modifying antirheumatic drug (DMARD) abatacept as safe and effective treatments for RA, the researchers launched a randomized, double-blind, phase 3 clinical trial dubbed SELECT-CHOICE at 120 sites in 28 countries. All patients had moderate to severe active disease after previously having inadequate responses to at least one biologic DMARD. Slightly more than 82% of the participants were female, with a mean age of 55 years and mean RA duration of 12 years.

Patients were assigned either 15 mg of oral upadacitinib daily (n = 303) or intravenous abatacept at day 1 and weeks 2, 4, 8, 12, 16 and 20 (n = 309) with dosage tied to body weight, each in combination with stable synthetic DMARDs. Disease activity was measured after 12 weeks via the Disease Activity Score for 28 joints using C-reactive protein (DAS28-CRP). A DAS28-CRP of more than 5.1 was categorized as high disease activity, while 3.2-5.1 meant moderate disease activity, 2.6-3.2 meant low disease activity, and less than 2.6 indicated remission.

The mean DAS28-CRP at baseline was 5.70 in the upadacitinib group and 5.88 in the abatacept group. After 12 weeks, the mean change from baseline was –2.52 points and –2.00 points, respectively (difference, –0.52 points; 95% confidence interval, –0.69 to –0.35; P < .001 for noninferiority; P < .001 for superiority). In patients with a DAS28-CRP of less than 2.6, the percentage of those having remission was 30% with upadacitinib and 13.3% with abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P < .001 for superiority).

Over the 24-week trial period, the incidence of all adverse events (209 vs. 189) and serious adverse events (10 vs. 5) was higher in the upadacitinib group than in the abatacept group. There were 23 cases of hepatic disorder with upadacitinib, compared with 5 with abatacept; 2 thromboembolic events with upadacitinib, compared with 0 with abatacept; and 2 deaths with upadacitinib, compared with 1 with abatacept.

“The thing that bothers me, actually, is the adverse events,” Daniel E. Furst, MD, professor of medicine (emeritus) and rheumatology at the University of California, Los Angeles, said in an interview. “There were a fair number of them, all of which were a little higher in upadacitinib. They certainly made very little of those.”

He noted several other concerns about the study, including a potential geographic effect stemming from 60% of the study’s centers being in South and Central America and Eastern Europe. “Those patients don’t always have very good medical care,” he said. “They have an inherent, underlying placebo response that can be much different than Western Europe and North America.”

He also questioned their choice of primary endpoint metric.

“I think a much more legitimate way at looking at remission is the CDAI [Clinical Disease Activity Index] rather than the DAS28,” he said. “The DAS28, even at its best, is low disease activity, not true remission.”

“Bottom line,” he added, “this is a legitimate study that supports previous findings. One more important thing that is overlooked, though, is an economic analysis. A true economic analysis would be very important to place this in the armamentarium.”
 

Study affirms upadacitinib’s place in the RA treatment pecking order

By showing that upadacitinib was not only noninferior but superior to abatacept in decreasing disease activity, Rubbert-Roth and colleagues have positioned the JAK inhibitor at “the forefront of treatment for rheumatoid arthritis,” wrote Guro L. Goll, MD, PhD, and Tore K. Kvien, MD, PhD, of Diakonhjemmet Hospital in Oslo, in an accompanying editorial.

Though the authors noted that the 24-week trial was likely too short to make meaningful assumptions about long-term outcomes, they recognized the notably improved treatment outcomes over the study period and stated the importance of “head-to-head trials ... to inform evidence-based clinical decisions.” Similar to Dr. Furst, however, they stated an interest in “detailed data on changes in the CDAI score as a continuous measure.”

They also acknowledged the significant increase in adverse events among patients in the upadacitinib group, underlining the need to learn more in forthcoming, lengthier trials. “Rheumatologists will be looking hard at future data,” they wrote, “to assess whether improved treatment outcomes justify an increased risk of adverse events.”

The study was supported by AbbVie. The authors acknowledged numerous potential conflicts of interest, including receiving research grants and fees from various pharmaceutical companies for consulting, lectures, and being on advisory boards.

SOURCE: Rubbert-Roth A et al. N Engl J Med. 2020 Oct 14. doi: 10.1056/NEJMoa2008250.

Treatment-naive HIV patients had similar rates of treatment failure and virologic failure on standard triple therapy and a variety of dual therapy regimens, based on a meta-analysis including data from more than 5,000 patients.

Although triple therapy remains the standard of care, the availability of more potent drugs has revived interest in dual and mono therapies, wrote Pisaturo Mariantonietta, MD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues.

In a study published in Clinical Microbiology and Infection, the researchers identified 14 articles including 5,205 treatment-naive HIV adults. The studies were published between 2008 and 2020; 13 were randomized, controlled trials.

The dual therapies used in the studies included atazanavir/r plus maraviroc; lopinavir/r plus lamivudine; raltegravir plus darunavir/r; lopinavir/r plus tenofovir, raltegravir, efavirenz, or maraviroc; atazanavir/r plus raltegravir and darunavir/r plus maraviroc; and dolutegravir plus lamivudine.

Overall, no significant differences occurred in the primary endpoint of treatment failure across 10 studies between dual therapy and triple therapy patients based on data at 48 weeks (relative risk 1.20). “The rate of treatment failure did not differ among the two groups when stratifying the patients according to the drug used in the dual regimen,” the researchers said.

Low viral load’s link to treatment failure

Among 2,398 patients with a low HIV viral load (less than 100,000 copies/mL), dual therapy patients were significantly more likely to experience treatment failure than were triple therapy patients (RR, 1.47, P = .007). No differences were noted between dual and triple therapy failure among patients with high HIV viral loads at baseline. Patterns were similar at 96 weeks, but only three studies included 96-week data, the researchers said.

The rate of discontinuation because of adverse events was not significantly different between the groups at 48 weeks.

The study findings were limited by several factors, including the use of different regimens in the dual strategies, some of which are no longer in use, as well as there being insufficient data to fully compare outcomes at 96 weeks, and lack of information on cerebrospinal fluid viral load, the researchers noted.

However, the results suggest that dual therapy might be considered for HIV-naive patients with a low viral load, they said.

“Further RCTs that will evaluate the efficacy of antiretroviral regimens in use today among difficult-to-treat populations, such as patients with high viral load, including both intention-to-treat and per-protocol analysis, are needed to address this topic,” they concluded.

Consider range of patient factors when choosing therapies

Conducting the study at this time was important because of the expanding options for treating HIV patients, Donna E. Sweet, MD, an HIV specialist and professor of medicine at the University of Kansas, Wichita, said in an interview.

“We now have two single tablet formulations that are dual rather than triple therapy, and as treaters we are all trying to know when to use them,” she explained.

Dr. Sweet said she was not surprised by the study findings, given that well-conducted, randomized, controlled trials allowed the combination therapies to be approved.

Some of the key challenges to identifying the optimal treatment for HIV patients include factoring in the use of concomitant medications that could lead to drug-drug interactions, noted Dr. Sweet, who serves an editorial advisory board member of Internal Medicine News.

The take-home message for clinicians, in her opinion, is that “less drugs may mean less toxicity, but we don’t want to sacrifice efficacy,” she said. “There may be patients who are better suited than others for two vs. three drugs,” Dr. Sweet emphasized.

The next steps for research on the value of dual vs. triple therapy should include longer term efficacy studies, especially in those with lower CD4 counts and higher viral loads, said Dr. Sweet. In addition to factors such as CD4 counts and viral load, the food requirements of certain ART regimens could affect adherence and therefore a clinician decision to use two drugs rather than three, she noted.

Dr. Sweet disclosed past relationships with ViiV, Gilead, Merck, and Janssen on their speakers bureaus, and current advisory roles with Gilead and ViiV.

The study received no outside funding. Lead author Dr. Mariantonietta and several coauthors disclosed relationships with companies including ViiV Healthcare, AbbVie, Janssen-Cilag and Gilead Science, and Merck Sharp & Dohme, but no conflicts in connection with this study.

SOURCE: Mariantonietta P et al. Clin Microbiol Infect. 2020 Oct 5. doi: 10.1016/j.cmi.2020.09.048.

Treatment-naive HIV patients had similar rates of treatment failure and virologic failure on standard triple therapy and a variety of dual therapy regimens, based on a meta-analysis including data from more than 5,000 patients.

Although triple therapy remains the standard of care, the availability of more potent drugs has revived interest in dual and mono therapies, wrote Pisaturo Mariantonietta, MD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues.

In a study published in Clinical Microbiology and Infection, the researchers identified 14 articles including 5,205 treatment-naive HIV adults. The studies were published between 2008 and 2020; 13 were randomized, controlled trials.

The dual therapies used in the studies included atazanavir/r plus maraviroc; lopinavir/r plus lamivudine; raltegravir plus darunavir/r; lopinavir/r plus tenofovir, raltegravir, efavirenz, or maraviroc; atazanavir/r plus raltegravir and darunavir/r plus maraviroc; and dolutegravir plus lamivudine.

Overall, no significant differences occurred in the primary endpoint of treatment failure across 10 studies between dual therapy and triple therapy patients based on data at 48 weeks (relative risk 1.20). “The rate of treatment failure did not differ among the two groups when stratifying the patients according to the drug used in the dual regimen,” the researchers said.

Low viral load’s link to treatment failure

Among 2,398 patients with a low HIV viral load (less than 100,000 copies/mL), dual therapy patients were significantly more likely to experience treatment failure than were triple therapy patients (RR, 1.47, P = .007). No differences were noted between dual and triple therapy failure among patients with high HIV viral loads at baseline. Patterns were similar at 96 weeks, but only three studies included 96-week data, the researchers said.

The rate of discontinuation because of adverse events was not significantly different between the groups at 48 weeks.

The study findings were limited by several factors, including the use of different regimens in the dual strategies, some of which are no longer in use, as well as there being insufficient data to fully compare outcomes at 96 weeks, and lack of information on cerebrospinal fluid viral load, the researchers noted.

However, the results suggest that dual therapy might be considered for HIV-naive patients with a low viral load, they said.

“Further RCTs that will evaluate the efficacy of antiretroviral regimens in use today among difficult-to-treat populations, such as patients with high viral load, including both intention-to-treat and per-protocol analysis, are needed to address this topic,” they concluded.

Consider range of patient factors when choosing therapies

Conducting the study at this time was important because of the expanding options for treating HIV patients, Donna E. Sweet, MD, an HIV specialist and professor of medicine at the University of Kansas, Wichita, said in an interview.

“We now have two single tablet formulations that are dual rather than triple therapy, and as treaters we are all trying to know when to use them,” she explained.

Dr. Sweet said she was not surprised by the study findings, given that well-conducted, randomized, controlled trials allowed the combination therapies to be approved.

Some of the key challenges to identifying the optimal treatment for HIV patients include factoring in the use of concomitant medications that could lead to drug-drug interactions, noted Dr. Sweet, who serves an editorial advisory board member of Internal Medicine News.

The take-home message for clinicians, in her opinion, is that “less drugs may mean less toxicity, but we don’t want to sacrifice efficacy,” she said. “There may be patients who are better suited than others for two vs. three drugs,” Dr. Sweet emphasized.

The next steps for research on the value of dual vs. triple therapy should include longer term efficacy studies, especially in those with lower CD4 counts and higher viral loads, said Dr. Sweet. In addition to factors such as CD4 counts and viral load, the food requirements of certain ART regimens could affect adherence and therefore a clinician decision to use two drugs rather than three, she noted.

Dr. Sweet disclosed past relationships with ViiV, Gilead, Merck, and Janssen on their speakers bureaus, and current advisory roles with Gilead and ViiV.

The study received no outside funding. Lead author Dr. Mariantonietta and several coauthors disclosed relationships with companies including ViiV Healthcare, AbbVie, Janssen-Cilag and Gilead Science, and Merck Sharp & Dohme, but no conflicts in connection with this study.

SOURCE: Mariantonietta P et al. Clin Microbiol Infect. 2020 Oct 5. doi: 10.1016/j.cmi.2020.09.048.

Treatment-naive HIV patients had similar rates of treatment failure and virologic failure on standard triple therapy and a variety of dual therapy regimens, based on a meta-analysis including data from more than 5,000 patients.

Although triple therapy remains the standard of care, the availability of more potent drugs has revived interest in dual and mono therapies, wrote Pisaturo Mariantonietta, MD, of the University of Campania Luigi Vanvitelli, Naples, Italy, and colleagues.

In a study published in Clinical Microbiology and Infection, the researchers identified 14 articles including 5,205 treatment-naive HIV adults. The studies were published between 2008 and 2020; 13 were randomized, controlled trials.

The dual therapies used in the studies included atazanavir/r plus maraviroc; lopinavir/r plus lamivudine; raltegravir plus darunavir/r; lopinavir/r plus tenofovir, raltegravir, efavirenz, or maraviroc; atazanavir/r plus raltegravir and darunavir/r plus maraviroc; and dolutegravir plus lamivudine.

Overall, no significant differences occurred in the primary endpoint of treatment failure across 10 studies between dual therapy and triple therapy patients based on data at 48 weeks (relative risk 1.20). “The rate of treatment failure did not differ among the two groups when stratifying the patients according to the drug used in the dual regimen,” the researchers said.

Low viral load’s link to treatment failure

Among 2,398 patients with a low HIV viral load (less than 100,000 copies/mL), dual therapy patients were significantly more likely to experience treatment failure than were triple therapy patients (RR, 1.47, P = .007). No differences were noted between dual and triple therapy failure among patients with high HIV viral loads at baseline. Patterns were similar at 96 weeks, but only three studies included 96-week data, the researchers said.

The rate of discontinuation because of adverse events was not significantly different between the groups at 48 weeks.

The study findings were limited by several factors, including the use of different regimens in the dual strategies, some of which are no longer in use, as well as there being insufficient data to fully compare outcomes at 96 weeks, and lack of information on cerebrospinal fluid viral load, the researchers noted.

However, the results suggest that dual therapy might be considered for HIV-naive patients with a low viral load, they said.

“Further RCTs that will evaluate the efficacy of antiretroviral regimens in use today among difficult-to-treat populations, such as patients with high viral load, including both intention-to-treat and per-protocol analysis, are needed to address this topic,” they concluded.

Consider range of patient factors when choosing therapies

Conducting the study at this time was important because of the expanding options for treating HIV patients, Donna E. Sweet, MD, an HIV specialist and professor of medicine at the University of Kansas, Wichita, said in an interview.

“We now have two single tablet formulations that are dual rather than triple therapy, and as treaters we are all trying to know when to use them,” she explained.

Dr. Sweet said she was not surprised by the study findings, given that well-conducted, randomized, controlled trials allowed the combination therapies to be approved.

Some of the key challenges to identifying the optimal treatment for HIV patients include factoring in the use of concomitant medications that could lead to drug-drug interactions, noted Dr. Sweet, who serves an editorial advisory board member of Internal Medicine News.

The take-home message for clinicians, in her opinion, is that “less drugs may mean less toxicity, but we don’t want to sacrifice efficacy,” she said. “There may be patients who are better suited than others for two vs. three drugs,” Dr. Sweet emphasized.

The next steps for research on the value of dual vs. triple therapy should include longer term efficacy studies, especially in those with lower CD4 counts and higher viral loads, said Dr. Sweet. In addition to factors such as CD4 counts and viral load, the food requirements of certain ART regimens could affect adherence and therefore a clinician decision to use two drugs rather than three, she noted.

Dr. Sweet disclosed past relationships with ViiV, Gilead, Merck, and Janssen on their speakers bureaus, and current advisory roles with Gilead and ViiV.

The study received no outside funding. Lead author Dr. Mariantonietta and several coauthors disclosed relationships with companies including ViiV Healthcare, AbbVie, Janssen-Cilag and Gilead Science, and Merck Sharp & Dohme, but no conflicts in connection with this study.

SOURCE: Mariantonietta P et al. Clin Microbiol Infect. 2020 Oct 5. doi: 10.1016/j.cmi.2020.09.048.

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
 

Cardiovascular disease focus represents a ‘major paradigm shift’

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD call for ‘a different emphasis’

“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.

Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.

“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.

Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
 

‘Clinical inertia’ could be a danger

Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.

Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.

“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.

Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

[email protected]

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
 

Cardiovascular disease focus represents a ‘major paradigm shift’

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD call for ‘a different emphasis’

“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.

Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.

“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.

Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
 

‘Clinical inertia’ could be a danger

Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.

Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.

“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.

Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

[email protected]

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide–1) receptor agonists, they advised.
 

Cardiovascular disease focus represents a ‘major paradigm shift’

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It’s an approach “driven by data from the cardiovascular outcome trials,” that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents “a major paradigm shift,” a “change from a glucose-centric approach to an approach driven by cardiovascular disease events,” summed up Dr. Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC’s 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D “based on cardiovascular disease risk classification,” he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD call for ‘a different emphasis’

“There is a different emphasis” in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Dr. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

“The ADA and EASD recommendations “look primarily at glucose control, with cardiovascular disease management as secondary.” In contrast, the ESC guidelines “are primarily cardiovascular disease risk guidelines, with a glucose interest,” Dr. Grant declared.

Despite his involvement in writing the ESC guidelines, Dr. Grant tilted toward the ADA/EASD statement as more globally relevant.

“There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease,” including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

“It’s important that we’re not glucocentric any more, but it’s equally important that we treat glucose because it has such a benefit for microvascular disease.” Dr. Grant also cited metformin’s long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on “knowing we’re doing it right,” said Dr. Grant.

Dr. Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.
 

‘Clinical inertia’ could be a danger

Dr. Cosentino played down a major disagreement between the two guidelines, suggesting that “focusing on the differences leads to clinical inertia” by the practicing community when they are unsure how to reconcile the two positions.

Dr. Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. “Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs,” metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it’s time to generally steer clear of sulfonylurea drugs. “We have evidence for harmful effects from sulfonylureas,” Dr. Cosentino said.

“I’d dump sulfonylureas,” was Dr. Grant’s assessment, but he added that they still have a role for patients who need additional glycemic control but can’t afford the newer drugs.

Dr. Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Dr. Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

[email protected]

A final report from the multinational placebo-controlled ACTT-1 trial confirms that remdesivir is effective and well tolerated for shortening the time to recovery from COVID-19 infection.

In May 2020, remdesivir received Food and Drug Administration approval for emergency treatment of severe COVID-19 on the basis of a preliminary report on this trial. In August 2020, the FDA expanded the indication to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection irrespective of severity.

“Our findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19,” reported a team of investigators led by John H. Beigel, MD, of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, in the New England Journal of Medicine.

The drug’s broadened indication was not based on the ACTT-1 trial, according to Dr. Beigel. “Other data have demonstrated that remdesivir shortens recovery in patients with lower acuity. In our study, evidence of pneumonia was an enrollment requirement,” he explained in an interview.

In the newly published final ACTT-1 data, the median time to recovery was 10 days for those on active therapy versus 15 days for those randomized to placebo. With a rate ratio of 1.29 (P less than .001), this translated to a recovery that was about one third faster.

In this final report, remdesivir’s significant advantage over placebo regarding the trial’s primary endpoint was reinforced by efficacy on multiple secondary endpoints.

This benefits on multiple secondary endpoints included a 50% greater odds ratio (OR, 1.5; 95% CI, 1.2-1.9) of significant clinical improvement by day 15 after adjustment for baseline severity, a shorter initial length of hospital stay (12 vs. 17 days) and fewer days on oxygen supplementation (13 vs. 21 days) for the subgroup of patients on oxygen at enrollment.

Although the numerically lower mortality in the remdesivir arm (6.75 vs. 11.9%) did not reach statistical significance, Dr. Beigel said, “mortality was moving in the same direction as the other key endpoints.”

According to the study investigators, the types of rates of adverse events on remdesivir, which inhibits viral replication, “were generally similar in the remdesivir and placebo groups.”

In ACTT-1, 1,062 patients were randomized to remdesivir (200 mg loading dose followed by 100 mg daily for up to 9 days) or placebo. Patients were enrolled at study sites in North America, Europe, and Asia.

The data of ACTT-1 confirm a benefit from remdesivir in hospitalized COVID-19 patients with severe disease, but Dr. Beigel said he agrees with the current FDA indication that supports treatment in any hospitalized COVID-19 patient.

“We saw bigger benefits in patients with more severe infections. The benefits are not as large in patients with mild disease, but I think remdesivir should be considered in any hospitalized patient,” Dr. Beigel said.

This point of view is shared.

“I would give this drug to anyone in the hospital infected with COVID-19 assuming there was an ample supply and no need for rationing,” said Donna E. Sweet, MD, professor of internal medicine, University of Kansas, Wichita. She noted that this study has implications for hospital and hospital staff, as well as for patients.

“This type of reduction in recovery time means a reduction in potential exposures to hospital staff, a reduced need for PPE [personal protective equipment], and it will free up beds in the ICU [intensive care unit],” said Dr. Sweet, who also serves as an editorial advisory board member for Internal Medicine News.

An infectious disease specialist at the University of Minnesota also considers remdesivir to have an important role for conserving resources that deserves emphasis.

The reduction in time to recovery “is of benefit to the health system by maintaining hospital bed capacity,” said David R. Boulware, MD, professor of medicine at the University of Minnesota, Minneapolis.

According to his reading of the available data, including those from ACTT-1, the benefit appears to be greatest in those with a moderate degree of illness, which he defined as “sick enough to be hospitalized and require oxygen, yet not severely sick [and] requiring a ventilator or [extracorporeal membrane oxygenation].”

This does not preclude a benefit in those with more severe or milder disease, but patients with mild disease “are likely to recover regardless – or despite – whatever therapy they receive,” he said.

Dr. Beigel, the principal investigator of this trial, reports no potential conflicts of interest.

SOURCE: Beigel JH et al. N Engl J Med. 2020 Oct 8. doi: 10.1056/NEJMoa2007764.

A final report from the multinational placebo-controlled ACTT-1 trial confirms that remdesivir is effective and well tolerated for shortening the time to recovery from COVID-19 infection.

In May 2020, remdesivir received Food and Drug Administration approval for emergency treatment of severe COVID-19 on the basis of a preliminary report on this trial. In August 2020, the FDA expanded the indication to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection irrespective of severity.

“Our findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19,” reported a team of investigators led by John H. Beigel, MD, of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, in the New England Journal of Medicine.

The drug’s broadened indication was not based on the ACTT-1 trial, according to Dr. Beigel. “Other data have demonstrated that remdesivir shortens recovery in patients with lower acuity. In our study, evidence of pneumonia was an enrollment requirement,” he explained in an interview.

In the newly published final ACTT-1 data, the median time to recovery was 10 days for those on active therapy versus 15 days for those randomized to placebo. With a rate ratio of 1.29 (P less than .001), this translated to a recovery that was about one third faster.

In this final report, remdesivir’s significant advantage over placebo regarding the trial’s primary endpoint was reinforced by efficacy on multiple secondary endpoints.

This benefits on multiple secondary endpoints included a 50% greater odds ratio (OR, 1.5; 95% CI, 1.2-1.9) of significant clinical improvement by day 15 after adjustment for baseline severity, a shorter initial length of hospital stay (12 vs. 17 days) and fewer days on oxygen supplementation (13 vs. 21 days) for the subgroup of patients on oxygen at enrollment.

Although the numerically lower mortality in the remdesivir arm (6.75 vs. 11.9%) did not reach statistical significance, Dr. Beigel said, “mortality was moving in the same direction as the other key endpoints.”

According to the study investigators, the types of rates of adverse events on remdesivir, which inhibits viral replication, “were generally similar in the remdesivir and placebo groups.”

In ACTT-1, 1,062 patients were randomized to remdesivir (200 mg loading dose followed by 100 mg daily for up to 9 days) or placebo. Patients were enrolled at study sites in North America, Europe, and Asia.

The data of ACTT-1 confirm a benefit from remdesivir in hospitalized COVID-19 patients with severe disease, but Dr. Beigel said he agrees with the current FDA indication that supports treatment in any hospitalized COVID-19 patient.

“We saw bigger benefits in patients with more severe infections. The benefits are not as large in patients with mild disease, but I think remdesivir should be considered in any hospitalized patient,” Dr. Beigel said.

This point of view is shared.

“I would give this drug to anyone in the hospital infected with COVID-19 assuming there was an ample supply and no need for rationing,” said Donna E. Sweet, MD, professor of internal medicine, University of Kansas, Wichita. She noted that this study has implications for hospital and hospital staff, as well as for patients.

“This type of reduction in recovery time means a reduction in potential exposures to hospital staff, a reduced need for PPE [personal protective equipment], and it will free up beds in the ICU [intensive care unit],” said Dr. Sweet, who also serves as an editorial advisory board member for Internal Medicine News.

An infectious disease specialist at the University of Minnesota also considers remdesivir to have an important role for conserving resources that deserves emphasis.

The reduction in time to recovery “is of benefit to the health system by maintaining hospital bed capacity,” said David R. Boulware, MD, professor of medicine at the University of Minnesota, Minneapolis.

According to his reading of the available data, including those from ACTT-1, the benefit appears to be greatest in those with a moderate degree of illness, which he defined as “sick enough to be hospitalized and require oxygen, yet not severely sick [and] requiring a ventilator or [extracorporeal membrane oxygenation].”

This does not preclude a benefit in those with more severe or milder disease, but patients with mild disease “are likely to recover regardless – or despite – whatever therapy they receive,” he said.

Dr. Beigel, the principal investigator of this trial, reports no potential conflicts of interest.

SOURCE: Beigel JH et al. N Engl J Med. 2020 Oct 8. doi: 10.1056/NEJMoa2007764.

A final report from the multinational placebo-controlled ACTT-1 trial confirms that remdesivir is effective and well tolerated for shortening the time to recovery from COVID-19 infection.

In May 2020, remdesivir received Food and Drug Administration approval for emergency treatment of severe COVID-19 on the basis of a preliminary report on this trial. In August 2020, the FDA expanded the indication to include all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 infection irrespective of severity.

“Our findings were consistent with the findings of the preliminary report: a 10-day course of remdesivir was superior to placebo in the treatment of hospitalized patients with COVID-19,” reported a team of investigators led by John H. Beigel, MD, of the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, in the New England Journal of Medicine.

The drug’s broadened indication was not based on the ACTT-1 trial, according to Dr. Beigel. “Other data have demonstrated that remdesivir shortens recovery in patients with lower acuity. In our study, evidence of pneumonia was an enrollment requirement,” he explained in an interview.

In the newly published final ACTT-1 data, the median time to recovery was 10 days for those on active therapy versus 15 days for those randomized to placebo. With a rate ratio of 1.29 (P less than .001), this translated to a recovery that was about one third faster.

In this final report, remdesivir’s significant advantage over placebo regarding the trial’s primary endpoint was reinforced by efficacy on multiple secondary endpoints.

This benefits on multiple secondary endpoints included a 50% greater odds ratio (OR, 1.5; 95% CI, 1.2-1.9) of significant clinical improvement by day 15 after adjustment for baseline severity, a shorter initial length of hospital stay (12 vs. 17 days) and fewer days on oxygen supplementation (13 vs. 21 days) for the subgroup of patients on oxygen at enrollment.

Although the numerically lower mortality in the remdesivir arm (6.75 vs. 11.9%) did not reach statistical significance, Dr. Beigel said, “mortality was moving in the same direction as the other key endpoints.”

According to the study investigators, the types of rates of adverse events on remdesivir, which inhibits viral replication, “were generally similar in the remdesivir and placebo groups.”

In ACTT-1, 1,062 patients were randomized to remdesivir (200 mg loading dose followed by 100 mg daily for up to 9 days) or placebo. Patients were enrolled at study sites in North America, Europe, and Asia.

The data of ACTT-1 confirm a benefit from remdesivir in hospitalized COVID-19 patients with severe disease, but Dr. Beigel said he agrees with the current FDA indication that supports treatment in any hospitalized COVID-19 patient.

“We saw bigger benefits in patients with more severe infections. The benefits are not as large in patients with mild disease, but I think remdesivir should be considered in any hospitalized patient,” Dr. Beigel said.

This point of view is shared.

“I would give this drug to anyone in the hospital infected with COVID-19 assuming there was an ample supply and no need for rationing,” said Donna E. Sweet, MD, professor of internal medicine, University of Kansas, Wichita. She noted that this study has implications for hospital and hospital staff, as well as for patients.

“This type of reduction in recovery time means a reduction in potential exposures to hospital staff, a reduced need for PPE [personal protective equipment], and it will free up beds in the ICU [intensive care unit],” said Dr. Sweet, who also serves as an editorial advisory board member for Internal Medicine News.

An infectious disease specialist at the University of Minnesota also considers remdesivir to have an important role for conserving resources that deserves emphasis.

The reduction in time to recovery “is of benefit to the health system by maintaining hospital bed capacity,” said David R. Boulware, MD, professor of medicine at the University of Minnesota, Minneapolis.

According to his reading of the available data, including those from ACTT-1, the benefit appears to be greatest in those with a moderate degree of illness, which he defined as “sick enough to be hospitalized and require oxygen, yet not severely sick [and] requiring a ventilator or [extracorporeal membrane oxygenation].”

This does not preclude a benefit in those with more severe or milder disease, but patients with mild disease “are likely to recover regardless – or despite – whatever therapy they receive,” he said.

Dr. Beigel, the principal investigator of this trial, reports no potential conflicts of interest.

SOURCE: Beigel JH et al. N Engl J Med. 2020 Oct 8. doi: 10.1056/NEJMoa2007764.