Journal of Clinical Outcomes Management

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

[email protected]

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

[email protected]

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

No specific treatment is currently available for human coronaviruses to date, but numerous antiviral agents are being identified through a variety of approaches, according to Thanigaimalai Pillaiyar, PhD, and colleagues in a review published in Drug Discovery Today.

Using the six previously discovered human coronaviruses – human CoV 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1); severe acute respiratory syndrome (SARS) CoV; and Middle East respiratory syndrome (MERS) CoV – the investigators examined progress in the use and development of therapeutic drugs, focusing on the potential roles of virus inhibitors.

“Research has mainly been focused on SARS- and MERS-CoV infections, because they were responsible for severe illness when compared with other CoVs,” Dr. Pillaiyar, of the department of pharmaceutical and medicinal chemistry at the University of Bonn (Germany), and colleagues wrote.

2019-nCov has been linked genomically as most closely related to SARS, and the Coronavirus Study Group of the International Committee on Virus Taxonomy, which has the responsibility for naming viruses, has designated the new virus SARS-CoV-2.
 

Examining extant drugs

The first approach to identifying possible antiviral agents reevaluates known, broadly acting antiviral drugs that have been used for other viral infections or other indications. The initial research into coronavirus therapeutics, in particular, has examined current antiviral therapeutics for their effectiveness against both SARS-CoV and MERS-CoV, but with mixed results.

For example, in a search of potential antiviral agents against CoVs, researchers identified four drugs – chloroquine, chlorpromazine, loperamide, and lopinavir – by screening drug libraries approved by the Food and Drug Administration. They were all able to inhibit the replication of MERS-CoV, SARS-CoV, and HCoV-229E in the low-micromolar range, which suggested that they could be used for broad-spectrum antiviral activity, according to Dr. Pillaiyar and colleagues.

Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach, which included a number of broad-spectrum inhibitors of HCoVs (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) that showed strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations and suppressed the replication of all CoVs in a dose-dependent manner. Findings from in vivo studies showed lycorine protected mice against lethal HCoV-OC43 infection.

Along with the aforementioned drugs, a number of others have also shown potential usefulness, but, as yet, none has been validated for use in humans.
 

Developing new antivirals

The second approach for anti-CoV drug discovery involves the development of new therapeutics based on the genomic and biophysical understanding of the individual CoV in order to interfere with the virus itself or to disrupt its direct metabolic requirements. This can take several approaches.

MERS-CoV and SARS-CoV PL protease inhibitors

Of particular interest are antiviral therapies that attack papain-like protease, which is an important target because it is a multifunctional protein involved in proteolytic deubiquitination and viral evasion of the innate immune response. One such potential therapeutic that takes advantage of this target is disulfiram, an FDA-approved drug for use in alcohol-aversion therapy. Disulfiram has been reported as an allosteric inhibitor of MERS-CoV papain-like protease. Numerous other drug categories are being examined, with promising results in targeting the papain-like protease enzymes of both SARS and MERS.

Replicase inhibitors

Helicase (nsP13) protein is a crucial component required for virus replication in host cells and could serve as a feasible target for anti-MERS and anti-SARS chemical therapies, the review authors wrote, citing as an example, the recent development of a small 1,2,4-triazole derivative that inhibited the viral NTPase/helicase of SARS- and MERS-CoVs and demonstrated high antiviral activity and low cytotoxicity.

Membrane-bound viral RNA synthesis inhibitors

Antiviral agents that target membrane-bound coronaviral RNA synthesis represent a novel and attractive approach, according to Dr. Pillaiyar and colleagues. And recently, an inhibitor was developed that targets membrane-bound coronaviral RNA synthesis and “showed potent antiviral activity of MERS-CoV infection with remarkable efficacy.”

Host-based, anti-CoV treatment options

An alternate therapeutic tactic is to bolster host defenses or to modify host susceptibilities to prevent virus infection or replication. The innate interferon response of the host is crucial for the control of viral replication after infection, and the addition of exogenous recombinant interferon or use of drugs to stimulate the normal host interferon response are both potential therapeutic avenues. For example, nitazoxanide is a potent type I interferon inducer that has been used in humans for parasitic infections, and a synthetic nitrothiazolyl-salicylamide derivative was found to exhibit broad-spectrum antiviral activities against RNA and DNA viruses, including some coronaviruses.

Numerous other host pathways are being investigated as potential areas to enhance defense against infection and replication, for example, using inhibitors to block nucleic acid synthesis has been shown to provide broad-spectrum activity against SARS-CoV and MERS-CoV.

One particular example is remdesivir, a novel nucleotide analog antiviral drug, that was developed as a therapy for Ebola virus disease and Marburg virus infections. It was later shown to provide “reasonable antiviral activity against more distantly related viruses, such as respiratory syncytial virus, Junin virus, Lassa fever virus, and MERS-CoV,” the authors wrote.

Also of interest regarding remdesivir’s potential broad-spectrum use is that it has shown potent in vitro “antiviral activity against Malaysian and Bangladesh genotypes of Nipah virus (an RNA virus, although not a coronavirus, that infects both humans and animals) and reduced replication of Malaysian Nipah virus in primary human lung microvascular endothelial cells by more than four orders of magnitude,” Dr. Pillaiyar and colleagues added. Of particular note, all remdesivir-treated, Nipah virus–infected animals “survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment.”

In a press briefing earlier this month, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, reported that a randomized, controlled, phase 3 trial of the antiviral drug remdesivir is currently underway in China to establish whether the drug would be an effective and safe treatment for adults patients with mild or moderate 2019 Novel Coronavirus (2019-nCoV) disease.

“Our increasing understanding of novel emerging coronaviruses will be accompanied by increasing opportunities for the reasonable design of therapeutics. Importantly, understanding this basic information about CoV protease targets will not only aid the public health against SARS-CoV and MERS-CoV but also help in advance to target new coronaviruses that might emerge in the future,” the authors concluded.

Dr. Pillaiyar and colleagues reported that they had no financial conflicts of interest.

[email protected]

SOURCE: Pillaiyar T et al. Drug Discov Today. 2020 Jan 30. doi: 10.1016/j.drudis.2020.01.015.

SNOWMASS, COLO. – If ever there was a major chronic disease that’s teed up and ready to be stamped into submission through diligent application of preventive medicine, it’s the epidemic of heart failure.

Bruce Jancin/MDedge News

“The best way to treat heart failure is to prevent it in the first place. There will be more than 1 million new cases of heart failure this year, and the vast majority of them could have been prevented,” Gregg C. Fonarow, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Using firmly evidence-based, guideline-directed therapies, it’s often possible to prevent patients at high risk for developing heart failure (HF) from actually doing so. Or, in the terminology of the ACC/American Heart Association heart failure guidelines coauthored by Dr. Fonarow, the goal is to keep patients who are stage A – that is, pre-HF but at high risk because of hypertension, coronary artery disease, diabetes, family history of cardiomyopathy, or other reasons – from progressing to stage B, marked by asymptomatic left ventricular dysfunction, a prior MI, or asymptomatic valvular disease; and blocking those who are stage B from then moving on to stage C, the classic symptomatic form of HF; and thence to end-stage stage D disease.

Heart failure is an enormous public health problem, and one of the most expensive of all diseases. The prognostic impact of newly diagnosed HF is profound, with 10-15 years of life lost, compared with the general population. Even today, roughly one in five newly diagnosed patients won’t survive for a year, and the 5-year mortality is about 50%, said Dr. Fonarow, who is professor of cardiovascular medicine and chief of the division of cardiology at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center, also in Los Angeles.

Symptomatic stage C is “the tip of the iceberg,” the cardiologist stressed. Vastly more patients are in stages A and B. In order to keep them from progressing to stage C, it’s first necessary to identify them. That’s why the 2013 guidelines give a class IC recommendation for periodic evaluation for signs and symptoms of HF in patients who are at high risk, and for a noninvasive assessment of left ventricular ejection fraction in those with a strong family history of cardiomyopathy or who are on cardiotoxic drugs (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-239).

The two biggest risk factors for the development of symptomatic stage C HF are hypertension and atherosclerotic cardiovascular disease. Close to 80% of patients presenting with heart failure have prevalent hypertension, and a history of ischemic heart disease is nearly as common.

Other major modifiable risk factors are diabetes, overweight and obesity, metabolic syndrome, dyslipidemia, smoking, valvular heart disease, and chronic kidney disease.
 

Hypertension

Most patients with high blood pressure believe they’re on antihypertensive medication to prevent MI and stroke, but in reality the largest benefit is what Dr. Fonarow termed the “phenomenal” reduction in the risk of developing HF, which amounted to a 52% relative risk reduction in one meta-analysis of older randomized trials. In the contemporary era, the landmark SPRINT trial of close to 10,000 randomized hypertensive patients showed that more-intensive blood pressure lowering to a target systolic BP of less than 120 mm Hg resulted in a 38% reduction in the risk of new-onset HF, compared with standard treatment to a target of less than 140 mm Hg. That’s why the 2017 focused update of the HF guidelines gives a strong class IB recommendation for a target blood pressure of less than 130/80 mm Hg in hypertensive patients with stage A HF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803).

Atherosclerotic cardiovascular disease

Within 6 years after diagnosis of an MI, 22% of men and 46% of women will develop symptomatic heart failure. Intensive statin therapy gets a strong recommendation post MI in the guidelines, not only because in a meta-analysis of four major randomized trials it resulted in a further 64% reduction in the risk of coronary death or recurrent MI, compared with moderate statin therapy, but also because of the 27% relative risk reduction in new-onset HF. ACE inhibitors get a class IA recommendation for prevention of symptomatic HF in patients who are stage A with a history of atherosclerotic disease, diabetes, or hypertension. Angiotensin receptor blockers get a class IC recommendation.

Diabetes

Diabetes markedly increases the risk of developing HF: by two to four times overall and by four to eight times in younger diabetes patients. The two chronic diseases are highly comorbid, with roughly 45% of patients with HF also having diabetes. Moreover, diabetes in HF patients is associated with a substantially worse prognosis, even when standard HF therapies are applied.

Choices regarding glycemic management can markedly affect HF risk and outcomes. Randomized trials show that the peroxisome proliferator-activated receptor agonists double the risk of HF. The glucagonlike peptide–1 receptor agonists are absolutely neutral with regard to HF outcomes. Similarly, the dipeptidyl peptidase–4 inhibitors have no impact on the risks of major adverse cardiovascular events or HF. Intensive glycemic control has no impact on the risk of new-onset HF. Insulin therapy, too, is neutral on this score.

“Depressingly, even lifestyle modification with weight loss, once you have type 2 diabetes, does not lower the risk,” Dr. Fonarow continued.

In contrast, the sodium-glucose transporter 2 (SGLT2) inhibitors have impressive cardiovascular and renal protective benefits in patients with type 2 diabetes, as demonstrated in a meta-analysis of more than 34,000 participants in the randomized trials of empagliflozin (Jardiance) in EMPA-REG OUTCOME, canagliflozin (Invokana) in CANVAS/CANVAS-R, and dapagliflozin (Farxiga) in DECLARE-TIMI 58. The SGLT2 inhibitors collectively reduced the risk of HF hospitalization by 21% in participants with no baseline history of the disease and by 29% in those with a history of HF. Moreover, the risk of progression of renal disease was reduced by 45% (Lancet. 2019 Jan 5;393[10166]:31-9).

More recently, the landmark DAPA-HF trial established SGLT2 inhibitor therapy as part of standard-of-care, guideline-directed medical therapy for patients with HF with reduced ejection fraction regardless of whether they have comorbid type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

These are remarkable medications, generally very well tolerated, and it’s critical that cardiologists get on board in prescribing them, Dr. Fonarow emphasized. He alerted his colleagues to what he called an “incredibly helpful” review article that provides practical guidance for cardiologists in how to start using the SGLT2 inhibitors (JACC Heart Fail. 2019 Feb;7[2]:169-72).

“It’s pretty straightforward,” according to Dr. Fonarow. “If you’re comfortable enough in using ACE inhibitors, angiotensin receptor blockers, and beta-blockers, I think you’ll find these medications fit similarly when you actually get experience in utilizing them.”

He reported serving as a consultant to 10 pharmaceutical or medical device companies.

[email protected]

SNOWMASS, COLO. – If ever there was a major chronic disease that’s teed up and ready to be stamped into submission through diligent application of preventive medicine, it’s the epidemic of heart failure.

Bruce Jancin/MDedge News

“The best way to treat heart failure is to prevent it in the first place. There will be more than 1 million new cases of heart failure this year, and the vast majority of them could have been prevented,” Gregg C. Fonarow, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Using firmly evidence-based, guideline-directed therapies, it’s often possible to prevent patients at high risk for developing heart failure (HF) from actually doing so. Or, in the terminology of the ACC/American Heart Association heart failure guidelines coauthored by Dr. Fonarow, the goal is to keep patients who are stage A – that is, pre-HF but at high risk because of hypertension, coronary artery disease, diabetes, family history of cardiomyopathy, or other reasons – from progressing to stage B, marked by asymptomatic left ventricular dysfunction, a prior MI, or asymptomatic valvular disease; and blocking those who are stage B from then moving on to stage C, the classic symptomatic form of HF; and thence to end-stage stage D disease.

Heart failure is an enormous public health problem, and one of the most expensive of all diseases. The prognostic impact of newly diagnosed HF is profound, with 10-15 years of life lost, compared with the general population. Even today, roughly one in five newly diagnosed patients won’t survive for a year, and the 5-year mortality is about 50%, said Dr. Fonarow, who is professor of cardiovascular medicine and chief of the division of cardiology at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center, also in Los Angeles.

Symptomatic stage C is “the tip of the iceberg,” the cardiologist stressed. Vastly more patients are in stages A and B. In order to keep them from progressing to stage C, it’s first necessary to identify them. That’s why the 2013 guidelines give a class IC recommendation for periodic evaluation for signs and symptoms of HF in patients who are at high risk, and for a noninvasive assessment of left ventricular ejection fraction in those with a strong family history of cardiomyopathy or who are on cardiotoxic drugs (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-239).

The two biggest risk factors for the development of symptomatic stage C HF are hypertension and atherosclerotic cardiovascular disease. Close to 80% of patients presenting with heart failure have prevalent hypertension, and a history of ischemic heart disease is nearly as common.

Other major modifiable risk factors are diabetes, overweight and obesity, metabolic syndrome, dyslipidemia, smoking, valvular heart disease, and chronic kidney disease.
 

Hypertension

Most patients with high blood pressure believe they’re on antihypertensive medication to prevent MI and stroke, but in reality the largest benefit is what Dr. Fonarow termed the “phenomenal” reduction in the risk of developing HF, which amounted to a 52% relative risk reduction in one meta-analysis of older randomized trials. In the contemporary era, the landmark SPRINT trial of close to 10,000 randomized hypertensive patients showed that more-intensive blood pressure lowering to a target systolic BP of less than 120 mm Hg resulted in a 38% reduction in the risk of new-onset HF, compared with standard treatment to a target of less than 140 mm Hg. That’s why the 2017 focused update of the HF guidelines gives a strong class IB recommendation for a target blood pressure of less than 130/80 mm Hg in hypertensive patients with stage A HF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803).

Atherosclerotic cardiovascular disease

Within 6 years after diagnosis of an MI, 22% of men and 46% of women will develop symptomatic heart failure. Intensive statin therapy gets a strong recommendation post MI in the guidelines, not only because in a meta-analysis of four major randomized trials it resulted in a further 64% reduction in the risk of coronary death or recurrent MI, compared with moderate statin therapy, but also because of the 27% relative risk reduction in new-onset HF. ACE inhibitors get a class IA recommendation for prevention of symptomatic HF in patients who are stage A with a history of atherosclerotic disease, diabetes, or hypertension. Angiotensin receptor blockers get a class IC recommendation.

Diabetes

Diabetes markedly increases the risk of developing HF: by two to four times overall and by four to eight times in younger diabetes patients. The two chronic diseases are highly comorbid, with roughly 45% of patients with HF also having diabetes. Moreover, diabetes in HF patients is associated with a substantially worse prognosis, even when standard HF therapies are applied.

Choices regarding glycemic management can markedly affect HF risk and outcomes. Randomized trials show that the peroxisome proliferator-activated receptor agonists double the risk of HF. The glucagonlike peptide–1 receptor agonists are absolutely neutral with regard to HF outcomes. Similarly, the dipeptidyl peptidase–4 inhibitors have no impact on the risks of major adverse cardiovascular events or HF. Intensive glycemic control has no impact on the risk of new-onset HF. Insulin therapy, too, is neutral on this score.

“Depressingly, even lifestyle modification with weight loss, once you have type 2 diabetes, does not lower the risk,” Dr. Fonarow continued.

In contrast, the sodium-glucose transporter 2 (SGLT2) inhibitors have impressive cardiovascular and renal protective benefits in patients with type 2 diabetes, as demonstrated in a meta-analysis of more than 34,000 participants in the randomized trials of empagliflozin (Jardiance) in EMPA-REG OUTCOME, canagliflozin (Invokana) in CANVAS/CANVAS-R, and dapagliflozin (Farxiga) in DECLARE-TIMI 58. The SGLT2 inhibitors collectively reduced the risk of HF hospitalization by 21% in participants with no baseline history of the disease and by 29% in those with a history of HF. Moreover, the risk of progression of renal disease was reduced by 45% (Lancet. 2019 Jan 5;393[10166]:31-9).

More recently, the landmark DAPA-HF trial established SGLT2 inhibitor therapy as part of standard-of-care, guideline-directed medical therapy for patients with HF with reduced ejection fraction regardless of whether they have comorbid type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

These are remarkable medications, generally very well tolerated, and it’s critical that cardiologists get on board in prescribing them, Dr. Fonarow emphasized. He alerted his colleagues to what he called an “incredibly helpful” review article that provides practical guidance for cardiologists in how to start using the SGLT2 inhibitors (JACC Heart Fail. 2019 Feb;7[2]:169-72).

“It’s pretty straightforward,” according to Dr. Fonarow. “If you’re comfortable enough in using ACE inhibitors, angiotensin receptor blockers, and beta-blockers, I think you’ll find these medications fit similarly when you actually get experience in utilizing them.”

He reported serving as a consultant to 10 pharmaceutical or medical device companies.

[email protected]

SNOWMASS, COLO. – If ever there was a major chronic disease that’s teed up and ready to be stamped into submission through diligent application of preventive medicine, it’s the epidemic of heart failure.

Bruce Jancin/MDedge News

“The best way to treat heart failure is to prevent it in the first place. There will be more than 1 million new cases of heart failure this year, and the vast majority of them could have been prevented,” Gregg C. Fonarow, MD, asserted at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Using firmly evidence-based, guideline-directed therapies, it’s often possible to prevent patients at high risk for developing heart failure (HF) from actually doing so. Or, in the terminology of the ACC/American Heart Association heart failure guidelines coauthored by Dr. Fonarow, the goal is to keep patients who are stage A – that is, pre-HF but at high risk because of hypertension, coronary artery disease, diabetes, family history of cardiomyopathy, or other reasons – from progressing to stage B, marked by asymptomatic left ventricular dysfunction, a prior MI, or asymptomatic valvular disease; and blocking those who are stage B from then moving on to stage C, the classic symptomatic form of HF; and thence to end-stage stage D disease.

Heart failure is an enormous public health problem, and one of the most expensive of all diseases. The prognostic impact of newly diagnosed HF is profound, with 10-15 years of life lost, compared with the general population. Even today, roughly one in five newly diagnosed patients won’t survive for a year, and the 5-year mortality is about 50%, said Dr. Fonarow, who is professor of cardiovascular medicine and chief of the division of cardiology at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center, also in Los Angeles.

Symptomatic stage C is “the tip of the iceberg,” the cardiologist stressed. Vastly more patients are in stages A and B. In order to keep them from progressing to stage C, it’s first necessary to identify them. That’s why the 2013 guidelines give a class IC recommendation for periodic evaluation for signs and symptoms of HF in patients who are at high risk, and for a noninvasive assessment of left ventricular ejection fraction in those with a strong family history of cardiomyopathy or who are on cardiotoxic drugs (J Am Coll Cardiol. 2013 Oct 15;62[16]:e147-239).

The two biggest risk factors for the development of symptomatic stage C HF are hypertension and atherosclerotic cardiovascular disease. Close to 80% of patients presenting with heart failure have prevalent hypertension, and a history of ischemic heart disease is nearly as common.

Other major modifiable risk factors are diabetes, overweight and obesity, metabolic syndrome, dyslipidemia, smoking, valvular heart disease, and chronic kidney disease.
 

Hypertension

Most patients with high blood pressure believe they’re on antihypertensive medication to prevent MI and stroke, but in reality the largest benefit is what Dr. Fonarow termed the “phenomenal” reduction in the risk of developing HF, which amounted to a 52% relative risk reduction in one meta-analysis of older randomized trials. In the contemporary era, the landmark SPRINT trial of close to 10,000 randomized hypertensive patients showed that more-intensive blood pressure lowering to a target systolic BP of less than 120 mm Hg resulted in a 38% reduction in the risk of new-onset HF, compared with standard treatment to a target of less than 140 mm Hg. That’s why the 2017 focused update of the HF guidelines gives a strong class IB recommendation for a target blood pressure of less than 130/80 mm Hg in hypertensive patients with stage A HF (J Am Coll Cardiol. 2017 Aug 8;70[6]:776-803).

Atherosclerotic cardiovascular disease

Within 6 years after diagnosis of an MI, 22% of men and 46% of women will develop symptomatic heart failure. Intensive statin therapy gets a strong recommendation post MI in the guidelines, not only because in a meta-analysis of four major randomized trials it resulted in a further 64% reduction in the risk of coronary death or recurrent MI, compared with moderate statin therapy, but also because of the 27% relative risk reduction in new-onset HF. ACE inhibitors get a class IA recommendation for prevention of symptomatic HF in patients who are stage A with a history of atherosclerotic disease, diabetes, or hypertension. Angiotensin receptor blockers get a class IC recommendation.

Diabetes

Diabetes markedly increases the risk of developing HF: by two to four times overall and by four to eight times in younger diabetes patients. The two chronic diseases are highly comorbid, with roughly 45% of patients with HF also having diabetes. Moreover, diabetes in HF patients is associated with a substantially worse prognosis, even when standard HF therapies are applied.

Choices regarding glycemic management can markedly affect HF risk and outcomes. Randomized trials show that the peroxisome proliferator-activated receptor agonists double the risk of HF. The glucagonlike peptide–1 receptor agonists are absolutely neutral with regard to HF outcomes. Similarly, the dipeptidyl peptidase–4 inhibitors have no impact on the risks of major adverse cardiovascular events or HF. Intensive glycemic control has no impact on the risk of new-onset HF. Insulin therapy, too, is neutral on this score.

“Depressingly, even lifestyle modification with weight loss, once you have type 2 diabetes, does not lower the risk,” Dr. Fonarow continued.

In contrast, the sodium-glucose transporter 2 (SGLT2) inhibitors have impressive cardiovascular and renal protective benefits in patients with type 2 diabetes, as demonstrated in a meta-analysis of more than 34,000 participants in the randomized trials of empagliflozin (Jardiance) in EMPA-REG OUTCOME, canagliflozin (Invokana) in CANVAS/CANVAS-R, and dapagliflozin (Farxiga) in DECLARE-TIMI 58. The SGLT2 inhibitors collectively reduced the risk of HF hospitalization by 21% in participants with no baseline history of the disease and by 29% in those with a history of HF. Moreover, the risk of progression of renal disease was reduced by 45% (Lancet. 2019 Jan 5;393[10166]:31-9).

More recently, the landmark DAPA-HF trial established SGLT2 inhibitor therapy as part of standard-of-care, guideline-directed medical therapy for patients with HF with reduced ejection fraction regardless of whether they have comorbid type 2 diabetes (N Engl J Med. 2019 Nov 21;381[21]:1995-2008).

These are remarkable medications, generally very well tolerated, and it’s critical that cardiologists get on board in prescribing them, Dr. Fonarow emphasized. He alerted his colleagues to what he called an “incredibly helpful” review article that provides practical guidance for cardiologists in how to start using the SGLT2 inhibitors (JACC Heart Fail. 2019 Feb;7[2]:169-72).

“It’s pretty straightforward,” according to Dr. Fonarow. “If you’re comfortable enough in using ACE inhibitors, angiotensin receptor blockers, and beta-blockers, I think you’ll find these medications fit similarly when you actually get experience in utilizing them.”

He reported serving as a consultant to 10 pharmaceutical or medical device companies.

[email protected]

In 2017, roughly 3 years after evidence from several studies made endovascular thrombectomy first-line treatment for selected acute ischemic stroke patients, the treatment was available at barely more than one-third of all U.S. stroke centers, available within 30-minute access to just over 30% of Americans, and available within 15-minute access to one-fifth of U.S. residents, based on information in a comprehensive U.S. database.

Heba Sarraj

These numbers showed that “current direct EVT [endovascular thrombectomy] access in the United States is suboptimal under predominate EMS routing protocols,” Amrou Sarraj, MD, and his associates wrote in an article published online in Stroke on Feb. 12. “Only in eight states did the coverage exceed 25% of the population, and nine states had coverage for less than 10% of the population. These results reflect limited access to an effective treatment modality that would improve clinical outcomes in patients with large strokes and prevent potentially devastating disability,” wrote Dr. Sarraj, chief of the general neurology service at Memorial-Hermann Hospital in Houston and coauthors.

Their analysis of data collected in 2017 by the Medicare Provider Analysis and Review (MEDPAR) database, maintained by the Centers for Medicare & Medicaid Services, identified two apparently effective ways to improve EVT access for acute ischemic stroke patients: First, systematically divert patients to a nearby center that offers EVT even when it means bypassing a closer stroke center that does not perform EVT when the added travel time is less than 15 minutes. Second, convert selected stroke centers that currently do not perform EVT into centers that do. Between these two approaches, the strategy of having ambulances bypass stroke centers that do not perform EVT and continuing to ones that do generally has the greater potential to boost access, the authors found. They based their analysis exclusively on their calculations of expected consequences rather than actual experience.

The calculations showed that bypassing non-EVT centers when the added bypass time computed to less than 15 minutes linked with an anticipated overall U.S. gain in access of about 17%, or 52 million people, extending the ability of acute ischemic stroke patients able to quickly reach an EVT center to about 37% of the American public. The second approach to boost access, converting the top 10% of stroke centers based on case volume that currently do not provide EVT to centers that do offer it, would result in expanded access for about 23 million additional Americans, raising the total with access to about 27% of the public, the new report said.

As part of this analysis, the MEDPAR data identified 1,941 U.S. centers providing stroke services during 2017, of which 713 (37%) had performed at least one EVT procedure. By comparison, 2015 MEDPAR data showed 577 U.S. stroke centers performing EVT, indicating that during the 2-3 years following several reports in early 2015 on the net benefits of EVT for acute ischemic stroke patients, the number of U.S. stroke centers offering this treatment had grown by a relative 24%. Based on the locations of the stroke centers that made EVT available in 2017, Dr. Sarraj and coauthors calculated that the 713 EVT-capable stroke centers provided emergency access within a 15-minute ground-ambulance trip for 61 million Americans (20% of the U.S. population), and within a 30-minute ground-transport trip to 95 million residents (31%).

Boosting these numbers by implementing a systematic bypass of stroke patients past non-EVT stroke centers to nearby centers that are EVT capable “has the benefit of ease of implementation and requires less time and resources,” the authors said. However, they also noted the heterogeneity of circumstances based on variables like population density and stroke center distribution, which means that in some locations the most effective way to boost access would be by increasing the number of stroke centers that provide EVT.

In 2018, Dr. Sarraj and associates reported results from a similar analysis of MEDPAR data that used 30-minute and 60-minute ground-transport times as the criteria for their calculations.

The study received no commercial funding. Dr. Sarraj reported receiving research funding from Stryker Neurovascular outside of this work. One coauthor reported serving in roles for the University of Texas Health System for which the institution has been funded via various industry and government grants, and another coauthor reported receiving research funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, Genentech, and CSL Behring, as well as consulting fees from Frazer Ltd.

[email protected]

SOURCE: Sarraj A et al. Stroke. 2020 Feb 12. doi: 10.1161/STROKEAHA.120.028850.

In 2017, roughly 3 years after evidence from several studies made endovascular thrombectomy first-line treatment for selected acute ischemic stroke patients, the treatment was available at barely more than one-third of all U.S. stroke centers, available within 30-minute access to just over 30% of Americans, and available within 15-minute access to one-fifth of U.S. residents, based on information in a comprehensive U.S. database.

Heba Sarraj

These numbers showed that “current direct EVT [endovascular thrombectomy] access in the United States is suboptimal under predominate EMS routing protocols,” Amrou Sarraj, MD, and his associates wrote in an article published online in Stroke on Feb. 12. “Only in eight states did the coverage exceed 25% of the population, and nine states had coverage for less than 10% of the population. These results reflect limited access to an effective treatment modality that would improve clinical outcomes in patients with large strokes and prevent potentially devastating disability,” wrote Dr. Sarraj, chief of the general neurology service at Memorial-Hermann Hospital in Houston and coauthors.

Their analysis of data collected in 2017 by the Medicare Provider Analysis and Review (MEDPAR) database, maintained by the Centers for Medicare & Medicaid Services, identified two apparently effective ways to improve EVT access for acute ischemic stroke patients: First, systematically divert patients to a nearby center that offers EVT even when it means bypassing a closer stroke center that does not perform EVT when the added travel time is less than 15 minutes. Second, convert selected stroke centers that currently do not perform EVT into centers that do. Between these two approaches, the strategy of having ambulances bypass stroke centers that do not perform EVT and continuing to ones that do generally has the greater potential to boost access, the authors found. They based their analysis exclusively on their calculations of expected consequences rather than actual experience.

The calculations showed that bypassing non-EVT centers when the added bypass time computed to less than 15 minutes linked with an anticipated overall U.S. gain in access of about 17%, or 52 million people, extending the ability of acute ischemic stroke patients able to quickly reach an EVT center to about 37% of the American public. The second approach to boost access, converting the top 10% of stroke centers based on case volume that currently do not provide EVT to centers that do offer it, would result in expanded access for about 23 million additional Americans, raising the total with access to about 27% of the public, the new report said.

As part of this analysis, the MEDPAR data identified 1,941 U.S. centers providing stroke services during 2017, of which 713 (37%) had performed at least one EVT procedure. By comparison, 2015 MEDPAR data showed 577 U.S. stroke centers performing EVT, indicating that during the 2-3 years following several reports in early 2015 on the net benefits of EVT for acute ischemic stroke patients, the number of U.S. stroke centers offering this treatment had grown by a relative 24%. Based on the locations of the stroke centers that made EVT available in 2017, Dr. Sarraj and coauthors calculated that the 713 EVT-capable stroke centers provided emergency access within a 15-minute ground-ambulance trip for 61 million Americans (20% of the U.S. population), and within a 30-minute ground-transport trip to 95 million residents (31%).

Boosting these numbers by implementing a systematic bypass of stroke patients past non-EVT stroke centers to nearby centers that are EVT capable “has the benefit of ease of implementation and requires less time and resources,” the authors said. However, they also noted the heterogeneity of circumstances based on variables like population density and stroke center distribution, which means that in some locations the most effective way to boost access would be by increasing the number of stroke centers that provide EVT.

In 2018, Dr. Sarraj and associates reported results from a similar analysis of MEDPAR data that used 30-minute and 60-minute ground-transport times as the criteria for their calculations.

The study received no commercial funding. Dr. Sarraj reported receiving research funding from Stryker Neurovascular outside of this work. One coauthor reported serving in roles for the University of Texas Health System for which the institution has been funded via various industry and government grants, and another coauthor reported receiving research funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, Genentech, and CSL Behring, as well as consulting fees from Frazer Ltd.

[email protected]

SOURCE: Sarraj A et al. Stroke. 2020 Feb 12. doi: 10.1161/STROKEAHA.120.028850.

In 2017, roughly 3 years after evidence from several studies made endovascular thrombectomy first-line treatment for selected acute ischemic stroke patients, the treatment was available at barely more than one-third of all U.S. stroke centers, available within 30-minute access to just over 30% of Americans, and available within 15-minute access to one-fifth of U.S. residents, based on information in a comprehensive U.S. database.

Heba Sarraj

These numbers showed that “current direct EVT [endovascular thrombectomy] access in the United States is suboptimal under predominate EMS routing protocols,” Amrou Sarraj, MD, and his associates wrote in an article published online in Stroke on Feb. 12. “Only in eight states did the coverage exceed 25% of the population, and nine states had coverage for less than 10% of the population. These results reflect limited access to an effective treatment modality that would improve clinical outcomes in patients with large strokes and prevent potentially devastating disability,” wrote Dr. Sarraj, chief of the general neurology service at Memorial-Hermann Hospital in Houston and coauthors.

Their analysis of data collected in 2017 by the Medicare Provider Analysis and Review (MEDPAR) database, maintained by the Centers for Medicare & Medicaid Services, identified two apparently effective ways to improve EVT access for acute ischemic stroke patients: First, systematically divert patients to a nearby center that offers EVT even when it means bypassing a closer stroke center that does not perform EVT when the added travel time is less than 15 minutes. Second, convert selected stroke centers that currently do not perform EVT into centers that do. Between these two approaches, the strategy of having ambulances bypass stroke centers that do not perform EVT and continuing to ones that do generally has the greater potential to boost access, the authors found. They based their analysis exclusively on their calculations of expected consequences rather than actual experience.

The calculations showed that bypassing non-EVT centers when the added bypass time computed to less than 15 minutes linked with an anticipated overall U.S. gain in access of about 17%, or 52 million people, extending the ability of acute ischemic stroke patients able to quickly reach an EVT center to about 37% of the American public. The second approach to boost access, converting the top 10% of stroke centers based on case volume that currently do not provide EVT to centers that do offer it, would result in expanded access for about 23 million additional Americans, raising the total with access to about 27% of the public, the new report said.

As part of this analysis, the MEDPAR data identified 1,941 U.S. centers providing stroke services during 2017, of which 713 (37%) had performed at least one EVT procedure. By comparison, 2015 MEDPAR data showed 577 U.S. stroke centers performing EVT, indicating that during the 2-3 years following several reports in early 2015 on the net benefits of EVT for acute ischemic stroke patients, the number of U.S. stroke centers offering this treatment had grown by a relative 24%. Based on the locations of the stroke centers that made EVT available in 2017, Dr. Sarraj and coauthors calculated that the 713 EVT-capable stroke centers provided emergency access within a 15-minute ground-ambulance trip for 61 million Americans (20% of the U.S. population), and within a 30-minute ground-transport trip to 95 million residents (31%).

Boosting these numbers by implementing a systematic bypass of stroke patients past non-EVT stroke centers to nearby centers that are EVT capable “has the benefit of ease of implementation and requires less time and resources,” the authors said. However, they also noted the heterogeneity of circumstances based on variables like population density and stroke center distribution, which means that in some locations the most effective way to boost access would be by increasing the number of stroke centers that provide EVT.

In 2018, Dr. Sarraj and associates reported results from a similar analysis of MEDPAR data that used 30-minute and 60-minute ground-transport times as the criteria for their calculations.

The study received no commercial funding. Dr. Sarraj reported receiving research funding from Stryker Neurovascular outside of this work. One coauthor reported serving in roles for the University of Texas Health System for which the institution has been funded via various industry and government grants, and another coauthor reported receiving research funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, Genentech, and CSL Behring, as well as consulting fees from Frazer Ltd.

[email protected]

SOURCE: Sarraj A et al. Stroke. 2020 Feb 12. doi: 10.1161/STROKEAHA.120.028850.

Top-line results from the seminal phase 2/3 Dominantly Inherited Alzheimer’s Network–Trials Unit (DIAN-TU) study show that the novel drugs gantenerumab (Roche) and solanezumab (Lilly) did not meet the primary endpoint in patients with early-stage, dominantly inherited Alzheimer’s disease (AD), investigators have announced.

In the international trial, which included almost 200 participants, the two experimental agents were evaluated separately. However, initial analyses showed that neither significantly slowed cognitive decline, the primary outcome measure, nor memory loss.

Still, the researchers noted that they will continue exploring data from DIAN-TU’s cognitive and clinical outcomes and are awaiting analyses of various biomarkers.

“Although the drugs we evaluated were not successful, the trial will move us forward in understanding Alzheimer’s,” principal investigator Randall J. Bateman, MD, of Washington University, St. Louis, said in a news release.

Funders for the trial included the National Institute on Aging and the Alzheimer’s Association.

“While the top-line data fell short, the Alzheimer’s Association looks forward to a more complete report at upcoming scientific conferences. We learn from every trial,” Maria Carrillo, PhD, chief scientific officer at the Alzheimer’s Association, noted in the organization’s own release.

Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, agreed with Dr. Carrillo that, although the results were disappointing, the data will be beneficial for the field.

“It’s always a difficult day when we get news like this,” Dr. Edelmayer said in an interview. However, “this research is going to absolutely provide valuable information once we can really pick through all of the data.”

Rare condition

Dominantly inherited AD, also known as familial AD or autosomal dominant AD, is rare but can affect memory and cognitive skills in individuals as young as age 30. It is caused by mutations on chromosomes 21, 14, and/or 1 that play a part in the breakdown of amyloid proteins and formation of amyloid plaques.

Both gantenerumab and solanezumab were created to target and neutralize amyloid-beta, albeit through different mechanisms. Both are also being assessed in other trials as treatment for more common forms of AD.

As reported by Medscape Medical News, results of the phase 3 EXPEDITION3 trial of solanezumab in patients with mild AD were negative, as were two other phase 3 trials. The drug is now being evaluated in the ongoing solanezumab Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.

Although the phase 3 SCARLET ROAD trial of gantenerumab for mild AD was stopped early for futility in 2014, it was continued as an open-label extension at the high dose for 2 years. During that period, follow-up analyses showed a dramatic decline in amyloid-beta deposition in the participants – leading to the launch of the phase 3 GRADUATE 1 and GRADUATE 2 trials.

Starting in 2012, DIAN-TU was conducted at 24 sites in the United States, the United Kingdom, Canada, Europe, and Australia. It followed 194 adult patients for up to 7 years (average duration, 5 years). Its original estimated completion date was December 2020, as stated on clinicaltrials.gov.

All participants had family members with a genetic mutation that causes early-onset Alzheimer’s disease. They already had very mild symptoms of cognitive decline and memory loss at the start of the trial or were expected to develop symptoms within 15 years of enrollment.

“People who inherit the mutation are all but guaranteed to develop symptoms at about the same age their parents did,” the release noted.

“While devastating for families, such mutations allow researchers to identify people in the early stages of the disease before their behavior and memory begin to change,” it added.

The Alzheimer’s Association noted in its release that a child of a parent with the mutation has a 50/50 chance of inheriting the disease. “This form affects less than 1% of the individuals living with Alzheimer’s disease today,” Dr. Edelmayer noted.

Detailed data coming soon

Trial participants were randomly assigned to receive either solanezumab, gantenerumab, or matching placebo. To act as a comparator group, family members without the AD mutation were also included.

The primary measure was change from baseline in the DIAN-TU cognitive composite score. Secondary measures included changes on the Mini-Mental State Examination, the Functional Assessment Scale, the Neuropsychiatric Inventory Questionnaire, the 12-item International Shopping List Test, the Memory Complaint Questionnaire, and the Wechsler Memory Scale Logical Memory/Paragraph Memory test.

The researchers also conducted imaging scans and collected samples of blood and cerebrospinal fluid.

Along with announcing the negative top-line results for the trial, the investigators noted that “a more detailed analysis of the trial’s data” will be presented at the Advances in Alzheimer’s and Parkinson’s Therapies in Vienna on April 2, 2020, and at the Alzheimer’s Association International Conference in Amsterdam in July.

The researchers will continue to explore all data gathered – but already new insights have been discovered into the development and progression of AD, Dr. Bateman noted.

Included among these discoveries is that brain changes that occur as the disease progresses are similar among those with the inherited, early-onset form of AD and the late-onset form.

“The trial’s innovative design ... will make advances for future Alzheimer’s trials. Ongoing and continued research and trials will bring us closer to our goal to stop Alzheimer’s,” Dr. Bateman said. “We will continue until we are successful.”

“These results reflect the difficult nature of treating [AD] and the great need for continued research,” said Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Labs.

“If we have learned one thing after more than 30 years of Alzheimer’s research, it is that even negative results propel the science forward,” he added.

Lilly noted in a statement that the DIAN-TU top-line results will not affect its ongoing A4 study of solanezumab. Roche noted in its own statement that the findings also will not affect the company’s ongoing GRADUATE studies of gantenerumab.

“The work doesn’t stop here”

Richard J. Hodes, MD, director of the National Institute on Aging, said that DIAN-TU will advance the field’s knowledge about a complex disease.

“We look forward to learning more through the published, peer-reviewed data, which will provide a broad range of scientists with crucial information and guidance for future research,” he said.

Howard Fillit, MD, founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), agreed.

“While we are disappointed that patients in this study did not see a benefit, we need to keep in mind that Alzheimer’s is a complicated disease due to complex, multifactorial causes,” he said in a statement.

“ADDF has long supported a broader approach that moves past targeting beta-amyloid and advances a diverse pipeline of drugs addressing multiple targets” in AD, Dr. Fillit added. “We need multiple ‘shots on goals’ to discover effective drugs.”

Dr. Edelmayer said the results emphasize that “this story isn’t yet completely told” and that there is still a lot to learn from the data, especially regarding the biomarkers that were tested.

“With that information, we will gain valuable insight into the outcomes that have been released but will also probably better understand where we should be putting our energies and focus moving forward,” she said.

Going forward, “we will continue this fight until we have an effective treatment for all individuals living with Alzheimer’s, whether it’s dominantly inherited [AD] or the more common version, which is the late-onset or sporadic form of the disease,” said Dr. Edelmayer.

“We have to stay optimistic. The work doesn’t stop here.”

The trial was funded by Eli Lilly, Roche, the Alzheimer’s Association, the National Institute on Aging, the GHR Foundation, and FBRI.

This article first appeared on Medscape.com.

Top-line results from the seminal phase 2/3 Dominantly Inherited Alzheimer’s Network–Trials Unit (DIAN-TU) study show that the novel drugs gantenerumab (Roche) and solanezumab (Lilly) did not meet the primary endpoint in patients with early-stage, dominantly inherited Alzheimer’s disease (AD), investigators have announced.

In the international trial, which included almost 200 participants, the two experimental agents were evaluated separately. However, initial analyses showed that neither significantly slowed cognitive decline, the primary outcome measure, nor memory loss.

Still, the researchers noted that they will continue exploring data from DIAN-TU’s cognitive and clinical outcomes and are awaiting analyses of various biomarkers.

“Although the drugs we evaluated were not successful, the trial will move us forward in understanding Alzheimer’s,” principal investigator Randall J. Bateman, MD, of Washington University, St. Louis, said in a news release.

Funders for the trial included the National Institute on Aging and the Alzheimer’s Association.

“While the top-line data fell short, the Alzheimer’s Association looks forward to a more complete report at upcoming scientific conferences. We learn from every trial,” Maria Carrillo, PhD, chief scientific officer at the Alzheimer’s Association, noted in the organization’s own release.

Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, agreed with Dr. Carrillo that, although the results were disappointing, the data will be beneficial for the field.

“It’s always a difficult day when we get news like this,” Dr. Edelmayer said in an interview. However, “this research is going to absolutely provide valuable information once we can really pick through all of the data.”

Rare condition

Dominantly inherited AD, also known as familial AD or autosomal dominant AD, is rare but can affect memory and cognitive skills in individuals as young as age 30. It is caused by mutations on chromosomes 21, 14, and/or 1 that play a part in the breakdown of amyloid proteins and formation of amyloid plaques.

Both gantenerumab and solanezumab were created to target and neutralize amyloid-beta, albeit through different mechanisms. Both are also being assessed in other trials as treatment for more common forms of AD.

As reported by Medscape Medical News, results of the phase 3 EXPEDITION3 trial of solanezumab in patients with mild AD were negative, as were two other phase 3 trials. The drug is now being evaluated in the ongoing solanezumab Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.

Although the phase 3 SCARLET ROAD trial of gantenerumab for mild AD was stopped early for futility in 2014, it was continued as an open-label extension at the high dose for 2 years. During that period, follow-up analyses showed a dramatic decline in amyloid-beta deposition in the participants – leading to the launch of the phase 3 GRADUATE 1 and GRADUATE 2 trials.

Starting in 2012, DIAN-TU was conducted at 24 sites in the United States, the United Kingdom, Canada, Europe, and Australia. It followed 194 adult patients for up to 7 years (average duration, 5 years). Its original estimated completion date was December 2020, as stated on clinicaltrials.gov.

All participants had family members with a genetic mutation that causes early-onset Alzheimer’s disease. They already had very mild symptoms of cognitive decline and memory loss at the start of the trial or were expected to develop symptoms within 15 years of enrollment.

“People who inherit the mutation are all but guaranteed to develop symptoms at about the same age their parents did,” the release noted.

“While devastating for families, such mutations allow researchers to identify people in the early stages of the disease before their behavior and memory begin to change,” it added.

The Alzheimer’s Association noted in its release that a child of a parent with the mutation has a 50/50 chance of inheriting the disease. “This form affects less than 1% of the individuals living with Alzheimer’s disease today,” Dr. Edelmayer noted.

Detailed data coming soon

Trial participants were randomly assigned to receive either solanezumab, gantenerumab, or matching placebo. To act as a comparator group, family members without the AD mutation were also included.

The primary measure was change from baseline in the DIAN-TU cognitive composite score. Secondary measures included changes on the Mini-Mental State Examination, the Functional Assessment Scale, the Neuropsychiatric Inventory Questionnaire, the 12-item International Shopping List Test, the Memory Complaint Questionnaire, and the Wechsler Memory Scale Logical Memory/Paragraph Memory test.

The researchers also conducted imaging scans and collected samples of blood and cerebrospinal fluid.

Along with announcing the negative top-line results for the trial, the investigators noted that “a more detailed analysis of the trial’s data” will be presented at the Advances in Alzheimer’s and Parkinson’s Therapies in Vienna on April 2, 2020, and at the Alzheimer’s Association International Conference in Amsterdam in July.

The researchers will continue to explore all data gathered – but already new insights have been discovered into the development and progression of AD, Dr. Bateman noted.

Included among these discoveries is that brain changes that occur as the disease progresses are similar among those with the inherited, early-onset form of AD and the late-onset form.

“The trial’s innovative design ... will make advances for future Alzheimer’s trials. Ongoing and continued research and trials will bring us closer to our goal to stop Alzheimer’s,” Dr. Bateman said. “We will continue until we are successful.”

“These results reflect the difficult nature of treating [AD] and the great need for continued research,” said Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Labs.

“If we have learned one thing after more than 30 years of Alzheimer’s research, it is that even negative results propel the science forward,” he added.

Lilly noted in a statement that the DIAN-TU top-line results will not affect its ongoing A4 study of solanezumab. Roche noted in its own statement that the findings also will not affect the company’s ongoing GRADUATE studies of gantenerumab.

“The work doesn’t stop here”

Richard J. Hodes, MD, director of the National Institute on Aging, said that DIAN-TU will advance the field’s knowledge about a complex disease.

“We look forward to learning more through the published, peer-reviewed data, which will provide a broad range of scientists with crucial information and guidance for future research,” he said.

Howard Fillit, MD, founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), agreed.

“While we are disappointed that patients in this study did not see a benefit, we need to keep in mind that Alzheimer’s is a complicated disease due to complex, multifactorial causes,” he said in a statement.

“ADDF has long supported a broader approach that moves past targeting beta-amyloid and advances a diverse pipeline of drugs addressing multiple targets” in AD, Dr. Fillit added. “We need multiple ‘shots on goals’ to discover effective drugs.”

Dr. Edelmayer said the results emphasize that “this story isn’t yet completely told” and that there is still a lot to learn from the data, especially regarding the biomarkers that were tested.

“With that information, we will gain valuable insight into the outcomes that have been released but will also probably better understand where we should be putting our energies and focus moving forward,” she said.

Going forward, “we will continue this fight until we have an effective treatment for all individuals living with Alzheimer’s, whether it’s dominantly inherited [AD] or the more common version, which is the late-onset or sporadic form of the disease,” said Dr. Edelmayer.

“We have to stay optimistic. The work doesn’t stop here.”

The trial was funded by Eli Lilly, Roche, the Alzheimer’s Association, the National Institute on Aging, the GHR Foundation, and FBRI.

This article first appeared on Medscape.com.

Top-line results from the seminal phase 2/3 Dominantly Inherited Alzheimer’s Network–Trials Unit (DIAN-TU) study show that the novel drugs gantenerumab (Roche) and solanezumab (Lilly) did not meet the primary endpoint in patients with early-stage, dominantly inherited Alzheimer’s disease (AD), investigators have announced.

In the international trial, which included almost 200 participants, the two experimental agents were evaluated separately. However, initial analyses showed that neither significantly slowed cognitive decline, the primary outcome measure, nor memory loss.

Still, the researchers noted that they will continue exploring data from DIAN-TU’s cognitive and clinical outcomes and are awaiting analyses of various biomarkers.

“Although the drugs we evaluated were not successful, the trial will move us forward in understanding Alzheimer’s,” principal investigator Randall J. Bateman, MD, of Washington University, St. Louis, said in a news release.

Funders for the trial included the National Institute on Aging and the Alzheimer’s Association.

“While the top-line data fell short, the Alzheimer’s Association looks forward to a more complete report at upcoming scientific conferences. We learn from every trial,” Maria Carrillo, PhD, chief scientific officer at the Alzheimer’s Association, noted in the organization’s own release.

Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, agreed with Dr. Carrillo that, although the results were disappointing, the data will be beneficial for the field.

“It’s always a difficult day when we get news like this,” Dr. Edelmayer said in an interview. However, “this research is going to absolutely provide valuable information once we can really pick through all of the data.”

Rare condition

Dominantly inherited AD, also known as familial AD or autosomal dominant AD, is rare but can affect memory and cognitive skills in individuals as young as age 30. It is caused by mutations on chromosomes 21, 14, and/or 1 that play a part in the breakdown of amyloid proteins and formation of amyloid plaques.

Both gantenerumab and solanezumab were created to target and neutralize amyloid-beta, albeit through different mechanisms. Both are also being assessed in other trials as treatment for more common forms of AD.

As reported by Medscape Medical News, results of the phase 3 EXPEDITION3 trial of solanezumab in patients with mild AD were negative, as were two other phase 3 trials. The drug is now being evaluated in the ongoing solanezumab Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.

Although the phase 3 SCARLET ROAD trial of gantenerumab for mild AD was stopped early for futility in 2014, it was continued as an open-label extension at the high dose for 2 years. During that period, follow-up analyses showed a dramatic decline in amyloid-beta deposition in the participants – leading to the launch of the phase 3 GRADUATE 1 and GRADUATE 2 trials.

Starting in 2012, DIAN-TU was conducted at 24 sites in the United States, the United Kingdom, Canada, Europe, and Australia. It followed 194 adult patients for up to 7 years (average duration, 5 years). Its original estimated completion date was December 2020, as stated on clinicaltrials.gov.

All participants had family members with a genetic mutation that causes early-onset Alzheimer’s disease. They already had very mild symptoms of cognitive decline and memory loss at the start of the trial or were expected to develop symptoms within 15 years of enrollment.

“People who inherit the mutation are all but guaranteed to develop symptoms at about the same age their parents did,” the release noted.

“While devastating for families, such mutations allow researchers to identify people in the early stages of the disease before their behavior and memory begin to change,” it added.

The Alzheimer’s Association noted in its release that a child of a parent with the mutation has a 50/50 chance of inheriting the disease. “This form affects less than 1% of the individuals living with Alzheimer’s disease today,” Dr. Edelmayer noted.

Detailed data coming soon

Trial participants were randomly assigned to receive either solanezumab, gantenerumab, or matching placebo. To act as a comparator group, family members without the AD mutation were also included.

The primary measure was change from baseline in the DIAN-TU cognitive composite score. Secondary measures included changes on the Mini-Mental State Examination, the Functional Assessment Scale, the Neuropsychiatric Inventory Questionnaire, the 12-item International Shopping List Test, the Memory Complaint Questionnaire, and the Wechsler Memory Scale Logical Memory/Paragraph Memory test.

The researchers also conducted imaging scans and collected samples of blood and cerebrospinal fluid.

Along with announcing the negative top-line results for the trial, the investigators noted that “a more detailed analysis of the trial’s data” will be presented at the Advances in Alzheimer’s and Parkinson’s Therapies in Vienna on April 2, 2020, and at the Alzheimer’s Association International Conference in Amsterdam in July.

The researchers will continue to explore all data gathered – but already new insights have been discovered into the development and progression of AD, Dr. Bateman noted.

Included among these discoveries is that brain changes that occur as the disease progresses are similar among those with the inherited, early-onset form of AD and the late-onset form.

“The trial’s innovative design ... will make advances for future Alzheimer’s trials. Ongoing and continued research and trials will bring us closer to our goal to stop Alzheimer’s,” Dr. Bateman said. “We will continue until we are successful.”

“These results reflect the difficult nature of treating [AD] and the great need for continued research,” said Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Labs.

“If we have learned one thing after more than 30 years of Alzheimer’s research, it is that even negative results propel the science forward,” he added.

Lilly noted in a statement that the DIAN-TU top-line results will not affect its ongoing A4 study of solanezumab. Roche noted in its own statement that the findings also will not affect the company’s ongoing GRADUATE studies of gantenerumab.

“The work doesn’t stop here”

Richard J. Hodes, MD, director of the National Institute on Aging, said that DIAN-TU will advance the field’s knowledge about a complex disease.

“We look forward to learning more through the published, peer-reviewed data, which will provide a broad range of scientists with crucial information and guidance for future research,” he said.

Howard Fillit, MD, founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), agreed.

“While we are disappointed that patients in this study did not see a benefit, we need to keep in mind that Alzheimer’s is a complicated disease due to complex, multifactorial causes,” he said in a statement.

“ADDF has long supported a broader approach that moves past targeting beta-amyloid and advances a diverse pipeline of drugs addressing multiple targets” in AD, Dr. Fillit added. “We need multiple ‘shots on goals’ to discover effective drugs.”

Dr. Edelmayer said the results emphasize that “this story isn’t yet completely told” and that there is still a lot to learn from the data, especially regarding the biomarkers that were tested.

“With that information, we will gain valuable insight into the outcomes that have been released but will also probably better understand where we should be putting our energies and focus moving forward,” she said.

Going forward, “we will continue this fight until we have an effective treatment for all individuals living with Alzheimer’s, whether it’s dominantly inherited [AD] or the more common version, which is the late-onset or sporadic form of the disease,” said Dr. Edelmayer.

“We have to stay optimistic. The work doesn’t stop here.”

The trial was funded by Eli Lilly, Roche, the Alzheimer’s Association, the National Institute on Aging, the GHR Foundation, and FBRI.

This article first appeared on Medscape.com.

The U.S. Multi-Society Task Force on Colorectal Cancer (CRC) recently updated recommendations for patient follow-up after colonoscopy and polypectomy.

The new guidance was based on advancements in both research and technology since the last recommendations were published in 2012, reported lead author Samir Gupta, MD, AGAF, of the University of California, San Diego, and colleagues.

“[Since 2012,] a number of articles have been published on risk of CRC based on colonoscopy findings and patient characteristics, as well as the potential impact of screening and surveillance colonoscopy on outcomes, such as incident CRC and polyps,” the investigators wrote in Gastroenterology. “Further, recent studies increasingly reflect the modern era of colonoscopy with more awareness of the importance of quality factors (e.g., adequate bowel preparation, cecal intubation, adequate adenoma detection, and complete polyp resection), and utilization of state of the art technologies (e.g., high-definition colonoscopes).”

The task force, which comprised the American College of Gastroenterology, the American Gastroenterological Association, and the American Society of Gastrointestinal Endoscopy, identified key topics using PICO (patient, intervention, comparison, and outcome) questions before conducting a comprehensive literature review that included 136 articles. Based on these findings, two task force members generated recommendations that were further refined through consensus discussion. The recommendations were copublished in the March issues of the American Journal of Gastroenterology, Gastroenterology, and Gastrointestinal Endoscopy.

According to Dr. Gupta and colleagues, some of the new recommendations, particularly those that advise less stringent follow-up, may encounter resistance from various stakeholders.

“Patients, primary care physicians, and colonoscopists may have concerns about lengthening a previously recommended interval, and will need to engage in shared decision making regarding whether to lengthen the follow-up interval based upon the guidance here or utilize the recommendation made at the time of the prior colonoscopy,” the task force wrote.

The most prominent recommendations of this kind concern patients who undergo removal of tubular adenomas less than 10 mm in size. For patients who have 1-2 of these adenomas removed, the task force now recommends follow-up after 7-10 years, instead of the previously recommended interval of 5-10 years.

“[This decision was] based on the growing body of evidence to support low risk for metachronous advanced neoplasia,” the task force wrote. “In this population, the risk for metachronous advanced neoplasia is similar to that for individuals with no adenoma. Importantly, the observed risk for fatal CRC among individuals with 1-10 adenomas less than 10 mm is lower than average for the general population.”

Along similar lines, patients who undergo removal of 3-4 small adenomas now have a recommended 3-5 year follow-up window, instead of the previously strict recommendation for follow-up at 3 years.

But not all of the new guidance is less stringent. While the task force previously recommended a follow-up period of less than 3 years after removal of more than 10 adenomas, they now recommend follow-up at 1 year. This change was made to simplify guidance, the investigators wrote, noting that the evidence base in this area “has not been markedly strengthened” since 2012.

Compared with the old guidance, the updated publication offers more detailed recommendations for follow-up after removal of serrated polyps. On this topic, 10 clinical scenarios are presented, with follow-up ranging from 6 months after piecemeal resection of a sessile serrated polyp greater than 20 mm to 10 years after removal of 20 or fewer hyperplastic polyps less than 10 mm that were located in the rectum or sigmoid colon. Incidentally, these two recommendations are strong and based on moderate evidence, whereas the remaining recommendations for serrated polyps are weak and based on very-low-quality evidence.

Because of such knowledge gaps, the investigators emphasized the need for more data. The publication includes extensive discussion of pressing research topics and appropriate methods of investigation.

“Our review highlights several opportunities for research to clarify risk stratification and management of patients post-polypectomy,” the task force wrote. “In order to optimize risk-reduction strategies, the mechanisms driving metachronous advanced neoplasia after baseline polypectomy and their relative frequency need to be better understood through studies that include large numbers of patients with interval cancers and/or advanced neoplasia after baseline polypectomy. Mechanisms may include new/incident growth, incomplete baseline resection, and missed neoplasia; each of these potential causes may require different interventions for improvement.”

The task force also suggested that some basic questions beyond risk stratification remain unanswered, such as the impact of surveillance on CRC incidence and mortality.

“Such evidence is needed given the increasing proportion of patients who are having adenomas detected as part of increased participation in CRC screening,” the task force wrote.

Other suggested topics of investigation include age-related analyses that incorporate procedural risk, cost-effectiveness studies, and comparisons of nonendoscopic methods of surveillance, such as fecal immunochemical testing.

The study was funded by the National Institutes of Health and the Department of Veterans Affairs. The investigators reported relationships with Covidien, Ironwood, Medtronic, and others.

SOURCE: Gupta S et al. Gastroenterology. 2020 Feb 7. doi: 10.1053/j.gastro.2019.10.026.

The U.S. Multi-Society Task Force on Colorectal Cancer (CRC) recently updated recommendations for patient follow-up after colonoscopy and polypectomy.

The new guidance was based on advancements in both research and technology since the last recommendations were published in 2012, reported lead author Samir Gupta, MD, AGAF, of the University of California, San Diego, and colleagues.

“[Since 2012,] a number of articles have been published on risk of CRC based on colonoscopy findings and patient characteristics, as well as the potential impact of screening and surveillance colonoscopy on outcomes, such as incident CRC and polyps,” the investigators wrote in Gastroenterology. “Further, recent studies increasingly reflect the modern era of colonoscopy with more awareness of the importance of quality factors (e.g., adequate bowel preparation, cecal intubation, adequate adenoma detection, and complete polyp resection), and utilization of state of the art technologies (e.g., high-definition colonoscopes).”

The task force, which comprised the American College of Gastroenterology, the American Gastroenterological Association, and the American Society of Gastrointestinal Endoscopy, identified key topics using PICO (patient, intervention, comparison, and outcome) questions before conducting a comprehensive literature review that included 136 articles. Based on these findings, two task force members generated recommendations that were further refined through consensus discussion. The recommendations were copublished in the March issues of the American Journal of Gastroenterology, Gastroenterology, and Gastrointestinal Endoscopy.

According to Dr. Gupta and colleagues, some of the new recommendations, particularly those that advise less stringent follow-up, may encounter resistance from various stakeholders.

“Patients, primary care physicians, and colonoscopists may have concerns about lengthening a previously recommended interval, and will need to engage in shared decision making regarding whether to lengthen the follow-up interval based upon the guidance here or utilize the recommendation made at the time of the prior colonoscopy,” the task force wrote.

The most prominent recommendations of this kind concern patients who undergo removal of tubular adenomas less than 10 mm in size. For patients who have 1-2 of these adenomas removed, the task force now recommends follow-up after 7-10 years, instead of the previously recommended interval of 5-10 years.

“[This decision was] based on the growing body of evidence to support low risk for metachronous advanced neoplasia,” the task force wrote. “In this population, the risk for metachronous advanced neoplasia is similar to that for individuals with no adenoma. Importantly, the observed risk for fatal CRC among individuals with 1-10 adenomas less than 10 mm is lower than average for the general population.”

Along similar lines, patients who undergo removal of 3-4 small adenomas now have a recommended 3-5 year follow-up window, instead of the previously strict recommendation for follow-up at 3 years.

But not all of the new guidance is less stringent. While the task force previously recommended a follow-up period of less than 3 years after removal of more than 10 adenomas, they now recommend follow-up at 1 year. This change was made to simplify guidance, the investigators wrote, noting that the evidence base in this area “has not been markedly strengthened” since 2012.

Compared with the old guidance, the updated publication offers more detailed recommendations for follow-up after removal of serrated polyps. On this topic, 10 clinical scenarios are presented, with follow-up ranging from 6 months after piecemeal resection of a sessile serrated polyp greater than 20 mm to 10 years after removal of 20 or fewer hyperplastic polyps less than 10 mm that were located in the rectum or sigmoid colon. Incidentally, these two recommendations are strong and based on moderate evidence, whereas the remaining recommendations for serrated polyps are weak and based on very-low-quality evidence.

Because of such knowledge gaps, the investigators emphasized the need for more data. The publication includes extensive discussion of pressing research topics and appropriate methods of investigation.

“Our review highlights several opportunities for research to clarify risk stratification and management of patients post-polypectomy,” the task force wrote. “In order to optimize risk-reduction strategies, the mechanisms driving metachronous advanced neoplasia after baseline polypectomy and their relative frequency need to be better understood through studies that include large numbers of patients with interval cancers and/or advanced neoplasia after baseline polypectomy. Mechanisms may include new/incident growth, incomplete baseline resection, and missed neoplasia; each of these potential causes may require different interventions for improvement.”

The task force also suggested that some basic questions beyond risk stratification remain unanswered, such as the impact of surveillance on CRC incidence and mortality.

“Such evidence is needed given the increasing proportion of patients who are having adenomas detected as part of increased participation in CRC screening,” the task force wrote.

Other suggested topics of investigation include age-related analyses that incorporate procedural risk, cost-effectiveness studies, and comparisons of nonendoscopic methods of surveillance, such as fecal immunochemical testing.

The study was funded by the National Institutes of Health and the Department of Veterans Affairs. The investigators reported relationships with Covidien, Ironwood, Medtronic, and others.

SOURCE: Gupta S et al. Gastroenterology. 2020 Feb 7. doi: 10.1053/j.gastro.2019.10.026.

The U.S. Multi-Society Task Force on Colorectal Cancer (CRC) recently updated recommendations for patient follow-up after colonoscopy and polypectomy.

The new guidance was based on advancements in both research and technology since the last recommendations were published in 2012, reported lead author Samir Gupta, MD, AGAF, of the University of California, San Diego, and colleagues.

“[Since 2012,] a number of articles have been published on risk of CRC based on colonoscopy findings and patient characteristics, as well as the potential impact of screening and surveillance colonoscopy on outcomes, such as incident CRC and polyps,” the investigators wrote in Gastroenterology. “Further, recent studies increasingly reflect the modern era of colonoscopy with more awareness of the importance of quality factors (e.g., adequate bowel preparation, cecal intubation, adequate adenoma detection, and complete polyp resection), and utilization of state of the art technologies (e.g., high-definition colonoscopes).”

The task force, which comprised the American College of Gastroenterology, the American Gastroenterological Association, and the American Society of Gastrointestinal Endoscopy, identified key topics using PICO (patient, intervention, comparison, and outcome) questions before conducting a comprehensive literature review that included 136 articles. Based on these findings, two task force members generated recommendations that were further refined through consensus discussion. The recommendations were copublished in the March issues of the American Journal of Gastroenterology, Gastroenterology, and Gastrointestinal Endoscopy.

According to Dr. Gupta and colleagues, some of the new recommendations, particularly those that advise less stringent follow-up, may encounter resistance from various stakeholders.

“Patients, primary care physicians, and colonoscopists may have concerns about lengthening a previously recommended interval, and will need to engage in shared decision making regarding whether to lengthen the follow-up interval based upon the guidance here or utilize the recommendation made at the time of the prior colonoscopy,” the task force wrote.

The most prominent recommendations of this kind concern patients who undergo removal of tubular adenomas less than 10 mm in size. For patients who have 1-2 of these adenomas removed, the task force now recommends follow-up after 7-10 years, instead of the previously recommended interval of 5-10 years.

“[This decision was] based on the growing body of evidence to support low risk for metachronous advanced neoplasia,” the task force wrote. “In this population, the risk for metachronous advanced neoplasia is similar to that for individuals with no adenoma. Importantly, the observed risk for fatal CRC among individuals with 1-10 adenomas less than 10 mm is lower than average for the general population.”

Along similar lines, patients who undergo removal of 3-4 small adenomas now have a recommended 3-5 year follow-up window, instead of the previously strict recommendation for follow-up at 3 years.

But not all of the new guidance is less stringent. While the task force previously recommended a follow-up period of less than 3 years after removal of more than 10 adenomas, they now recommend follow-up at 1 year. This change was made to simplify guidance, the investigators wrote, noting that the evidence base in this area “has not been markedly strengthened” since 2012.

Compared with the old guidance, the updated publication offers more detailed recommendations for follow-up after removal of serrated polyps. On this topic, 10 clinical scenarios are presented, with follow-up ranging from 6 months after piecemeal resection of a sessile serrated polyp greater than 20 mm to 10 years after removal of 20 or fewer hyperplastic polyps less than 10 mm that were located in the rectum or sigmoid colon. Incidentally, these two recommendations are strong and based on moderate evidence, whereas the remaining recommendations for serrated polyps are weak and based on very-low-quality evidence.

Because of such knowledge gaps, the investigators emphasized the need for more data. The publication includes extensive discussion of pressing research topics and appropriate methods of investigation.

“Our review highlights several opportunities for research to clarify risk stratification and management of patients post-polypectomy,” the task force wrote. “In order to optimize risk-reduction strategies, the mechanisms driving metachronous advanced neoplasia after baseline polypectomy and their relative frequency need to be better understood through studies that include large numbers of patients with interval cancers and/or advanced neoplasia after baseline polypectomy. Mechanisms may include new/incident growth, incomplete baseline resection, and missed neoplasia; each of these potential causes may require different interventions for improvement.”

The task force also suggested that some basic questions beyond risk stratification remain unanswered, such as the impact of surveillance on CRC incidence and mortality.

“Such evidence is needed given the increasing proportion of patients who are having adenomas detected as part of increased participation in CRC screening,” the task force wrote.

Other suggested topics of investigation include age-related analyses that incorporate procedural risk, cost-effectiveness studies, and comparisons of nonendoscopic methods of surveillance, such as fecal immunochemical testing.

The study was funded by the National Institutes of Health and the Department of Veterans Affairs. The investigators reported relationships with Covidien, Ironwood, Medtronic, and others.

SOURCE: Gupta S et al. Gastroenterology. 2020 Feb 7. doi: 10.1053/j.gastro.2019.10.026.

The Centers for Disease Control and Prevention announced the number of confirmed cases of the 2019 Novel Coronavirus (2019-nCoV) in the United States has reached 13.

Gregory Twachtman/MDedge News

The latest case, announced Feb. 11, 2020, by the CDC, was in a person in California who was previously under federal quarantine because the patient had traveled to Wuhan, China.

The CDC is currently looking into who the patient may have come in contact with to understand the potential for further spread of the coronavirus.

“The contact investigation is ongoing,” CDC principal deputy director Anne Schuchat, MD, said during a Feb. 11 press conference to provide an update on coronavirus containment activities being taken by the CDC.

Dr. Schuchat also addressed issues related to the laboratory test, as the patient in California was initially thought to be negative for the coronavirus.

“With other cases around the country that we are evaluating, we have been doing serial tests to understand whether they are still infectious” and to gather other information about how results change over time, Dr. Schuchat said.

She noted that the CDC does not “have as much information as we would like on the severity of the virus,” noting that there are many cases in China with severe reactions, while the 13 cases in the United States represent a much more mild reaction to the virus so far.

With the latest case in California, she noted that there was “probably a mix-up and the original test wasn’t negative,” although she did not elaborate on what the nature of the mix-up was, stating that was all the information that she had.

In general, Dr. Schuchat touted the actions taken by the CDC and the federal government focused primarily on containing the spread of the virus in the United States, including the implementation of travel advisories, quarantining passengers returning from China, as well as the new test kits that are being distributed by the agency across the nation and around the world. She also mentioned CDC staff are being deployed around the world to monitor the spreading of the disease and highlighted the outreach efforts to keep the public informed.

Dr. Schuchat highlighted the fact that, of the 13 cases in the United States, 11 were with patients that were in Wuhan, and only 2 were because of close contact with a patient, something that she attributed to the actions being taken.

She also noted that cases in the United States have not been as severe as they have been in China, where deaths have been attributed to the coronavirus outbreak. She added that there have been only two deaths outside of mainland China attributed to the coronavirus.

“Some of the steps the CDC has taken have really put us in better shape should widespread transmission occur in the United States,” she said.

Dr. Schuchat also highlighted that the first charter flight of people quarantined after returning from Wuhan have reached the 14-day milestone and should be on their way home beginning today.

[email protected]

The Centers for Disease Control and Prevention announced the number of confirmed cases of the 2019 Novel Coronavirus (2019-nCoV) in the United States has reached 13.

Gregory Twachtman/MDedge News

The latest case, announced Feb. 11, 2020, by the CDC, was in a person in California who was previously under federal quarantine because the patient had traveled to Wuhan, China.

The CDC is currently looking into who the patient may have come in contact with to understand the potential for further spread of the coronavirus.

“The contact investigation is ongoing,” CDC principal deputy director Anne Schuchat, MD, said during a Feb. 11 press conference to provide an update on coronavirus containment activities being taken by the CDC.

Dr. Schuchat also addressed issues related to the laboratory test, as the patient in California was initially thought to be negative for the coronavirus.

“With other cases around the country that we are evaluating, we have been doing serial tests to understand whether they are still infectious” and to gather other information about how results change over time, Dr. Schuchat said.

She noted that the CDC does not “have as much information as we would like on the severity of the virus,” noting that there are many cases in China with severe reactions, while the 13 cases in the United States represent a much more mild reaction to the virus so far.

With the latest case in California, she noted that there was “probably a mix-up and the original test wasn’t negative,” although she did not elaborate on what the nature of the mix-up was, stating that was all the information that she had.

In general, Dr. Schuchat touted the actions taken by the CDC and the federal government focused primarily on containing the spread of the virus in the United States, including the implementation of travel advisories, quarantining passengers returning from China, as well as the new test kits that are being distributed by the agency across the nation and around the world. She also mentioned CDC staff are being deployed around the world to monitor the spreading of the disease and highlighted the outreach efforts to keep the public informed.

Dr. Schuchat highlighted the fact that, of the 13 cases in the United States, 11 were with patients that were in Wuhan, and only 2 were because of close contact with a patient, something that she attributed to the actions being taken.

She also noted that cases in the United States have not been as severe as they have been in China, where deaths have been attributed to the coronavirus outbreak. She added that there have been only two deaths outside of mainland China attributed to the coronavirus.

“Some of the steps the CDC has taken have really put us in better shape should widespread transmission occur in the United States,” she said.

Dr. Schuchat also highlighted that the first charter flight of people quarantined after returning from Wuhan have reached the 14-day milestone and should be on their way home beginning today.

[email protected]

The Centers for Disease Control and Prevention announced the number of confirmed cases of the 2019 Novel Coronavirus (2019-nCoV) in the United States has reached 13.

Gregory Twachtman/MDedge News

The latest case, announced Feb. 11, 2020, by the CDC, was in a person in California who was previously under federal quarantine because the patient had traveled to Wuhan, China.

The CDC is currently looking into who the patient may have come in contact with to understand the potential for further spread of the coronavirus.

“The contact investigation is ongoing,” CDC principal deputy director Anne Schuchat, MD, said during a Feb. 11 press conference to provide an update on coronavirus containment activities being taken by the CDC.

Dr. Schuchat also addressed issues related to the laboratory test, as the patient in California was initially thought to be negative for the coronavirus.

“With other cases around the country that we are evaluating, we have been doing serial tests to understand whether they are still infectious” and to gather other information about how results change over time, Dr. Schuchat said.

She noted that the CDC does not “have as much information as we would like on the severity of the virus,” noting that there are many cases in China with severe reactions, while the 13 cases in the United States represent a much more mild reaction to the virus so far.

With the latest case in California, she noted that there was “probably a mix-up and the original test wasn’t negative,” although she did not elaborate on what the nature of the mix-up was, stating that was all the information that she had.

In general, Dr. Schuchat touted the actions taken by the CDC and the federal government focused primarily on containing the spread of the virus in the United States, including the implementation of travel advisories, quarantining passengers returning from China, as well as the new test kits that are being distributed by the agency across the nation and around the world. She also mentioned CDC staff are being deployed around the world to monitor the spreading of the disease and highlighted the outreach efforts to keep the public informed.

Dr. Schuchat highlighted the fact that, of the 13 cases in the United States, 11 were with patients that were in Wuhan, and only 2 were because of close contact with a patient, something that she attributed to the actions being taken.

She also noted that cases in the United States have not been as severe as they have been in China, where deaths have been attributed to the coronavirus outbreak. She added that there have been only two deaths outside of mainland China attributed to the coronavirus.

“Some of the steps the CDC has taken have really put us in better shape should widespread transmission occur in the United States,” she said.

Dr. Schuchat also highlighted that the first charter flight of people quarantined after returning from Wuhan have reached the 14-day milestone and should be on their way home beginning today.

[email protected]

A network meta-analysis of migraine treatments in children found little evidence that prophylactic medicines work in this population.

Marta Ortiz/iStock/Getty Images Plus

Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.

The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.

In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.

The results had an overall low to moderate certainty.

When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.

In a long-term analysis (greater than 6 months), no treatment outperformed placebo.

The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.

“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.

The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.

Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.

Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.

Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.

SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.

A network meta-analysis of migraine treatments in children found little evidence that prophylactic medicines work in this population.

Marta Ortiz/iStock/Getty Images Plus

Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.

The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.

In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.

The results had an overall low to moderate certainty.

When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.

In a long-term analysis (greater than 6 months), no treatment outperformed placebo.

The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.

“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.

The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.

Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.

Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.

Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.

SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.

A network meta-analysis of migraine treatments in children found little evidence that prophylactic medicines work in this population.

Marta Ortiz/iStock/Getty Images Plus

Clinicians hoped that medications used in adults – such as antidepressants, antiepileptics, antihypertensive agents, calcium channel blockers, and food supplements – would find similar success in children. Unfortunately, researchers found only short-term signs of efficacy over placebo, with no benefit lasting more than 6 months.

The study, conducted by a team led by Cosima Locher, PhD, of Boston Children’s Hospital, included 23 double-blind, randomized, controlled trials with a total of 2,217 patients; the mean age was 11 years. They compared 12 pharmacologic agents with each other or with placebo in the study, published online in JAMA Pediatrics.

In a main efficacy analysis that included 19 studies, only two treatments outperformed placebo: propranolol (standardized mean difference, 0.60; 95% confidence interval, 0.03-1.17) and topiramate (SMD, 0.59; 95% CI, 0.03-1.15). There were no statistically significant between-treatment differences.

The results had an overall low to moderate certainty.

When propranolol was compared to placebo, the 95% prediction interval (–0.62 to 1.82) was wider than the significant confidence interval (0.03-1.17), and comprised both beneficial and detrimental effects. A similar result was found with topiramate, with a prediction interval of –0.62 to 1.80 extending into nonsignificant effects (95% CI, 0.03-1.15). In both cases, significant effects were found only when the prediction interval was 70%.

In a long-term analysis (greater than 6 months), no treatment outperformed placebo.

The treatments generally were acceptable. The researchers found no significant difference in tolerability between any of the treatments and each other or placebo. Safety data analyzed from 13 trials revealed no significant differences between treatments and placebo.

“Because specific effects of drugs are associated with the size of the placebo effect, the lack of drug efficacy in our NMA [network meta-analysis] could be owing to a comparatively high placebo effect in children. In fact, there is indirect evidence [from other studies] that the placebo effect is more pronounced in children and adolescents than in adults,” Dr. Locher and associates said. They suggested that studies were needed to quantify the placebo effect in pediatric migraine, and if it was large, to develop innovative therapies making use of this.

The findings should lead to some changes in practice, Boris Zernikow, MD, PhD, of Children’s and Adolescents’ Hospital Datteln (Germany) wrote in an accompanying editorial.

Pharmacological prophylactic treatment of childhood migraine should be an exception rather than the rule, and nonpharmacologic approaches should be emphasized, particularly because the placebo effect is magnified in children, he said.

Many who suffer migraines in childhood will continue to be affected in adulthood, so pediatric intervention is a good opportunity to instill effective strategies. These include: using abortive medication early in an attack and using antimigraine medications for only that specific type of headache; engaging in physical activity to reduce migraine attacks; getting sufficient sleep; and learning relaxation and other psychological approaches to counter migraines.

Dr. Zernikow had no relevant financial disclosures. One study author received grants from Amgen and other support from Grunenthal and Akelos. The study received funding from the Sara Page Mayo Endowment for Pediatric Pain Research, Education, and Treatment; the Swiss National Science Foundation; the Schweizer-Arau-Foundation; and the Theophrastus Foundation.

SOURCES: Locher C et al. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5856; Zernikow B. JAMA Pediatrics. 2020 Feb 10. doi: 10.1001/jamapediatrics.2019.5907.

Women with breast cancer may be receiving treatments that are discordant with guideline recommendations for genetic subtypes of disease, based on a retrospective analysis of more than 20,000 patients.

Radiotherapy and chemotherapy practices were particularly out of alignment with guidelines, reported lead author Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues.

“Integrating genetic testing into breast cancer care has been complex and challenging,” the investigators wrote in JAMA Oncology. “There is wide variability in which clinicians order testing and disclose results, in the clinical significance of results, and in how clinicians interpret results to patients.”

According to the investigators, while germline testing is on the rise, little is known about how these test results are translating to clinical care.

To learn more, the investigators evaluated data from 20,568 women with stage 0-III breast cancer who entered the Surveillance, Epidemiology, and End Results registries of Georgia and California between 2014 and 2016.

Three treatment types were evaluated: surgery (bilateral vs. unilateral mastectomy), radiotherapy after lumpectomy, and chemotherapy. Treatment selection was compared with test results for breast cancer–associated genes, such as BRCA1/2, TP53, PTEN, and others. Associations were then compared with guideline recommendations.

Data analysis suggested that many clinicians were correctly using genetic test results to guide surgical decisions. For example, almost two-thirds (61.7%) of women with a BRCA mutation underwent bilateral mastectomy, compared with one-quarter (24.3%) who were BRCA negative (odds ratio, 5.52). For other pathogenic variants, the rate of bilateral mastectomy was still elevated, albeit to a lesser degree (OR, 2.41).

Generally, these practices align with recommendations, the investigators wrote, noting that research supports bilateral mastectomy with BRCA1/2, TP53, and PTEN variants, while data are lacking for other genetic subtypes.

Radiotherapy and chemotherapy practices were more discordant with guidelines. For example, women with a BRCA mutation were 78% less likely to receive radiotherapy after lumpectomy (OR, 0.22) and 76% more likely to receive chemotherapy for early-stage, hormone-positive disease (OR, 1.76). According to investigators, these findings suggest possible trends in undertreatment and overtreatment, respectively.

“We believe more research is needed to confirm our results and to evaluate long-term outcomes of pathogenic variant carriers to understand treatment decision making and consequences,” the investigators concluded.

The study was funded by the National Institutes of Health and the California Department of Public Health. The investigators reported relationships with Myriad Genetics, Genomic Health, Roche, and other companies.

SOURCE: Kurian AW et al. JAMA Oncol. 2020 Feb 6. doi: 10.1001/jamaoncol.2019.6400.

Women with breast cancer may be receiving treatments that are discordant with guideline recommendations for genetic subtypes of disease, based on a retrospective analysis of more than 20,000 patients.

Radiotherapy and chemotherapy practices were particularly out of alignment with guidelines, reported lead author Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues.

“Integrating genetic testing into breast cancer care has been complex and challenging,” the investigators wrote in JAMA Oncology. “There is wide variability in which clinicians order testing and disclose results, in the clinical significance of results, and in how clinicians interpret results to patients.”

According to the investigators, while germline testing is on the rise, little is known about how these test results are translating to clinical care.

To learn more, the investigators evaluated data from 20,568 women with stage 0-III breast cancer who entered the Surveillance, Epidemiology, and End Results registries of Georgia and California between 2014 and 2016.

Three treatment types were evaluated: surgery (bilateral vs. unilateral mastectomy), radiotherapy after lumpectomy, and chemotherapy. Treatment selection was compared with test results for breast cancer–associated genes, such as BRCA1/2, TP53, PTEN, and others. Associations were then compared with guideline recommendations.

Data analysis suggested that many clinicians were correctly using genetic test results to guide surgical decisions. For example, almost two-thirds (61.7%) of women with a BRCA mutation underwent bilateral mastectomy, compared with one-quarter (24.3%) who were BRCA negative (odds ratio, 5.52). For other pathogenic variants, the rate of bilateral mastectomy was still elevated, albeit to a lesser degree (OR, 2.41).

Generally, these practices align with recommendations, the investigators wrote, noting that research supports bilateral mastectomy with BRCA1/2, TP53, and PTEN variants, while data are lacking for other genetic subtypes.

Radiotherapy and chemotherapy practices were more discordant with guidelines. For example, women with a BRCA mutation were 78% less likely to receive radiotherapy after lumpectomy (OR, 0.22) and 76% more likely to receive chemotherapy for early-stage, hormone-positive disease (OR, 1.76). According to investigators, these findings suggest possible trends in undertreatment and overtreatment, respectively.

“We believe more research is needed to confirm our results and to evaluate long-term outcomes of pathogenic variant carriers to understand treatment decision making and consequences,” the investigators concluded.

The study was funded by the National Institutes of Health and the California Department of Public Health. The investigators reported relationships with Myriad Genetics, Genomic Health, Roche, and other companies.

SOURCE: Kurian AW et al. JAMA Oncol. 2020 Feb 6. doi: 10.1001/jamaoncol.2019.6400.

Women with breast cancer may be receiving treatments that are discordant with guideline recommendations for genetic subtypes of disease, based on a retrospective analysis of more than 20,000 patients.

Radiotherapy and chemotherapy practices were particularly out of alignment with guidelines, reported lead author Allison W. Kurian, MD, of Stanford (Calif.) University, and colleagues.

“Integrating genetic testing into breast cancer care has been complex and challenging,” the investigators wrote in JAMA Oncology. “There is wide variability in which clinicians order testing and disclose results, in the clinical significance of results, and in how clinicians interpret results to patients.”

According to the investigators, while germline testing is on the rise, little is known about how these test results are translating to clinical care.

To learn more, the investigators evaluated data from 20,568 women with stage 0-III breast cancer who entered the Surveillance, Epidemiology, and End Results registries of Georgia and California between 2014 and 2016.

Three treatment types were evaluated: surgery (bilateral vs. unilateral mastectomy), radiotherapy after lumpectomy, and chemotherapy. Treatment selection was compared with test results for breast cancer–associated genes, such as BRCA1/2, TP53, PTEN, and others. Associations were then compared with guideline recommendations.

Data analysis suggested that many clinicians were correctly using genetic test results to guide surgical decisions. For example, almost two-thirds (61.7%) of women with a BRCA mutation underwent bilateral mastectomy, compared with one-quarter (24.3%) who were BRCA negative (odds ratio, 5.52). For other pathogenic variants, the rate of bilateral mastectomy was still elevated, albeit to a lesser degree (OR, 2.41).

Generally, these practices align with recommendations, the investigators wrote, noting that research supports bilateral mastectomy with BRCA1/2, TP53, and PTEN variants, while data are lacking for other genetic subtypes.

Radiotherapy and chemotherapy practices were more discordant with guidelines. For example, women with a BRCA mutation were 78% less likely to receive radiotherapy after lumpectomy (OR, 0.22) and 76% more likely to receive chemotherapy for early-stage, hormone-positive disease (OR, 1.76). According to investigators, these findings suggest possible trends in undertreatment and overtreatment, respectively.

“We believe more research is needed to confirm our results and to evaluate long-term outcomes of pathogenic variant carriers to understand treatment decision making and consequences,” the investigators concluded.

The study was funded by the National Institutes of Health and the California Department of Public Health. The investigators reported relationships with Myriad Genetics, Genomic Health, Roche, and other companies.

SOURCE: Kurian AW et al. JAMA Oncol. 2020 Feb 6. doi: 10.1001/jamaoncol.2019.6400.

For the second time during the 2019-2020 flu season, activity measures have climbed into noteworthy territory.

The proportion of outpatient visits for influenza-like illness (ILI) reached its highest December level, 7.1%, since 2003 and then dropped for 2 weeks. Three weeks of increases since then, however, have the outpatient-visit rate at 6.7% for the week ending Feb. 1, 2020, the Centers for Disease Control and Prevention reported. The baseline rate for the United States is 2.4%.

That rate of 6.7% is already above the highest rates recorded in eight of the last nine flu seasons, and another increase could mean a second, separate trip above 7.0% in the 2019-2020 season – something that has not occurred since national tracking began in 1997, CDC data show.

Those same data also show that, from 1997-1998 to 2018-2019, the United States has spent a total of 11 weeks above the 7.0% mark for ILI-related visits.

Another important measure on the rise, the proportion of respiratory specimens testing positive for influenza, reached a new high for the season, 29.8%, during the week of Feb. 1, the CDC’s influenza division said.

Tests at clinical laboratories also show that predominance is continuing to switch from type B (45.6%) to type A (54.4%), the influenza division noted. Overall predominance for the season, however, continues to favor type B, 59.3% to 40.7%.

The percentage of deaths caused by pneumonia and influenza, which passed the threshold for epidemic of 7.2% back in early January, has been trending downward for the last 3 weeks and was 7.1% as of Feb. 1, according to the influenza division.

ILI-related deaths among children continue to remain high, with a total count of 78 for the season after another 10 deaths were reported during the week ending Feb. 1, the CDC reported. Comparable numbers for the last three seasons are 44 (2018-2019), 97 (2017-2018), and 35 (2016-2017).

The CDC estimates put the total number of ILIs at around 22 million for the season so far, leading to 210,000 hospitalizations. The agency said that it expects to release estimates of vaccine effectiveness later this month.

[email protected]

For the second time during the 2019-2020 flu season, activity measures have climbed into noteworthy territory.

The proportion of outpatient visits for influenza-like illness (ILI) reached its highest December level, 7.1%, since 2003 and then dropped for 2 weeks. Three weeks of increases since then, however, have the outpatient-visit rate at 6.7% for the week ending Feb. 1, 2020, the Centers for Disease Control and Prevention reported. The baseline rate for the United States is 2.4%.

That rate of 6.7% is already above the highest rates recorded in eight of the last nine flu seasons, and another increase could mean a second, separate trip above 7.0% in the 2019-2020 season – something that has not occurred since national tracking began in 1997, CDC data show.

Those same data also show that, from 1997-1998 to 2018-2019, the United States has spent a total of 11 weeks above the 7.0% mark for ILI-related visits.

Another important measure on the rise, the proportion of respiratory specimens testing positive for influenza, reached a new high for the season, 29.8%, during the week of Feb. 1, the CDC’s influenza division said.

Tests at clinical laboratories also show that predominance is continuing to switch from type B (45.6%) to type A (54.4%), the influenza division noted. Overall predominance for the season, however, continues to favor type B, 59.3% to 40.7%.

The percentage of deaths caused by pneumonia and influenza, which passed the threshold for epidemic of 7.2% back in early January, has been trending downward for the last 3 weeks and was 7.1% as of Feb. 1, according to the influenza division.

ILI-related deaths among children continue to remain high, with a total count of 78 for the season after another 10 deaths were reported during the week ending Feb. 1, the CDC reported. Comparable numbers for the last three seasons are 44 (2018-2019), 97 (2017-2018), and 35 (2016-2017).

The CDC estimates put the total number of ILIs at around 22 million for the season so far, leading to 210,000 hospitalizations. The agency said that it expects to release estimates of vaccine effectiveness later this month.

[email protected]

For the second time during the 2019-2020 flu season, activity measures have climbed into noteworthy territory.

The proportion of outpatient visits for influenza-like illness (ILI) reached its highest December level, 7.1%, since 2003 and then dropped for 2 weeks. Three weeks of increases since then, however, have the outpatient-visit rate at 6.7% for the week ending Feb. 1, 2020, the Centers for Disease Control and Prevention reported. The baseline rate for the United States is 2.4%.

That rate of 6.7% is already above the highest rates recorded in eight of the last nine flu seasons, and another increase could mean a second, separate trip above 7.0% in the 2019-2020 season – something that has not occurred since national tracking began in 1997, CDC data show.

Those same data also show that, from 1997-1998 to 2018-2019, the United States has spent a total of 11 weeks above the 7.0% mark for ILI-related visits.

Another important measure on the rise, the proportion of respiratory specimens testing positive for influenza, reached a new high for the season, 29.8%, during the week of Feb. 1, the CDC’s influenza division said.

Tests at clinical laboratories also show that predominance is continuing to switch from type B (45.6%) to type A (54.4%), the influenza division noted. Overall predominance for the season, however, continues to favor type B, 59.3% to 40.7%.

The percentage of deaths caused by pneumonia and influenza, which passed the threshold for epidemic of 7.2% back in early January, has been trending downward for the last 3 weeks and was 7.1% as of Feb. 1, according to the influenza division.

ILI-related deaths among children continue to remain high, with a total count of 78 for the season after another 10 deaths were reported during the week ending Feb. 1, the CDC reported. Comparable numbers for the last three seasons are 44 (2018-2019), 97 (2017-2018), and 35 (2016-2017).

The CDC estimates put the total number of ILIs at around 22 million for the season so far, leading to 210,000 hospitalizations. The agency said that it expects to release estimates of vaccine effectiveness later this month.

[email protected]

A single dose of the human papillomavirus vaccine is as effective as two or three doses for preventing cervical cancer in girls and women vaccinated at 15-19 years of age, based on data from a retrospective study of more than 100,000 girls and women.

The Centers for Disease Control and Prevention’s current recommendations include a two-dose vaccine schedule for the HPV vaccine for girls and boys younger than 15 years, and a three-dose schedule for girls and young women aged 16-26 years who had their first dose before turning 15.

However, rates of HPV vaccination in the United States fall short of those in other developed nations, and evidence supporting the protective value of a specific number of vaccine doses are mixed, wrote Ana M. Rodriguez, MD, MPH, of the University of Texas Medical Branch at Galveston, and colleagues. Fewer than three doses could have benefits, including easier logistics, lower costs, higher acceptance rates, and fewer side effects, they said. The study was published in Cancer.

The researchers reviewed data from 66,541 girls and women aged 9-26 years who had received at least one dose of HPV vaccine (4vHPV) between Jan. 1, 2006, and June 30, 2015, and 66,541 matched unvaccinated controls. The primary outcomes were histologically confirmed preinvasive cervical disease and high-grade cytology.

Overall, the adjusted hazard ratios for histologically confirmed preinvasive cervical disease among patients vaccinated at the ages of 15-19 years with one, two, and three doses were similar, at 0.64, 0.72, and 0.66, respectively, compared with unvaccinated individuals.

The risk of high-grade cytology was significantly lower for girls and women who received three doses at age 15-19 years, compared with unvaccinated individuals, but no difference was seen in high-grade cytology between unvaccinated individuals and those who received one or two doses. In addition, the unadjusted rate of preinvasive cervical disease at 5 years was 2.65% for unvaccinated teens aged 15-19 years, compared with 1.62%, 1.99%, and 1.86% in the one-, two- and three-dose groups, respectively.The findings were limited by several factors, including the use of billing codes to determine outcomes and the inability to determine potential vaccination through multiple insurance carriers, and the inclusion only of privately insured patients from the claims database, the researchers noted.

However, the results support findings from previous studies and show a similar level of association between varying vaccine doses and preinvasive cervical lesions in the 15- to 19-year-old population, they said.

“Efforts should focus on not only the need to initiate the HPV vaccine but also the need for beginning and continuing cervical cancer screening among young women who are vaccinated at older ages (18 years and older),” they said.

In an editorial accompanying the study, Julia M.L. Brotherton, PhD, MPH, and Karin Sundström, MD, PhD, of the University of Melbourne, Australia, and the Karolinska Institutet, Stockholm, respectively, wrote that the study’s strengths included the large numbers of girls and women who received a single dose of the HPV vaccine, compared with previous studies, as well as the adjustments for histories of sexually transmitted infections and pregnancy (Cancer. 2020 Feb 10. doi: 10.1002/cncr.32696). “Initial observational data from vaccination programs did not support equivalent one-dose protection against genital warts or cervical disease, but such data may have been confounded by potentially higher risk characteristics of women who only ever received one or two doses of an intended three-dose course i.e., women noncompliant with the vaccine program [amplified by the monitoring of outcomes among the initial catch-up populations of already infected women]) and by the inherent bias that prevalent infection/disease is more likely to become apparent coincidently with the earlier doses in a vaccine course,” they said. The study findings have implications for global goals to eliminate cervical cancer, the editorial authors noted.

“If one dose of an HPV vaccine were sufficient for effective protection, HPV vaccine implementation and scale-up would require less logistics (while being amenable to a periodic campaign approach), available doses could be extended further, and the overall cost would be lower,” they said.

The study was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health, and by the Cancer Prevention Research Institute of Texas. The researchers had no financial conflicts to disclose.

Dr. Brotherton disclosed serving as an investigator for Seqirus and Merck; Dr. Sundström disclosed research funding for her institution from Merck and MSD Sweden.

SOURCE: Rodriguez AM et al. Cancer. 2020 Feb 10. doi: 10.1002/cncr.32700.

A single dose of the human papillomavirus vaccine is as effective as two or three doses for preventing cervical cancer in girls and women vaccinated at 15-19 years of age, based on data from a retrospective study of more than 100,000 girls and women.

The Centers for Disease Control and Prevention’s current recommendations include a two-dose vaccine schedule for the HPV vaccine for girls and boys younger than 15 years, and a three-dose schedule for girls and young women aged 16-26 years who had their first dose before turning 15.

However, rates of HPV vaccination in the United States fall short of those in other developed nations, and evidence supporting the protective value of a specific number of vaccine doses are mixed, wrote Ana M. Rodriguez, MD, MPH, of the University of Texas Medical Branch at Galveston, and colleagues. Fewer than three doses could have benefits, including easier logistics, lower costs, higher acceptance rates, and fewer side effects, they said. The study was published in Cancer.

The researchers reviewed data from 66,541 girls and women aged 9-26 years who had received at least one dose of HPV vaccine (4vHPV) between Jan. 1, 2006, and June 30, 2015, and 66,541 matched unvaccinated controls. The primary outcomes were histologically confirmed preinvasive cervical disease and high-grade cytology.

Overall, the adjusted hazard ratios for histologically confirmed preinvasive cervical disease among patients vaccinated at the ages of 15-19 years with one, two, and three doses were similar, at 0.64, 0.72, and 0.66, respectively, compared with unvaccinated individuals.

The risk of high-grade cytology was significantly lower for girls and women who received three doses at age 15-19 years, compared with unvaccinated individuals, but no difference was seen in high-grade cytology between unvaccinated individuals and those who received one or two doses. In addition, the unadjusted rate of preinvasive cervical disease at 5 years was 2.65% for unvaccinated teens aged 15-19 years, compared with 1.62%, 1.99%, and 1.86% in the one-, two- and three-dose groups, respectively.The findings were limited by several factors, including the use of billing codes to determine outcomes and the inability to determine potential vaccination through multiple insurance carriers, and the inclusion only of privately insured patients from the claims database, the researchers noted.

However, the results support findings from previous studies and show a similar level of association between varying vaccine doses and preinvasive cervical lesions in the 15- to 19-year-old population, they said.

“Efforts should focus on not only the need to initiate the HPV vaccine but also the need for beginning and continuing cervical cancer screening among young women who are vaccinated at older ages (18 years and older),” they said.

In an editorial accompanying the study, Julia M.L. Brotherton, PhD, MPH, and Karin Sundström, MD, PhD, of the University of Melbourne, Australia, and the Karolinska Institutet, Stockholm, respectively, wrote that the study’s strengths included the large numbers of girls and women who received a single dose of the HPV vaccine, compared with previous studies, as well as the adjustments for histories of sexually transmitted infections and pregnancy (Cancer. 2020 Feb 10. doi: 10.1002/cncr.32696). “Initial observational data from vaccination programs did not support equivalent one-dose protection against genital warts or cervical disease, but such data may have been confounded by potentially higher risk characteristics of women who only ever received one or two doses of an intended three-dose course i.e., women noncompliant with the vaccine program [amplified by the monitoring of outcomes among the initial catch-up populations of already infected women]) and by the inherent bias that prevalent infection/disease is more likely to become apparent coincidently with the earlier doses in a vaccine course,” they said. The study findings have implications for global goals to eliminate cervical cancer, the editorial authors noted.

“If one dose of an HPV vaccine were sufficient for effective protection, HPV vaccine implementation and scale-up would require less logistics (while being amenable to a periodic campaign approach), available doses could be extended further, and the overall cost would be lower,” they said.

The study was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health, and by the Cancer Prevention Research Institute of Texas. The researchers had no financial conflicts to disclose.

Dr. Brotherton disclosed serving as an investigator for Seqirus and Merck; Dr. Sundström disclosed research funding for her institution from Merck and MSD Sweden.

SOURCE: Rodriguez AM et al. Cancer. 2020 Feb 10. doi: 10.1002/cncr.32700.

A single dose of the human papillomavirus vaccine is as effective as two or three doses for preventing cervical cancer in girls and women vaccinated at 15-19 years of age, based on data from a retrospective study of more than 100,000 girls and women.

The Centers for Disease Control and Prevention’s current recommendations include a two-dose vaccine schedule for the HPV vaccine for girls and boys younger than 15 years, and a three-dose schedule for girls and young women aged 16-26 years who had their first dose before turning 15.

However, rates of HPV vaccination in the United States fall short of those in other developed nations, and evidence supporting the protective value of a specific number of vaccine doses are mixed, wrote Ana M. Rodriguez, MD, MPH, of the University of Texas Medical Branch at Galveston, and colleagues. Fewer than three doses could have benefits, including easier logistics, lower costs, higher acceptance rates, and fewer side effects, they said. The study was published in Cancer.

The researchers reviewed data from 66,541 girls and women aged 9-26 years who had received at least one dose of HPV vaccine (4vHPV) between Jan. 1, 2006, and June 30, 2015, and 66,541 matched unvaccinated controls. The primary outcomes were histologically confirmed preinvasive cervical disease and high-grade cytology.

Overall, the adjusted hazard ratios for histologically confirmed preinvasive cervical disease among patients vaccinated at the ages of 15-19 years with one, two, and three doses were similar, at 0.64, 0.72, and 0.66, respectively, compared with unvaccinated individuals.

The risk of high-grade cytology was significantly lower for girls and women who received three doses at age 15-19 years, compared with unvaccinated individuals, but no difference was seen in high-grade cytology between unvaccinated individuals and those who received one or two doses. In addition, the unadjusted rate of preinvasive cervical disease at 5 years was 2.65% for unvaccinated teens aged 15-19 years, compared with 1.62%, 1.99%, and 1.86% in the one-, two- and three-dose groups, respectively.The findings were limited by several factors, including the use of billing codes to determine outcomes and the inability to determine potential vaccination through multiple insurance carriers, and the inclusion only of privately insured patients from the claims database, the researchers noted.

However, the results support findings from previous studies and show a similar level of association between varying vaccine doses and preinvasive cervical lesions in the 15- to 19-year-old population, they said.

“Efforts should focus on not only the need to initiate the HPV vaccine but also the need for beginning and continuing cervical cancer screening among young women who are vaccinated at older ages (18 years and older),” they said.

In an editorial accompanying the study, Julia M.L. Brotherton, PhD, MPH, and Karin Sundström, MD, PhD, of the University of Melbourne, Australia, and the Karolinska Institutet, Stockholm, respectively, wrote that the study’s strengths included the large numbers of girls and women who received a single dose of the HPV vaccine, compared with previous studies, as well as the adjustments for histories of sexually transmitted infections and pregnancy (Cancer. 2020 Feb 10. doi: 10.1002/cncr.32696). “Initial observational data from vaccination programs did not support equivalent one-dose protection against genital warts or cervical disease, but such data may have been confounded by potentially higher risk characteristics of women who only ever received one or two doses of an intended three-dose course i.e., women noncompliant with the vaccine program [amplified by the monitoring of outcomes among the initial catch-up populations of already infected women]) and by the inherent bias that prevalent infection/disease is more likely to become apparent coincidently with the earlier doses in a vaccine course,” they said. The study findings have implications for global goals to eliminate cervical cancer, the editorial authors noted.

“If one dose of an HPV vaccine were sufficient for effective protection, HPV vaccine implementation and scale-up would require less logistics (while being amenable to a periodic campaign approach), available doses could be extended further, and the overall cost would be lower,” they said.

The study was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health, and by the Cancer Prevention Research Institute of Texas. The researchers had no financial conflicts to disclose.

Dr. Brotherton disclosed serving as an investigator for Seqirus and Merck; Dr. Sundström disclosed research funding for her institution from Merck and MSD Sweden.

SOURCE: Rodriguez AM et al. Cancer. 2020 Feb 10. doi: 10.1002/cncr.32700.