Non-opioid medication on the rise as U.S. combats opioid crisis

Use of opioid-alternative pain medications is surging as the U.S. tries to wean off the addictive painkillers, giving physicians concern that the opioid crisis will be substituted by a new prescription drug epidemic, according to a new report.

Nearly two-thirds of primary-care physicians shared that sentiment while nearly three-quarters worry that chronic pain patients will turn to illicit drugs if they do not have access to prescription opioids, according to a new report from Quest Diagnostics, which polled 500 primary-care doctors and analyzed 4.4 million lab test results. The report reflects physicians’ apprehension that the healthcare system is ill-equipped to properly transition from an over-utilization of opioids.

“What most fail to realize is that we have a dual crisis in this country,” said Dr. Jeffrey Gudin, a senior medical advisor for Quest and a pain management specialist at Englewood Hospital and Medical Center in New Jersey. “There is no question that people misuse substances that make them feel good, but there is also a crisis of chronic pain, of which there is no cure.”

Providers worry that the opioid manufacturing caps and restrictions from insurers and providers are cutting off the much-needed supply for cancer patients and others with chronic pain.

It is considerably harder to treat chronic pain patients, 83% of physicians surveyed in the report said. A similar share said they are reluctant to take on patients who are currently prescribed opioids.

“Not a day passes that a patient doesn’t shed real tears about having opioid doses tapered,” said Gudin, adding that guidelines the Centers for Disease Control and Prevention issued in 2016 led to a widespread reduction in opioid doses without alternative treatment options.

More than 70% of doctors said that although there will likely be a decrease in opioid-related deaths, more patients will not have their pain properly managed.

Meanwhile, gabapentin—an anticonvulsant that can be used to relieve neuropathic pain and is often prescribed as an alternative to opioids for managing chronic pain—was detected in more than half of opioid overdose deaths, according to the CDC. Quest’s data show that 13.4% of patient test results showed non-prescribed gabapentin in 2018, up from 9.6% in 2017. Gabapentin trailed only marijuana and alcohol at 14% each.

Gabapentin is one of only three drug groups for which misuse, often improper combinations of drugs, increased from 2017 to 2018. The other two were alcohol and nonprescribed fentanyl. Physicians were also concerned about the abuse of benzodiazepines and amphetamines.

“Pain patients have learned if their psychiatrist gives them Valium, then they don’t tell their doctor because they won’t give them opioids,” Gudin said. Part of it is on the patient; part is on the clinician, he said, adding that Quest has been promoting a major educational campaign about drug mixing.

Physicians may be overconfident in their ability to recognize prescription drug misuse and drug mixing is often underestimated, the report indicated. Nearly all doctors felt confident in their ability to discuss risks associated with prescription drug misuse with patients, but only 55% said they actually addressed it with most of their patients who were prescribed controlled substances in the past month.

Physicians recognized that they need help monitoring prescription drug use. At least seven out of 10 doctors said that they wish they had more training on how to taper off opioids, when to refer patients to pain specialists, how to spot addictive behavior and what to do after the fact.

Prescription drug monitoring helps, the vast majority of physicians said, but half indicated that there are cost and access obstacles.

More patients are using acupuncture, physical therapy, massage and other pain-management alternatives, although payer coverage issues remain, Gudin said

“These are things that are not taught in medical school,” he said. “I think the medical society needs to do a better job educating doctors on the front line, which are primary-care clinicians.”

https://www.modernhealthcare.com/providers/non-opioid-medication-rise-us-combats-opioid-crisis

CBO estimate on Pelosi drug bill misses its long-term impact on health

House Democrats got an early Halloween treat with the Congressional Budget Office’s review of HR 3, Speaker Nancy Pelosi’s proposed drug pricing reform, also known as the Lower Drug Costs Now Act. The headline was the estimated $345 billion Medicare savings over seven years. Key to the CBO’s score was the provision in the bill authorizing the health and human services secretary to negotiate prices for 125 branded drugs, plus insulin, with a price ceiling tied to international benchmarks.
There is no doubt that the Pelosi bill would reduce drug prices. A fair question — which critics are asking — is whether CBO considered the long-term consequences, especially for health. Most people understand there is a tradeoff between prices and innovation. As research has made clear, revenues generated by today’s top-selling drugs finance the innovation necessary to discover new treatments, and the U.S. is the source of perhaps 70% of global industry profits.
Lowering prices in the U.S. will certainly suppress innovation.

The CBO estimated that the Pelosi bill would cause eight to 15 fewer drugs to come to market over the next 10 years while 300 total new drugs would be marketed over that period — leading to about a 4% reduction in the rate of innovation.

How did CBO get its figure? Much of the evidence is buried in footnotes. But this is actually an active area of research. Economists have tried to identify how prices affect innovation, often relying on natural experiments that affect the demand for drugs, rather than the supply. These include changes in the demographic composition of the population, trends in mortality rates, or policy changes like the passage of Medicare Part D.
In all cases, price reductions are associated with less innovation, although the magnitude varies. A 1% reduction in price has been estimated to reduce innovation — meaning the number of new drugs launched — by as little as 0.25% or as much as 4%.
What the CBO missed, however, is important. It scored the policy going out 10 years — and three of them are missed because the law wouldn’t take effect until 2023. Compare that with Tuft University’s estimate that the process to develop and win approval for new drugs takes 15 years. Thus, the CBO scoring window misses the period when the policy might have the largest effects.
Economists know that long-run effects of policy are often greater than short-run effects. When a company is making decisions about investments that might pay off in 15 years, policy uncertainty comes into play. If the Pelosi bill is seen as just the start, with more drugs likely to become subject to government price negotiation, then the effects on innovation will be even more dramatic — something the CBO probably did not factor into its calculations.
What we ultimately care about is not the impact on drug launches but the impact on population health. Here the news is not good. Companies seeking cures for our most vexing diseases — like Alzheimer’s or diabetes — will give up potential avenues of research.

Several colleagues and I examined the long-term consequences of price controls using the Future Elderly Model, an economic-demographic microsimulation developed at the University of Southern California’s Roybal Center for Health Policy Simulation with funding from the National Institute on Aging. This model has been used to explore a variety of policy questions, ranging from the fiscal future of the U.S. to the role biomedical innovation can play in future health outcomes.
The model showed that price controls in the U.S. would harm health in the long run. Our best estimate — published in the journal Health Affairs — is that once controls are fully implemented, life expectancy at older ages would be reduced by about 3%. This may not seem like a lot, but that is similar to the effect if the U.S. “forgot” how to reopen blocked cardiac arteries after a heart attack.
Perhaps an analogy with climate change is appropriate. Many believe the long-term effects are so horrendous that we need to act now to avoid them. In the case of drug price controls, the long-term harm could also be horrendous, but there is an easy policy solution: tread carefully.
Dana P. Goldman is a professor of public policy, pharmacy, and economics at the University of Southern California and director of the Leonard D. Schaeffer Center for Health Policy & Economics. He is a scientific adviser to and holds equity in Precision Health Economics, a consultancy to life sciences companies.

CBO estimate on Pelosi drug bill misses its long-term impact on health

Glenmark spin-out aims to challenge Amgen, others in cancer bispecific field

A new spin-out of an Indian company best known for making generic drugs aims to compete with top biotechs like Amgen and Regeneron in one of oncology’s biggest research areas.
Officially launched Tuesday, Ichnos Sciences is an offshoot of Glenmark Pharmaceuticals, from which it will inherit five experimental medicines, two research laboratories and roughly 350 employees.
While its pipeline encompasses autoimmune diseases and pain, Ichnos will focus foremost on a type of cancer drugs known as bispecific antibodies.
For years a sideshow in oncology research, bispecifics are now at the center of efforts to find new ways to recruit the body’s immune system in an attack on tumors.

Amgen’s widely considered a leader in the field, having won U.S. approval five years ago for the first cancer bispecific in its leukemia drug Blincyto. The biotech is advancing nearly a dozen more through clinical testing.
Other large drugmakers, most notably Roche and Regeneron, are investing as well, aiming first at blood cancers like lymphoma, multiple myeloma and leukemia.
Ichnos is well aware of the competition it faces. Yet CEO Alessandro Riva, who left a high-profile post running Gilead’s cancer business to join the new company, argues the science behind designing bispecifics has yet to be settled.
“This is a still evolving field,” he said in an interview with BioPharma Dive. “No company has declared victory in terms of having identified the best composition of an immune cell engager. There is a lot to do and we’re just at the beginning.”
Unlike regular antibodies, bispecifics can bind to two cell targets rather than one. This characteristic allows drugmakers to design a therapy that brings immune cells into contact with tumor cells, potentially precipitating a potent immune response.
In theory, bispecifics could offer a simpler approach than CAR-T cell therapy, which also seeks to involve the immune system in an attack on cancer.
Practically, however, initial efforts to build a bispecific resulted in molecules with structural disadvantages. Amgen’s Blincyto, for example, has a short half life in the blood and must be dosed continuously due to how the drug is constructed.
Bispecifics are newly in vogue, though, because some of those early challenges have been solved and a second generation of clinical candidates are yielding promising data.
To start, Ichnos will advance two bispecific drugs. One, in Phase 1 testing for breast cancer, targets the HER2 protein along with an immune cell protein called CD3. The other, also in Phase 1, binds to CD3 as well as a protein called CD38 that’s often found on multiple myeloma cells.
While efforts by Amgen and others are better known, Ichnos’ myeloma candidate actually entered human testing before a similar candidate from Amgen. Results won’t be available for some time, though, with data readouts anticipated in 2021.
Glenmark will fund Ichnos’ work for now, although the spin-out plans to eventually consider an initial public offering, Riva said.
“We’re covered for a certain period of time,” Riva said. “This time is precious for us to continue to build up Ichnos science and make sure we’re fully independent and then able to go to the next step, which is a potential IPO.”
Ichnos will operate two research centers, one in Switzerland and another in India, as well as a development site in New Jersey, out of which it will be based.
Advancing its bispecific platform in cancer will be a priority, but the company is also staked from Glenmark with an anti-OX40 antibody in Phase 2b testing for atopic dermatitis. Data for that program are expected in 2020.
Two Phase 2 candidates in pain will be seen through development, but Ichnos does not plan to invest in pain research more broadly, Riva said.
In spinning out Ichnos, Glenmark is betting new drug development will progress more quickly outside of its walls than alongside its generic and active ingredient businesses.
“The mindset is completely different,” said Riva. “You need to be credible in front of the community with regard to what you’re planning and the science you’re implementing.”
https://www.biopharmadive.com/news/ichnos-glenmark-spin-out-cancer-bispecific-riva/565010/

Drug Delivers ‘Remarkable’ Reduction in Head Injury Deaths

Tranexamic acid (TXA) (multiple brands), an antifibrinolytic used to treat or prevent excessive blood loss, significantly reduces mortality from traumatic brain injury (TBI), results of a large, multicenter, randomized control trial show.
Investigators found that administering TXA within 3 hours of head trauma was associated with a 20% reduction in deaths among those with mild to moderate TBI, with no evidence of adverse effects or complications.
However, there was no apparent reduction in mortality among those with severe head injury.
“This is a landmark study. After decades of research and many unsuccessful attempts, this is the first-ever trial to show that a drug can reduce mortality after traumatic brain injury. Not only do we think this could save hundreds of thousands of lives worldwide, but it will no doubt renew the enthusiasm for drug discovery research for this devastating condition,” study coinvestigator Antonio Belli, MD, neurosurgeon and professor of trauma neurosurgery, University of Birmingham, United Kingdom, said in a statement.
Results of the CRASH-3 study suggest that “all trauma patients should get tranexamic acid at the scene of the injury or as soon as possible thereafter,” study coinvestigator Ian Roberts, MB, professor of epidemiology and public health, London School of Hygiene and Tropical Medicine, told Medscape Medical News.
The study was published online October 14 in the Lancet.

TBI Rising

It is estimated that more than 60 million new cases of TBI occur worldwide every year, and the number is rising. Motor vehicle accidents and falls are the main causes.

Intracranial bleeding is a common complication of TBI. Ongoing intracranial bleeding can lead to an increase in intracranial pressure, as well as brain herniation and death.
TXA reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots.
Several studies in surgical patients “show that if you give them tranexamic acid just before the surgeon cuts them, they bleed less than if you give them a placebo,” said Roberts.
Research has also shown that TXA reduces risk of bleeding in women with postpartum hemorrhage.
An earlier study ― the CRASH­2 trial ― showed that in patients with trauma and major extracranial bleeding, administration of TXA within 3 hours of injury reduced bleeding deaths by one third. However, even a short delay in treatment led to a reduction in benefit.
On the basis of these results, TXA was included in guidelines for the prehospital care of patients with trauma. However, those with isolated TBI were excluded.
“People wondered whether tranexamic acid would be effective in isolated TBI,” said Roberts. “There was no evidence that it’s effective in patients with just head injuries.”

Injury Severity a Factor

For the study, 12,737 patients from 29 countries were randomly assigned to receive either TXA or matching placebo within 3 hours of TBI.

The primary endpoint was head injury death in hospital within 28 days of injury. There were 2560 deaths; the median time to death was 59 hours after injury.
Researchers had outcome data on 9127 patients. Among these, the risk for head injury–related death was 18.5% among the patients who received TXA and 19.8% among those who received placebo (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.86 – 1.02).
A sensitivity analysis excluded patients whose Glasgow Coma Scale (GCS) score was 3 and those with bilateral unreactive pupils.

“For all intents and purposes, these patients are considered unrecoverable at baseline, so before they even received trial treatment,” said Roberts. “They were obviously going to be equally distributed between groups and dilute any treatment effect.”
In this sensitivity analysis, the rate of head injury–related death was 12.5% in the TXA group, compared to 14.0% in the placebo group (RR, 0.89; 95% CI, 0.80 – 1.00).
“When we excluded these patients who were unsurvivable before treatment, there was a bigger treatment effect; the benefit was larger,” said Roberts.

Although the sensitivity analysis excluded patients with bilateral unreactive pupils, patients with unilateral unreactive pupils were not excluded. “If we had excluded those individuals, the treatment effect would get even bigger,” said Roberts.
“The treatment looks very good at preventing head injury deaths where there’s a potential for benefit, so in people who are salvageable, it’s very effective. But the closer you get to unsalvageable, the less and less effective it gets,” he said.

No Adverse Events

With regard to time to treatment, for patients who received the intervention within an hour of injury, the RR of head injury–related death was 0.96 (95% CI, 0.79 – 1.17); for those who received the intervention more than 1 to 3 hours after injury, the RR was 0.93 (95% CI 0.85 to 1.02); and for those who received the intervention more than 3 hours after injury, the RR was 0.94 (95% CI 0.81 to 1.09).
The investigators note that patients who are treated soon after TBI often have more severe trauma, and so the effect of time to treatment may be confounded by injury severity.
After adjusting for GCS, systolic blood pressure, and age, early treatment was more effective than later treatment in patients with mild or moderate head injury (P = .005), but there was no obvious effect of time to treatment among patients with severe head injury (P = .73).
The drug is more effective in less severely injured patients because “you can only prevent something that hasn’t already happened,” said Roberts.
“It’s probably less effective in severely comatose patients because they have already bled into their brain. The most potential for benefit is in patients with mild or moderate head injury who are bleeding more slowly into the brain,” he said.
The analysis also showed a substantial reduction in head injury–related deaths within 24 hours of the injury in treated patients.
The findings should make guidelines simpler ― perhaps with the recommendation that all trauma patients receive a 1-g injection of TXA as soon as possible after a head injury, said Roberts. Ideally, treatment should occur at the scene of the accident or in the ambulance on the way to the hospital, he added.
The researchers assessed the effect of TXA on disability in survivors by comparing the mean Disability Rating Scale score between the TXA and placebo groups. The mean scores were similar between groups and for patients treated within 3 hours and after 3 hours of treatment.
The risk for vascular occlusive events and other complications was similar for both groups. There was no evidence that TXA increased fatal or nonfatal stroke. The risk for seizures was similar between groups, as was the number of other adverse events.
“We know this intervention is safe; there are absolutely no side effects whatsoever,” said Roberts.

Remarkable, Practice Changing

In an accompanying editorial, Andrew P. Cap, MD, PhD, US Army Institute of Surgical Research, Fort Sam Houston, Texas, described the findings as “remarkable” and said they “will change practice.”
It represents “an enormous effort in studying a difficult clinical problem,” said Cap.
Together, CRASH-3, CRASH-2, and the trial of women with peripartum hemorrhage involved more than 53,000 patients in the study of the effects of TXA on bleeding.

“The results of each study independently and together are clear: tranexamic acid reduces risk of death due to bleeding, regardless of the cause,” he writes.
Future studies might explore the effects of increased TXA doses in bleeding patients, or possibly alternative routes of administration, such as intramuscular administration, which might facilitate earlier intervention, he added.
It may also be worth considering combining the antifibrinolytic effects of TXA on bleeding with blockade of bradykinin receptors, which could reduce brain edema and potentially yield greater reductions in mortality.

Commenting on the study for Medscape Medical News, TBI specialist Frank Conidi, MD, immediate past president, Florida Society of Neurology, and director, Florida Center for Headache and Sports Neurology, said he was “quite impressed” with the number of enrolled patients, which provided “significant power” to the results.
Although it’s “wonderful” that the study showed a positive reduction in patient mortality, “the real outcome that you want to look at is disability and quality of life,” said Conidi. “From a clinical perspective, I think there is potential for patients with higher GCS scores, especially given the low adverse event profile.”
Conidi said he would like to know whether the medication’s efficacy differed among patients with different subtypes of bleeding, for example, intracranial hemorrhage, subarachnoid hemorrhage, epidural hematoma, and subdural hematoma.
The study was funded by the JP Moulton Charitable Trust, the National Institute for Health Research Health Technology Assessment, Joint Global Health Trials, the Medical Research Council, the UK Department for International Development, the Global Challenges Research Fund, and the Wellcome Trust. Roberts, Belli, Cap, and Conidi report no relevant financial relationships.
Lancet. Published online October 14, 2019. Full text, Editorial
https://www.medscape.com/viewarticle/919952#vp_1

Lawsuits start for Juul

The suggestion that only black market vape products are connected to vape-related deaths and illness is entirely inaccurate, if you ask two lawyers representing the mother of 18-year-old David Wakefield who suffered from asthma and died while fighting a two-year addiction to Juul Labs Inc.’s nicotine e-cigarettes.

Angela Nehmens and Mahzad Kazempour Hite filed what they say they believe is the first wrongful death lawsuit against e-cigarette giant, Juul Labs. The lawsuit, filed Tuesday in federal district court for the Northern District of California, was brought by Wakefield’s mother, Lisa Vail, on behalf of her son’s estate.

“He continued using Juul and he passed away in the middle of the night,” Nehmens told Yahoo Finance. “His mom has described it to me as someone who came in the middle of the night and stole her son, because otherwise a healthy, active 18-year-old boy doesn’t die out of nowhere. And we know that there are studies that demonstrate that Juul can cause asthma or exacerbate existing asthma.”

‘It’s not just asthma’

Vail alleges that Juul caused her son’s death by regularly inundating him with Juul advertisements and marketing materials that led him to believe the company’s e-cigarettes were safe and did not pose any health risks. Nehmens said Wakefiled was not exhibiting any signs of asthma the day he died, and that his history of asthma was minor. An autopsy is underway. Wakefield’s death certificate currently lists asthma as the cause of death.

Juul can expect additional claims from plaintiffs who exclusively used its products.

“It’s not just asthma,” Nehmens said. “We have other clients who began using Juul when they were minors, who have been intubated. We have one woman who was hospitalized for 30 days after using Juul for three months. She was an exclusive Juul user, and so was Daniel.”

Hite calls into question vape pen ingredients like propylene glycol, a synthetic liquid substance known as safe to ingest, and converts into the toxin formaldehyde when heated to a certain temperature.

“These are things that should have been studied by Juul,” Hite said.

Roswell Park Comprehensive Cancer Center toxicologist and associate professor of oncology, Maciej Goniewicz, told Yahoo Finance in September that formaldehyde is also present in some cigarette tobacco smoke. He raised concerns over solvents used to extract nicotine, and possibly THC.

“Actually it’s the heating of the nicotine solvent, not the nicotine itself, but propylene glycol and vegetable glycerin — those are the solvents for nicotine — and this is what creates this vapor effect. And these two chemicals if they are overheated, if temperatures go too high, then they decompose. And once they decompose, they create some of the toxic chemicals, and one of those toxic chemicals is formaldehyde.”

‘We are getting calls nearly every day’

The lawyers say media reports and warnings from the Center for Disease Control and Prevention (CDC) concerning dangers associated with vaping have increased awareness and the number of allegedly injured parties seeking legal advice.

“We have upwards of 100 clients and we are getting calls nearly every day,” Nehmens said. “We know that these injuries are being seen in exclusively Juul users. They are not cigarette smokers, they’re not using the vape pens for THC oil or anything like that.”

As of October 8, the CDC confirmed 26 deaths associated with the use of e-cigarettes, or vaping, and 1,299 lung injury cases.

Hite said that before 2018 when Juul was required by federal regulators to change its marketing materials and disclosures of potential harm, it had no warning and focused its marketing conversation on Juul as a safer alternative to cigarette smoke. Those types of statements, she said, made their way into Wakefield’s Gmail inbox.

“There’s no actual scientific support for the statement,” that Juul is a safer alternative to cigarette smoking, she said.

“They created an epidemic of young users, most of who did not actually know that they were inhaling a product that even contained nicotine, so they couldn’t appreciate the risk.”

The multi-count complaint seeks compensatory and punitive damages, plus an injunction that would prohibit acts by Juul that the court may conclude threaten injury to members of the public. Vail says Juul is responsible for product design defects, negligence, failure to warn of e-cigarette risks, failure to recall the products, fraudulent concealment of risks, and violations of the Unfair Competition Law Act.

Juul did not immediately respond to a request for comment.

https://finance.yahoo.com/news/juul-labs-lisa-vail-lawsuit-211045744.html

Moody’s: How a public option could impact health insurers’ bottom lines

As the public debate on health reform rolls on, a new report from Moody’s Investors Service analyzes how these different approaches could impact insurers’ bottom lines.

Perhaps unsurprisingly, the analysts warn a full single-payer overhaul would pose an “existential threat” to the finances of health insurers, though a single-payer system would likely include a role of some kind for private payers.
However, the introduction of a public option plan would have a less dramatic impact—depending on how many people enroll in the plan, that is.

“All three of the proposal types we examined focus on increasing access to care while reigning in costs,” Jonathan Siegel, vice president at Moody’s and one of the report’s authors, said in a statement.
“However, they would also affect revenue and profitability across the healthcare industry, although credit implications would depend largely on how many people switch from an existing private insurance plan to a public plan,” Siegel said.

Under a limited public option, the government-run plan would compete in the market directly with insurers, but relatively few people would be eligible, leaving much of their current consumer base intact, Moody’s said.
Moody’s analysts estimate that roughly 20 million people who currently purchase plans on the individual market would be eligible to enroll in a limited public option plan. A public option plan could also attract some of the uninsured population into the health system.
However, under this model the 150 million people who are covered through their employers would be undisturbed, Moody’s said.
A more extensive public option plan, by contrast, would prove more disruption, according to the analysis, as it would give people with employer plans the choice to opt out of that coverage and to instead enroll in the public plan.
If a large number of people were drawn into the public option, it would significantly impact the financial performance of private insurers, Moody’s said. Some public option proposals would automatically enroll some of the uninsured population into the plan, which could further chip away at the employer market, according to the report.
“A public option that can provide similar benefits to those of private plans at reduced costs would eat into the market shares of private insurers and pressure them to lower premiums or increase benefits, eroding their profitability,” the Moody’s analysts wrote.
https://www.fiercehealthcare.com/payer/moody-s-how-a-public-option-could-impact-insurers-bottom-lines

Surgery Beats Meds for True Refractory Heartburn

Use of laparoscopic Nissen fundoplication was significantly superior to medical therapy at 1 year in selected patients with true refractory heartburn, although a third of surgery patients did not respond to the procedure, a randomized Veterans Affairs (VA) study found.
The study also found that actual proton pump inhibitor (PPI)-refractory and reflux-related heartburn was present in only a minority of trial-eligible patients.

Stuart J. Spechler, MD, of Baylor University Medical Center in Houston, and colleagues concluded that systematic workup, including esophageal multi-channel intraluminal impedance-pH (MII-pH) monitoring, is needed to identify a subgroup of patients with PPI-refractory heartburn and reflux hypersensitivity that benefits from surgery.
Writing online in the New England Journal of Medicine, the researchers found the following incidence of treatment success at 1 year in 78 patients from VA medical centers; all the patients had true PPI-refractory heartburn, with success defined as a decrease of at least 50% in the Gastroesophageal Reflux Disease Health-Related Quality of Life score:

• Anti-reflux surgery: 18 of 27 patients (67%, P<0.001)

• Medical treatment: seven of 25 patients (28%, P=0.007)

• Control medical treatment: three of 26 patients (12%, P<0.001)

The difference in the incidence of treatment success between the active medical group and the control medical group was 16 percentage points (95% CI –5 to 38, P=0.17).
In 42 patients referred for PPI-refractory heartburn, gastroesophageal reflux disease (GERD) was in fact relieved with a standardized preliminary 2-week trial of omeprazole (Losec, Prilosec) twice daily, the team reported. Systematic evaluation showed that GERD was not the likely cause of heartburn for an additional 122 patients, with 99 diagnosed with functional heartburn, and 23 with a non-GERD organic disorder.
Spechler and co-authors explained that some patients with reflux symptoms unresponsive to PPIs may not respond to surgery either. This outcome might result from preoperative failure to document that symptoms are truly reflux-related. Alternatively, for patients with reflux hypersensitivity, surgical reduction of reflux might not relieve symptoms generated by a hypersensitive esophagus.

One previous study found that surgery was more likely to fail in patients with atypical symptoms, no response to acid-reducing drugs, or morbid obesity.
Study Details
From August 2012 to December 2015, the investigators recruited 366 patients (280 were men), with a mean age of 48.5.
After the 2-week omeprazole trial, participants with persistent heartburn underwent endoscopy, esophageal biopsy, esophageal manometry, and MII-pH. Following preliminary exclusions, 78 patients, of whom 64 were men and 54 were white, were deemed to have true refractory heartburn. They were randomly assigned to receive the following:

• Laparoscopic Nissen fundoplication to strengthen the lower esophageal sphincter

• Active medical treatment with omeprazole plus baclofen, which reduces esophageal sphincter relaxation, with the neuromodulator desipramine added depending on symptoms

• Control medical treatment (omeprazole plus placebo)

Approximately 40%-50% of patients in each arm of the study had esophageal visceral hypersensitivity alone, with the remainder having abnormal acid reflux on MII-pH monitoring despite continuing PPI use.

The researchers said that despite the superiority of fundoplication shown at 1 year, surgery was not successful in a third of patients, and patients should be advised of that risk beforehand.
“This trial highlights the critical importance of systematic evaluation … for managing the care of patients with PPI-refractory heartburn,” Spechler and associates emphasized.
Last year, an expert panel concluded that anti-reflux surgery was indicated for only a select minority of PPI non-responders.
Not One Disease Process
Writing in an accompanying editorial titled “Think First, Cut Last — Lessons from a Clinical Trial of Refractory Heartburn,” Nicholas J. Talley, MD, PhD, of the University of Newcastle in New Lambton Heights, New South Wales, said it is a mistake to think of GERD as a single disease process responsive to incremental acid suppression. The underlying mechanisms are probably diverse and contribute in varying combinations, he explained. “These range from increased transient relaxations of the esophageal sphincter, to anatomical derangements of the esophageal sphincter, with or without esophageal hypersensitivity plus psychological distress.”

Talley pointed out that 79% of the recruited study patients did not meet the criteria for surgery and, in addition, the results may not be generalizable beyond the population of mostly male veterans. “The findings should not translate into more patients with refractory heartburn being offered surgery without each case being judiciously evaluated on its merits, and only after extended trials of medical therapy,” he said.
Few options exist for patients with persistent reflux after surgery, aside from repeat esophageal testing and another trial of acid suppression, Talley continued, noting that there are no well-established endoscopic alternatives to surgery for acid-related heartburn, although research is ongoing. “Even though behavioral therapy approaches that involve techniques such as diaphragmatic breathing may be of value, clinical trials are few and not definitive. We need personalized medical options that target the underlying causes of GERD.”
Study limitations, the researchers said, include its relatively small sample size and the predominance of white men, reflecting the veteran patient population. In addition, with no sham-surgery group, the study could not determine the contribution of the placebo effect to the incidence of treatment success with surgery. Furthermore, because MII-pH monitoring was performed only while patients were taking PPIs, it was not possible to determine how many of the patients would have abnormal acid reflux when not taking these drugs.
Another limitation involved the intra-trial protocol amendments required to enable completion, Spechler and co-authors noted, adding that although the incidence of success did not differ significantly between active medical treatment and control medical treatment (28% and 12%, respectively), the amended trial was insufficiently powered to rule out an important benefit of medical therapy.

The study was funded by the Department of Veterans Affairs Cooperative Studies Program.
Spechler reported a financial relationship with Ironwood Pharmaceuticals; several co-authors disclosed ties to various private-sector companies.
Talley reported financial relationships with various private-sector companies and reported holding patents on products related to GI disease.

• Primary Source

  The New England Journal of Medicine

  Source Reference: Spechler SJ, et al “Randomized trial of medical versus surgical treatment for refractory heartburn” NEJM 2019; doi: 10.1056/NEJMoa1811424.

• Secondary Source

  The New England Journal of Medicine

  Source Reference: Talley NJ “Think first, cut last – lessons from a clinical trial of refractory heartburn” NEJM 2019; doi: 10.1056/NEJMe1911623.

https://www.medpagetoday.com/gastroenterology/gerd/82772