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VONOPRAZAN (VOQUEZNA®), FIRST IN CLASS GERD DRUG

Vonoprazan (Voquezna®), a new stomach acid-reducing drug with a novel mechanism, recently became available. It works by competing with potassium ions at gastric H+/K+-ATPase proton pumps; this differs from traditional PPIs that inhibit the pump through covalent binding. Proposed advantages of vonoprazan over PPIs include: (1) longer half-life (9 hours vs 1 - 2 hours); (2) acid stable, which gives it a more rapid onset of action; and (3) food-independent effects. A study (N=1024) comparing vonoprazan 20 mg daily to lansoprazole 30 mg in patients with erosive esophagitis found that vonoprazan was superior for endoscopic healing at 8 weeks (92.9% vs 84.6%, p<0.0001). Maintenance of healing at 24 weeks also favored vonoprazan (79.2% vs 72%), but heartburn-free days did not differ significantly between groups. Side effects are mild and similar to placebo. One notable drug interaction is clopidogrel, whose conversion to the active form may be blocked by vonoprazan through CYP2C19 inhibition, also a known effect of omeprazole and esomeprazole.

Voquezna TV commercials are starting to air so patients may be asking about it. In short, it appears to be slightly better than PPIs at healing erosive esophagitis, but its effects on reflux symptoms, the reason most people take these drugs, are no better than PPIs. Given that PPIs are cheap and ubiquitous, insurance companies will not be inclined to cover Voquezna, making prior authorizations and formulary exclusions likely.

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Platelet-rich plasma (PRP) injections ineffective in yet another study
platelet-rich plasma knee injection
Despite negative studies, providers who give PRP injections continue to promote them as miracle treatments for all things joint- and tendon-related. In a recent study, researchers randomized 120 patients undergoing ACL reconstruction to post-op PRP knee injections once monthly for 3 months or no injection. At 12 months post-op, there was no difference between groups in knee pain or function. Study participants were not blinded, favoring a placebo effect in the PRP group. Even so, PRP showed no benefit.

BETA BLOCKERS IN COPD AND ASTHMA

Beta-2 receptors are present in lung airways, where they facilitate smooth muscle relaxation and bronchodilation when stimulated. Nonselective beta blockers, which block beta-1 and beta-2 receptors, can theoretically worsen asthma and COPD; selective beta blockers, which primarily inhibit beta-1 receptors, also block beta-2 receptors to a small degree. Observational studies evaluating the effects of beta blockers in patients with COPD and asthma have found no evidence of adverse effects, and in some COPD studies, a potential benefit was observed. To examine the issue, researchers randomized 519 patients with COPD to bisoprolol, a selective beta blocker, or placebo and compared the number of patient-reported COPD exacerbations between groups. After one year, there was no significant difference between bisoprolol and placebo (2.03 events/year vs 2.01 events/year, respectively; HR 0.97 95%CI [0.84-1.13])

All beta blockers carry warnings about their use in patients with COPD or asthma. Despite this, they are frequently prescribed to these patients to treat hypertension, heart failure, and angina. Some observational studies have suggested a beneficial effect in COPD patients; however, the study above did not find one, nor did a previous study that evaluated metoprolol. [PMID 31633896] Bisoprolol did not worsen COPD symptoms, while in the metoprolol study, COPD hospitalizations were more common in the metoprolol group.

Overall, the potential benefits of selective beta blockers likely outweigh the risks in COPD patients with indications for their use.
Study evaluates beta-blockers in MI Patients With preserved EF
tablets with ECG
In the past, beta-blockers were routinely recommended for patients with myocardial infarction (MI), regardless of heart failure status. This guidance was based on studies primarily performed in the 1980s, which showed beta-blockers improved survival across a broad range of patients. Since then, mechanical (e.g., PCI) and pharmaceutical advances, along with earlier detection and treatment, have improved MI outcomes, and the effects of beta-blockers in contemporary care are unknown. Studies have shown they have an indisputable benefit in patients with reduced ejection fraction (EF), but their role in patients without heart failure is less clear. To answer these questions, researchers randomized 5020 patients with acute MI who had undergone coronary angiography and had an EF ≥ 50% to beta-blocker therapy (metoprolol or bisoprolol) or no beta blocker. After a median follow-up of 3.5 years, the primary outcome, a composite of death from any cause or new myocardial infarction, was not significantly different between groups (beta-blocker 7.9%, no beta-blocker 8.3%, p=0.64).

Medical advances have improved MI detection and treatment so that myocardial damage is often limited and heart failure is prevented. This study answers an important question, showing that beta-blockers are not routinely beneficial in CAD patients without heart failure. Recent AHA guidelines, which only recommend beta-blockers in CAD patients with an EF of less than 50%, are consistent with these findings.
petri dish with antibiotic discs

PIVMECILLINAM (PIVYA®), A NEW ANTIBIOTIC FOR UTI

Pivmecillinam (Pivya®), a penicillin-class antibiotic, was recently approved to treat female UTIs caused by Escherichia coli, Proteus mirabilis, and Staphylococcus saprophyticus. Its effects were evaluated in a trial where 259 women with an acute uncomplicated UTI were randomized to pivmecillinam 185 mg three times a day for 3 days or cephalexin 250 mg four times a day for 7 days. Treatment success, defined as symptom resolution with a negative urine culture on Day 10, occurred in 72% of pivmecillinam-treated patients and 76% of those treated with cephalexin. Side effects are generally mild and include nausea (4.3%), diarrhea (2.1%), and vaginal yeast infection (1.8%). One precaution worth noting is that pivmecillinam contains pivalate, an acid that improves absorption but also depletes carnitine, a compound involved in muscle fatty acid metabolism. It should not be given to patients with carnitine deficiency or those receiving other carnitine-depleting drugs, including valproic acid, valproate, carbamazepine, and phenytoin.

New antibiotics are always welcome; however, pivmecillinam doesn't appear to improve on available therapies. Its thrice-daily dosing and higher cost make it less attractive than other options. In the study above, it had a 72% cure rate, similar to nitrofurantoin but less than the 90% or greater rates seen with fluoroquinolones.

If it's COVID, (you probably don't need) Paxlovid
paxlovid box
Paxlovid, an antiviral containing nirmatrelvir and ritonavir, received an emergency use authorization to treat COVID-19 in December 2021 based on results of the EPIC-HR trial, where it lowered the absolute risk of COVID-19-related hospitalization or death by 5.54% in unvaccinated patients with risk factors for severe COVD. Since then, a large portion of the population has been vaccinated, and the virus has evolved, raising questions about its effects on newer strains in vaccinated patients. To address these issues, the drug's manufacturer conducted the EPIC-SR study (N=1296) that compared Paxlovid to placebo in vaccinated subjects with risk factors for severe disease and unvaccinated subjects without risk factors (57% of participants had been vaccinated). At the study's conclusion, the primary outcome, median days to symptom resolution, was not significantly different between Paxlovid and placebo (12 vs 13 days, respectively, p=0.60). A secondary outcome that included COVID-19 hospitalizations and overall mortality was also nonsignificant.

The EPIC-SR study found that Paxlovid was not beneficial in a mostly vaccinated population. Notedly, vaccinated was defined as having received a complete primary series with or without boosters. Half of the subjects had one or more risk factors for severe COVID, although this designation is soft, considering BMI > 25 and hypertension were two of the top qualifying conditions. According to the Pfizer website, 75% of Americans have one or more "severe" risk factors. Obese patients (18%) and those older than 65 (5%) were underrepresented, so it was not possible to judge its effects in the most susceptible patients.

In summary, Paxlovid does not improve outcomes in vaccinated and unvaccinated subjects with mostly modest risk factors for severe disease. Providers can safely reserve its use for patients with significant comorbidities, including morbid obesity, elderly (> 70), marked respiratory disease, and immunosuppression.

NEWS IN BRIEF

CDC recommends doxycycline PEP in some patients

cdc
The DoxyPEP Study (N=501) found that one 200 mg dose of doxycycline within 72 hours of condomless intercourse reduced the absolute risk of gonorrhea, chlamydia, or syphilis by 20% compared to usual care in men who have sex with men and transgender women (Infection rate: Doxycycline - 11%, Usual care - 31%). Based on these findings, the CDC issued a recommendation that doxycycline postexposure prophylaxis (PEP) be offered to this patient population for self-administration within 72 hours of oral, vaginal, or anal sex.

Prazosin + cyproheptadine for alcohol use disorder

shots of liquor
Animal studies have suggested that alcohol addiction may be caused in part by abnormal regulation of noradrenergic and serotonergic regions of the brain. The combination of prazosin, a noradrenergic alpha blocker used to treat hypertension, and cyproheptadine, an antihistamine with antiserotonergic activity, has been shown to reduce alcohol cravings in mice. To evaluate their effects in humans, researchers randomized 154 people with a baseline average alcohol consumption of 7.8 drinks/day to cyproheptadine + prazosin (2 different doses) or placebo. After 3 months, patients receiving cyproheptadine 12/prazosin 10 mg (high dose group) reduced their daily alcohol intake by 3.4 drinks compared to 2.4 in the placebo group.

Does d-mannose prevent UTIs?

woman with uti
D-mannose, a sugar found in many fruits that theoretically blocks bacteria from adhering to the urinary epithelium, has been found to prevent recurrent UTIs in unblinded studies. To get a definite answer, researchers randomized 598 women with recurrent UTIs (2 in the previous six months or 3 in twelve) to d-mannose 2 grams daily or placebo. After 6 months, there was no significant difference in the incidence of UTIs between the d-mannose group and placebo (51% and 55.7%, respectively, p=0.26)

AASLD proposes new name for fatty liver disease

fatty liver
If you find the terms "fatty" or "nonalcoholic" offensive, you will be relieved to know the American Association For the Study of Liver Diseases (AASLD) has taken up the cause to protect us all from these divisive labels. In a recent publication, they recommend abolishing the terms "nonalcoholic fatty liver disease" and "nonalcoholic steatohepatitis" because they are "stigmatizing" and replacing them with "metabolic dysfunction–associated steatotic liver disease," or MASLD for short. They claim, "The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification." A recent study in the JAMA already adopted the new name (see link below).

Over-the-counter birth control now available

Opill box
Opill®, a progestin-only birth control pill containing norgestrel, is now available, making it the first oral contraceptive sold over-the-counter in the U.S. A one-month pack retails for $19.99, and a three-month pack costs $49.99. It can also be purchased directly from the manufacturer, Perrigo, on their website. The pill should be taken at the same time every day, and the box instructs patients to use a barrier method for 48 hours if they are more than 3 hours late in taking it. Another company is currently in talks with the FDA about marketing an over-the-counter combined oral contraceptive.

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  • Meniscal surgery - It's one of the most common orthopedic procedures performed, but does it do anything?
  • CPAP for sleep apnea - Sleep doctors are on every corner it seems, but what are the benefits of diagnosing and treating sleep apnea?
  • Knee injections - these treatments are popular among orthopedists and primary care doctors, but are they effective?
  • Pneumonia vaccines in adults - vaccine manufacturers, the CDC, and Medicare want everyone to get a pneumonia vaccine, so they must be highly effective, right?
FTC bans noncompete clauses
On April 23rd, the Federal Trade Commission (FTC) announced it plans to ban noncompete clauses, agreements many healthcare providers practice under. According to federal law, the ban will take effect 120 days after it is published in the Federal Register. However, the final say will not likely come for some time, as it's unclear whether the FTC has the authority to do this, and legal challenges have already been filed. I found myself under one in my last job, and foolishly, I didn't read it until I was unhappy and thinking of leaving. It was very restrictive, prohibiting me from working within a 25-mile radius for two years, essentially leaving me unemployed unless I was willing to drive hours every day. Fortunately, my employer had already broken other parts of the contract, so I was able to get out of it.

As far as healthcare is concerned, I can see arguments on both sides. A medical group doesn't want to fund a practice startup just so the provider can leave and open a clinic across the street once he acquires a full slate of patients. Conversely, a business threatening an employee with a lawsuit if they try to work in the same city after quitting seems draconian and undemocratic.

Even though I was miffed by my clause (truthfully, at myself for not reading it), at the end of the day, this is America, and I believe an individual and a business should be allowed to enter into an agreement and be bound by its terms. Since my ordeal, I've quizzed other providers about their contracts and have yet to find one who could tell me what their noncompete says. I suspect this is probably a big reason employers are able to impose them, as many healthcare providers, including myself, are not good at reading their contracts and considering the long-term consequences.
Resmetirom (Rezdiffra™) - The first drug approved to treat NASH
rezdiffra label
Resmetirom, a thyroid hormone receptor-beta (THR-β) agonist, received accelerated FDA approval to treat nonalcoholic steatohepatitis (NASH) in patients with moderate to advanced liver fibrosis. In NASH, hepatic THRs are impaired, leading to fatty acid accumulation and fibrosis. Resmetirom stimulates THR receptors, promoting triglyceride metabolism and reducing hepatic adiposity. The effects of resmetirom on NASH-induced liver disease were evaluated in the ongoing MAESTRO-NASH trial (N=966), where 52-week interim results showed that it was superior to placebo for the two primary outcomes, NASH resolution (30% vs 9.7%) and fibrosis improvement (26% vs 14.2%). The full trial is planned for 54 months and will include the following endpoints: mortality, hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal bleeding), and liver transplant.

Resmetirom is given as a once-daily tablet with weight-based dosing. Common side effects are diarrhea (33%), nausea (15%), pruritus (10%), vomiting (8%), and constipation (8%). Notable drug interactions requiring dose adjustments include certain statins and CYP2C8 inhibitors.

In the past, I've been reluctant to pursue extensive NASH workups since the only real treatment was weight loss. Now, I have to give it more consideration. The main challenge is identifying patients who will benefit the most from resmetirom, as it is expensive, and the majority of NASH patients do not progress to cirrhosis. For primary care doctors, selecting appropriate candidates may follow the following sequence: (1) Calculate a FIB-4 score; (2) If FIB-4 is > 1.3, order an ELF test; (3) If ELF is > 7.7, order a liver biopsy; (4) if F2 or F3 fibrosis is present, start resmetirom. Given its projected cost of $47,400 per year, it's likely insurance companies will require prior authorization that includes proof of liver fibrosis.

CLINICAL CHALLENGE

A 45-year-old female comes to see you for her annual physical. She reports having gastric bypass surgery three years ago and says she followed up with her surgeon once and never went back. She asks you to order her routine lab work.

Given her history of gastric bypass, what lab work is recommended? Are any other studies indicated? Find out at the link below.